Tom Rivers: reflections on a life in medicine and science : an oral history memoir 9780262020268

Citation preview

Tom Rivers Reflections on a Life in Medicine and Science

BLANK PAGE

tom Rivers Reflections on a Life in Medicine and Science

An Oral History Memoir prepared by

Saul Benison

} The M.LT. Press Massachusetts Institute of Technology Cambridge, Massachusetts, and London, England

Copyright © 1967 by The Massachusetts Institute of Technology

Set in Linotype Electra and printed and bound in the United States of America by Vail-Ballou Press, Inc., Binghamton, New York

All rights reserved. This book may not be reproduced, in whole or in part, in any form (except by reviewers for the public press), without written permission from the publishers. Library of Congress catalog card number: 67-16500

For Professor Allan Nevins

Known to my generation at Columbia

as the Little Shepherd From one of the sheep

Whoever elects to study history, as far as | am concerned, may bring to bear the most pathetic and childish belief in the classifying power

of our spirit and methods, but apart from this and in spite of it he should have respect for the incomprehensible truth, reality, and singularity of events. ‘I’o deal with history my friend is no jest and no irresponsible game.

Herman Hesse, Magister Ludi

Historyans is like doctors. ‘They are always looking f’r symptoms. Those iv them that writes about their own times examines th’ tongue an’ feels th’ pulse an’ makes a wrong dygnosis. Th’ other kind iv

histhry is a post mortem examination. It tells ye what a counthry died iv. But I’d like to know what it lived iv. Peter Finley Dunne, Observations by Mr. Dooley

Introduction

On February 5, 1962, one hundred distinguished microbiologists, virologists, and biochemists, including four Nobel laureates, met in a

New York hotel to pay tribute to Dr. Thomas Rivers, a member emeritus of the Rockefeller Institute for Medical Research. A fifth Nobel laureate, Dr. John Enders, ill in Boston and unable to attend the festivities, telegraphed the following message to Dr. Rivers: “We the members of the church salute the apostolic father.”

The recognition that Dr. Enders and others accorded Dr. Rivers that day was singularly appropriate. For a period of almost forty years, Dr. Rivers had been a dominant figure both as an investigator and as an administrator in virus research in the United States. Three months

later, at the age of 73, he was dead. Dr. Rivers’ death did not mark the end of one era in virology or the beginning of another. His career in essence spanned the development of virology from its status at the beginning of the twentieth century as an adjunct to bacteriological study to its current position as an independent discipline, as much concerned with the fundamental problems posed by molecular biology as with the diseases caused by viral agents.

This oral history memoir is an attempt to chart the evolution of Dr. Rivers’ career. Oral history is a relatively new phenomenon in American historiography, and a note as to its development, purpose and procedures may serve to put Dr. Rivers’ memoir in perspective. In 1938 Professor Allan Nevins, in his handbook of historiography, The Gateway to History, urged his fellow historians to establish an vii

Vill Introduction organization which would make a systematic attempt to obtain from the lips and papers of living Americans an expansive personal record of their participation in the political, economic, and cultural life of the nation. It was his hope that in this way a unique archive of autobiographical material might be prepared for the use of future historians. ‘l‘here was precedence for Professor Nevins’ proposal. Autobiography was an old and vital tradition in western historiography. Further, during the nineteen twenties several notable projects had been organized for the collection of autobiographies to elucidate the his-

tory of psychology and medicine. Equally important, other social scientists, in particular anthropologists and folklorists, had long demonstrated the usefulness of oral traditions for historical research. Professor Nevins’ proposals, however, elicited little enthusiasm from his contemporaries. Some voiced reservations about the wisdom of having historians gather memoirs from the living. ‘They felt that such a procedure would of necessity compromise the historians’ objectivity and in the end lead to the production of self-serving, partisan accounts of recent events. Others argued that historians had neither the skills nor funds necessary to capture autobiographical interviews

verbatim. In spite of these and other objections, Professor Nevins continued to proselytize for his idea. In 1948, soon after the tape recorder was perfected for commercial use, he secured funds from several foundations and established an oral history research office at Columbia University to carry out the plans he had projected a decade before. Professor Nevins’ persistence not only showed a belief in his own original vision and purpose, it also reflected the growing need of those who worked in contemporary history to find a way of coping with some of the complexities created for historical research by modern technology.

Historians are agreed that modern society rests in part on foundations created by printing and paper making. These are important not

only because they rank among the oldest of modern industrial processes but because they also serve as catalysts of human thought. Newspapers, magazines, books, and a vast mechanically produced correspondence all testify to the pervasiveness of print and paper communication in all facets of our daily public and private life. Indeed the one constant result of both business and government seems to be

Introduction 1X the production of new records. It is a condition that has provoked some archivists to make the irreverent suggestion that the best possi- | ble thing that could happen to modern historical records was a good fire.

Paradoxically, the industrial process which has created this superabundance of records has also produced a technology which threatens to deprive the historian in future of a great deal of the substance, detail, and variety usually found in the process of human events. This technology, of which the automobile, airliner, radio, television, and the telephone are but a part, has created a revolution in communication that has made the world smaller, changed the tempo of living, and transformed the nature and uses of time. Its hallmark is talk. As a result of new sound and visual communication, much of the detail of human experience, which was previously put to paper because of the exclusive nature of print and writing communication, has today been sapped from the record and become fleeting and ephemeral. Such experience, if preserved at all, is only to be found in the memory of liying men. It is this paradox of simultaneous plenty and scarcity in contemporary records that in large measure defines the tasks of those who work in oral history.

In an important sense oral history is misnamed. While it is true that the oral historian helps gather an oral memoir, it is equally true that such an account is based on a written record. It is precisely this record which ultimately determines the course and substance of his work. ‘That work may be divided into four parts. Once a subject has been chosen to be interviewed, the oral historian, like any other historian, must prepare himself in extant primary and secondary source material so as to see and define relevant. historical relationships and

problems. Second, armed with a tape recorder, he must so handle himself and his preparation as to spur the chosen subject’s memory of past events. ‘Third, he must gather from his subjects, and other people, supporting documents of contemporary demonstration, both as a check on the tenuousness of memory and to supplement the account

gathered. Fourth, he must edit or aid the subject in editing the final preparation of the memoir so that it says what the subject wants it to say.

The memoir that emerges as a result of this process is a new kind of

Xx Introduction historical document. Although it has been created by a participant in past events, it is also the creation of the historian-interviewer who has in fact determined the historical problems and relationships to be ex-

| amined. ‘This mutual creation contributes to both the strength and weakness inherent in oral history memoirs. And it is for this reason

that the circumstances surrounding the production of any given memoir must be clearly set forth. ‘The events leading to the creation of Dr. Rivers’ memoir were these.

In the spring of 1961, soon after beginning research on a projected history of poliomyelitis and ‘The National Foundation, I asked Dr.

Rivers, then Vice President for Medical Affairs of ‘The National Foundation, to allow me to record his memoirs. ‘This was not the first such request I had made of Dr. Rivers. Five years before, while gathering medical and other scientific memoirs for the Oral History Research Office at Columbia University, I had presented a similar petition and was refused. ‘This time he consented. I was helped in obtaining that decision by an untoward circumstance. A short time before I had approached Dr. Rivers, he was operated on for a malignancy in

one of his lungs. It so happened that on the day I met with him he was more than usually bored by the inactivity that convalescence had forced on him, and he seized on my request as a way of escaping the confinement of recovery. Dr. Rivers’ consent was not without restrictions. Although he agreed to talk with me about his career in science, he stipulated that under no circumstances would he speak to me of

his family or his private life. When I remonstrated that posterity would never believe that he had appeared, fully grown and armed, from Zeus’s forehead, he agreed to tell me a little about his father and mother, but nothing more.. Both the circumstance of Dr. Rivers’ illness and the restrictions he placed on our talks are important because they serve to explain some of the content of his memoirs.

By nature Dr. Rivers was a curmudgeon.* He had a keen critical * Dr. Richard Shope, a long-time associate of Dr. Rivers at the Rockefeller Institute, characterized him as follows in a biographical notice he wrote soon after Dr. Rivers’

~ death.

“Although Dr. Rivers was by nature a friendly person, he had the capacity of being irascible and pugnacious. He was a difficult and formidable person to oppose and could be stubbornly inflexible in maintaining a position. His discussion at scientific meetings of findings with which he disagreed could on occasion be so stinging that the audience,

Introduction XI mind, possessed a waspish tongue, and loved a good fight. His illness ° accented some of these characteristics. Further, from the beginning of

_ his illness he knew he was suffering from a malignancy. While he initially hoped that the operation he had undergone might stem its development, by the end of the summer of 1961 he knew he did not have long to live. These circumstances not only contributed to his candor about himself and his work, they also encouraged him to make

uninhibited comments and judgments about people he knew in .sclence—comments that in ordinary circumstances might have been more discreet. His illness affected the conduct of the interviews as well. Although on several occasions I saw Dr. Rivers socially in his home, at no time would he permit interviews to be held there. All interviews were held in his office at ‘The National Foundation or his offices and sickroom at the Rockefeller Hospital. I felt that he insisted on this for two reasons. First, it allowed him to keep the interviews on a formal plane, and second, by arranging interviews in his office he created an added incentive for himself to carry on his daily activities as he had before his operation. In the last seven months of his life he came into his office at The National Foundation five days a week until his illness required hospitalization two weeks before his death. - I particularly regretted Dr. Rivers’ decision not to speak about his

family and private life, because it meant that I was unable toexamine with him his home environment and the larger social environment of

the New South in which he came of age. More important, it prevented me from discussing with him his social beliefs or to examine the impact of his scientific career on those beliefs. As a result of both Dr. Rivers’ restrictions and my ultimate purpose in writing a history of poliomyelitis and ‘The National Foundation, I concentrated my interviews on four basic subjects or problems: the development of Dr. Rivers’ medical and scientific education, the evolution of his virus research, an examination of those scientific institueven though realizing the correctness of Rivers’ position, often had their personal sym-

pathies entirely with Rivers’ opponent. Many of those who have known Dr. Rivers best have felt the sting that he could so picturesquely deliver in an argument. Few of us have had the nerve openly to side with his opposition in one of these “knock down’ and ‘drag out’ discussions.”’ R. E. Shope, “Tom Rivers.” Journal of Bacteriology, 84:385— 388, 1962.

Xl | Introduction tions and organizations in which he had played a singular or important role, and finally an examination of problems in the administration of scientific research, as exemplified by the development of polio

research during the nineteen forties and fifties. | My preparation for the interviews began several months before the first interview actually took place and was continued throughout the course of the interviews, a period of approximately 15 months. Interviews were so arranged as to facilitate research and were usually held at the beginning and end of each week. In general, the interviews ran for no longer than an hour, though an occasional one ran for an hour and a half or an hour and three quarters.

At the end of each interview I would not only outline for Dr. Rivers the subject matter or problems that the next interview would cover, I would also supply him with copies of letters, documents, and scientific papers that might serve to refresh his memory. For his part, Dr. Rivers would frequently direct my attention to material that he thought might be useful to me in my preparation. In this sense the interviews were “prepared.” At every interview I came armed with relevant books and documentary material so that if the need to look at or quote from such material arose it was immediately to hand. On several occasions Dr. Rivers quoted passages from such documents or books or asked that such material be inserted later in the memoir. Once an interview was completed, it was immediately transcribed. While the end product of oral history often looks neat and logical, the process itself isn’t, because man’s memory and the course of conversation are frequently untidy. Although I tried to examine all subjects and problems with Dr. Rivers chronologically, so as to establish a rudimentary outline of development, I was not always successful.

| Often during the pursuit of a subject, both Dr. Rivers and I were led by the nature of conversation and subject matter into making digressions. At times Dr. Rivers would repeat himself. On other occasions he would forget a precise date or name of a person. At such time he would ask me to find the date or name and insert it in the memoir. Such forgetfulness is common at any age and was in no sense characteristic of Dr. Rivers’ memory. His recall of substantive matters was prodigious—so much so that it was often a conversation piece among

Introduction , Xl his long-time colleagues at the Rockefeller Institute and his associates ~ at The National Foundation. When interviews on a given subject were completed, I edited that

portion of the transcript and submitted it to Dr. Rivers for his approval. My editing chores in the main consisted in arranging the ma-

terial in chronological and chapter order, eliminating repetitious material, and inserting blank dates and names. No attempt was made to alter Dr. Rivers’ language, to make him grammatical, nor were the expletives and other expressions he was fond of eliminated. Errors of fact and interpretation, even when known to be errors, were kept because such mistakes were often revealing of the man and his thought. These I have footnoted passim. In the end my method of proceeding chronologically and editing

the transcript while the interviews were still in progress worked against me, because Dr! Rivers died before I could carry my investiga-

tions and interviews much beyond 1958. I was unable therefore to examine with Dr. Rivers at least two important subjects, the development of the Sabin vaccine after 1958 and the scientific background of

the decision of ‘The National Foundation to enter the field of birth defects and arthritis. After Dr. Rivers’ death, I sent portions of his memoir to several of

his former colleagues and friends mentioned in the text for critical comment. Among those who commented on the manuscript were Dr. Peter Olitsky, Dr. Peyton Rous, Dr. John Enders, Dr. Joseph Stokes, Jr., Dr. Albert Sabin, Dr. David Bodian, Dr. Hilary Koprowski, Dr. Thomas Turner, Dr. Jonas Salk, Dr. Joseph Smadel, Dr. Harry Weaver, and Dr. Walter Schlesinger. They sent valuable critical material which is appended in various footnotes throughout the text. It is an impertinence to tell a reader how to read a book. ‘The nature of a book, however, must be understood. Dr. Rivers’ oral history memoir is an account of some aspects of the recent history of American virology from a particular moment in time filtered by individual experience. In no sense is it presented as an exclusive historical

source. It is rather a corroborative source and guide. As such it is a beginning of interpretation, not an end.

ACKNOWLEDGMENTS This work could not have been completed without assistance from many quarters. My profoundest debt is to Mr. Basil O’Connor, the President of The National Foundation, for his continual support, encouragement, and cooperation with my work on a history of poliomy-

elitis and The National Foundation. Without the help of ‘The National Foundation there would have been no memoir of Dr. Rivers. Mr. Joseph Nee, the Senior Vice President of The National Foundation, and Mr. George Voss, Vice President for Public Relations, facilitated my research at critical times by gaining access for me to special

materials relating to Dr. Rivers’ work with the Foundation. Dr. Theodore Boyd, Director of Research at The National Foundation, put at my disposal his vast store of knowledge of virus research in the

United States and freely discussed with me special problems in the history of poliomyelitis. ‘hese discussions were invaluable in my preparation. Mr. Joseph Mori, a senior member of the Division of Public Information and a trained microbiologist, helped guide me through the vast polio literature of the last 25 years and rendered spe-

cial assistance in the preparation of a glossary of scientific terms which is appended to the memoir. Mr. Gabriel Stickle, Executive Assistant to Mr. Basil O’Connor and Statistician to The National Foundation, instructed me on some of the finer aspects of the history of the gamma globulin and Salk vaccine field trials in which he played a significant role. It should also be recorded that Mr. Charles Ben-

nett, Mrs. Dorothy Davis, and Mr. Josef Berger of the Division of Public Relations met with singular patience a stream of unending requests for newspaper and magazine articles, and with equally great forbearance the author’s penchant for telling “stories” he believed to be funny. I am also heavily indebted to many of Dr. Rivers’ associates at the Rockefeller Institute (now the Rockefeller University) for their help and advice throughout the course of my work. Dr. Detlev Bronk, the ~ President of the Rockefeller University, facilitated my research by generously granting me access to the reports made to the Board of

Acknowledgments XV Scientific Directors of the Rockefeller Institute from 1907 to 1953. These reports constitute one of the most important primary sources of medical and biological research. in the United States in the first half of the twentieth century. Dr. George Corner, Executive Officer of the American Philosophical Society and historian of the Rockefeller University, made available to me a copy of his History of the Rockefeller Institute before publication and guided me to collections of manuscript material he knew would be helpful to me in my own research. He also made me welcome at meetings of the History of Science Seminar at the University over which he presided, and on two occasions allowed me to present papers on my work with Dr. Rivers. Special mention must be made of the assistance given to me by the late Dr. Peter K. Olitsky. When I began my studies in the history of poliomyelitis, Dr. Olitsky, although in retirement, undertook to tutor me in virology and spent long hours discussing with me the manifold problems involved in research on neurotropic viruses in which he was expert. He also read Dr. Rivers’ memoir in its entirety and at various

points added information which I have since incorporated in the memoir as footnotes. Beyond this, Dr. Olitsky extended his friendship. One of the great satisfactions of my research at the Rockefeller University was that it gave me the opportunity to meet and know this very rare human being. Throughout the course of my research I benefited from discussions with various members of the University on problems in the history of science and medicine, among them Drs. Alexander Bearn, Merrill Chase, René Dubos, Stuart Krasner, Alfred Mirsky, Eugene Opie, Peyton Rous, Howard Schneider, Edward ‘Tatum, and the late Drs.

Ludwig Edelstein, Duncan MacInnes, Richard Shope, and Wayne Woolley. Miss Alice Lockie, the superintendent of the Rockefeller University Hospital, and Miss Georgianna Drew, the assistant super-

intendent, out of the goodness of their hearts, instructed me in the

| history of the Rockefeller University Hospital during Dr. Rivers’ administration and by many personal kindnesses facilitated my research and interviews with Dr. Rivers, especially during a special tenday hospitalization of Dr. Rivers in November of 1961. Miss Sonia

Wohl, the energetic associate librarian of the University, saved me precious hours with her amazing knowledge of scientific and historical

XV1 Acknowledgments literature and the special magic that seems to be hers alone of dis- | covering material not listed in library catalogues. Mr. Bernard Lupinek, the superintendent of building and grounds at the University, and Mr. Kenneth Schmitt, the assistant superintendent, arranged an excellent facility for me to work in, while Mr. Waldo E. Flinn, the business manager of the University, with great kindness assumed the onerous task of providing me daily with manuscript material usually kept in the University vaults for safekeeping. In retrospect it seems that the only thing that the Rockefeller University did not do for me

was to tuck me in at night. :

There is no history without documents, and I would like here to thank Mr. James Thomas Flexner and Dr. William Welch Flexner for giving me permission to examine the papers of their father, Dr. Simon Flexner, the first director of the Rockefeller Institute. Without this unique collection, it would have been difficult to undertake an analysis of the first fifteen years of Dr. Rivers’ tenure at the Rockefeller Institute. In my search for source material I derived great bene-

fit from the expert knowledge of Mr. Albert Leisinger, Miss Jane Smith, and Mr. Joseph Howerton of the United States National Archives, who guided me with sure hands through the vast records collections in their care. ‘The help which they extended was by any criterion far beyond the call of ordinary duty. I also received valuable assistance from Miss Ruth Doloboff of the Medical Division of the Metropolitan Life Insurance Company, who arranged an examination

of the papers of Dr. Donald Armstrong which were in her keeping. There is no way I know of measuring the value of the help given to me by the late Miss Florence Sweeney, Mrs. Rose Feder, Mrs. Mary C. Bachmaier and Mrs. Dora deVenau of The National Foundation Records Center. I can only note that they devotedly and effectively extracted from the more than 3000 linear feet of records that comprise ‘The National Foundation’s Archives the numerous special doc-

uments and correspondence that I needed in preparation for my interviews with Dr. Rivers. Oral history demands excellent secretarial assistance and I received

just such assistance from Mrs. Elizabeth Freidel and Mrs. Lenore Hogan, who perceptively transcribed Dr. Rivers’ tape recordings, and from Miss Olga Zurawel, Mrs. Josephine Calvert and Mrs. Marie Mc-

Acknowledgments XVli Loughlin of ‘The National Foundation’s secretarial staff, who helped me prepare the manuscript for publication. I must add that this assist-

ance confirmed me in the belief that extraordinary benefits can be gained by living under matriarchal rule.

In the past decade I have engaged in almost continual dialogue with Dr. Louis Starr, director of the Columbia University Oral History Research Office, and Dr. Harlan Phillips about principles of oral history. Although these discussions have often led to disagreements, they have nevertheless served to clarify my own thoughts about oral history for which I can only be grateful. In recent years I have especially benefited from discussions with Dr. Richard Shryock and Dr.

. Whitfield Bell of the American Philosophical Society, Dr. Nathan Reingold of the Smithsonian Institution, Dr. Thomas Kuhn of Princeton University, Dr. John Blake of the National Library of Medicine, and Dr. James Cassedy of the National Institutes of Health, about the special relation of oral history to the history of contemporary science and medicine. I owe a special debt of gratitude to

Mr. Melvin Glasser, former Executive Vice President of The National Foundation and currently Director of the Social Security Division of the International Union of the United Automobile Workers for originally pointing out to me the importance of studying voluntary health agencies for an understanding of contemporary social and scientific history. In a very real sense, Dr. Rivers’ oral history memoir only became a book because of the singular devotion and help of my friends, Professor George Dalton of Northwestern University, Professor Heyward Ehrlich of Michigan State University, Professor Jerome Y. Lettvin of Massachusetts Institute of ‘Technology, Professor Charles Hoffmann

, of the State University of New York at Stony Brook, and Professor Leonard Levy of Brandeis University. While those who know them hardly think of them as midwives, I can testify that they have talents in this direction—they were indispensable in getting my book born. There are some people who revel in anonymity and blanch at the thought of receiving public acknowledgment for the help that they have extended. In ordinary circumstances I would honor such wishes. Yet I believe it would be unfair if I didn’t acknowledge the assistance given me by two very special people. Mrs. Mabel Bright, executive

XVII Acknowledgments assistant to President Detlev Bronk of the Rockefeller University, by her wise counsel and aid, gave important impetus to my work during

my research at the Rockefeller University. I also owe a particular debt to Mrs. Elin Wolfe for allowing an old friend to persuade her to put important work aside and to assume the burden of preparing an index. Robert Frost onee wrote that “home is where they have to take you in.” ‘There are many homes where that ain’t necessarily so. I do know

that I would never have been able to complete my work were it not for the help-and affection given by my family. Although natural debaters and loud talkers, they provided me with the quiet and isolation

I sometimes needed and the laughter and understanding I needed at other times. They shaped the home environment to sustain me, and

, that is more than taking you in. Because people have helped me it does not necessarily mean they approve of what I have done, nor should they be held responsible for the work that follows. ‘That burden is mine.

. SAUL BENISON New York City November 1966

Contents

Introduction vii

l Beginnings l

2 The Young Physician 37

1922 67

3, The Rockefeller Institute for Medical Research— ,

4 Virology and Virologists—1926 109 5 The Process of Virus Research—1930 15] | © The Rockefeller Institute Hospital—1937 194

| XIX

7] The National Foundation for Infantile Paralysis:

Early Research Programs—Part I 226

XX Contents & The National Foundation for Infantile Paralysis:

Early Research Programs—Part 2 275 Q NAMRU 2—A Virologist at War 320

New York 359 1946-1948 397

LO The Public Health Research Institute of

L1 some Aspects of Poliomyelitis Research—

12 Active and Passive Immunization against

Poliomyelitis—1949-195 3 444 l 3, Prelude to the Salk Vaccine 488 14 Salk Vaccine and Sabin Vaccine—1954-1958 5 38

L5 Early Days of Retirement 579

APPENDIX A |

Remarks on a Paper Presented by Arthur Kendall, M.D., before a Meeting of the Association of American Physicians in 1932

Thomas Rivers, M.D. 597

APPENDIX B Discussion of Papers on Poliomyelitis by William H. Park, M.D., and Maurice Brodie, M.D., and by

John A. Kolmer, M.D., October 1935 |

Thomas M. Rivers, M.D. ) 599

Contents XXI APPENDIX C Summary of the Conclusions and Recommendations of Nomenclature and Classification of Poliovirus, First International Poliomyelitis Conference,

New York, July 14, 1948 - 602 APPENDIX D

| Confidential Information on Infantile Paralysis Presented to the Board of Managers, Children’s Hospital, Philadelphia, April 24, 1952

Joseph Stokes, Jr., M.D. 603 APPENDIX E Criteria for Live-Virus Vaccine Trials. World Health Organization Expert Committee on Poliomyelitis. Second Report. WHO ‘Technical Report Series 145.

Geneva, 1958 607 APPENDIX F , Glossary of Terms 610 APPENDIX G A Note on Manuscript Sources, Footnotes,

Appendices, and Bibliography 621

APPENDIX H

Index 661

Bibliography, Dr. ‘Thomas Milton Rivers 651

: BLANK PAGE

CHAPTER it | Beginnings Carter: Be both your legs bedfellows every night together? Faustus: Woulds’t thou make a colossus of me that thou asketh me such questions?

Carter: No, truly sir, I would make nothing of you, but I would fain know that.

: Christopher Marlowe, Dr. Faustus

. parents. . Q: Dr. Rivers, I wonder if you would tell me something about your ~

Rivers: My father was named Alonzo Burrill Rivers and was the son of Burrill Greene Rivers, who lived in Milner, Georgia. My father was

born either just before or during the Civil War. My Grandfather Rivers was in the Southern Army and received a wound which did not

incapacitate him. |

My mother was named Mary Martha Coleman and was born in Henry County, near McDonough, Georgia. Later my mother’s family moved to Jonesboro and bought a farm and a home there. In addition

to running a farm, they also ran a hotel in Jonesboro, and it was very | close to the railroad station where my father-to-be worked. This is the way my father met my mother.

QO: I take it the railroad was the Georgia Central.

Rivers: My father worked for the Central of Georgia Railroad as a railroad telegrapher. However, he got out of the railroad business when the Central of Georgia people insisted that he leave Jonesboro I

2 Chapter | and go to Jessup, Georgia. My mother, on the other hand, said that she would not marry him if he went to Jessup, since she didn’t have any idea or inclination to live there. In the end my father gave up his job with the railroad and got a job with a Mr. Hines who had a big warehouse and cotton business in Jonesboro. Then my father and mother got married. There was an older brother named Coleman Rivers who died when he was twelve years old.* I was born on the 3rd of September 1888 in a nice comfortable farmer’s home. The house was actually within the town limits of Jonesboro, and some of the farm was within the town limits. Jonesboro is a very old town and is actually much older than Atlanta, which is close by. Atlanta is a kind of an upstart. Originally I

think it was called Marthasville or Marysville, that is, before the Georgia Railroad and the Central of Georgia joined or met there. At that time, the town was renamed and was called Atlanta. It has since 1 Just before Rivers entered the Navy during World War II, he discovered that he did not have a birth certificate, and he wrote to his mother for a notarized statement about the date of his birth, so that he could complete his application form. His mother | sent the date with the following autobiographical letter: February 24th, 1942 Dear Tom,

Dear Son, ;

I am sending you a few dates. You might like to put them down. Alonzo Burrell Rivers was born in Pike County, Ga., June 26, 1859, and died Sunday morning Jan. 18, 1918, in Jonesboro Ga. Mary Martha Coleman was born in Henry County, Ga., Sept. 17th, 1863. We were married Nov. 28, 1882, in the Methodist Church in Jonesboro, Ga. in the afternoon. Rev. T. S. L. Harwell was the preacher, I was nearly 15 when I joined the Church in Jonesboro. Rev. John Bowden the preacher. Your brother, Alonzo, joined the Methodist Church in Jonesboro May 8, 1899. Rev. J. W. Stipe, the preacher. He was 6% years old. You were nearly 5 years old when you joined with Coleman. Dr. Blosser, the preacher. As you grow older you can’t remember all these things unless you have it written down. You remember you and Alonzo stood at your father’s grave in your uniforms of the first world war. You were already in service and left the next day for Texas. Now you are in again. God bless you! I know you will give the best and all you are in the service as you did before. I am proud of you and always have been and will be. We and all we are and ever will be is God’s anyway. So let Him use us. You are a great son and have no regrets as to me or any of us. You are dear to me and J love you. I give you willingly to your country. Bye bye, MOTHER

Although Dr. Rivers would not speak to me of his family, all his associates at the Rocke-

feller Hospital speak of his close attachment and devotion to his brother, Alonzo, a businessman who died sometime in the 1950’s, and his sister, Mrs. Sarah Turner, who still lives in Jonesboro, Georgia.

Beginnings 3 grown, of course, much more rapidly than Jonesboro. Jonesboro now is a suburb of Atlanta, and even though it’s 20 miles from Atlanta it is spoken of as being a part of the metropolitan area around Atlanta. Father worked at the warehouse, and eventually he bought out the business. Later he bought the farm from my mother’s father and became a farmer as well. His interest in the cotton business led him to build a large gin house that could gin 100 bales of cotton a day. Still

later he became a representative for a cottonseed oil business and bought cottonseed for half of the state of Georgia. He also became a salesman for one of the big fertilizer companies in Georgia. So my father was a fairly busy man, running a farm, a warehouse, and a gin, and traveling for a cottonseed oil company and a fertilizer company. I had a very happy time as a child, because the farm where I lived was nice and had all the nice things that go with farms, and still I was within walking distance of the schoolhouse and walking distance of the town.

Q: Was ita one-room schoolhouse?

Rivers: No. The schoolhouse was quite a large one. It was two stories tall. I don’t quite rrmember how many rooms it had, but I believe it had at least eight. Actually, I think the schoolhouse may have

been built before the Civil War. It was certainly built before my time. At one time I know they spoke of it as the Middle Georgia College. It might have been an academy, but for the most part, when | went to school there, it was just an ordinary school, with a principal and two or three teachers, all paid for by private tuition, no public

money. During my time they did take a try at having the Middle Georgia Military Academy there. I didn’t participate in the activities of the military part of the academy, although a lot of the boys bought uniforms and drilled and had this, that, and the other. I never could see much in that. That lasted for a couple of years, and then the Middle Georgia Military Academy disappeared. The schooling we received wasn’t too good, and at times it was so

bad that Father got a tutor for the children. Mrs. Land, who was a well-educated lady who lived in Jonesboro, tutored me for about two years before I went to college.

4 Chapter | When I got to be sixteen, my father thought that it was about time I went to college, because it didn’t seem that there was much more education to be had in Jonesboro. It was decided that I would go to Emory College. The college had this to recommend it: it was run pretty much by the Southern Methodist Church, and my family was Methodist, and it was not too far from home. However my schooling had been so bad that I couldn’t enter any higher than subfreshman, and naturally it took me five years to graduate. I missed four days from school in my subfreshman year, but in the next four years I never missed a class, nor was I late for any class, the whole time. I took the A.B. course at Emory and received a general education.

In order to take an A.B. at that time, you had to take an awful lot of Latin, an awful lot of Greek, and an awful lot of mathematics. In all frankness, I didn’t particularly like any of it. I could put up with the mathematics, but I didn’t do well in it. I didn’t really get much fun out of college until I became a junior. I should explain that, in the A.B. course, you were pretty well told what subjects you could take until the junior year. But in your junior and senior years, you could select subjects of your own choice. I chose as much ‘biology and chemistry as I could.

QO: What made you choose those subjects?

Rivers: Dr. Duncan who had charge of the courses in biology was an old bachelor who lived at the same boarding house that I did, and we

ate at the same table. He had a great deal of influence on me and helped persuade me to choose electives in biology and chemistry. Anyway, I did. I liked the work and became extremely interested in that area, and soon after I decided that I wanted to be a physician. | think that if I hadn’t taken these courses in biology and chemistry that I might have gone back to Jonesboro and helped my father. My father was not very well at the time, and he was very anxious that I go into business with him. I didn’t, and he proved willing for me to go to medical school. I stood first in my class at Emory. The time that I was there, my average for the five years was higher than any average that had ever been made at the college, and I graduated summa cum laude.

Beginnings 5 I had no difficulty in getting into Johns Hopkins, even though I came from a small southern college.

QO: What made you choose the Hopkins?

Rivers: It was about the only one I knew. You know, I lived in the South, and I didn’t hear much about Harvard and Yale and such places. But I .had heard of the Hopkins from Dr. Duncan, and he seemed to think it was just about the best school there ever was, and so, naturally, not knowing very much about the others and having heard a lot about this one, the choice was very easy.

Q: Dr. Rivers, did you see much disease in Georgia as a young man?

I know that in South Carolina Dr. James W. Babcock was doing some very interesting work in pellagra, and I daresay you must have seen some pellagra in Georgia.

Rivers: We had pellagra in Georgia. Many of the southern states had it. Pellagra, as you know, is a food-deficiency disease caused by a lack of nicotinic acid. However, some of the ideas about the cause of pellagra held by southern physicians in my youth were rather curious and unique. Dr. Stuart Roberts, one of the physicians I knew in At-

lanta, I believe at one time wrote a book showing that the eating of cornbread was the cause of pellagra. And he wasn’t the only one who believed that. Others believed it too. I’m afraid Dr. Roberts—I knew him very well—didn’t know how to go about a scientific investigation, and I’m not surprised he arrived at the wrong conclusions. Dr. Joseph

Goldberger of the U.S. Public Health Service did know how to experiment, and he and Dr. Claude Lavinder in a beautiful series of experiments demonstrated the true nature of the disease. Actually, I shouldn’t run Stuart Roberts down too much, because he was pretty close by marriage to our family.” * Rivers’ memory does not serve him well in this instance. Although Claude Lavinder

of the United States Public Health Service played a key role in arousing medical interest in pellagra in the United States, he did not work with Joseph Goldberger when the latter engaged in his pellagra investigations. Dr. Goldberger’s associates, among others,

were David G. Willetts, C. H. Waring, G. A. Wheeler, and Edgar Sydenstricker. For further information see C. H. Lavinder, “Pellagra, brief comments on our present. knowledge of the disease,’ Public Health Repts. (U.S.), vol. 28:2461 (1913); J. Goldberger,

6 Chapter 1 Another disease we had plenty of when I was a boy was typhoid fever. In 1900, when I was twelve years old, I had typhoid and stayed

in bed from the 26th of June until the 15th of October. The treatment was heroic: it was starvation and freezing. From time to time they also gave me something called peptinoids. I don’t know what it was, but it sure was awful tasting stuff; it was supposed to be nourishing. Actually, I had very little food, and I used to dream about food. Ever so often, they would wrap me in a sheet with ice around it to bring the temperature down. Of course, by the time I got to Hopkins. and was a student there and later an interne, they were not starving typhoid patients; they were actually feeding them. Some of the patients I had as an interne gained weight while they were having the

disease. Instead of getting ice cold baths; they were giving tepid baths. That kind of treatment was much more sensible and much more gentle than the kind that [ got. QO: Did you ever have hookworm?

Rivers: ‘The Rockefeller Sanitary Commission*® had not yet made the famous hookworm survey of the southern states when I was a boy so I really don’t know whether I ever had hookworm or not. But as a boy I went barefooted every summer up until the time I went to col-

lege, and I had ground itch. I have been told that ground itch is caused by the larvae of the worm getting beneath the skin. Well, I had ground itch in between my toes, and so I suppose that I had C.H. Waring, and D. G. Willetts, ““The prevention of pellagra. A test of diet among institutional inmates,” Public Health Repts. (U.S.), vol. 30:3117 (1915); J. Goldberger and G.A. Wheeler, ““The experimental production of pellagra in human subjects by

means of diet,” Hyg. Lab. Bull., No. 120, 7-116 (1920); E. Sydenstricker, “The prevalence of pellagra. Its possible relation to the rise in cost of food,” Public Health Repts. (U.S.), vol. 30:3132 (1915). These are by no means all of the papers produced by Dr. Goldberger and his associates on the problem of pellagra and are only representative of two facets of his early work. Rivers’ strictures on Stuart Roberts are not completely fair. Dr. Roberts’ later observations that pellagra sometimes occurred among well-to-do people because of eccen-

tricities in diet were not unimportant. See S.R. Roberts, “Types and treatment of pellagra,” J. Amer. Med. Assoc., vol. 75:21 (1920). * The Rockefeller Sanitary Commission (1909-1914) was established for the purpose of eliminating hookworm from the southern United States. An account of its work is furnished by R. B. Fosdick, The Story of the Rockefeller Foundation. Harper & Brothers, New York, 1952, pp. 30-43.

Beginnings 7 hookworm. However, by the time I got old enough and went places where somebody would know what hookworm eggs looked like, I didn’t have hookworm. I think I’ve been fairly active, enough so that no one would accuse me of being lazy because of hookworm.

QO: Was the transition from Jonesboro and Emory College to Baltimore and the Johns Hopkins difficult?

Rivers: It was not too easy. The boys from Harvard, the boys from Yale, and the boys from other old and well-established institutions, such as Princeton, didn’t think much of.us boys that came from the South, and more particularly from a small college that had only 350 students. ‘They didn’t think much of us, and they used to make an awful lot of fun of us. Well, it didn’t bother me very much. But it did worry some of the boys. Some of the northern boys were rather rough

on the poor southern boys. I didn’t mind that very much, because I was fairly strong physically and could take care of myself. However, it

was hard to get into certain of the medical fraternities unless you came from the nght family or knew someone. And you must remember that fraternities at least had, as one of their functions, providing an eating place. Well nonfraternity boys had to eat too. Luckily there were some nice women along North Broadway that were perfectly willing to provide meals for nonfraternity boys—an Aunt Dora Gordon was one of them. Aunt Dora set a table with the most delicious

food, and it cost us $1 a day for three meals. It makes my mouth water yet to think about getting all that delicious food for $1 a day.

Later, after I graduated and got out of the army after the First World War, I had a room and facilities for bathing (there was not a private bath) at Aunt Dora’s for $8 a month. QO: Where did you room as a student?

, Rivers: Part of the time I roomed at 424 North Broadway, with people named Harrison. They were an old couple, and they let me have a front room on the second floor which I shared with Bill Hayden, a classmate of mine at Emory. Bill and I roomed together the first two years, until I dropped out of school. Later, I roomed at a fra-

8 Chapter | ternity house. Since none of the older Hopkins fraternities would take us southern boys, Pi Mu, an old fraternity—Dr. Hugh Young was a member of Pi Mu—came in and set up a new fraternity chapter. QO: What was the nature of your preclinical training?

Rivers: ‘The Hopkins had a very strong preclinical group when I was a student. ‘his was true for anatomy, pathology, physiology, pharmacology, and chemistry. For example, I had John Abel for pharmacology. John Abel was a most distinguished pharmacologist and had, at

the turn of the century, discovered epinephrine. A short time later with the aid of ‘Takamine he purified and crystallized epinephrine, which was no mean feat. Walter Jones in physiological chemistry was

of like caliber as was William H. Howell who taught physiology. Howell was a wonderful teacher and man, and | don’t know how many generations of medical students were brought up on Howell’s

Textbook of Physiology. In my day it was used throughout the United States. Later, when Howell retired from his professorship of physiology, he succeeded Popsy Welch as dean of the School of Public Health at Johns Hopkins. I, of course, had Popsy Welch as my professor of pathology, and he is so well known that I need not make further comment. _ The fellow I want to talk about is Franklin P. Mall, who was my professor of anatomy. At the time I took anatomy at the Hopkins, Dr. Mall had two wonderful assistants. One was Eliot R. Clark who later became professor of anatomy at the University of Pennsylvania, and the other was Florence Sabin, who was in charge of the course in histology. Later Dr. Sabin went to the Rockefeller Institute, where she worked on tuberculosis and various diseases of the blood. When she retired, she went back to Denver to live with her sister, and there in the twilight of her life began a new career in public health. I don’t think that it is too much to say that she was the driving force behind the public health renaissance that Colorado had in the late thirties and early forties. It always amused me to hear the mayor of Denver and the governor of Colorado refer to Dr. Sabin as “a little old lady.” She was little and she did live to the age of 84 or thereabouts, but she had more iron in her than the whole state of Colorado. Now all of this is prologue to saying that Franklin P. Mall paid lit-

Beginnings 9 tle attention to his students. He didn’t think that we were worth paying any attention to. Mall was a brilliant scientist but did not believe in lectures and other orthodox techniques of teaching. From time to time he would speak to us; however, most of the teaching that we got

came from people like Clark, Sabin, and others who would come around and instruct us while we were working in the laboratory. Mall was not a good teacher,* but he was a brilliant man, probably greater than any one of the four doctors—Osler, Welch, Kelly and Halsted * Alan Gregg of the Rockefeller Foundation presents a different view of Dr. Mall’s teaching in his unpublished autobiographical reminiscences. In the spring vacation of my senior year I left the tutoring job that I had in New York

and went down to Baltimore. On arrival at the Hopkins I wandered into the anatomy building. I saw a very sharp looking person with very intelligent eyes there in the hall, and

he came over to me and said, “Is there anything you are looking for?” I said, “No.” “Well,” he said, “You are looking around.’ I said, ‘I don’t mean to bother you with my own affairs but I am trying to decide what medical school to go to.” This individual was Franklin P. Mall, whom I didn’t know from a hole in the wall. He gave me about fifteen minutes of talk about what Johns Hopkins was. I left in a pertect

storm. I wanted to sign on so much. I went out into the street and I saw . . . a fellow I had been a counselor with up in a YMCA camp in my freshman year. He looked at me with astonishment and said, “Why Alan Gregg, what the hell are you doing here?” I said, “Why, I am trying to make up my mind what medical school to go to. I am going to go to medical school next autumn.” He said, “You come here. You won’t make any mistake. We have wonderful pro-

fessors. In physiology there is Howell. Popsy Welch is in pathology. Then there is Thayer in medicine.” He was all enthusiastic, and then he added,-‘‘All except one son of a bitch.” I said, rather guardedly, thinking that it would be a good thing to know early on, “And who is that?” “He thinks he’s our professor of anatomy. His name is Franklin P. Mall. I'll just tell you what he did to us. The first day he met us in anatomy he said, ‘Gentlemen, the dissection room will be open from nine o’clock in the morning until ten at night except on Saturday afternoon when you ought to go out and get some exercise anyhow. Up until six o’clock there'll always be somebody to get you out of any tangles you get into. I can recommend the three following textbooks, and when you are ready to take the examination let me know.’ Now,” said my young friend, “if you can beat that as a son of a bitch of laziness in a professor you’re going some.” Mall has stayed in my mind as a good example of excellent teaching completely wasted on a badly prepared student mind. This boy I spoke of just missed Franklin Mall by yards and yards and yards. I privately think that Mall’s teaching was designed for and appreciated by A No. | students, but that Mall had an appalling mortality because so many of his students thought, ‘‘Well, he must be interested in golf or something. He isn’t teaching.” This boy, incidentally, was 1908 at Yale, and the level of Yale instruction then completely failed to fit him for Johns Hopkins and Mall’s instruction. Mall was remarkable, and he’s far nearer to being the core of Hopkins than many people realize.—S. Benison, Alan Gregg, An Oral History Memoir. Columbia University Oral History Research Office, 1956, pp. 33-35. For another positive view of Dr. Mall as a teacher, see F. R. Sabin, Franklin P. Mall: The Story of a Mind. The Johns Hopkins Press, Baltimore, 1934, pp. 220-222.

10 Chapter 1] —that Sargent painted. In spite of his poor teaching I would say that he had a great influence on the development of the Johns Hopkins Medical School. In a word he provided standards of excellence.

work? .

QO: Did any of your preclinical teachers attract you to do research

Rivers: ‘They wanted me to, and they tried to, but I didn’t do a bit of research. When I went to Hopkins, I was determined to be a practicing physician, and I was going to be as good a one as I could. It never occurred to me that doing research would make me a top notch practicing physician, and [ went through school, my interneships, and residencies without doing any real research. However, I did learn as much physiology, anatomy, and pathology as I could, and by the end of my second year I was quite adept in bacteriological and pathological laboratory work.

QO: Could you then tell me why you dropped out of medical school at the end of your second year?

Rivers: Well, I don’t know how many people know the reason, because I kept it quiet for a long time. When I was in college, I was considered the strongest man in the entire student body. I took a great deal of interest in athletics, particularly in gymnasium, and during the last two years in college, after our regular gym professor left, I conducted two classes a day in gymnasium, in addition to my regular classwork. I was a pretty good-looking physical specimen when I got into the Hopkins. However, during my second year—I don’t remem-

ber just when—I began to notice that my left hand was getting weaker and smaller and losing a lot of muscle.

Finally, I went to see Dr. Henry ‘Thomas, who was a professor of neurology, and had him examine me. Then Dr. Lewellys F. Barker, the professor of medicine, who also knew a great deal about neurology, also went over me. They told me that I had progressive central muscular atrophy of the Aran-Duchenne type, and that the disease usually ran a fairly rapid and fatal course, with an exception here and

Beginnings | dl there. After they told me, they advised me to drop out of medical school and go back home.

Well, I returned to Jonesboro and after mooning around for a while I kind of got fed up waiting to die. At that time I had a friend named Claude Winn, who was a doctor in charge of the laboratory at the San ‘Tomas Hospital in Panama. I wrote Claude asking if he had any jobs open for a laboratory assistant, and he replied, “If you can get Popsy Welch to write you a recommendation, you won’t have any difficulty getting a job down here.”

I thereupon took a train to Baltimore and went around to call on Dr. Welch. I told Dr. Welch that I wanted this job in Panama, and

that Dr. Winn had told me that if I could get a recommendation from him [’d have no difficulty in getting the job.

I said, “Dr. Welch, would you mind giving me a recommendation?” He looked at me, and said, “Yes. What’s your name?” I don’t believe Popsy Welch knew me from Adam, but he sat down and wrote me a glowing recommendation in longhand. If I had that

recommendation today, I think I could be elected President of the United States! At this point, I might tell a story that went the rounds at the Hopkins while I was there; even after I left Baltimore, I heard it on sev-

thing like this: :

) eral occasions in different parts of the country. The story went someDr. Mall was pretty indifferent toward his students. He never lec-

tured very much, and he saw very little of his students. Apparently some members of the faculty thought Mall should give more attention to the students, and so they appointed Welch to go over and talk to Mall. Welch was true to his charge and chided Mall about not lecturing and not knowing more about his students, to all of which Mall replied, “Yes, all of that’s true. It’s true. I believe everything you say.” And that ended that visit.

Several months later, Mall went over to see Welch, and said, “Welch, I’ve been thinking about that talk that you had with me seyeral months ago about the way I neglected my students. You were quite right. I have been neglecting them: I understand that you know

students and don’t neglect them, and I just thought I’d come over

12 | Chapter 1 and admit my shortcomings and ask you about Sam Jones who is in your Class.”

Popsy said, “Yes, I know Sam Jones,” and they talked for a while about Sam. ‘Then Dr. Mall said, “I’m sure you must also know Eddie Blythe.” Dr. Welch said, “Yes, I know Eddie,” and he talked about him for a while.

Dr. Mall subsequently mentioned several other names, and Dr. Welch talked about them. After this had gone on for half an hour or more, Dr. Mall said to Welch, “Now, look, Welch, you're just a damned liar. None of those boys are in your class. They’re just names I made up!”

Now I don’t know if this story is true but I think that it reflected the truth of what went on at the Hopkins. Mind you, not the truth as Welch or Mall understood or looked at it, but the truth of what other folks thought they saw.

OQ: Was your trip to Panama the first time you were out of the country?

Rivers: Oh, I’d been to Baltimore. I wasn’t like some of the folks in Jonesboro. Some of my townmates—I won’t mention any names— heard one day that so-and-so had been over to a place in Alabama,

and this townmate of mine said, “Well, that must have been the first } time he ever went out of the country.” I wasn’t quite that bad. I did read the newspapers. I did know the boundaries of the United States. And I knew what was going on down on the Canal, and I wanted to see what was going on there for myself. However, I didn’t realize just what I'd have to go through to reach Panama. I borrowed my railroad and steamship fare from my father before I left Jonesboro, and I boarded a train to New Orleans. About 50 miles out of New Orleans, the firebox of the engine fell out, and we were left stranded in the middle of a bayou with no way to get into New Orleans except to walk the crossties. Originally we were scheduled to reach New Orleans the early part of the morning, around 7 to 8, and my boat was to sail somewhere around midday. As a consequence of this mishap, I missed my boat to Panama. I had figured pretty closely

Beginnings 13 | on the amount of money I’d need to get to Panama, but I hadn't figured on a layover for four days in New Orleans.

While I was waiting for the spare engine to come out and pick us up and drag us in, I noticed that there was a good-looking girl back in the observation car, and I got to talking to her. I soon discovered that she was a school teacher and was on her way to New Orleans to visit her brother. When I told her that I didn’t know the name of a single hotel in New Orleans, she told me that her brother was the desk clerk

at the Monteleone Hotel, that she was stopping there, and that it would be nice if I stopped there.

Well, I stopped at the Monteleone Hotel, and for the next four : days I saw the sights and went to shows with this girl and her brother.

When the time came for me to catch my boat to Panama, I discovered that I didn’t have enough money to pay my hotel bill. Well this girl’s brother proved to be very understanding, and for some reason or other said, “Ill hang your bill on the hook, and you can pay it back when you get your paycheck in Panama.”

The trip to Panama took several days and again I spent more money than | had. When I arrived in Panama, I found that I didn’t have enough money to buy a ticket across the Canal to Panama City.

This time I was rescued by a friendly Panamanian shipboard acquaintance who loaned me $10 to cross the Canal. I was honest enough. I paid my bill at the Monteleone Hotel, and I repaid the $10 I borrowed from my Panamanian friend. QO: What was Panama City like when you got there?

Rivers: Panama City was under the jurisdiction of the Panamanian government and was just a kind of an island at the western end of the Canal. Actually it ran right into Ancon, the American city that grew up adjacent to it. ‘he Ancon Hospital, which was the American Hospital, was in Ancon. I lived in Panama City, in the San ‘Tomas Hospital, which was quite an old hospital. Like most European hospitals it was originally built as kind of an almshouse where the needy and the sick would come. The hospital was built around an entire square and was surrounded by a brick wall. ‘To enter it you had to pass through

. 14 Chapter | an iron gate that led into a patio surrounded by several buildings. One

of the buildings housed a priest. The building I lived in housed the operating rooms and was quite old. The hospital at that time had approximately 350 beds and was run by a Junta or Board composed of Americans and Panamanians. The only difficulty in that situation was

that the Americans had one more vote than the Panamanians had, and so controlled the Board. I thought that it was handled diplomatically. The Panamanians didn’t. The whole time I was at the San _

Tomas Hospital, Dr. Bill Caldwell was superintendent. Actually Panama City was not too bad a place to live. But the Panamanians didn’t like us, and they still don’t like us. The main reason they didn’t

like us, at that time, was that we promised to pay them $250,000 a year rent for the Canal Zone, but we never gave them the $250,000. What we did was to spend it on putting in proper sewage, putting in proper waterworks, paving the streets, and doing the things that we thought the politicians down there would never do. ‘The Panamanians just didn’t like the way we spent their money. And I must admit that we were a bit highhanded.

QO: What were your duties in the hospital?

Rivers: In the beginning I was laboratory assistant, and it was my job to count bloods, do urine analysis, stain pathological tissues, and do the dirty work on autopsies. As I learned, I was given more interesting things to do. When I arrived in Panama I started to take lessons in Spanish and after about three months I began to speak it—it’s not too difficult a language. One day Dr. Caldwell called me to his

ofice and asked me if I could speak Spanish. When I said that I could, he told me that the Salana brothers, two doctors who were running the dispensary, had left, and that I was to go over and take charge of the dispensary. I said, “Dr. Caldwell, I can speak Spanish,

but I don’t know how to take care of patients.” “Oh,” he said, “that’s easy. I am sure you can take care of patients and better than the Salana brothers, and I paid them $200 a month. You go over and take care of the patients in the dispensary.”

Following Dr. Caldwell’s instructions, I went to the dispensary, and immediately after I got in there, since they were short of hands,

Beginnings 15 they worked me into assisting at operations. Initially I gave anesthesias. Then one of the internes decided he’d go back to the States, and so one fine day Dr. Caldwell called me in and said, “Rivers, go over and take care of the prison ward and the police ward.” I said, “Dr. Caldwell, I can’t do that. I’m only a second-year medical student. There are a lot of major operations on those two wards. I

just ought not todothat.” ~ He said, “Don’t worry about that. I’m in charge of those two wards, [ll take all the responsibility. You go on and take over.” But he didn’t say anything about giving me any more money. So I said, “Look, Dr. Caldwell, I came down here for $75 a month and my keep. I took over the dispensary and saved you $200 a month, and you

didn’t give me any extra money. Now I’m taking over two more wards, and I’m saving you another $150 to $200 a month. Don’t I get any raise?”’

“Look, Rivers,” he said, “You're not a doc, and I am giving you a chance to do things that a man with your training would never get to do.”” Well I argued with him a while, and he finally agreed to give me

an increase of $25 a month; in the end I got $100 a month and my keep. But he was right, I learned a tremendous amount.

Q: When you say you learned a tremendous amount, was this in surgery or clinical medicine?

Rivers: In terms of everything. In terms of what to do. But more important, in terms of what not to do. I think a lot of doctors have to

learn what not to do, and I sure learned what not to do. I did 85 major operations. ‘The first operation I ever did was a double herniot-

omy on a policeman. A little Negro boy name of Joseph—he was about 20 years old—gave the anesthesia, while the head nurse of the operating room, Schwester Schuman (Sister Schuman), a German, assisted me. I saw quite a bit of this policeman afterward, and the repair was still holding up to the time I left Panama. So it wasn’t too bad. Actually the boys in the operating room were pretty nice, and when I assisted they instructed me in what they were doing. Most of the boys believed in keeping the blood tied up, and I became adept at not losing too much blood during the course of an operation.

16 Chapter 1 I must admit that the medical student or interne in this country never was exposed to the crudities of medicine that I saw in Panama. For instance, the first ambulance case that came in, when I was officer of the day, after I had taken over the police ward and the prison ward, was a dislocation of the shoulder. It was a Negro patient. A big ambulance man and other attendants dragged this man in and put him on an examining table. I didn’t know what was the matter with him, but the ambulance man said, “He’s got a dislocated shoulder.” I still kept looking at him, and he said, “You don’t know how to set it, do you?”

I said, “No, I don’t know how to set that dislocated shoulder, and you know I don’t.”

“Well, PIL show you,” he said, and with that he took his big foot and put it up on the poor patient, took hold of his arm, and pulled the damned shoulder back in place. I didn’t know whether it was set right or not, but he got the shoulder back in place, and the man went out of there with a perfectly good shoulder. QO: Did the San ‘Tomas Hospital have x-ray at the time?

Rivers: Yes. Soon after | came to Panama an x-ray machine arrived at the hospital, and the man who installed it showed me how to run it. It was a huge machine with two large plates, and every time a picture was taken a huge spark would cross between the two plates. ‘The reason I never burned myself was that the machine came equipped with a small room for the operator, so I was safe enough. I still don’t un-

derstand how I missed electrocuting the poor patients. I should say here that, since I was the young guy, everything dirty, everything new was pushed off on me. I even had to pull teeth. But there was nothing

I could do about it, since most of the doctors in the hospital were teaching me, and even though they were not much older than I was, they were teaching me and I didn’t want to risk making them mad by complaining, so I kept my mouth shut. I think the most famous x-ray picture I ever took was a picture of the hand of President Poris of the Republic of Panama. ‘The San Blas Indians of Panama were not a very friendly group of Indians, and for years they would not swear allegiance to the Republic of Panama.

Beginnings 17 Panama was never able to get tax money out of them or, for that mat-

ter, anything else. While I was in Panama, they finally sent one of their chiefs in to Panama City to reach some agreements with the Republic of Panama. While this chief was in Panama City, President Poris brought him over to see San Tomas Hospital. Poris had never seen an x-ray, and the San Blas chief had never seen an x-ray, and I’m sure that the interpreter who came with them hadn’t seen one. I was

amused that the San Blas who acted as interpreter could speak perfectly good English. “Where did you learn to speak English?” I asked

him. “Oh,” he said, “T lived in the United States a long time.” ““W here?”

“I was a streetcar conductor in Philadelphia for many years,” he replied.

Their interest in the machine was so great that I took President Poris over and took a picture of his hand. I must say that the President and the Indians were all greatly impressed. But I should stress that I only took x-ray pictures, I wasn’t responsible for interpreting them—that was the duty of the regular doctors.

O: What was the nature of the diseases that you saw at the San Tomas Hospital?

Rivers: One of the diseases I saw a great deal of was lobar pneumonia. When we think of Panama we usually think of tropical diseases, but it should be remembered that one of Dr. Gorgas’s great achievements in Panama was his campaign against pneumonia. Many of the laborers in Panama lived in congested conditions in poor huts that were lined with tiers of beds. ‘There was never any real honest-toGod dry season in Panama; there was only a wet season and a wetter season. In such an environment, laborers in Panama came down with lobar pneumonia. There was little to be done for lobar pneumonia in those days. There was, for example, no useful drug therapy, and each doctor went his own way. Some gave a little digitalis for the heart, which didn’t do any good. Some gave alcohol, but most treatment was symptomatic. I don’t think that our death rate was higher than it

should have been. I think that letting patients alone was about as good a treatment as one could think of in those days. Gorgas made a

18 Chapter 1 dent in the rate of lobar pneumonia by campaigning against congested living conditions in these huts. Later that technique was adopted by Sir Almroth Wright in his campaign against lobar pneumonia among mine laborers in Johannesburg, South Africa.®

Another disease I saw a great deal of in Panama was tuberculosis. The San ‘Tomas Hospital had a very large TB ward, but there was little that we could do at that time for the patients. Nothing was known

about how to handle such patients, and even if it had been known you still could do nothing for them. For one thing, there was not much money available for the feeding of patients in the hospital. If I remember correctly, it cost the Panamanian government 11 cents a day to feed a patient, and even in 1912 and 1913 that was a small sum of money to pay for three daily meals. QO: Did you see much venereal disease?

Rivers: Yes I did. It was while I was in Panama that I learned how to do the so-called Wassermann test. In 1905 Schaudinn discovered the Treponema pallidum, and a year or two later August Wassermann helped devise a complement-fixation test for the diagnosis of syphilis. Wassermann’s name is usually affixed to this test, but to my mind Jules Bordet deserves the credit because he developed the first

complement-fixation test. Well, when I came to Panama, Wassermanns were being done at the American hospital in Ancon. When I went to work in the dispensary, Dr. Caldwell gave me instructions to

learn how to do the Wassermann test, and I learned how to do it from one of the books we had in the library. I am not so sure about whether I was exactly as I should have been on the first Wassermanns

that I did, but before I left Panama I had learned quite a bit about how to do a Wassermann and my results were more accurate. You might say that the worst that I did for a patient on that deal was to have some poor guy get some Salvarsan that didn’t need it, or maybe miss giving a person Salvarsan who should have had it.

Fortunately, nobody died from the Salvarsan that I administered. 1 * Almroth Wright’s biographer, Dr. Leonard Colebrook, states that Dr. Wright attempted to control the pneumonia outbreak in Johannesburg with a pneumonia vaccine. L. Colebrook, Almroth Wright. Heineman, London, 1954, pp. 65-69.

Beginnings 19 mention this because the Salvarsan that I gave was the old “606.” It was not the neo-Salvarsan that is sometimes given today. The Salvarsan that I gave had to be mixed with distilled water and an alkali, since it was very acid and had to be made properly alkaline before being given. So there was some danger. If you missed the vein in administering the Salvarsan, you caused the patient a great deal of pain, because it was terrifically irritating to the tissues. Of course, we at that time thought that one dose of Salvarsan was sufficient. There

was reason for that. In Panama there was a good bit of tertiary _ syphilis, which often manifested itself by big gummas on the body, , and frequently they would disappear like magic after a single dose of Salvarsan. We were ready to kiss our patients goodbye, but they were

not well. It took us some time to realize that we had to follow the

patients for quite a period. } Q: Was the Wassermann sufficient for diagnosis?

Rivers: ‘here were many problems in diagnosis, and one of the problems we had to face in Panama was that there were diseases in __ that area that would give you a positive Wassermann. More specifically, there is a disease called yaws that is usually present in tropical regions, and it too is caused by a spirochete. Yaws can give you a posi-

tive Wassermann, and I can tell you that it tested a man’s clinical ability when it came to telling the difference between yaws and syphilis in making a diagnosis. I suppose we at the San ‘Tomas Hospital made the usual number of mistakes.

Since I did the Wassermanns and administered my fair share of Salvarsan, at one point I thought I would try to see what Salvarsan would do for leprosy. We saw a certain amount of leprosy in Panama. Many of the lepers were not Panamanians but came from Colombia in South America. In Panama, when a diagnosis of leprosy was made, the patient was picked up and immediately sent to a leper colony. In Colombia, they had no leper colony, and they allowed the lepers to go about their business. When a suspected case of leprosy was picked up,

what we would do was to make an incision of the extant nodules either on the hand or ear lobe to see if we could get the acid-fast organism that was necessary for diagnosis. If it didn’t turn up from this

20 Chapter | procedure we usually took a nasal smear. It was my experience that you would always get an acid-fast organism from the nasal smear of a leprous patient. If the patient was a Colombian, we’d tell him what the diagnosis was and try to persuade him to go home, because the leper colony was not a nice place for anybody to go to, and we felt that as a Colombian he should have a choice. If the patient was a Panamanian, we had no choice in the matter.

Well, I tried to treat a number of my leprous patients with Salvarsan. I need not say that nothing happened, because that’s what did happen—nothing—except that, during the course of such treatment I saw sensitization to a chemical for the first time. I gave one lady patient 12 injections of Salvarsan. Along about the 10th injection she had a mild reaction; at the 11th she had a more severe reaction; at the 12th injection she had a severe enough reaction so I was sure I was never going to give her another one. It was hard for me to understand why a person would become sensitive to a chemical agent, because at that time most people believed that a person could only become sensitive to a protein. Some time

later, Homer Swift, at the Rockefeller Institute, and Hans Zinsser noted sensitivity of patients to certain drugs and postulated that chemicals united with some proteins of the body, altering them sufh-

ciently so that they would become antigenic for the human body. Landsteiner later proved this supposition experimentally, but, back in 1912 and 1913, it was all very nebulous why a patient would become sensitive to a chemical agent.

O: Dr. William C. Gorgas is known for his achievement of ridding Havana and Panama of yellow fever. Were there any cases of yellow fever in Panama City during your stay in Panama?

Rivers: During the whole time I was in Panama, I only saw one case of yellow fever in the San Tomas Hospital. But that case came from Guayaquil. Actually, when I was in Panama, they had a fairly severe outbréak of yellow fever in Guayaquil and a special commission was sent from the United States to investigate that outbreak. The reason I remember that is because one of the members of that commission

Beginnings 21 was George Whipple, who later was to win the Nobel prize for his work on anemia—a prize he shared with George Minot of Boston. I might have said hello to Dr. Whipple at that time; if I did, it'was all I said, because after all I was only a laboratory assistant, and what was

he going to waste his time for talking to the likes of me? The thing , that most impressed me about George Whipple at that time was that such a good-looking hombre—and he was more good looking than he had a right to be—was also such a serious-minded fellow. If I saw only one case of yellow fever, I should add that I did see plenty of malaria on the wards of the San Tomas Hospital. Now, few of these cases originated from the Canal Zone; in the main they came from other parts of Panama. By this time old Dr. Henry Carter had just about cleared up malaria in the Canal Zone. I not only saw the ordinary type of malaria, I also saw the cerebral type which is pretty rare now but was not so rare at that time. A man might be walking down the street and suddenly drop. When the doctor came, one of the first things he did was to smell the guy’s breath to see if he was drunk. ‘The second thing he would do was to test his urine to see if he had diabetic coma. ‘The third thing was to take a smear of the blood

to see if he had malaria.

I never failed to find malaria on the first go round of cerebral cases,

because cerebral malaria was caused by the plugging of the small blood vessels in the brain by malarial parasites. We usually had autopsies of such cases, and I want to tell you that these pathological sections were the most fantastic I ever saw, because these small blood vessels were just crammed with malarial parasites until you wondered how in hell the patient walked around as long as he did. We had a pretty drastic method for treatment, because it usually killed one out of every three patients. When you knew that you had a case of cerebral malaria on your hands you usually gave him an intra venous injection of hydrochloride of quinine, and about one of every three would fall over dead before you could get the syringe out of the vein—the other two would live. It gave you pause when you realized that when you put the needle in the guy’s arm he might not make it, but there was no option, because it was a question of saving two out of three patients,

22 Chapter |] QO: Dr. Rivers, your comments on malaria raise the question in my mind whether you received any formal instruction in pathology during your stay in Panama?

Rivers: You can’t be exposed to as much pathology as I was exposed to in Panama without learning something. Actually a number of people had a hand in instructing me in pathology while I was in Panama. One, of course, was my friend Claude Winn who arranged the job for me as a lab assistant; another was William Deeks who at that time was in charge of the American hospital in Ancon. Dr. Deeks later became the chief medical officer of the United Fruit Company. He was

an enormously fat man; as a matter of fact, he was just too fat to walk, and, since the Ancon Hospital was composed of many buildings, Deeks, in order to keep up with his medical duties, rode from building to building in a step-in carriage called a phaeton. In spite of his enormous bulk, he was really an excellent doctor. The fellow I learned the most from was a doctor named Sam Darling. Sam was an extraordinary malariologist and very early went to work in Panama; as a matter of fact, he lived for and through the development of the Panama Canal and its medical activities. His initial pay, I believe was $50 a month. Later he became a field officer for the International Health Board of the Rockefeller Foundation and had a most distinguished career until he was killed in an auto accident in the Balkans somewhere around 1925. Sam loved to swim, and we frequently went on swimming parties to a beach about six miles out of Panama City. They had wonderful bath houses, and the beach was a delightful one, except that it was pretty rough. They had 12-foot tides on the Pacific side and only about a 3-foot tide on the Atlantic side. This difference in tides was one reason among many why it was difficult to build a sea-level canal.

Well, one night we had a swimming party at this beach, and the wife of one of Sam’s assistants got too close to some rocks as the tide was coming in, and she was in trouble. I’m not a very good swimmer,

but I was the man closest to this lady, and I started to swim toward her. Well, I didn’t know whether she’d drown, or whether both of us would drown, but somehow I got over to her, got hold of her, and I must say that I yelled as loud as she did, In the end, three or four

Beginnings 23 good swimmers made their way to where we were and took this lady in to the beach. They were sure taking care of this good-looking lady,

but no one, not even Sam, paid any attention to me. The truth is, they didn’t give a damn whether I drowned or not.

QO: What decided you to return to medical school? | Rivers: After eighteen months in Panama, I got the impression that I liked the practice of medicine. Now, medicine had appealed to me before I went to Panama, but being directly in contact with it, even in a crude and rough way, I made the discovery that it was interesting. I

began to appreciate that there was a great deal that we didn’t know that we thought we knew about disease. I saw things as a laboratory assistant in Panama that a student doesn’t ordinarily see until he has had more training. When you are at medical school, everyone is making damned sure that you don’t get too close to anything. In Panama I was just mixed up in it, I was right in the middle of it, I was on top of it, and by God it was impressive.

When I decided to return to the Hopkins, I just wrote to the dean and told him of my wish to return. He told me to come on ahead, and I went

OQ: What role did history-taking play in the clinical instruction of medical students at the Hopkins?

Rivers: ‘The teaching of history-taking was deemed most important and regarded as a prime tool in making diagnosis. We were taught that doctors might get important leads in diagnosis from a good his-

tory, leads that might otherwise be overlooked. ‘The teaching of history-taking began when the boys went over to the hospital for their third and fourth years’ training. When we started in the dispensary, for example, we had such excellent clinicians as Louis Hamman and Thomas Futcher teaching us, and they were very specific in their instructions about how to take a history. When we went on the wards in the fourth year, we were also made responsible for taking histories. These histories were checked by the interne, and if we took an inadequate one or a bad one, the interne would make it pretty sorry for us,

24 Chapter | and that would only be the half of it, because the professor who held rounds the next morning would harass us as well. An important adjunct to taking history was physical diagnosis, and in our clinical years we were drilled in relying on touch, hearing, sight,

and smell, and we became adept in it. ‘Taking a good history and . doing a thorough physical were two of the most important things you

could do to arrive at a diagnosis, because at that time, outside of doing bloods and urines, there were few diagnostic aids, save x-ray. When I was a student, one of the great pioneers in x-ray, Dr. Frederick Baetjer, taught at the Hopkins. You might say that Baetjer was one of the first clinical roentgenologists in the United States, and like Walter B. Cannon at Harvard was also a victim of his work. Because of exposure to x-ray, Baetjer developed a malignancy of the skin and lost several fingers from his hands, and in the end lost an eye from a malignancy of the retina caused by x-ray. Baetjer taught us how to interpret x-rays. In class he would use x-rays that had been taken of patients several days before. He never asked the names, age, or sex of

the patients before presenting them to the class, but invariably he would tell us how old the patient was, whether they were male or female, and finally whether the picture showed a normal or pathological condition. He rarely missed. Of course, I suppose a man having seen as many x-rays as Baetjer had would sooner or later be able to recognize the difference between the bones of a male and female and distinguish between the bones of the young and old. But I must say that it seemed miraculous to a student to see Baetjer go down the line.

QO: Was the clinical pathological conference then in use for teaching purposes?

Rivers: I don’t know when the Hopkins began to use the CPC, but it was certainly in use when I was a student. The CPC was the best show of the week and was always a tug of war between the pathologist, the clinician, and the surgeon, and the students dearly loved it. Popsy Welch, and Dr. Milton Winternitz who later became dean of the Yale School of Medicine, were the two pathologists who usually presided at the CPC in my day. The cases chosen for the CPC were chosen by the pathology department, and I don’t think that I am far

Beginnings 25 from the mark when I say that, for the most part, cases were chosen

with the idea that they would show up the clinicians and surgeons. | Q: Were excellent clinicians like Dr. Lewellys Barker and Dr. William Thayer, or surgeons like Dr. ‘Thomas Cullen and Dr. John M. T. Finney, shown up very often by the CPC? The reason I ask the question is to get some notion of the validity of the statistical medicine which was then used.

Rivers: Lewellys Barker was an extremely intelligent man, but I don’t think that he was a great clinician. Prior to coming to the Hopkins to replace Osler, who had resigned to become the Regius Pro-

fessor at Oxford, Barker had been a professor of anatomy at the University of Chicago. He was appointed professor of medicine but that didn’t make him a clinician. I watched Barker when I was an interne, and when he walked on the ward to make rounds he would always choose a patient who had been previously well worked up. If the patient were well worked up and Barker had the histories or notes from excellent diagnosticians like ‘Thayer, Futcher, or Hamman, he would take the case. ‘T’o listen to him discuss the history and the nature of a given disease was beautiful. Barker was a-master at that. And his rounds and his clinics were not a complete bust, because he did add something. But he never liked to show a patient at a clinic unless he’d been previously well worked up. The reason I know this is because, every now and then when a patient was going to be shown in the clinic the next day, Barker would have me look up the literature and fetch the necessary books to his office. So I know that on certain occasions Barker knew what the diagnosis was on a patient for the next day, and he had a chance to cram up on the literature. Theodore Janeway, on the other hand, was just the opposite. He did not want to know what the patient had and he did not want to have the patient worked up before he saw him on the ward or even in

the clinic. He wanted to take a crack at it cold. Now, that was the , difference between Barker and Janeway. Barker I don’t think would have gotten to first base if he’d taken a crack at a case cold. Janeway

knocked a double, frequently a triple, and occasionally a home run, on the patient that he saw.

26 Chapter ] I would like to illustrate how Janeway worked. On one occasion _ when I was an interne, I had just taken over Ward M, which was the ~ men’s colored ward. A very interesting case had come in the night before, and I took the history and worked up the case. The next morning

when Dr. Janeway came in to make rounds, I tried to get him to go over and see this patient who I thought was so very interesting. But Janeway would have nothing to do with it. He saw an elderly Negro man sitting in a bed over on the other side of the ward and said, “I

want to see that man.”

I said, “Dr. Janeway, that man’s been here a long time. Everybody has seen him and examined him, and no one has ever quite figured

out the diagnosis.” Janeway said, “Well, I know what’s the matter with him. I want to

see him.”

I said, “All right, we'll go over and see him.” Well I went over the history and gave Janeway the findings of the other doctors who had previously examined him and finally came to the stone wall in diagnosis, namely, that nobody, but nobody, knew what was wrong with this poor fellow. Janeway said, “I know what’s wrong with that man. I don’t have to examine him. He’s got a carcinoma of the prostate, with metastases to his spine and his pelvic bones.”

I said, “Dr. Janeway, the GU people have been over here, and they examined him and said his prostate was all right. ‘here’s nothing in the world wrong with his prostate.” Janeway replied, “I don’t care who’s examined him, I know what he’s got.” I said, “Dr. Janeway, this is a little bit disturbing.” He said, ““There’s nothing distirbing about it.”

“Well,” I said, ““won’t you tell the students why you know what’s the matter with him?”

“T don’t mind,” he said. “It’s the way he’s sitting in bed.” “My father—and this was a joke, because he was always talking about his father—I saw several patients with my father in New York, and they were sitting in bed like this fellow is, and they all had carcinoma of the prostate with metastases.” I said, “Well, [’ll take your word for it.”

Beginnings 27 He said, “You don’t have to take my word. We'll take the man over to x-ray.” So Janeway went along with us to x-ray and had the pelvic bones and spine of this old colored man x-rayed, and, lo and behold, he had metastases in his pelvic bones and the lower part of the spine. Janeway had never laid his hand on the man. He made a diagnosis from the way the man was sitting in bed. Q: Did Hugh Young miss this carcinoma?

Rivers: Hugh Young didn’t miss it. Hugh Young did not examine this patient. He was examined by other people in the Department of Urology, but I’m not so sure that, in this instance, it wouldn’t have been missed by any GU man, because you just don’t always feel everything that’s. in a prostate. Janeway was full of surprises. Barker was never a surprise. Most of us young fellows who had been around the hospital any length of time knew his limitations. Later Barker was offered the full-time professorship in medicine and turned it down to go into private practice. Just let me say that Barker was one of the few practitioners of his day that actually made a million dollars from the practice of medicine and the investment of what he made at the practice of medicine. But even in private practice, his success depended

on two people, Dr. Thomas Sprunt and young Dr. Walter Baetjer, who were two of the best diagnosticians in Baltimore. Getting back to your original question, 1 would guess that no mat-

ter how good diagnosticians were at the Hopkins, and some of them were very good, they were never more than 65 to 70 per cent right in their diagnoses—and I believe I am being rather generous in my esti-

mates. When you look back, even if they were night, there was | precious little that they could do. At the time I was a student, there | were not many drugs that could be used for the treatment of disease.

When you got through with digitalis for the heart, quinine for malaria, mercury and Salvarsan for syphilis, and one or two drugs for intestinal worms, you had almost run out of therapeutic agents. Actually, the Rockefeller Institute in New York had its origin in the fact that one of John D. Rockefeller’s advisors, Frederick ‘T’. Gates, who was a Baptist minister, early recognized that while doctors were fairly

28 Chapter 1 adept in making diagnosis they had no way of treating diseases after they diagnosed them. It was Gates who urged Mr. Rockefeller to start an institute devoted not only to research on the nature of diseases but on how to treat them as well. Abraham Flexner in his autobiography gives most of the credit of the founding of the Institute to Dr. William H. Welch, and I must agree that Dr. Welch played an early and important role in the development of the Institute. He was a key fig-

ure on the Board of Scientific Directors of the Institute and was largely responsible for getting Dr. Simon Flexner appointed the first director of the Institute, but, no matter what Dr. Welch’s role was, the idea for the Rockefeller Institute was indisputably Gates’s. Recently a copy of a memorandum ° that Mr. Gates prepared for Starr J. Murphy in 1915 on the origins of the Rockefeller Institute came to my attention, and I would like to submit it for the record, since it is a

unique document in the history of American medicine and casts much light on the beginning of one of the great medical research institutes in the United States and, for that matter the world. December 31st, 1915

Dear Mr. Murphy: You asked me the other day to write you my recollections of the origin of the Rockefeller Institute for Mr. Rockefeller’s private files. You wished me to trace the very idea back to its sources, and accordingly, so far as my recollections will serve, I will give you what may be termed the pre-natal

history of the Institute. I have no doubt that the history of the Institute will some time be written, and I am aware that these obscure questions of

origin however unimportant have a greater interest often than the later and more obvious facts. Moreover, if we who are acquainted with the earlier facts leave no record of them, it will be impossible for our successors to recover them when we have passed away. I therefore leave with you, for the files of Mr Rockefeller and the Institute, my recollections of the early history of the Institute in this my compliance with your request, ° This memorandum was originally quoted in part by Simon Flexner and James T. Flexner in their biography of William H. Welch. George Corner has since reproduced it as an appendix in his recent history of the Rockefeller Institute. When Dr. Rivers inserted it during his oral history interviews in the late spring of 1961, it had not yet been printed in its entirety. In order not to disturb the continuity of Dr. Rivers’ remarks

it is reprinted here again. S. Flexner and J.T. Flexner, William H. Welch and the Heroic Age of American Medicine. Viking Press, New York, 1941, pp. 269-272. G. W. Corner, A History of the Rockefeller Institute. Rockefeller Institute Press, New York, 1964, pp. 575-584.

Beginnings 29 But first of all, the historian of the Institute should be made acquainted with what I may call the atmosphere or spirit of Mr Rockefeller’s private ofhce. During all the twenty-five years in which I have been intimately associated with Mr Rockefeller, he has been sincerely desirous of employ-

ing his great fortune in the service of mankind, at home and abroad, whether that employment be in investments or in bestowal on private or public charity. It has been during all these years my chief end in life, as a member of Mr. Rockefeller’s staff, to assist him in this aim, both in the sphere of investment and in the sphere of bestowal. It is not too much to say that every day and hour of my life during these years has had for its underlying motive, watchfulness for such opportunities of public service. With this introductory explanation, to you personally quite unnecessary, but perhaps useful to other eyes, I pass to the narrative. This I will make as full and comprehensive as possible. Origins are often very humble. Christianity itself was born in a manger. It is so with the Institute. During the years 1880 to 1888 I was the pastor of the Central Baptist Church of Minneapolis. In my congregation was a

young boy named Elon W. [sic] Huntington, a member of one of the most useful families in the church, a family which for many reasons was particularly dear to me. Elon himself I baptized as a boy in his teens. In due time he was graduated from the University of Minnesota. His father, Jong deceased, had been a physician and Elon chose his father’s profession. Not finding in the West the best facilities for the study of medicine, Elon

| came to New York and became a student in the College of Physicians and Surgeons. ‘I’his was in the early 90’s; probably 1894. I had left my pastorate in Minneapolis in 1888 and at this time was living in Montclair as a member of Mr. Rockefeller’s staff, assisting him in his private business investments and in his benefactions in the spirit of my introductory words above.

Elon Huntington was a lonely student without a friend and almost without an acquaintance in New York, and he used to come out to visit us in Montclair, often spending the night or the Sunday with us to relieve his loneliness. In this way he spent many hours with me. We used to take long walks together and the subject of our conversation was quite naturally medicine, the subject in which he was most interested and in which he was

then most intelligent. Thus, in simply entertaining Elon I found myself intensely interested in medicine. My interest reached a point in which I determined to know something more definite about medicine, and in the spring of 1897, when Elon if I recall it, was about to graduate, I told him that I would like to read medicine and I asked him if he could suggest to me a book which a layman like me might be able to understand and to read with profit. I remember telling him that I did not want any of the ordinary medical books for the family. I wanted to know what the best doctors are reading; I wanted the literature that was being taught currently in the best

30 Chapter | schools to medical students. Was there any such book pre-eminently good?

He replied that there was one such book;‘it was Osler’s Principles and Practice of Medicine and said that this book was being taught to students in the College of Physicians and Surgeons and that it was written in a style so clear that with very slight knowledge of medicine I could read it with understanding and interest. He suggested further that I get a little pocket

dictionary of medicine entitled “T'wenty Thousand Medical Terms” or something to that effect, and he named the place in New York, a medical book store on 17th Street, if I remember, where I could get Osler’s book and the little dictionary that ought to accompany it.

I took my first opportunity to hunt up this book store and there I bought my precious volume in June 1897. At this time my sole purpose was to become reasonably intelligent, as a layman, on the subject of medicine.

Perhaps I ought to delay here long enough to say that this question of medicine had for many years been a subject of more interest to me than rt

is to laymen in general. My father, before he became a minister, had studied medicine. Then as a pastor from 1880 to 1888, I had been brought of course into direct and sympathetic relation with hundreds of sickrooms and with both schools of medicine. I had come into confidential relations also with several physicians, and I shall confess that I had come to acquire a profound scepticism about medicine of both schools as it was currently practised. I had read from beginning to end Dr. Hanneman’s [sic] book

known as the New Testament of Homeopathic Medicine. He was the originator of that school and I had come to believe from the reading of that book that Dr. Hanneman [sic], founder of the Homeopathic School, must have been to speak charitably little less than a lunatic, a belief cordially shared by a homeopathic physician friend. I would not be true to my feeling at the time, whether right or wrong, if I used any milder terms. Many years afterwards I wrote a review of Homeopathy in five chapters,

which sought to exhibit its errors and impossibilities. But I had hardly more confidence in the allopathic school. My intimate conversations with allopathic physicians, who practised in my church had led me to see clearlv that at least nine-tenths of their practice without guilt on their part was based substantially on the ignorance and credulity of their patients. I remember very distinctly the impression made on my mind, an impression entirely confirmatory of my previous observation by the remark to me of one of the most prominent allopathic practitioners in Minneapolis, that at least nine out of every ten calls made by physicians, might, for any possible good they did their patients, precisely as well not be made. I introduce the facts to fully explain my interest in medicine and why and in what spirit I began to read in June 1897, Osler’s Principles and Practice of Medicine. The book came into my hands at a time of abundant leisure. I spent a

Beginnings 31 considerable part of the months of July and August following with my family in the Catskill Highlands, at Lake Liberty, in Sullivan County, New

York, and I had opportunity to give my undivided attention to Osler’s book for considerable part of every day. My wife’s diary of those days shows how my time was divided between kites, water-wheels and frog hunting with my children and reading Osler’s Principles and Practice of Medicine. I read the whole book without skipping any of it. I speak of this not to commemorate my industry but to celebrate Osler’s charm. Osler’s Principle and Practice of Medicine is one of the very few scientific books that I have ever read possessed of literary charm. There was a fascination

about the style itself that led me on and having once started I found a hook in my nose that pulled me from page to page, and chapter to chapter, until the whole of about a thousand closely written pages brought me to

the end. But there were other things besides its style that attracted and constantly, in fact, intensified my interest. I had been a sceptic before, not only as to homeopathic medicine but as to allopathic medicine as currently practised. This book not only confirmed my scepticism but its revelation absolutely astounded and appalled me, sceptic as I was. Let me name some of the things, which, commonplace as they are to intelligent physicians, were absolutely appalling to me, a layman, although supposing himself to

be a sceptic. I found, for illustration, that the best medical practice did not, and did not pretend to cure more than four or five diseases. ‘That 1s, medicine had, at that time, specifics for about as many diseases as there are

fingers on one hand. It was nature, and not the doctor, and in most instances nature practically unassisted, that performed the cures. I learned that with the exception of two or three, the physician had nothing whatever to prescribe for the infectious diseases, which could effect a cure. Osler’s own attitude toward drugs was interesting and I came at length to approach his curative suggestion with a smile. His chapter on any particular disease would begin with a profound and learned discussion of the definition of the disease, of its extension throughout the world, of the history of discovery about it, of the revelations of innumerable postmortems, of the symptoms, cause and probable results of the disease, and the permanent complications and consequences likely to follow, but when he came to the vital point, namely, the treatment of the aforesaid disease, our author, who had up to this time been treading on solid grounds with the confidence and delight of sure knowledge, would almost invariably disclose a mental attitude of doubt and scepticism. He would suggest that such and such had found that this or that treatment was efficacious but such had not been his own experience; perhaps this or that might be found to be useful

in some cases. ‘To the layman student, like me, demanding cures, and specifics, he had no word of comfort whatever. In fact, I saw clearly from

32 Chapter 1 the work of this able and honest man, that medicine had, with the few exceptions above mentioned, no cures and that about all that medicine up to 1897 could do was to nurse the patients and alleviate in some degree the suffering. Beyond this, medicine as a science, had not progressed. I found further that a large number of the most common diseases, especially of the young and middle aged, were simply infectious or contagious, were caused by infinitesimal germs that are breathed in with the atmosphere, or are imparted by contact or are taken in with the food or communicated by the

incision of insects in the skin, which serves as a protective covering. I learned that of these germs, only a very few had been identified and isolated. I made a list, and it was a very long one at that time, much longer than it is now, of the germs which we might reasonably hope to discover but which as yet had never been, with certainty, identified, and I made a very much longer list of the infectious or contagious diseases for which there had been as yet no specific found.

When I laid down this book, I had begun to realize how woefully neglected in all civilized countries and perhaps most of all in this country, had been the scientific study of medicine. I saw very clearly also why this was true. In the first place, the instruments for investigation, the microscope, the science of chemistry, had not until recently been developed. Pasteur’s germ theory of disease was very recent. Moreover, while other departments of science, astronomy, chemistry, physics, etc. had been endowed very generously in colleges and universities throughout the whole civilized world, medicine, owing to the peculiar commercial organization of medical colleges, had rarely, if ever, been anywhere endowed, and research and instruction alike had been left to shift for itself dependent altogether on such chance as the active practitioner might steal from his practice. It became clear to me that medicine could hardly hope to become a science until medicine should be endowed and qualified men could give themselves to uninterrupted study and investigation, on ample salary, entirely independ-

| ent of practice. To this end, it seemed to me an Institute of medical research ought to be established in the United States. Here was an opportunity, to me the greatest, which the world could afford, for Mr. Rockefeller to become a pioneer. This idea took possession of me. ‘he more I thought

of it the more enthusiastic I became. I knew nothing of the cost of research; I did not realize its enormous difficulty; the only thing I saw was the overwhelming need and the infinite promise, worldwide, universal, eternal. Filled with these thoughts and enthusiasms, I returned from my vacation on July 24th; the year was, as I have stated, 1897. I brought my Osler into the office at #426 Broadway, and there I dictated to Mr. Jones, my secretary, for Mr. Rockefeller’s eye, a memorandum in which I aimed

to show to him, the to me amazing discoveries that I had made of the actual condition of medicine in the United States and the world as dis-

Beginnings 33 closed by Osler’s book. I enumerated the infectious diseases and pointed out how few of the germs had yet been discovered and how great the field of discovery, how few specifics had yet been found and how appalling was the unremedied suffering. I pointed to the Koch Institute in Berlin and at greater length to the Pasteur Institute in Paris. It was either in this connec-

tion or a little later, for I kept up my inquiries on the subject, that I pointed out, as I remember the fact, that the results in dollars or francs of Pasteur’s discoveries about anthrax and on the diseases of fermentation had saved for the French nation a sum far in excess of the entire cost of the Franco-German War. I remember insisting in this or some subsequent memorandum, that even if the proposed institute should fail to discover anything, the mere fact that he, Mr. Rockefeller, had established such an institute of research, if he were to consent to do so, would result in other institutes of a similar kind, or at least other funds for research being established, until research in this country would be conducted on a great scale and that out of the multitudes of workers, we might be sure in the end of abundant rewards even though those rewards did not come directly from the institute which he might found. Mr. Rockefeller was at this time in Cleveland. I myself soon took a very long trip of a month or so to the Pacific Coast on business. I never saw my memorandum again. But that Mr. Rockefeller was impressed by the force of these considerations I have documentary evidence. These studies and memoranda, as I have said, took place in the summer and fall of 1897. In January 1898 an event took place which discloses to us the effect of these considerations on Mr. Rockefeller’s mind. Mr. Rockefeller had begun the work of founding the University of Chicago with a gift in 1889. ‘The University opened its doors in 1892 and for five years had been rapidly expanding. The outlines of the proposed Insti-

tute of Research were, of course, only vaguely drawn in our minds at the

time of its inception in 1897. We did not know whether the Institute would be practicable or possible. I had indeed received encouragement from such friends as I had addressed on the subject, notably from my physician

in Montclair, Dr. J.S. Brown. What counsel, if any, Mr. Rockefeller had taken, I do not know but it is quite certain that our earliest conceptions associated the proposed medical institution with some great institution of learning and with some great medical school. Mr. Rockefeller was interested in the University of Chicago, as founder, and it was in his mind, as it was in my mind, that the institution of research would be associated, if the idea were ever realized, with that young and flourishing institution.

In 1894 an attempt had been made to associate the Rush Medical College in Chicago with the new university. ‘The matter was discouraged by Mr. Rockefeller in 1894, and the interviews and correspondence on that subject culminating in 1895 led Mr. Rockefeller to suppose that no further

34 Chapter | attempt would ever be made to associate Rush Medical College with the University of Chicago. To Mr. Rockefeller’s very great surprise, and to mine, for I had been privy to all the previous negotiation, we were informed in January 1898 that official action had just been taken affiliating Rush Medical College with the University of Chicago. ‘The practical effect of this association would be, as we foresaw it, to make Rush Medical College the medical college of the University of Chicago. The history and the

ideals of Rush College at that time rendered it an unsuitable basis on which to rear an institute of research. Accordingly, under Mr. Rockefeller’s

direction, I immediately addressed a letter of earnest dissent to the authorities at Chicago. This letter was dated January 12th, 1898. As the letter

was important and as our relations with the University of Chicago were extremely intimate, the letter, before being sent, was very carefully considered and was scrutinized, in advance of its being sent, by Mr. Rockefeller

personally. Among other things, the letter contained the following pregnant and significant passage:

“IT have no doubt that Mr. Rockefeller would favor an institution that was neither allopath nor homeopath, but simply scientific in its investigations into medical science. That is the ideal. For that the University should wait and reserve the great weight of its influence, authority and prestige, instead of bestowing the same gratuitously on Rush Medical College. Such an institution would have to be endowed and would run on a far higher principle than the principle of Rush College or any other of the ordinary institutions.” In the original letter, and in the letterbook copy from which I take this

] quotation, these words were made the central point of the entire letter by running along the margin of each side a heavy line. My purpose was to intimate to Dr. Goodspeed, official secretary to the University, to whom the letter was addressed, that this passage contained for him a pregnant mean-

ing. It intended to intimate to him that if he would quietly wait, the founder would probably endow an institute of research in connection with the University of Chicago. Mr. Rockefeller understood the implication of

these words of course as well as I did and he not only permitted, but ordered the letter to be sent with all the implications that it contained. This discloses clearly the fact that at that time the idea of an institution for investigation had already taken root and was germinating in Mr. Rockefeller’s mind. ‘This was January 12th, 1898, within six months after my studies in Osler’s Principles and Practice of Medicine. Dr. Goodspeed promptly replied, undertaking to justify and excuse, and perhaps to minimize the action of the University. ‘This led to a second let-

ter still more insistent than the first one. This letter was dated January 19th, 1898, just one week later than the first letter. In that letter was a

Beginnings 35 passage still more significant than the one from the first letter which I have quoted above. ‘The passage is as follows:

“The whole effect and tendency of this movement will be to make Rush ultimately the medical department of the University of Chicago, as against that far higher and better conception, which has been one of the dreams of my own mind at least of a medical college in this country, conducted by the University of Chicago, magnificently endowed, devoted PRIMARILY

TO INVESTIGATION, MAKING PRACTICE ITSELF AN INCIDENT OF INVESTIGATION and taking as its students only the choicest spirits quite irrespective of the question of funds. Against that ideal and possibility, a tremendous if not fatal current has been turned; I believed the ideal to be practicable and I hoped to live to see it realized.” You will observe here that the central thought is an institution for investigation. An institution in which whatever practice of medicine there is shall be in itself an incident of investigation, that while I said this was a dream of my own I qualified by saying “at least of my own mind”, imply-

ing that it might also be a dream in another mind, and I not only stated that I believed it to be practical, but I added that I thought it was possible. This letter, with all these implications, passed under the very critical eye of Mr. Rockefeller. He understood the implications perfectly, he knew perfectly well that those who read that letter, although I signed it, would understand and give just the same significance to it as if he signed it himself. I was acting as his secretary, if not his amanuensis in sending it. This statement, therefore, of a week later, reveals still more clearly that the idea of an institution of research had taken such possession of Mr. Rockefeller’s mind and that he was prepared to endorse the quasi public committal to it

which is made in this letter. :

But from this time forward Mr. Rockefeller never associated the proposed institute with the University of Chicago. I, for my part, while I still continued to cherish the idea, of an institute of research, found it impossible to pursue it in an effective way owing to the multiplicity of other ab-

sorbing duties. The matter, however, continued to be referred to and conferred upon for a year or two, particularly with Mr. John D. Rockefeller, Jr., who shared all my interest in it. Any active steps toward founding the institution would involve extensive conference with the leading men of research in this country, a study of the history of similar institutions in Europe and an amount of thought, correspondence and travel, that might well engage a large part of the time of a competent man. | therefore suggested one day to Mr. John D. Rockefeller, Jr., that we employ a man for this exclusive service and suggested a man entirely qualified

whom I thought we could command for such a service, my friend and neighbor in Montclair, Mr. Starr J. Murphy.

36 Chapter 1 After my enumeration of Mr. Murphy’s rare qualifications, Mr. Rocke-

feller was so far impressed that he met Mr. Murphy and arrangements were made for his undertaking the work. For several years there was no other thought than that the proposed Institute of Research should be associated in the traditional way with some powerful University. Indeed, negotiations were for a time actively conducted with Harvard, but in the end it

was thought best that the Institute be wholly independent, and time has justified the wisdom of this decision.

The story of your conferences and correspondence with the leaders in medical research in the United States, the first cautious tentative experimental gift made under their expert counsel, the gradual confidence of your advisers, and the final splendid scheme, awaits your own authoritative and graceful pen. Very truly, F. ‘T’. GATES

Mr. Starr J. Murphy, 61 Broadway, New York

CHAPTER 2

The Young Physician Think for a moment, sir, of the situation in which we physicians are placed. We have no legislative chambers to enact laws for us. We are our own lawgivers, or rather we must discover the laws, on which our profession rests. We must discover them and not invent them; for the laws of nature are not to be invented. Dr. Paul C. A. Louis to Dr. James Jackson, March 22, 1833

Rivers: When I went to the Hopkins I swore to myself that I would never stand first in any class again. I was first in my class at Emory, ~ and I want to say that not missing a class and getting a summa cum

laude put a pretty severe strain on me. I was determined when I reached the Hopkins not to get mixed up in such a thing again. Well, I made lots of efforts during my first two years to avoid such a goal, and I must say that I raised bloody hell. I was certainly no model of good deportment and behavior, but I did pass my examinations, and I did try to increase my knowledge about the practice of medicine. I didn’t make any effort to do research, and in the end I stood first in

my class. Now that didn’t mean that I was the smartest in my class—I was far from that—it only meant that the fellows who had plenty on the ball were devoting their time to research instead of preparing for ordinary everyday quizzes. If they hadn’t taken on the extra burdens that research entailed, [ would have easily been beaten out.

One of the advantages of standing first in your class at that time was that your interneship was assured and there was no problem where you would go. ‘Top man had first choice of the kind of interneship that he wanted at the Johns Hopkins Hospital, second man had next choice, and so on down the line for the first thirteen men in the 37

38 Chapter 2 class. Now, a fellow might want a medical interneship, but if his standing only permitted a surgical interneship he ended up in surgery. Actually a number of boys in my class took the surgical interneship and finally became surgeons although their original inclination was to

go into clinical medicine. ‘Ihe choice was made so that they could stay at the Hopkins. In those far-off days, if you took your interneship and residency at the Johns Hopkins Hospital, your medical career was assured.’

The medical interneship was supposed to be the choice interneship, and I broke all the rules when I went over to Dr. John Howland and asked him to give me the interneship in pediatrics. When I told him that I wanted to take my interneship in pediatrics, he looked at me as if I had lost my mind. It was the first time that the top man in the class had ever asked for that interneship. Pediatrics at that time was not the specialty that it is today. ‘There was Luther Emmet Holt

and there was John Howland, and most of the other fellows were laughingly referred to as baby feeders. Actually it was not a very attractive field.

QO: If that was the case, what was it that attracted you to pediatrics?

Rivers: You will probably laugh when I tell you. Adults have a way of lying to their doctors. I noticed it in Panama, and I saw it at the

Johns Hopkins Hospital during my junior and senior years, and I must say that it bothered me. Children on the other hand (and I saw a good bit of children during my senior year) have a way of always telling the truth. It was my experience, when I took a history that they would straight away let you know what the trouble was; even

though the mama would say, “Shut up, shut up,” invariably they blurted out the truth. Actually, I think most children if left alone, *A.R. Dochez, who was a member of the class of 1907 at Johns Hopkins, recounts a similar story. Originally, Dr. Dochez had interest in becoming a cardiologist. However, because he was not among the first thirteen members of the class, he did not receive an interneship at the Johns Hopkins Hospital and later, because he missed an examination, he also lost an opportunity of a post in a hospital in New York. A chance meeting with Dr. MacCallum in the corridors of the Johns Hopkins Hospital led to an appointment as a research assistant in bacteriology and an eventual career as a bacteriologist. S. Benison, The Reminiscences of Dr. A. R. Dochez. Oral History Memoir, Columbia University Oral History Research Office, 1955, pp. 21-23.

Young Physician 39 would be more or less truthful and natural. ‘They do just what comes handy, whether it’s eating or peeing on the floor. I liked pediatrics because children appealed to me, and I couldn’t stand neurotic women and lying men. One of the reasons I later gave up pediatrics was that I discovered that babies had mamas and grandmamas, and even though the babies

didn’t lie their mamas and grandmamas were still lying. You can therefore say that I gave up adult medicine because I found that my patients lied, and I later gave up pediatrics because I couldn’t eliminate the adults from the world of children.

Q: Did Dr. Howland give you the interneship?

Rivers: No. He advised me, and I think rightly so: “If you are really interested in going into pediatrics, you’d better go over and take your interneship in medicine under Janeway. You will be a better pediatrician for having worked a year under Janeway.” He was, of course,

right. Janeway, as I have indicated, was a superb clinician, and | learned much from him. I should.explain that at the Hopkins, if you were an interne in medicine, you spent the whole year in medicine. In that respect, it was entirely different from the interneships in other places, which usually rotated from service to service and lasted approximately eighteen months.

The year I spent with Janeway, I saw a great deal of lobar pneumonia and typhoid fever. It just so happened that I had the white male ward during the summer, and that’s where I saw my typhoid, and I had the male Negro ward in the winter, and that’s where I saw

my lobar pneumonia. The thing that sticks in my mind was the stoicism of my Negro patients. Frequently they would come into the hospital with lobar pneumonia and walk as far as they could without

any assistance, until they would fall over in a dead faint. With typhoid, I knew several patients who worked with a high fever and only came into the hospital because they had perforated. At that time my Negro patients did not seem to give up in the face of typhoid or lobar pneumonia as fast as my white patients. Lobar pneumonia was very painful, and although typhoid fever was not too painful—except for the terrible headaches and backaches in the beginning of the

AQ Chapter 2 disease—you could get terrible pains if you were unfortunate enough to perforate. My Negro patients carried their pains with little complaint, and I want to tell you it made an impression on me. It was during my year with Janeway that I published my first clini-

cal papers. I wrote my first paper in collaboration with D. Sclater Lewis, and it was only out of the goodness of his heart that my name

: appeared at all, because I played a very minor role in the work that went into that paper. A young lady of about 20 was admitted to the Johns Hopkins Hospital, having swallowed some bichloride of mercury. Bichloride of mercury is a common disinfectant, and we often used it at the hospital in washing our hands to get ready for surgery. I don’t remember whether this little lady swallowed the bichloride of mercury intentionally or not. ‘That was of no immediate import to us. What made the case interesting was that although she didn’t urinate for eight days, by the time she left the hospital she had made a com-

plete recovery and her kidneys were functioning quite normally. I want to say that the treatment she received was something: she received gastric lavages three times daily, water was forced on her, she was given sweat baths twice a day for almost two weeks, and special diets. ‘he case was well worth reporting, and Dr. Lewis made one of the most detailed clinical analyses of bichloride poisoning that had appeared up to that time. Internes were kept busy for the better part of twenty-four hours, seven days a week. It is said that at one time an interne reported to the Johns Hopkins Hospital wearing a new straw hat and then didn’t

have any occasion to wear it until he completed his interneship. ‘There are many such stories, and as far as I am concerned they are all probably true. When you were an interne, there was little chance to leave the hospital, and you hardly saw anybody except the people you were working with and your patients. During my interneship the people I saw most of, among my contemporaries, were Vergil P. Sydenstricker who later became the professor of medicine at the University of Georgia Medical School at Augusta, and Vernon Mason, who later went to the west coast and developed a very successful private prac-

tice. ‘Together we helped institute citrate blood transfusions at the Johns Hopkins Hospital. In 1915 giving a blood transfusion was still a very tricky and expen-

Young Physician 41 sive procedure; it might even be termed a new procedure. For exam-

ple, it was only in 1901 that Karl Landsteiner had made his momentous discovery of the existence of different blood groups, and while we had learned to match bloods to prevent agglutination, transfusion was still a laborious procedure. You could either transfuse by

the old direct method or use the method devised by Dr. Edward Lindeman in New York, of taking blood from a donor by syringe and putting it straight away into the vein of the patient. The only problem there was that you had to use syringe after syringe, because you had to worry about the blood clotting; blood clots in from three

to five minutes outside the human body. In 1915 Dr. Richard Lewisohn of the Mt. Sinai Hospital in New York, using sodium citrate, discovered the minimum amount necessary that would keep a

donor’s blood from clotting and still not be toxic to the patient. I should point out that Lewisohn was not the only fellow working with sodium citrate for these purposes. If 1 remember correctly, two Russian doctors named Yurewitch and Rosenberg and Dr. Richard Weil in New York were working along the same lines.” Using sodium citrate for transfusions was certainly in the air, but Lewisohn was the first to

have any success. When Sydenstricker, Mason, and I heard of Lewisohn’s work at Mt. Sinai, we went to Paul Clough, who was then the resident in medicine, and asked him for permission to try it out. Later we cleared it with Dr. Janeway. Everybody cooperated, and we got patients from Dr. Janeway, Dr. Howland, Dr. ‘Thayer and even from Dr. Halsted in surgery. ‘The citrate transfusions that we did were successful, and we later wrote a paper on the techniques we used for the Journal of the American Medical Association. ‘There was, I might add, one untoward incident in the initial series of transfusions that we did that indicated to us that it was not enough to do laboratory tests

of a donor’s blood and to take his case history, but that it was also necessary to give him a physical examination as well. In one case of an

anemia, a son presented himself as a blood donor for his father. His history was negative, his Wassermann was negative, and his blood *R. Lewisohn, “A new and greatly simplified method of blood transfusion: A pre-

liminary report,” Med. Rec., vol. 87:141 (1915); R. Weil, “Sodium citrate in the transfusion of blood,” J. Amer. Med. Assoc., vol. 64:425 (1915); E. Lindeman, ‘Simple

syringe transfusion with special cannulas,” Amer. J. Diseases Children, vol. 13:28 (1913).

42 Chapter 2 matched, and the transfusion was given. Several weeks later another

. transfusion was needed and again the son presented himself. ‘The Wassermann again was negative, the history was negative, and again we gave the transfusion. This time, however, the son was less truthful: he had a primary chancre that he didn’t tell us about, and as you might suspect it had disastrous results for the patient. Later the fa-

ther developed syphilitic gummas on his larynx and he died. If a physical had been done on the donor, that chancre would have been discovered and the tragedy avoided. In all, we treated 34 patients with approximately 100 transfusions,

and they were, I am proud to say, the first citrate transfusions ever

done atthe Hopkins.* When I had finished my year with Janeway, I went to see Dr. Howland and said, “Dr. Howland, I am now ready to start work in pediatrics.” “Fine,” he said, “I’l] make you an assistant resident.” Actually

I never worked as an interne on Dr. Howland’s service, and after a

year he appointed me a resident. | O: Could you give me a portrait of Dr. Howland as you saw him in 1916?

Rivers: There was something very attractive about John Howland. It was not only the medical side of him, there was just something very attractive about him as a man. In other words, he was a man’s man. He was good looking, but not too good looking, and was athletic. At

one time, I think he stood within the first ten tennis players of the country. When I once asked him why he quit playing tennis, he said, “T had to either quit playing tennis or quit medicine, and I decided that I’d quit tennis.” Still later, he took up golf and became one of the best golf players at the Baltimore Country Club.

— Q: Dr. W.C. Davison, in a biographical sketch of Dr. Howland, claims that Dr. Howland kept the nail of his forefinger sharp and *B. Bernheim, Adventures in Blood Transfusion. Smith and Durrell, New York, 1942, is an interesting popular history of blood transfusion and also has data on its development at the Johns Hopkins Hospital.

Young Physician 43 pointed because he liked to open retropharyngeal abscesses in this way.*

Rivers: ‘The story certainly has foundation. Dr. Howland loved to open retropharyngeal abscesses with his nail, and I saw him do it on many occasions. Actually, if I had a kid, I would rather have had Dr. Howland open the abscess in his unorthodox way than have a surgeon

do it. The only thing I am not sure about is that Dr. Howland kept his nail pruned for that particular purpose. I kind of doubt that, because John Howland was proud of his hands. They were beautiful hands. You know, a hand that is good looking is good looking. And John Howland, I think, was vain about his hands. I never heard him say so, and I never heard of anybody that had nerve enough to tell him. But, you know, he’d stand up before the class and give a lecture,

and suddenly he’d put his hands up and look at them. | always thought he put them up to admire them. They were good-looking hands, and they were competent hands; they could open up retropharyngeal abscesses, shoot a good game of

golf, or do intubations. As a matter of fact, it was Howland who taught me to intubate. I believe that, up until the time I left, the only people who had ever done any intubation at the Harriet Lane Home were Dr. Howland, Dr. Kenneth Blackfan, and myself.

Q: Did you do any tracheotomies?

Rivers: Very few. Occasionally we had to do one, particularly in a diphtheria where the membrane went down a piece, but, generally speaking, Howland did not like to have tracheotomies done. His great

fear in both tracheotomies and intubations was that the patient might become a “chronic tuber,” and for that reason he would periodically take out the tube to see how long the patient could go without it. If the patient became very cyanotic he would put the tube back in. He would do this several times, until the patient could do without it. QO: How was John Howland as a clinician? *W.C. Davison, “John Howland, 1873-1926,” in B.S. Veeder (ed.), Pediatric Profiles. C.V. Mosby, St. Louis, 1957, p. 166.

4A Chapter 2 Rivers: I would say that John Howland was a great clinician, and | certainly would rank him with Luther Emmet Holt. As a matter of fact, he was closely associated with Holt in New York before coming to the Hopkins. As he grew in stature as a clinician, he came to realize the part that research was going to play in the future development of

medicine, and he made his mind up to be a part of it. He became a part of it by surrounding himself with people who were adept in laboratory research. Clemens Von Pirquet, who preceded Howland as

professor of pediatrics at Johns Hopkins, was the Herr Geheimrat Professor or a one-man show; Howland was a team man, and he worked beautifully with a team. Howland, for example, knew little chemistry, but he learned his chemistry from people like McKim Marriot. Originally Marriot had been trained in biochemistry at the Cornell Medical School. About 1911 or thereabouts he wandered out

to the Washington University Medical School in St. Louis as a chemist and it was there that he met Howland. Howland at the time was having a try at being professor of pediatrics, but it was a short romance and he returned very quickly to the Hopkins. A short time

later, Marriot joined Howland’s department as a chemist. Well, Howland picked Marriot’s brain for chemistry, and in the process Marriot became interested in clinical pediatrics. He was only a fair clinician, but with his background in chemistry he caught the attention of the people in St. Louis and returned as professor of pediatrics to the Washington University Medical School. Subsequently he had a most distinguished career as a pediatrician and made some excellent contributions to problems in pediatric nutrition. I don’t want to give the impression that Howland depended only on Marriot for chemistry; as a matter of fact, he also learned a great deal from James Gamble and Harold Higgins in this field and was never loathe to admit that he had learned from them. Howland was no less a team man on the clinical side, and here he leaned on people like Kenneth Blackfan, Ned Park, and Paul Shipley. Blackfan was known as Blackie and had joined forces with Dr. Howland at the Washington University Medical School in St. Louis. He was, I believe, the first resident that Howland had at the Hopkins. Blackfan was small of stature but of great capabilities of mind. He was a superb clinician and worked with Howland for almost a decade.

Young Physician 45 Eventually he was called to Harvard where he joined forces with James Gamble to create a beautiful Department of Pediatrics. Black-

fan was a gentleman and a very easy fellow to work with, which is | more than I could say for myself. Even as an assistant resident, I rode

anybody I could find, but not Blackfan, and it is no mistake that everybody liked him.

QO: Dr. Rivers, as a resident, you were reputed to have had enormous powers of concentration and recall; so great were these powers that it is said that, if Dr. Howland asked you during rounds what a given child’s temperature, age, or pulse was, you would always know, much to the disbelief and chagrin of other internes and residents.

Rivers: Well I wouldn’t say that it was concentration; I would say that it was merely a good memory.’ During rounds, Dr. Howland would frequently go up to a patient’s bed, while I would pick up the history and start to talk about the patient. Invariably, Howland would take the history from me, look at it and begin to quiz me on the details in it. Sometimes there were one hundred babies on that service, | and I had to know what every baby had, what he didn’t have, and what we thought he had. I had to be able to tell Howland a pretty straight story. I don’t know whether he got a big kick out of doing this, but I do know that he held me responsible. I got along well with Howland, but this doesn’t mean I agreed with him all the time. Actually, Howland did some things that I didn’t ap-

prove of. For example, he wouldn’t make rounds with his internes. While he always made rounds with his residents and people like Ned Park and James Gamble, his internes were not included, because he didn’t want to be bothered with them. Sometimes he was unfair in

| the matter of appointments. When I joined his service as assistant resident an earlier classmate of mine, Grover Powers was already there. Powers had a big fat tummy, a high-pitched voice, worked hard, *Peter Olitsky, a long-time associate of Rivers’ at the Rockefeller Institute, notes: “Dr. Rivers here is altogether too modest. Among his old associates he was known as the man with the ‘pigeon-hole’ brain. He could pick out from memory, in a moment, an amazing datum, or a series, giving numbers, dates, names and other facts—all accurate and precise and apropos, For this reason he was the very devil in an argument” (private communication),

46 Chapter 2 and got along well with children. By rights, Howland should have ap-

pointed him his second resident, but he never did; instead he appointed me. Although Grover Powers was not much of a laboratory

| man, he did do good clinical research and, as a matter of fact, possessed excellent clinical acumen. Later he moved to Yale with Ned Park, and I believe the record will show that when Park returned to the Hopkins to take Howland’s place, Powers was appointed professor of pediatrics at Yale and ran a bang-up department.

I also had my personal battles with Howland. One that I still remember began as a skirmish between myself and the superintendent of nurses at the Harriet Lane Home.® I had ordered a croup tent for some children that were suffering pretty badly from cough, since the steam provided by such a tent was always helpful. Well, when I made rounds on this particular day, I discovered that Miss Stein, the superintendent of nurses, was using a gas burner to heat the water in the tent. I have always been deathly afraid of fires in a hospital, and particularly in a children’s ward, and so I ordered the gas burner discon-

tinued and an electric heater substituted in its place. Miss Stein __ thought I was encroaching on her preserves, and she refused to do it.

When I insisted, she went to Dr. Howland to complain, and I understand she complained loudly and bitterly. At the time I was resident, the tennis courts were on the inside of

the Johns Hopkins grounds—they’re not now. I was playing tennis when Dr. Howland came out of the Harriet Lane Home, called me over, told me about Superintendent Stein’s complaint, and asked me to rescind my order. “Dr. Howland,” I said, “I’m not going to change that order, because I think I have done the proper thing, and when | _ think I have done the proper thing for the safety of the children, I don’t pay any attention to the superintendent of nurses.”

He demurred, and we had some further conversation about it. Finally I said, “Dr. Howland, if you have any idea of going in there and countermanding my order, I just want to tell you that, if you do, *The Harriet Lane Home for Invalid Children was organized in Baltimore in 1883 by Harriet Lane Johnston, the niece of President James Buchanan. On September 1, 1906, under terms of a special endowment, the home was established on the grounds of the Johns Hopkins Hospital, and its administration was taken over by the hospital. A.M. Chesney, The Johns Hopkins Hospital and the Johns Hopkins University School of Medicine, 1893-1905. Vol 2. The Johns Hopkins Press, Baltimore, 1958, p. 442.

Young Physician 47 you'll have to get yourself another resident immediately. I think I’m

right, and I’m not taking any bossing from the superintendent of nurses of the Harriet Lane Home about something she really doesn’t know much about. Either I’m running the place, or I’m not.”

The upshot was that Dr. Howland went back and told Superintendent Stein to get an electric heater. I should add that I was quite prepared to leave. I didn’t make threats then, and still don’t make threats, that I’m not ready to carry out.

O: Dr. Rivers, during the late summer of 1917, there was a dysentery epidemic at the Harriet Lane Home, and Dr. Ned Park sent to the Rockefeller Institute for some serum to combat it. You were charged with testing the serum and you found it wanting. ‘The incident raises the question of the use of serum therapy for various infectious diseases at that time. I wondered if you would speak to that point.’

Rivers: When I was a resident, a number of serums had been devised for the treatment of various infectious diseases. Dr. Simon Flexner at the Rockefeller Institute had devised an effective serum against meningococcic infections, and Rufus Cole and Oswald T. Avery also of the Rockefeller Institute, developed a serum for the treatment of lobar pneumonia. Dr. Flexner had also made some serums against certain dysentery. organisms. Of course, there are several kinds of dysentery organisms. One is the Shiga bacillus, which was discovered by the Japanese bacteriologist Kiyoshi Shiga in the Far East about 1898. Another is the Flexner bacillus. In 1899 Dr. Flexner

along with William H. Park, Lewellys Barker, and several other physicians, was sent by the United States government to investigate an outbreak of dysentery in the Philippines.® In the course of that in7Edwards A. Park to Anna Von der Osten [Simon Flexner’s secretary], Sept. 12, 1917; Miss Von der Osten to Edwards A. Park, Sept. 13, 1917 (Flexner papers). ® Rivers here has reference to the medical expedition organized by Johns Hopkins University to cope with epidemic disease in the Philippine Islands after the SpanishAmerican War. The members of the commission included Simon Flexner, Lewellys Barker, Frederick Gay, Joseph Flint, and John W. Garrett. An account of the work of the expedition was later published. S. Flexner and L.F. Barker, “Report upon an expedition sent by the Johns Hopkins University to investigate the prevalent diseases

48 Chapter 2 vestigation, Dr. Flexner helped isolate the bacillus which today bears his name. When he returned to the United States he tried to devise a serum against it, and, since it was the common organism found during the epidemic at the Harriet Lane Home, Ned Park sent a request for the serum to the Rockefeller Institute. Well, it didn’t work, and I was surprised that anybody thought that it might. It didn’t work, be-

cause the dysentery organisms practically never invade the blood stream and act superficially on the intestinal mucosa.

I would like to make it clear that most of the bowel trouble that children had in those days was caused by wrong feedings rather than by dysentery. Feeding and infections were two of the major problems that we faced in the practice of pediatrics at that time. If a child was fed improperly, it was not unusual for him to get diarrhea. Now, there is a distinct difference in medical circles between the use of the word diarrhea and dysentery. A dysentery usually means that there is blood in the stools and that an infection is the cause of the condition. I remember that in those days there were intricate formulas for diluting

milk, Dr. Howland didn’t follow the straightforward rule used in most places, and Ned Park frequently fought with Howland on the subject of dilution. Park always thought that a child could take whole

cow’s milk, as well as whole human milk, without any untoward effect, and when Park was in charge of the wards in the summer he would feed a child whole cow’s milk instead of diluting it. That battle continued for a long time among pediatricians.

Q: Dr. Rivers, among the infections that raged among children at that time were meningitis and influenzal meningitis. Was it difficult to make a differential diagnosis between them?

Rivers: I learned to make a diagnosis of influenzal meningitis before I left the Harriet Lane Home to go into the army. At that time it was difficult to grow influenza bacilli, but if you took a smear of the spinal uid you could see the Gram-negative, short, pleomorphic bacilli common to such cases. These smears were quite different from the ones you would get in an ordinary meningitis, which in children was frein the Philippines,” Johns Hopkins Hosp. Bull., vol. 11:37 (1900). William H. Park was not a member of the commission.

Young Physician 49 quently caused by colon bacillus. I was interested in influenzal meningitis infections while I was at the Harriet Lane Home and frequently took care of them. One such case taught me a very definite lesson, or

rather I should say Dr. Howland taught me a lesson. A child came in and gave every indication and sign of having influenzal meningitis. My knowledge of the infection led me to believe that the outcome was liable to be fatal, since practically all such cases ended in death. | mentioned this to Howland and wondered if I should tell the parents about the severity of the infection and what the outcome was likely to be. Howland looked at me and said, “You'll do nothing of the sort. I want to tell you right now, never tell a patient’s father or mother that a baby is going to die, because as soon as you do, it will get well, and they will hold it against you and talk about it more than if you tell them it is going to get well and it dies. Never tell a baby’s parents

that it is going to die.” Bless my soul, if this kid with influenzal meningitis didn’t get well. He was the only case I ever saw that lived.

I will admit that he was deaf for the rest of his life, but he did live, and I learned my lesson.

| Now, that story doesn’t mean that Howland didn’t tell the truth; he was for telling the truth, but he always left himself an out. ‘There are ways and there are ways of telling the truth. For example, let us say that you have a woman patient that has a cancer, and you know pretty well that surgery, radium therapy or hormone therapy is not going to help. You don’t tell her, but you do tell a responsible member of the family what the outcome is likely to be. It is better to keep the patient with a little hope, even though he or she might suspect he

is going to die. To take away the last bit of hope makes the last months of one’s life pretty miserable, and I don’t think the doctor should do this to an adult patient. Now, while children don’t usually appreciate the meaning of death, by the same token, hope should not be completely taken away from a mother or father. In the case I had of influenzal meningitis the odds were that the child would die, but the child lived. Of course, the infections that I saw at the Harriet Lane Home were

not limited to meningitis, and I also saw a great deal of rheumatic fever, scarlet fever, and measles. Although many of the same infections are still seen in hospitals today, I believe that their nature has

50 Chapter 2 changed. For example, the rheumatic fevers that I saw as a resident were usually very virulent, and the children would have very paintul joints and severe aftereffects. ‘Today the disease is, for some reason or

other, milder. Now, I don’t know whether this is due to penicillin, which can rid the throat of streptococci in 48 hours, and can therefore cut down the likelihood of obstructive infections that in former times

resulted in rheumatic fever, or whether the nature of the hemolytic streptococcus which causes the infection has changed. Yet, even before we had sulfa drugs and antibiotics in the United States, there had been a change in the virulence of streptococcal infections of the throat and scarlet fever. Dr. Howland always maintained that the virulence of rheumatic fever and scarlet fever were cyclical in nature. Certainly in the 1930’s, when the virulence of scarlet fever infections

in the United States diminished somewhat, they became very hot indeed in Rumania. Dr. Francis Schwentker, who investigated the Rumanian scarlet fever for the Rockefeller Foundation, found that they were every bit as virulent as those I saw as a resident. Today, various antibiotics and chemotherapeutic agents keep such

infections under greater control than has heretofore been possible. But no one knows when these organisms are going to be able to jump

from under these controls and become virulent again. ‘There is increasing evidence that some organisms have already mutated and are no longer susceptible to antibiotics. Too many physicians give anti-

biotics indiscriminately, and many patients receive them for the slightest cold. The time may well come when a person will need an

antibiotic and find that the infective organism has built up a resistance to it. ‘This complaint does not mean that I want to go back to the so-called good old days. ‘There was nothing good about the infections that I saw or their sequelae. [ remember that a little girl of four or five from North Carolina was once brought in to the Harriet Lane Home with a diagnosis of abscess from diphtheria. It is true that she had a big swelling on one side of her throat; however, it was quite ob-

vious to Howland and to me that the child was peeling from an attack of scarlet fever. Peeling from scarlet fever is fairly easily diagnosed if you've seen it, and after we did a culture of the throat and discovered strep we were confirmed in our impression that the child

Young Physician 51 had had scarlet fever and developed an abscess as the result of the strep infection.

Walter Dandy was at that time the resident in surgery, and we called on him to open the abscess and drain the pus. He did his job with dispatch, packed the wound, and left. One night a short time later, when I was over in the main dining room getting a midnight lunch, the alarm bell went off, which meant that something serious was happening in the Harriet Lane Home. I rushed back and found this little girl lying in a pool of blood. She literally seemed to be floating in it, and it was obvious that it had come from the wound where

the abscess had been opened. I immediately got hold of the mother and matched her blood with the child’s and transfused the child. As soon as the child regained consciousness, I put further pressure on the

wound in the neck but I did not dare remove the packing in the wound,

The next morning, when Dr. Howland came in, I told him what had happened and took him in to see the youngster. We discussed the case, and Howland was pretty certain in his own mind, since he had seen a good many things like this, that the abscess, which had been a rather large one, had led to the erosion of an artery or vein. We then argued a bit as to which it might be. Well, you can argue such a question until the cows come home without coming to a conclusion, and we finally decided that the only thing to do was to get Walter Dandy over, and if necessary to have the common carotid or the jugular vein tied off. Since the child was on isolation, we thought to do the operation in her room. However, we hadn’t sterilized the instruments or

prepared the child for the operation when Dr. Dandy came in. He proceeded to make a lot of fun of Dr. Howland and myself and told us that medical people always were scared by a few drops of blood, and that he didn’t believe there was anything wrong with the child. He forthwith grabbed the packing in the wound and yanked it out, and the child’s blood spurted about a foot or two in the air. It was a terrific sight. We grabbed the child, and without any anesthesia or sterilized instruments, began the operation. Dandy soon discovered that the abscess had not only eroded the lingual and external carotid

arteries but the internal jugular vein as well. He was as cool asacu-

52 Chapter 2 cumber, and I will say this for Dandy, he had a ligature on those arteries in short order, he packed the vein. The child looked as if she were dead. Fortunately I had some citrated blood ready, and I transfused her. And I want to say that it was a wonderful sight to see the color come back to her cheeks and finally to hear her talk. This wasn’t the end of the story. The ligature wasn’t made under

: sterile conditions, and, as sometimes happens, it eroded before a firm clot was formed, and again there was secondary bleeding. Well, the ligature that Dandy had made was so far down that I knew another ligature wouldn’t do any good, so I just put pressure on the wound and transfused the child again. After six or seven weeks, the child made a recovery but had a terrible ugly scar on the side of her neck.

When she left the hospital we told the mother never to have an operation on her tonsils or throat without explaining to the surgeon the origin of the scar. I then lost sight of the child. About ten years later she showed up at the Rockefeller Hospital to seek my advice on the removal of the scar. I told her to see Alexis Carrel who advised her against it, explaining that because of the previous operations the collateral circulation in her neck was very queer indeed. ‘The little girl later became a nurse, and I am sorry to say that I eventually lost sight

of her. I think that this case was probably the most spectacular thing that happened to me while I was practicing pediatrics.

O: In 1916 Baltimore, like New York and Boston, was visited by a polio epidemic and I wondered if you saw any cases at the Harriet Lane Home.

Rivers: In September 1916, just after I took up my duties at the Harriet Lane Home, I did see a number of polio cases. At that time, Kenneth Maxcy, who was also an assistant resident, and I were called upon to make diagnoses of children brought to the hospital who were suspected of having polio. Just as often, we were asked to go out and make diagnoses of children in the home. Frequently we didn’t know whether we had a polio or a cerebrospinal meningitis, although in cerebrospinal meningitis the child usually had a higher fever and was much more obviously ill than in polio. But the clinical signs were not enough, and we did lumbar punctures to confirm the diagnosis. In

Young Physician 53 cerebrospinal meningitis, the spinal fluid when held up was usually cloudy; in polio it was invariably clear. At that time, we considered a cell count of ten per cc of spinal fluid normal, and anything above was considered abnormal. In polios, you’d get counts ranging from 50 to 200, but in cerebrospinal meningitis the count was in the thousands. Finally, in cases of cerebrospinal meningitis, you could always stain a bit of the fluid and see the Gram-negative meningococcus. ‘T’o distinguish between cerebrospinal meningitis and polio was, therefore, not too difficult, only time consuming. I am sure that we called some things polio then that we would now call a Coxsackie or an ECHO. But these were infections we knew nothing about at that time. Patients with polio were usually put on an isolation ward or sent to the orthopedic hospital which was run by Dr. William S. Baer. Little was done except quarantine or isolation of patients, although there was some talk of using convalescent serum. To my knowledge, we never used it at the Harriet Lane Home. There were people in Baltimore at the time who knew polio from the clinical side, one such person was the pediatrician, John Ruhrah. Later when Dr. Ruhrah was middle-aged, he contracted polio and became severely crippled.

QO: Did you find it difficult to leave the Harriet Lane Home to join the army during World War I? Rivers: I wanted to join the army as soon as we entered the war, but I found it difficult to pass the medical examining board which met at the Hopkins. One of the members of that board was named FE:veleth Bridgeman, and since Dr. Bridgeman knew that I had progressive muscular atrophy he vowed that I would never pass. Fortunately, a classmate of mine, John Murray was also on the board, and he promised to let me know when Dr. Bridgeman didn’t show up. One night, Bish Murray (we called him Bish because his father was an Episcopal

Bishop) called to tell me that Dr. Bridgeman hadn’t come to the board, and that if I showed up I would surely pass. As I mentioned before, I was quite an athletic individual my musculature was good, and the doctors didn’t look too closely and I passed. Once my papers were signed, Bish Murray came over and said, “Hey, this fellow’s got

54 Chapter 2 progressive muscular atrophy.” When the doc who had passed me heard that, he said, “Gimme those papers, this fellow’s not fit,” but Bish wouldn’t give them up, and I got into the army. Nobody noticed my muscular atrophy, although they did catch the fact that I had no

eardrum in my right ear. I had lost the eardrum as a result of an earlier mastoid operation, and [ had to give the army a waiver. They used gas warfare during the first world war, and since there was no gas mask that would protect my ear, which was as open as my Eustachian tube, a waiver was required. ‘This defect has not been a total loss, because I have won many a bet made with skeptics who never believed

me when I said I could blow smoke through my right ear. During World War II I had a commission in the navy, and no doctor ever spotted the fact that I had progressive muscular atrophy and lacked an eardrum in my right ear. If they had examined me carefully, i think they might have spotted it. I joined the army about the first of January 1918, bought my uniforms, and began to wait for orders. I probably would still be waiting if it hadn’t been for Dr. Howland. One day Dr. Howland was visiting the Surgeon General’s Office in Washington, when he ran into Rufus Cole of the Rockefeller Institute. Dr. Cole was complaining, “We have just formed a commission

to go down to the hospital at Fort Sam Houston in San Antonio, Texas, to investigate pneumonia following measles, and, while we have people who know about pneumonia, we haven’t a single man on

the commission who would know a case of measles if he saw it.” When Howland heard this, he said, “Well I have got a pup over at my place who has his commission and is waiting for orders who would know measles,” and on Howland’s say-so I was put on the Pneumonia Commission.? The commission was a very distinguished one and had Rufus Cole, Oswald T. Avery, Alphonse Dochez, Francis Blake of the Rockefeller

Institute, and William G. MacCallum and William C. Van Glahn from the Hopkins. ‘here may have been one or two other people, but

I have since forgotten. The people I found most congenial were °For another account of the work of the Pneumonia Commission at Fort Sam Houston, see S. Benison, The Reminiscences of Dr. A. R. Dochez. Oral History Memoir, Columbia University Oral History Research Office, 1955, pp. 64-73; and R. Cole and W.G. MacCallum, ‘Pneumonia at a base hospital,” J. Amer. Med. Assoc., vol. 70:1146

(1918). So

Young Physician 55 Dochez and Blake. Dochez was and still is a very handsome man, and I soon discovered that if I wanted to nde by automobile between Fort Sam Houston and San Antonio instead of the Toonerville trolley that

linked those two places, I should stick close to Dochez. Invariably, while we waited for the street car some good-looking girl would drive

by in an auto and ask Do, “Can I take you anywhere, Captain?” Dochez always rode by car, because the girls couldn’t resist picking up a handsome man, and I rode because I was with Dochez.

Blake was not much older than I was. Before the war, he had worked with Dr. Cole and Dr. Avery at the Rockefeller Hospital and so had much experience, particularly in pneumonia. He was an exceedingly nice person, albeit a quiet one. He never tooted his own horn, and I always felt that for a long time his work was kind of overlooked, in terms of honors, although it was very substantial. For example, after World War I, Blake collaborated with Russell Cecil on experimental lobar pneumonia and with James ‘Trask in producing experimental measles in monkeys. Actually Dr. Joseph Goldberger of the U.S. Public Health Service was the first to produce experimental measles in monkeys, but a lot of people didn’t believe him, because the experiments were hard to repeat. Blake and ‘Trask corroborated that work and added to it. In the early twenties, Dochez prepared an immune serum against scarlet fever that was able to blanch a scarlet fever rash, and Blake carried out the clinical testing of that serum at the New Haven Hospital. ‘This was only a part of the work that later gained Blake election to the National Academy of Sciences, but it was always my feeling that Blake had to wait too long for that election. My work at Fort Sam Houston was pretty cut and dried, because it didn’t take much of my time to make the diagnosis of measles. In the

epidemic they had at the time, you either had it or didn’t have it; there were no two ways about it. ‘he pneumonias were another story, and they were extraordinarily interesting. There were two types: one was a lobar pneumonia which wasn’t much different from what I saw in civilian life; the other was a bronchial pneumonia that invariably was fatal and was streptococcal in origin. When Eugene Opie later wrote up the influenza epidemic at Camp Pike, he likened the lungs of the person who had influenza to a uterus that had just been delivered of a foetus. At such a time, the uterus is susceptible to strepto-

56 Chapter 2 coccal infection. Opie felt that the lungs of those who had come down with influenza and pneumonia were also made more susceptible to whatever bacteria were around, whether they were pneumococci or streptococci. At Fort Sam Houston, it was always my feeling that the measles virus made these boys more susceptible to the pneumococcus and probably opened up the respiratory tract to infection. ‘The major work on streptococcal pneumonias at Fort Sam Houston was done by Dr. Avery and Dr. Dochez. ‘The streptococci that they isolated from

these cases were later taken back to the Rockefeller Institute to be typed, and if I am not mistaken the typing program of streptococci at the Rockefeller Institute dates from that time. It was natural that such a program be undertaken, because previously Dr. Avery at the Institute had begun a typing program on pneumococci.”

After the Pneumonia Commission had finished its work and left, Blake and I still found ourselves at Fort Sam Houston—our orders to go elsewhere simply had not come with the others. However, it was not a resting time. Very soon after the Pneumonia Commission had packed its tents, Kelly Field, which was a short distance away, began

to send ambulance load after ambulance load of German measles cases. That wasn’t too bad, but then one night enough men to fill two wards came in with an undiagnosed illness, and those boys were really sick. Blake and I diagnosed those cases as influenza, and a day or two

later we took to our beds in the Yale Hotel—it wasn’t much of a hotel, actually it was just some rooms above a Chinese laundry in San

Antonio. We had headache and felt generally miserable for several days, and then we were all right. We didn’t think much about this until we both served at Camp Pike during the pneumonia and influenza epidemic of the fall of 1918. We were both exposed plenty during that epidemic, and neither of us came down with influenza. Our good fortune led us both to the conclusion that the indisposition that we had had at the Yale Hotel had been a mild case of influenza, enough to afford us protection during the fall epidemic of 1918. * See, especially, O.T. Avery, A. R. Dochez, and R. Lancefield, “The bacteriology of Streptococcus hemolyticus,” Ann. Otol., Rhinol., Laryngol., vol. 28:350 (1919), which suggests the necessity of typing and classifying streptococci. This article was prepared for a special symposium on Streptococcus hemolyticus which was held under the auspices of the American Laryngological Society at Atlantic City, New Jersey, on June 16, 1919.

Young Physician 57 My work at Fort Sam Houston lasted about three months, and then I was transferred to a commission to study empyema at Camp Lee, Petersburg, Virginia. This commission was headed by Major Edward K. Dunham, and he was assisted by three fine surgeons. ‘The first was Jimmy Mitchell who had long served as a chef de clinique for William S. Halsted at the Hopkins. ‘The second was Alexis Moschowitz of the surgical staff at the Mt. Sinai Hospital in New York, and the third was Evarts Graham.

Evarts Graham at that time was an assistant surgeon at the Rush Medical College in Chicago, and it is my impression that his interest

in chest surgery received great impetus from his experience on the | Empyema Commission. Later, of course, he made a pioneer contribu-

tion to the development of pneumonectomy and lobectomy in the United States. The empyema that we saw at Camp Lee was the type that filled the pleural cavity with pus following streptococcal pneu-

monia, and I was one of the several clinicians attached to the com- : mission to help tell the surgeons where the pus was located. Sometimes, in the beginning of such an empyema, it was difficult to locate the pus without a meticulous physical examination. X-rays at that time were not as helpful as they might have been, because they were flat, and it was hard to tell whether the pus was in the front or ‘the back by merely looking at such an x-ray. I want to say that these surgeons were very busy, and the fact that they received such help from clinicians should in no way detract from their abilities, which were considerable. Mitchell, Moschowitz, and Graham were superb surgeons.

At that time it was usual to operate for empyema as quickly as possible, and there were, I must say, many fatalities. Dr. Eugene Opie,

who later did over 500 autopsies on streptococcal pneumonia at Camp Pike, supplied a reason for these fatalities. He maintained that

the streptococcus invariably. formed a bleb near the pleura of the lungs, and that when this bleb broke down the infection spread to the

pleura with a rapid accumulation of fluid in the chest. Under such

conditions, when the chest was opened in an early operation, a pneumothorax would occur. Frequently, it was difficult to reinflate | the lungs, because strep encouraged the growth of inflammatory tissue which bound the lungs down, and the outcome was usually

58 Chapter 2 fatal. To prevent such fatalities from occurring, the commission urged the postponement of empyema operations as long as possible, and later, when the operation was done, that open free drainage be

instituted. Later that procedure effectively cut empyema mortalities.**

I didn’t stay very long at Camp Lee, and in July 1918 I left the Empyema Commission to join Eugene Opie, Allen W. Freeman, James Small, and Francis Blake on the Permanent Pneumonia Board

at Fort Riley and Camp Funston in Oklahoma to examine another outbreak of pneumonia. Our findings here were similar to those made

earlier at Fort Sam Houston, with this exception: while working through the medical records at these places we found evidence of two separate epidemics of influenza the previous March and April. These cases were accurately diagnosed as influenza, but for some reason or

other notice of the epidemics was never taken in Washington. As a

: result of our investigations at Fort Riley and Camp Funston, we wrote an article for the Journal of the American Medical Association predicting another outbreak in the fall. Dr. Opie and I—Blake is long since dead—have never believed that the influenza epidemic in the fall of 1918 in the United States came from Spain, although there is much reference in the literature to so-called Spanish influenza. There is every evidence that, as early as the spring of 1918, there were influenza epidemics in various military camps in the United States. Early in September 1918, the Permanent Pneumonia Board was transferred to Camp Pike outside Little Rock, Arkansas, to examine the occurrence of some strange lobar pneumonias. An examination quickly proved that they were pneumonias following influenza. By the end of the month, there was no mistaking that we were in the midst of an influenza epidemic. If memory serves, there were approximately 1000 cases a day by the last week in September, and by the end of October the totals were well over 12,000. Dr. Opie and Dr. Small did , autopsies from morning until night while Blake and I tended the patients as best we could. The soldiers who suffered most of all were the big white farmer boys from the midwest and Negro troops from rural “The work of the Empyema Commission is described in detail in E. K. Dunham, “Empyema,” in Reports of the Medical Department of the United States Army in the World War. Vol. 11, part 2. Government Printing Office, Washington, D.C., 1924, pp. 33-392.

Young Physician 59 Louisiana and Mississippi. While they were healthy enough, they just had no immunity. The scrawny fellows from the big city slums by and large escaped, because they had acquired an immunity before they got to camp. As a result of the clinical, bacteriological, and pathological work we

did at Camp Pike, Opie, Blake, Small and I published a volume in 1922 called Epidemic Respiratory Diseases.”* I think it is one of the best books describing what happened during that pandemic that has ever been written, although I will admit that the books written by

Dr. William MacCallum and Dr. Milton Winternitz* have at. tracted more attention. There is, however, one chapter in the book that I wish had never been written. Blake and I and the others were brought up to believe that influenza was caused by the influenza bacillus or, as it was known, Pfeiffer’s bacillus, and naturally, when the epidemic broke out at Camp Pike, Blake and I made every effort to see if we could isolate influenza bacillus from our patients. Well, we managed to get influenza bacilli out of every person that had an attack of influenza. It is true that we had to take more than one culture, and we cultured material from the sputum as well as swabs from. the throat and nose. But we found it and quickly jumped to the con-

clusion that the influenza bacillus was the cause of the pandemic. Well, we were just 100-per-cent wrong, and it’s a chapter I wish had

never been written. Even though I helped write that chapter, it always bothered me that, if the influenza bacillus did cause the pandemic, why in the name of goodness didn’t we have any cases of influenzal meningitis? Of the thousands of cases that.I saw at Camp

Pike of influenza and pneumonia following influenza, there was not . one case of influenzal meningitis. And when I returned to Johns Hopkins, I began to study influenzal meningitis. In retrospect, I would say that it was my army experience that turned me from pediatrics to re-

search. |

% See also E. L. Opie, A. W. Freeman, F.G. Blake, J.C. Small, and T.M. Rivers, “Pneumonia at Camp Funston,” J. Amer. Med. Assoc., vol. 72:108 (1919), and “Pneumonia following influenza, Camp Pike, Arkansas,” J. Amer. Med. Assoc., vol. 72:556

) COW, MacCallum, Pathological Anatomy of Pneumonia Associated with Influenza. Johns Hopkins Hospital Reports, Vol. 20, Fasc. 2, 1921; The Pathology of the Pneumonia in the United States Army Camps During the Winter of 1917-18. Johns Hopkins Hospital Reports, Vol. 20, Fasc. 1, 1920; M.C. Winternitz, F. M. Wason, and F,D. McNamara, The Pathology of Influenza. Yale University Press, New Haven, 1920.

60 Chapter 2 I worked with the Permanent Pneumonia Board until the end of the war. However, once the war was over, I asked to be released from the army as soon as possible. My father had died during the war, and I had increased responsibilities toward my mother, and I felt it impor-

tant to get on with my medical career. When I returned to the Hop-

kins, I dreaded telling Dr. Howland that I didn’t want to go into pediatrics immediately, and that instead I wanted to take a shot at research. I postponed telling him for a while and finally went in to see him. “Dr. Howland,” I said, “I hope you are not too upset by my decision to go into research. I know you always thought that I would go

down south to teach them how to practice pediatrics.” He replied, “Yes, that’s true. But don’t get upset. If you want to do research, it’s all right with me.”

“Well,” I said, “Dr. Howland, I haven’t any money or a job.” “Oh,” he said, “I can give you a job and some money. Not much, to be sure, but perhaps later you can scare up some money from some place or other. However, I don’t have any room for you to do research in. Why don’t you see if Dr. MacCallum in bacteriology will let you have some space to work in?” I took the job that Dr. Howland offered me at $125 a month and went over to see Dr. MacCallum about a place to work. Dr. MacCallum was as nice as he could be and told me to come over. Looking back, I believe that Dr. Howland was happy about my decision to do research, or at least he sympathized with it. I am sure that, if he hadn’t thought it was all right, he wouldn’t have helped me. My first research after the war was examining the effect of different

bloods on the growth of B. influenzae. I had noticed that, on certain occasions when I had used cats’ or rabbits’ blood in culturing B. influenzae, | got rather large colonies, but when I used human blood the colonies were invariably tiny. Actually, I could only get a fair growth if [ heated my human blood to a dark chocolate brown. There was no mistaking that human blood retarded the growth of B. influenzae and, on examination, the inhibiting substance seemed to be in the

serum. Actually, it was inhibiting to the extent that I thought of using it in cases of influenzal meningitis in children. ‘The children who came in with influenzal meningitis weren’t always real sick at first. They could stand up and walk around the crib. It would take

Young Physician } 61 several days before they’d get real sick and die. One day a little Negro boy and girl came in with influenzal meningitis, and I decided to see

if human serum would be of any therapeutic help. I bled myself about several hundred cc and took my serum, which was highly in-

hibitory, to treat the children, I drew off all the spinal fluid that I could and injected my serum subthecally. It was a bright idea, but it didn’t work, even though human blood was inhibitory to the bacillus growing on blood agar plates. It was, I would say, a good idea, but that’s what happens to a lot of good ideas in research work when they are put to the test: they often go down the drain. QO: Did you continue your work with B. influenzae?

Rivers: Yes. I noticed other things about the bacillus that engaged my interest. One thing that early caught my attention was the fact that, when B. influenzae grew close to other bacteria like B. coli or Staphylococcus aureus, the colonies of influenzae were considerably larger than those that were distant from them. It was, you might say, a symbiotic relationship. ‘This, I should point out, was not an original observation on my part and had, as a matter of fact, been noticed for some years prior to the time that I had noticed it. But it was a strange phenomenon, and I devised a number of experiments to see if I could establish a reason for its occurrence. One of the things I did was to stow B. coli and Staphylococcus aureus on blood agar plates, and then try to change the pH or hydrogen-ion concentration of the medium in

| their immediate vicinity by taking some weak alkali and acid and drawing it across the plate with a glass rod. When it dried, I seeded

the plate with B. influenzae and began to chart the nature of its growth under the various conditions which I had set up. I soon found that, if the acid or alkali improved the pH for the growth of B. influenzae, the colonies were a little larger. But it was also my impression

that there was more in this than just a matter of pH: I thought that there were metabolic products given off by the B. coli and Staphylococcus dureus that changed some of the medium and made it more fruitful for the growth of B. influenzae. At the time of the influenza pandemic of 1918, all strains of influenza bacilli were considered more or less serologically alike, regardless

62 | Chapter 2 of morphology or virulence. After the war, workers began to differentiate between them in terms of hemolytic or nonhemolytic varieties,

and this differentiation in time led to a consideration of the growth requirements for each. Dr. Avery at the Rockefeller Institute showed that there were two factors in the blood necessary for the growth of ordinary influenza bacilli. One was called “V’’—which was later shown by André Lwoff at the Pasteur Institute to be a co-enzyme ™ —and the other was called “X” or heme, which came from hemoglobin. At one timé it was believed that the interaction of both factors was necessary for growth, but this theory was discarded when Dr. Ernest Stillman of the Rockefeller Institute demonstrated that there was a hemolytic organism that could be divided into two groups in terms of growth requirements, one group requiring both the “X” and

“V,” and the other merely the “V.” Later I discovered a nonhemolytic organism—which is called parainfluenza bacillus Rivers—

that only required “V” for growth. My final contribution to ending the debate of whether two factors were needed for growth came when I examined the B. hemoglobinophilus canis discovered by Dr. Ernst Friedberger in 1903 and learned that it only required “‘X.”’ Although my thinking and research took on a more chemical bent,

I did not give up my clinical work and, as a matter of fact, took on obligations in pathology. The $125 a month that Dr. Howland paid me, when $75 of it was going to my mother, didn’t leave me very much, and I began to look around for ways to earn more money. I soon discovered that St. Joseph’s Hospital in Baltimore was looking for someone to come in to do a certain amount of laboratory work and autopsies, and I applied for the job. I had had, by this time, a great deal of experience along such lines as a result of my service in Panama and with the Permanent Pneumonia Board during World War I, and so I felt qualified. I was honest enough, and I did tell them that I had a full-time job at the Hopkins that took up my time to five o’clock in the evening, but I promised that I would be avail4 A, Lwoff and M. Lwoff, “Studies on codehydrogenases. I. Nature of growth factor ‘V’; II. Physiological function of growth factor, ‘V.’”’ Proc. Roy. Soc. (London) Ser. B,

vol. 122:352 (1937); vol. 122:360 (1937). * FE. Friedberger, “Ueber ein neues zur Gruppe des Influenzabacillus gehériges hamoglobinophilus Bacterium (‘Bacillus hamoglobinophilus canis’),’’ Centr. Bacteriol., vol. 33:401 (1903).

Young Physician’ - 63 able after that time and would work as far into the night as they needed me, Saturdays and Sundays included. ‘They found this agreeable, and they hired me. St. Joseph’s was a Catholic institution and all the nurses wore nuns’

attire. The physician-in-chief, whose name I am ashamed to say I have forgotten, was a close friend of Cardinal Gibbons and I believe _ took care of him medically.*® [ found them all pretty nice people, although I couldn’t always agree with them. The sisters, of course, kept

a close watch on all the doctors to see that no abortions were done. That was to be expected, and it didn’t bother me; what did gripe me, however, were the attitudes of some of the doctors. Once one of the doctors came to me and asked me to run some tests on the blood of one of his patients. I did and discovered among other things a positive

Wassermann. When I told him that his patient had a 4 plus and probably had syphilis he asked me to do the test over. That was a reasonable request, because there are false positives, and I repeated the test two more times. There was no mistaking the results: his patient had a positive Wassermann. When I told him, he shook his head. “It can’t be,” he said, “my patient is from one of Baltimore’s most distin-

guished families. Look, Rivers,” he said, “I know you are wrong, be- . cause this man is also very happily married.” Well, it took me some time to convince him that the Treponema didn’t give a damn about social position and that the marriage bond was not a prophylactic. Q: Did the Hopkins know you took on this other job? Rivers: Sure, you can’t keep things like that hidden. ‘They didn’t object, although they did keep a pretty close watch on the amount of

time I put in, and I think they should have. Actually, I put in as much time at the Hopkins as was required and, if you ask me, a little bit more. I also put in plenty of time at St. Joseph’s. ‘The Hopkins was very nice to me, because the last year I was there they gave me a post in the Department of Bacteriology and Pathology and raised my salary. That raise with what I was getting at St. Joseph’s gave me a *® St. Joseph’s Hospital in Baltimore was founded in 1864 and was in the charge of the Sisters of the Third Order of St. Francis. Rivers here is, in all probability, referring to Dr. Charles O’Donovan, who was President of the Medical Board of St, Joseph’s.

64 Chapter 2 yearly income of $4500 and made it possible to take care of my mother and live fairly decently myself. QO: How would you rate the Hopkins circa 1922?

Rivers: It is a diffcult question to answer. Let me begin by saying that I think that the Hopkins was at its height at about the time I graduated in 1915. With the exception of Osler, who had left to take the Regius professorship at Oxford, all the old professors who were the glory of Hopkins were still active. In the years following, they began to die off and their replacements who were younger men—as they ‘should have been—were certainly not as experienced or well known. But you might say this is the kind of ebb and flow that goes on in any institution. After the war it was plain to see that the school had gone down and was not nearly as good as it was in say 1910 or 1912. I think that this fact was generally recognized, because about 1921 an effort was made to bring in new blood. Dr. Walter Palmer, then at Columbia, was persuaded to come down as professor of medicine. Well, he

| came and brought with him a brilliant group that included A. R. . Dochez, Robert Loeb, and Dana Atchley. Dr. Loeb and Dr. Atchley were young then, but they already gave evidence of the promise they so handsomely fulfilled later. This group got nowhere at the Hopkins, because the Hopkins group froze them out—they just couldn’t get

along. I should point out that both Dochez and Atchley were both originally Hopkins men, but that didn’t help them at all, and a year later, when an offer came from Columbia, Palmer and his boys returned to New York.

QO: Dr. Rivers, I wonder if you would tell me the circumstances of your shift from the Hopkins to the Rockefeller Institute in 1922.

Rivers: ‘The shift was rather sudden. All I know is that one day in the spring of 1922 Rufus Cole came down to see me in Baltimore and asked me if I was interested in coming to the Rockefeller Institute in the Department of the Hospital. Francis Blake, whom I had worked with during the war, had left the previous year to take a post at Yale,

and Cole indicated that he wanted me to set up a laboratory similar

Young Physician 65 to the one that Blake ran, with the exception that it would concentrate on studying viral diseases in man. Following Dr. Cole’s offer, I went to New York to look over the Rockefeller Institute. It was the first time I had seen it, and I was impressed, although I had heard

much about the Institute previously from Blake and Dochez. No one said anything to me during my visit, and | returned to Baltimore. ' Several weeks passed without a word. ‘Then one day I received a letter

from Dr. Simon Flexner, asking me if I would have breakfast with him at the Hotel Belvedere in Baltimore. I needn’t tell you that I went. I’d already had my breakfast, because I always ate early, but I sat with Dr. Flexner while he ate. We chatted a bit, and he offered me a position at the Rockefeller Hospital as an associate at a salary of

$5000 a year. He told me that I would not only have charge of the infectious disease ward but would also have the responsibility of conducting research in viral disease. I accepted as soon as the offer was _ made. From my point of view, the position was ideal: I would still be able to see patients and thus not lose contact with clinical medicine, and I would have the opportunity to do basic research.

There were other reasons that made the going easier. One of my closest friends, Dr. Stanhope Bayne-Jones, also left the Hopkins at the same time. He had just been made the first professor of bacteriology in the new School of Medicine that Dr. George Whipple had previously helped organize at Rochester. It was one less personal tie to cut. I have been asked from time to time how Dr. Howland felt about my leaving. Well, by the time I left the Hopkins, I was no longer in Dr. Howland’s department and had shifted to the Department of Pathology and Bacteriology. Dr. MacCallum who was my boss there, didn’t seem too badly upset by my decision to go to New York and neither did Howland for that matter. Actually, I believe that Howland was pleased. He had long followed the fortunes of the Rockefeller Institute through Luther Emmet Holt, who served on the Board of Scientific Directors, and I know that he held it in high regard. As a matter of fact, a short time after I came to the Institute, Dr. Howland himself was appointed to the Board of Scientific Directors. I was happy about that appointment, not only because Dr. Howland knew me, but because I felt that he would be a wise and good influence. He was a good influence wherever he was, but as fate would

66 Chapter 2 have it he died in 1926 of a cirrhosis of the liver, following an attack of a viral hepatitis, then known as catarrhal jaundice. His death was a blow to the Hopkins and to American medicine. I say this because John Howland was one of the greats of his day, and it has always been difficult to lose the mind that is out in front. Although my tenure was only for two years, my prospects seemed good, and on August 5, 1922, I married Theresa Riefele in Baltimore. | After a short honeymoon, we left for New York arriving on August

22, and immediately set up a home on Ingraham Street in Forest Hills. Three years later, we bought a home at 163 Greenway South in Forest Hills, a place where I still live today.

CHAPTER 34

The Rockefeller Institute for Medical Research—1922 . . . Never claim to have made a scientific discovery unless you have made due allowance for Nature’s misplaced sense of humor. Christopher Andrews, “Nature, the Scientist, and the Pitfall,” St. Bartholomew’s Hospital Journal, 1924

Q: Dr. Rivers, when you came to the Rockefeller Hospital was any division made between clinical responsibility and research or were the two so completely integrated that it was difficult to separate them?

Rivers: ‘The laboratories of the Rockefeller Institute were opened in 1901, and, while a hospital was spoken of from the beginning of the

Institute, it did not come into being until 1910. Now, what I am going to say about the original plans for research in the hospital is based on some letters I have seen which were written by Dr. Christian

Herter and Dr. Rufus Cole, remarks made to me by Dr. Cole throughout our long association, and hearsay. I won’t say that it is the

absolute truth or the only truth; let me just say that there is a great deal of truth in it. Originally, the person chosen to be the director of the hospital was Dr. Christian Herter. Herter had early made a name for himself by his observations on the nature of nervous diseases and had in 1905 helped establish the Journal of Biological Chemistry. He was a Close friend of Dr. Welch and, like him, early saw the necessity of having laboratories in the hospital, but, as far as clinical research was concerned, he seemed agreeable to having such research in part

initiated by the laboratories of the Institute. This view is best ex67

68 Chapter 3 pressed in a letter that he once wrote to Dr. Simon Flexner. Let me quote part of it here. It might at first seem superfluous to provide laboratories in the Hospital building since the large laboratories of the Institute still possess so much unassigned space. It is deemed of first importance that the physicians in charge of patients should be able to conduct certain routine examinations within the Hospital itself. ‘To carry on such routine examinations in the main laboratories would involve considerable loss of energy and imperfect coordination of observations. On the other hand, much research work connected with patients in the Hospital could be advantageously done in the

. existing laboratories. . . . Under the arrangement, the various problems should be attacked under the direction of workers in the Rockefeller Insti-

tute as such problems appear to them promising. . . . Certain elasticity would exist in regard to the problems studied in the Hospital. At one time most patients in the Hospital might be chosen with a view of furthering research originating in the laboratories. At another time relatively greater attention would be concentrated on patients chosen in connection with re-

search problems originated by the attending physicians. . . . It is conceivable that such occasions would arise where one type of disease would be studied in its different phases, on the one hand by the laboratory group of the Hospital, and on the other hand by one or more of the laboratory

departments of the existing laboratory. } There is little doubt in my mind that the character of clinical research at the Rockefeller Hospital would have been far different from what it eventually became had Herter taken up his post as originally planned. Unfortunately, the poor fellow came down with myasthenia

gravis, and, when it became obvious that he would be unable to assume the directorship of the hospital, Rufus Cole was chosen in his place. Dr. Cole was one of the early products of the Johns Hopkins Medical School of the era of Osler and Welch, a product, you might say, of the kind that helped establish the reputation of the Hopkins as the Mecca of the medical world. When Dr. Lewellys Barker came to

the Hopkins in 1905, Dr. Cole was chosen to run the Biological Laboratories. It was not an idle choice, since, for several years prior to Barker’s appointment, Dr. Cole had established a reputation as a clinical investigator and instructor in medicine. After approximately two

years in his post as director of the Biological Laboratories at Johns Hopkins, Dr. Cole was called to the Rockefeller Institute. I should * Christian Herter to Simon Flexner, April 15, 1907 (Flexner papers).

Rockefeller Institute for Medical Research—1922 69 point out, however, that he was originally called to be part of the hospital team under Herter. In 1908, before Cole assumed his duties as director, he made it abundantly clear to Dr. Flexner and the Board of Scientific Directors of the Institute that his ideas of clinical research in the hospital were quite different from those held by Dr. Herter. He

embodied these in a long memorandum which he submitted to the Board of Scientific Directors. ‘The nub of his argument is contained in the following excerpt: My conception of the hospital is that it is to apply the intensive methods to clinical study as opposed to the extensive or statistical methods formerly invoked. . . . To my knowledge this is the first hospital to be endowed, in

this country at least, for this exclusive purpose. Its further purpose is to extend the work of the Institute laboratories in which the method has of necessity been largely experimental. For clinical study must, from the nature of things, be largely investigative as opposed to the experimental method of a laboratory, yet I think the best results can be obtained only when the two methods can be applied simultaneously. . . . One thing that has most seriously delayed the advancement of medicine has been the physical and intellectual barrier between the laboratory and the wards of many of our hospitals. Clinical laboratories most often exist merely to aid diagnosis. I would therefore urge that the hospital laboratory be developed, so far as is possible, as a true research laboratory, and that moreover the residents of the hospital be permitted and urged to undertake experimental work on animals; and that, so far as is possible, facilities be given in the general Institute laboratories for such investigation whenever it is considered improper or impractical that such work be undertaken in the hospital laboratories. On the other hand, I think it proper and advisable that members and assistants of the Institute engaged primarily on pure experiments in the laboratory should have full opportunity in the hospital wards for the study of cases of the diseases which they are investigating. . . .

In order that neither privilege be abused, it is advisable that the rights and privileges of all be carefully defined. ‘The relation of the present members of the Institute to the hospital must therefore be carefully defined in

order that there may be the utmost harmony between them and the resident staff of the hospital. The greatest liberty of all can only be obtained by carefully defining the rights of all.?

Dr. Flexner’s ideas about the proposed role of the hospital were in turn quite different from those held by Dr. Cole. As I understand it, 2 Memorandum, Rufus Cole to the Board of Scientific Directors of the Rockefeller Institute for Medical Research, December 1908. Cole was appointed director of the hospital on March 1, 1909.

70 Chapter 3 Dr. Flexner wanted the hospital to act as a testing ground for the ideas generated by the people who worked under him in the laboratories. They were a brilliant group and contained Ph.D.’s as well as M.D.’s, among them Phoebus Levene, Jacques Loeb, Samuel Meltzer, Wade Hampton Brown, and others. Well, right then and there, there was a showdown. Cole made it clear that the hospital was not going to be a handmaiden to the laboratories and that he and his boys were not going to test Noguchi’s ideas, Meltzer’s ideas, or Levene’s ideas. (These are just names that I am using—I don’t know whether they actually came up.) Cole was adamant that the people who took care of the patients would do the research on them. Well, Cole won the argument hands down before he came, and as a result he urged all his doctors—and they were usually young men that came into the hospital—to be as proficient in bacteriology, immunology, chemistry, and physiology as any Ph.D., and they were. Later, a large number of the doctors in the hospital, because they became proficient in these basic sciences, were made members of the National Academy of Sciences. Cole was one, Avery was one, Dochez was one, and I was one, and there were others. I would like to make it clear that we weren't elected because we were M.D.’s, because there is no section on medicine or surgery in the National Academy of Sciences; we were elected on the basis of our proficiency in one of the basic sciences.

Every now and again, the battle over the role of the hospital would flare up, but Cole stuck to his guns. Cole is a modest man, a rather timid man, until you get him mad. You had to kind of back him into a corner and get him mad before he would really shoot the works. But if you did, you would find, generally to your sorrow, that the old boy wasn’t afraid to fight. ‘The fight over the role of the hospital was one of those where Cole went all the way and in so doing helped set the standards for clinical research at the Institute and elsewhere. When Dr. Gasser and I succeeded Dr. Flexner and Dr. Cole, we never once had any fight over the role of the laboratories and hospital in research. Nor has Dr. Bronk, who is currently running the Institute, ever made any attempt to impose the authority of the laboratories over the hospital. So actually the policy which Cole established in 1910 still holds.

A lot of people in the past have made fun of the Rockefeller Hospital—and some still do—and refused to give it credit for any-

Rockefeller Institute for Medical Research—1922 71 thing. But when you come right down to it and you force them to speak, they have to admit that the hospital has had a tremendous in-

fluence on clinical research throughout the country. Not nearly enotigh credit has been given to Rufus Cole for this influence. Cole _ did not begin clinical research in the United States, but he started the kind that demanded a lot more than was being demanded at the time he took charge of the Rockefeller Hospital.

Q: How rigid were the boundaries between the laboratories and the hospital? Did workers from these divisions ever collaborate with one another in research?

Rivers: ‘There was a great deal of crossing over; however, nobody in the Institute could force anybody in the hospital to work with somebody in the Institute, and vice versa. All collaboration between work-

ers in the hospital and workers in the laboratories of the Institute was on a voluntary basis. It was this way when I came to the hospital in 1922—I can’t speak of what went on before—and it was this way when I left the hospital in 1955. It’s the way things are done now: that is, if any of the boys in the hospital want to work with some of the boys in the laboratories they do it on a personal basis. They don’t

have to ask anyone’s permission. Nobody at the Institute ever objected to a collaboration between two people by mutual agreement; by the same token nobody ever forced a collaboration. To force anything in research is not the way to get it done. The way you get research done is to find the guy who wants to do it and then give him the chance he needs.

QO: Dr. Rivers, when you first came to the Rockefeller Hospital, were you asked to work on viral diseases in general, or were you given

a more specific assignment? The reason I ask is because there was a debate at the time between members of the Institute and other members of the medical profession on the nature of lethargic encephalitis.®

*See especially the reports of Simon Flexner to the Board of Scientific Directors of the Rockefeller Institute for Medical Research, 1920-1925; and S. Flexner and H. L. Amoss, “Contribution to the pathology of experimental virus encephalitis: I. An exotic

72 Chapter 3 Rivers: Lethargic encephalitis or sleeping sickness, as it is popularly known, was first noted in modern times in Eastern Europe during the first world war, and became established in the United States around _ 1918. For several years thereafter it was a serious problem, and as late as 1926 we still had enough around the country to cause concern. To this day, no one has ever isolated the cause of this type of encephalitis although from time to time there have been claims. For example, Dr.

Constantin Levaditi at the Pasteur Institute once thought he had found the cause, but Dr. Flexner and Dr. Harold Amoss took a great deal of trouble to show that he was simply working with herpes virus.

Now, herpes virus injected into the brains of rabbits will cause a beautiful encephalitis. Some strains will develop an encephalitis if the virus is dropped in the cornea of an eye—in such a case it scarifies,

causes a lesion, and eventually travels to the brain. Ernest Goodpasture once showed that the herpes virus could travel from the skin nerves up into the spinal cord and even down on the other side. At first, Goodpasture thought it was herpes zoster, but later it was dehnitely shown he was working with herpes virus, which in some cases can distribute itself in human beings and animals along nerve paths. To be sure, a debate such as you suggest was going on, but when I first came to the Rockefeller Hospital nobody told me what disease to work on, and no one even remotely suggested that I work on lethargic encephalitis.

The choice was my own to make, and I chose to work on chickenpox or to give it its medical name, varicella. I suppose I chose it in the first instance because there were a good many patients in the hospital at the time with chickenpox, and my attention was drawn to it. More important was the fact that chickenpox is a disease that you can see. Chickenpox has a vesicle. It’s nice. In human beings, for example, you

can differentiate chickenpox from other diseases that have vesicles, like smallpox, by the distribution of the lesions. In smallpox the distribution is mainly along the face and extremities, while in chickenpox they are mainly on the body. Furthermore, the lesions themselves show gross differences that you can see with the naked eye. Under the |

microscope one could also see that the inclusion bodies found in strain of encephalitogenic virus; IT. Herpetic strains of encephalitogenic virus; III. Varieties and properties of the herpes virus,” J. Exptl. Med., vol. 41:215, 233, 357 (1925).

Rockefeller Institute for Medical Research—1922 73 chickenpox were again quite different from those found in smallpox. In short, I chose to work with a disease that would give me something

more than an indefinite fever, and that would be easy to diagnose and : differentiate from other diseases that also lent themselves to experimentation. I figured that if I worked on chickenpox alone, I might not get anything and that I had better work with a similar virus to back me up. The Lord only knows why, but vaccine virus happens to be one of the nicest viruses that one could work with experimentally. Now I didn’t tell Dr. Cole or Dr. Flexner that I was going to work on chickenpox and vaccine virus. I didn’t have to. I started on chickenpox and, bless your soul, if I hadn’t worked on vaccinia as well, I probably wouldn’t have stayed at the Institute very long. ‘The fact is, I didn’t get much on chickenpox.

In the beginning, I attempted to establish chickenpox virus in rabbits and monkeys by getting material from the skin lesions of patients and injecting it into the testicles of my experimental animals, I suppose I proceeded in this fashion because Hideyo Noguchi at that time was also injecting vaccine virus into the testicles of rabbits, and I frankly copied him. I then began making serial transfers from testicle to testicle to testicle and, lo and behold, in a certain number of cases on the fourth or fifth transfer, my rabbits began to run high fevers of 105° and to have swollen testicles. When I took testicular material from such rabbits and scarified it on the skin of other rabbits, I would get a marked reddening of the skin. ‘To top it off, I found nuclear inclusions in such testicular material that looked very much like the nuclear inclusions in varicella. I was so sure of my findings that I wrote two papers with Dr. William ‘Tillett, who was working with me at that time, on the probable isolation of chickenpox in rabbits. To the Board of Scientific Directors of the Rockefeller Institute I confidently

reported as follows: |

We believe that we are working with a virus. Furthermore, we are certain as it is possible for us to be that the virus was recovered from chickenpox patients under the conditions outlined. It is not the virus of vaccinia or smallpox. While the virus produces lesions in the rabbits very much like

those of human chickenpox, we have not yet shown experimentally that the virus is the etiological agent of chickenpox. As soon as we can get some

fresh cases of chickenpox we will attempt the active immunization of a

74 Chapter 3 number of rabbits by injecting into them the blood of patients early in the disease. If after two or three weeks these rabbits are immune to our virus we will be warranted in assuming that we have been working with the etiological agent of varicella and furthermore we will be warranted in using the virus as a prophylactic measure against chickenpox in children.‘

Looking back, I can thank my lucky stars for the tentativeness that I included in my papers and report, because, when I conducted confirmatory experiments, I soon found that I didn’t have what I thought I had. It was known at that time that one of the striking characteristics of most viruses was that an infection caused by them led to the appearance of a lasting immunity in a recovered animal. We soon found, on further experimentation, that rabbits which recovered from primary inoculations of our virus were refractory to subsequent inoculations of the same virus. So far so good. It was when we took the next steps that we foundered. First, we tried to protect rabbits against our virus by intravenous injections of whole blood and blood serum from patients convalescent from chickenpox, and quickly learned that it was of no help at all. ‘Tillett and I assumed, and rightly so, that the serum of a patient who had recovered from chickenpox would neutralize

chickenpox virus; however, when we took such sera and tested it against our virus in vitro, we discovered, again to our dismay, that it

had no demonstrable neutralizing effect.

By this time, we were sure that we hadn’t transmitted chickenpox to rabbits and almost simultaneously got confirmation from Homer Swift’s laboratory in the hospital that we were in fact working with a new virus. Dr. Swift was a most interesting person. Originally he was trained at the Bellevue Hospital Medical School, but, if you ask me, one of the decisive influences in his life was his uncle, Dr. John A. Fordyce. Dr. Fordyce was a distinguished dermatologist, and then, as

now, one of the dermatologist’s responsibilities was the care and treatment of people who had become infected with syphilis. Through his uncle, Dr. Swift became interested in syphilis, and when he came to the Rockefeller Hospital in 1910 he made several early and impor-

tant improvements in serological diagnosis and treatment of the * Report of Thomas Rivers to the Board of Scientific Directors of the Rockefeller Institute for Medical Research, October 1923.

Rockefeller Institute for Medical Research—1922 75 disease. Dr. Swift was one of the first in the United States to assess the value of treating syphilis with Salvarsan. In the early days, syphilis

of the central nervous system (locomotor ataxia and paresis) did not respond favorably to intravenous injections of Salvarsan, and Dr. Swift, together with Dr. Arthur M. W. Ellis, a young Canadian at the Rockefeller Hospital, helped devise a treatment that effectively used Salvarsan for such cases. ‘The Swift-Ellis method, as it came to be known, was threefold in nature. First Salvarsan was injected intravenously into the patient; after some interval of time, a quantity of blood was withdrawn, and the serum containing a certain amount of Salvarsan was separated from the blood clot; this serum was then in-

jected intrathecally into the patient with central nervous system syphilis. It was an extremely effective treatment and remained in use

until penicillin supplanted Salvarsan as the treatment of choice in cases of syphilis.

Dr. Swift did not have a continuous tenure at the Rockefeller Hospital and in 1914 left to become an associate professor of medicine at the College of Physicians and Surgeons at Columbia. Some years later he moved to the Cornell University Medical School, but he barely

settled in his new post when he went on leave to join the Presbyterian | Hospital Unit overseas during World War I. After the war he returned to the Rockefeller Hospital and began his intensive studies of the streptococcus in relation to acute rheumatic fever, studies which were to occupy him for the rest of his life. At the time I was working

with chickenpox virus, Swift had a young English worker in his labor- ) atory named Christopher Andrewes. Dr. Andrewes was the son of Sir Frederick Andrewes, and I should add here that several years later Christopher Andrewes was knighted on his own for his accomplish-

ments in bacteriological and virological research. Today he is a member of the British Medical Council. As a matter of fact, I have always been convinced that he would have been knighted sooner if it wasn’t for his subtle and devastating sense of humor. I loved this side

of Chris Andrewes, but believe me when I tell you that it irritated some of his stuffer English brethren.

Since Dr. Swift’s department was working on problems of rheumatic fever, Andrewes thought he would have a try at isolating the causative agent, which he then believed was a virus. Following my ex-

76 Chapter 3 ample, he began to take blood and fluid from the joints of rheumatic fever patients and injected it into the testicles of rabbits. Lo and behold, after several testicular transfers, Andrewes’ rabbits came down with swollen testicles and high fevers. At first blush, he thought he had rheumatic fever going in rabbits, and he called me to examine sections taken from the testicles of his rabbits. I took one look and said, “Hell, Chris, you’ve got the same thing that I got, and neither one of us has anything except something we got out of rabbits.” ° It wasn’t chickenpox virus, and it wasn’t smallpox virus; it was a brand new virus and I called it Virus III. People always ask me why I

called it Virus III. The answer is simple: I didn’t want to give it a fancy Latin name, and since it was the third strain of the virus I experimented with, I just called it Virus III. So far as I know, it is only found in rabbits, and no other animals, including human beings, are susceptible to it. I want to make it clear that the original purpose of my experiments was to transmit chickenpox to rabbits, and in this I was unsuccessful.

However, when the results were all in, I found I had made a discovery. Now, lots of times discoveries are made through error. Have you ever heard of serendipity? Serendipity is when you start out in

one place and end up in another. Research is usually serendipity. Looking back, I think that my discovery of Virus III] was more important than finding that I could transmit chickenpox to rabbits. Prior to

' my work, nobody had ever seen Virus III in rabbits. It is a natural | disease that only manifests itself when you begin to favor the virus experimentally. ‘Then and only then, can you see the disease. Later it turned out that about 15 per cent of all the rabbits at the Rockefeller Institute were infected with Virus III. It was, you might say, also a hint that there were such things as latent viruses.

O: How did you begin to. handle a virus, circa 1923, when you couldn’t see it? How did you even know it existed?

Rivers: Oh, well, there are other things you know exist without being able to see them. The only time that Ernest Goodpasture and I °C, H. Andrewes has recorded a similar version of this episode in “Nature, the scientist and the pitfall,” St. Bartholomew’s Hosp. J., vol. 32:20 (1924).

Rockefeller Institute for Medical Research—1922 77 ever had any difference of opinion was when Goodpasture voiced the

idea that you couldn’t know a thing without seeing it. He told me that he knew about smallpox because he could see the Borrel bodies,

but he maintained that you just couldn’t know anything without seeing it. Well, I countered by quoting the Bible—the Devil, you

know, quotes the Bible, and I think it’s kind of a crime for a sinner like me to quote the Bible, but anyhow I did. “Ernest,” I said, “You

shall know them by their deeds.” And that is the way you knew viruses circa 1923, You knew them by what they did in experimental animals, or by what they did in human beings. For example, poliovirus paralyzed the rhesus monkey, and the pathological lesions in the

brain and cord were very much like the lesions to be found in the brain and cord of a human. Simon Flexner had no difficulty in working with poliomyelitis in monkeys, even though he couldn't see the

virus. I worked much the same way with Virus III in rabbits. I knew , what it did in my experimental animal, and I could back up these clinical and pathological observations with the immunological and serological methods I earlier described. I will say that, when you got used to the cumbersome way of doing things, it was a lot of fun. It

was Clinical observation that later led me to another nice piece of work with Dr. Bill Tillett. The case was an interesting one and involved a little baby girl no more than several months of age. I suppose the baby was born out of wedlock, because it was found discarded in an ashcan. When it was found, it was taken to a city hospital where an examination revealed that it was suffering from malnutrition, exposure, and chickenpox. Because of the latter condition, it was sent to the Rockefeller Hospi-

tal for further examination. ‘he moment I saw the patient, I realized that the distribution of the lesions was entirely different from the usual distribution of chickenpox lesions. In this case they were most pronounced on the face and extremities, with few if any lesions on the body. It didn’t take me very long to realize the cause of this: the child had congenital syphilis, and the chickenpox virus had localized itself in places that were irritated by the spirochete of syphilis. It was this irritation that accounted for the abnormal distribution of chickenpox lesions, and here they followed the distribution of the lesions of congenital syphilis. At various times I saw other examples of this with

78 Chapter 3 chickenpox—in one instance, where one of my patients had worn a very tight collar, I found that the chickenpox lesions made a perfect ring around the neck. I saw the same thing with measles virus. In this particular case, the child had been burned over one hip, and there were many more lesions in that area than on any other part of the body.

Now, this was a very well-known phenomenon, and neither I nor the doctors of my generation were the first to observe the effects of irritation of the skin on the distribution of lesions following certain diseases. Hundreds of years ago, the women in harems used to irritate

their bodies, particularly in the extremities, to localize smallpox lesions as far away from the face as possible. QO: Would you say that it was such clinical experience that later led to your experiments on the relation between trauma and infection?

Rivers: Oh, I got a lot of ideas from my patients. I think that it’s too bad that people doing research on things related to human beings don’t see more patients, because patients pose a lot of problems that

you wouldn’t think of by yourself. Many times it was the patient who presented the problem that I took to the laboratory. I don’t think that I would have done as well in research if I hadn’t seen patients. The early work that I did with streptococci came out of my clinical

experience at the Rockefeller Hospital. | In 1923 or thereabouts, quite a number of people like Dr. Frederick Gay of the College of Physicians and Surgeons at Columbia, and Dr.

Harold Amoss of the Rockefeller Institute, were interested in local immunity and local resistance against various infectious diseases. At that time it was not too clear what role the hemolytic streptococcus played in such diseases as scarlet fever, rheumatic fever, or erysipelas. Harold Amoss was working with streptococci and was of the belief

that they did cause erysipelas. As a matter of fact, he prepared an antiserum using a streptococcus that he had helped isolate from one of his patients. Actually he didn’t get much with his antiserum; at best I would say that he got a nonspecific effect, but he did contract a very severe facial erysipelas and he became my patient on Ward One

at the Hospital. It was with the streptococci that I isolated from

Rockefeller Institute for Medical Research—1922 79 Harold Amoss that I began my initial experiments on local passive immunity.

First, I tried to produce an immune serum by making repeated intracutaneous inoculations of streptococci into the rabbit. Such inoculations were continued for approximately a month, at intervals rang-

ing from seven to ten days. At the end of that time, I took my inoculated rabbits and bled them and pooled the sera. When I was sure that the sera I had obtained in this fashion had immunizing properties against strep, I proceeded with my experiments. I soon dis-

covered that an immune serum could neutralize streptococcus if I mixed the strep with the serum before injecting it into the skin of my rabbits. I also found out that, if I put the serum in ahead of time—as much as 12 hours ahead—and then later put the strep in the center of the area where the serum had previously been injected into the skin, the skin would protect against the strep, while in other areas of the animal’s body not treated with the serum, the streptococcus would

cause a lesion. :

I spoke of this as local passive immunity. I don’t know whether I was the first to use such a term. I do know, however, that other people at the same time were aware of the phenomenon, even if they didn’t use the phrase “local passive immunity” in the way I did. I

would like to point out that it was not always just the serum that produced this local passive immunity. I discovered that, if perfectly

normal sterile broth were injected into the skin of a rabbit 12 to 24 hours prior to the injection of streptococci, this injection of normal broth would also give a certain amount of local immunity. While it was not as good as that produced by immune serum, it was very obvi-

ous that there was protection in this area. Later, when we took sections of skin from such areas, although it looked perfectly normal to the naked eye, under the microscope it was different from skin taken from an area that had no injections of normal broth. The difference was in a marked influx of polymorphs, mononuclears, and other white cells of various kinds. I think the presence of such cells was the reason those areas were protected by normal broth. Actually, two of my friends, Francis Blake and Alphonse Dochez,

were doing similar work in relation to scarlet fever. They had discovered that, if they took serum from a patient who had recovered

80 Chapter 3 from scarlet fever and injected it into the skin of a patient showing a rash of scarlet fever, such an antiserum would blanch the rash of scar-

let fever. It was a very nice piece of pioneer work on their part. In some of my later experiments, I decided to see if my immune serum would have an effect in stopping the rash of erysipelas in rabbits. I inoculated my rabbits with strep and waited for the nice spreading rash that was characteristic of erysipelas, and when it appeared I placed my immune serum in a semicircle at the outer edge of the rashes. Invariably, the rash would come up to where the serum was and stop, but it would spread to the area that had no serum. ‘To me, this meant that the serum was acting locally, and I undertook to treat one or two of my patients who had erysipelas, using this technique. It would have been miraculous if such therapy had worked at the time. As you know, there are more than 40-odd types of group A strep and it would have been amazing if the antiserum against a type picked at random had matched the bug infecting my patients. If it had worked,

we would have drawn the wrong conclusions. ‘Thank God that it didn’t—it was just one obstacle less in the path of Rebecca Lancefield in her typing of strep. OQ: Did you work only with Dr. ‘Tillett at this time?

Rivers: No, I also worked with people outside of my own laboratory. Now, when I worked with people outside my own bailiwick, it was not because I liked the people especially, or because I had any particular interest in what they were doing, but rather because they were adept in certain techniques that I wanted to use in my own research. For example, while I was experimenting with streptococci and local immunity, an examination of the literature quickly showed me

that I had not made any new discoveries. Other people had worked with organisms that they had gotten from erysipelas—without calling them streptococci—and had also discovered that, if they irritated the ears of rabbits with turpentine prior to injecting their material into the rabbit, it inhibited growth. A man by the name of Camus teported that, if he exposed certain areas of the skin of rabbits to x-ray , and later tested such areas with organisms of erysipelas, the skin which had previously been exposed to x-ray did not respond to the

Rockefeller Institute for Medical Research—1922 _ 8] organism in the same way as untreated skin did.® Actually it was Camus’ results that led me to collaborate with Dr. Frederick L. Gates

on the effect of ultraviolet light on the growth of vaccinia. I just wanted to see if irritating the skin with ultraviolet would either increase or decrease the reaction to vaccinia.

I want to stress that other people saw the same things that I did. For example, Dr. Ernest Goodpasture was at the same time working on like problems, except that he used coal tar derivatives in his experi-

ments. Use of chemical agents took more than one application; a physical agent like ultraviolet light, on the other hand, was easier to handle. All you had to do was pick up your rabbit and expose him to the ultraviolet light for a certain length of time, and that’s all there was to it. [here was no profound reason for working with ultraviolet light, except that I was lazier than Goodpasture, and Freddy Gates knew about ultraviolet light. Nothing much came from these expetiments, except that we learned that the amount of energy required to kill staphylococci was approximately the same as was necessary to inactivate vaccinia.

O: How was Dr. Gates as a collaborator?

Rivers: Freddy was a smart boy, and he stood first in his class at the

Hopkins. He was extremely intelligent, but he was unfortunately never cut out to be a research man. He lacked the quality of imagina-

tion so necessary to research, and you just can’t make a good researcher unless you have that quality. Our collaboration was smooth,

and Freddy was an agreeable fellow to work with, but I seriously doubt that he understood what I was up to. Now, I am not saying that he wasn’t smart, because he was—he just wasn’t cut out to be a research man.’ °P. Carnot, L. Camus, H. Benard, “Action empéchante des radiations ultraviolettes sur la vaccine expérimentale du lapin,” Compt. rend. soc. biol., vol. 95:457 (1926). “George Corner, historian of the Rockefeller Institute, holds a different opinion of Dr. Gates as an investigator. He notes that Gates’s later work on the action spectra of ultraviolet light was the first definitive work on this subject, and that biophysicists today recognize him as a pioneer in this field. See G. W. Corner, A History of the Rockefeller Institute. Rockefeller Institute, Press, New York, 1964, p. 182. It is of interest that, in 1952, Rivers’ early work with Gates caught the attention of the English plant virologist, F. C. Bawden. Bawden at that time discovered that irradiated plants recovered

82 Chapter 3 Q: You worked with one other person outside your laboratory at this time, named Louise Pearce.

Rivers: Oh, well, now you are talking about someone else. Louise was a rather unusual person—or you might say an unusual woman. She stood very high in her class at the Hopkins, and it was high enough for her to get an interneship in medicine, which meant that she probably was in the first four or five in her class. She left an impression of herself at the Hopkins. As a matter of fact, I had heard of her long before I came to the Rockefeller Institute. Even when I got to know her at the Institute, she was a rather goodlooking person, and in her earlier days she must have been still better looking. I must say that by her actions at the Hopkins or at the Institute you wouldn't pick Dr. Pearce as a woman or a man. She was a research person—that is, I don’t think I ever thought of her, so far as her research activities were concerned, as to whether she was a male

or female. She was that good. Louise Pearce worked in Wade Hampton Brown’s department. His name should tell you that he was a southerner who came from South Carolina. I guess most kids who were born in South Carolina after the

Civil War were named after this leader of the Red Shirts. At that ~ time Dr. Brown’s department was working on diseases of the central nervous system, particularly those caused by syphilis, and Louise Pearce was definitely a part of the work that went on in that department. You kind of got to the point where you didn’t know that there were two people. It was Brown-Pearce this and Brown-Pearce that until you thought it was:'a hyphenated name.

One of the great achievements of the Institute in the early 1920’s was the use of ‘T’ryparsamide for trypanosomiasis, a disease common in tropical Africa, which involved the central nervous system and ended in the patient literally sleeping to death. It is commonly known as the African sleeping sickness. The compound of Tryparsamide was from initial susceptibility to virus only if they were illuminated after irradiation, and he

was anxious to learn whether the same thing had held true when Rivers and Gates conducted their early animal experiments with ultraviolet light. Rivers was both pleased

and surprised by the query, but unfortunately he could not help Bawden. See F.C. Bawden to T.M. Rivers, April 21, 1952; T. M. Rivers to F.C. Bawden, May 1, 1952 (folder, Personal correspondence, 1952, Rivers papers).

Rockefeller Institute for Medical Research—1922 §3 worked out in Wade Hampton Brown’s laboratory, and it was Louise Pearce who tested the effect of ‘Tryparsamide on trypanosomiasis in the Belgian Congo in 1920 or thereabouts.’ I have never been able to figure out why ['ryparsamide was chosen to be tested, except that you might say it was Louise Pearce’s intuition, because I understand that there were other compounds that showed up better in animal expertiments. ‘l’o this day, ‘Tryparsamide is probably the best drug for the

treatment of trypanosomiasis in human beings. As a result of her work in the Congo, Louise Pearce was decorated by the Belgian government. Dr. Brown was a member of the Institute; however, Dr. Pearce was not, and I think that it was shortsightedness on the part of the Institute that she was not made a member. She only attained the rank of

associate member. It was not too difficult for ladies to work at the Institute, but they always had trouble getting ahead—particularly the Ph.D. ladies. Whenever I found one that had promise, I always advised her to get out and get an M.D., because as long as she had just a Ph.D. no one was going to pay any attention to her. One of the people I so advised was Ann Kuttner. Well, Ann Kuttner followed my ad-

vice, went to the Hopkins for her M.D. and today is a professor of pediatrics at the New York University Medical School. During my tenure at the Rockefeller Institute, there were only two women mem-

bers. One was Florence Sabin. Dr. Sabin was a member because Popsy Welch told Simon Flexner to make her one—Simon Flexner just wasn’t giving memberships to ladies. The other woman member was Rebecca Lancefield. I should add that Dr. Lancefield’s membership came when she was about to retire and after a lifetime of superb research on streptococci.

In 1923 Dr. Constantin Levaditi and one of his associates at the Pasteur Institute, Dr. Stefan Nicolau, reported the growth of vaccine, virus in neoplasms of mice and rats. He reached several conclusions from this work, one of which was that cancer cells were unable to de-

velop an active immunity against infection with vaccine virus and § The chemical work on the compound Tryparsamide was done by Walter Jacobs and Michael Heidelberger. See G. W. Corner, op. cit., p. 146. Brown and Pearce studied its toxic action and its effect on trypanosomes. L. Pearce, The Treatment of Human Trypanosomiases with Tryparsamide. Monographs of the Rockefeller Institute for Medical Research, No. 23, 1930, is the fullest and best account of these latter studies.

— «84 Chapter 3 only passively partook of their host’s immunity. Levaditi’s observations seemed to hold great import for the biology of tumor cells and the growth of viruses.® I was intrigued enough with his findings to see

what effect if any my Virus II] had on the malignancy of a tumor, and whether it would grow in a tumor. Louise Pearce knew a great deal about tumors and had in fact been instrumental in the cultivation of an epithelial tumor called the Brown-Pearce tumor, which could be transferred from rabbit testicle to rabbit testicle. ‘The tumor would invariably metastasize to other parts of the body and was, in fact, very very nice to work with. I knew very little about the trans-

plantation of tumors in animals and still know little about it, but Louise Pearce knew a great deal about it, and when I told her my ideas of testing out Levaditi’s findings with Virus III she agreed to work with me.

One of the first things we tried to learn was whether Virus III would grow in the Brown-Pearce tumor. Well, we inoculated some actively growing tumors and pretty soon we found out that things weren't as easy as we had suspicioned. Within two or three weeks, we learned that all of our tumors were immune to Virus II] and, damn it all, we just couldn’t infect them. Well, it was a finding that we were

just not prepared for, but we had to accept it because it was so. We were kind of slow on the uptake here, because it took us some time to realize that what was happening was that we were transplanting the Brown-Pearce tumor to rabbits that were already infected with Virus

III, and that when we made transfer from such rabbits we passed Virus III along with the tumor. Well, we learned a number of things from this impasse; the first, that the virus accidentally introduced in the tumor multiplied and survived, and the second, that the tumor at one time accidentally infected with the virus had itself acquired an immunity which it conferred upon all of its subsequent hosts. After we discovered that the tumor carried the virus, we naturally tried to discover whether the character of the tumor was affected by its presence. We were helped here by one of those chance mistakes that frequently occur in the lab. One weekend one of our rabbits that had been inoculated with a Brown-Pearce tumor died and the animal °C, Levaditi and S. Nicolau, “Vaccine et néoplasmes,” Ann. Inst. Pasteur, vol. 37: 443 (1923).

Rockefeller Institute for Medical Research—1922 85 man just forgot to put the remains on ice. When we arrived on Monday morning, Louise Pearce and I decided to test the tumor. Don’t ask me why, unless it’s because a lab man never assumes that anything is dead or different until he tests it. To make a long story short,

we decided to transplant the tumor from the dead rabbit to some other rabbits and, lo and behold, we got some beautiful takes. When we examined the new transplants, we discovered that the tumor had

lost all of its Virus III components, and we finally had a straight Brown-Pearce tumor without any Virus III. We were at last now pre-

pared to study the effect of Virus III on the tumor. By rights, we should have gotten good results, because the Brown-Pearce tumor was epithelial in nature, and Virus III affected epithelial cells. Darn it, all we found was that while the virus would kill most of the cells it was

never able to kill all of them, and they just broke out again. I don’t know how many times we tried, and we transplanted in every conceivable place, but we never could get rid of all of the tumor cells. It has been 35 years since Louise Pearce and I tried to discover the possible oncolytic effect of Virus III on the Brown-Pearce tumor in rabbits. ‘Today the boys at the Memorial Hospital also talk. about oncolytic viruses and their possible effect on human cancers. I don’t know whether they know of the work that I did with Louise Pearce, | but the answers they have thus far come up with are no different from what we discovered. I tell you one thing, I ain’t going to take the luxury of making a prediction—I know enough not to. O: Dr. Rivers, I would like to read an excerpt of a letter to you and see if you can guess the writer.

The paper by Andrewes and Miller is unimpeachable by itself, but it — brings up a point which may mean adjustment, unless this has already been had. You will note that their title is: “A Filterable Virus Infection in Rabbits, Its Occurrence in Apparently Normal Rabbits.” ‘This is of course the virus of Rivers and Tillett, with which these authors have become familiar through several years of work, and which they were realizing to be inde-

pendent of the chickenpox material with which they began their rabbit inoculations. Unless Swift has an understanding with them, whereby his workers are permitted to jump into the game and announce derivation of this virus, I imagine that they will have some heartburning. A possible way . would be to alter the subhead of the above title to “Occurrence of the

86 Chapter 3 Rivers-Tillett Virus in Apparently Normal Rabbits.” This is doubtless an unscientific name to give to a virus, but the difficulty, if there be one, is yours to adjust.1°

Rivers: My guess is that it was either Rufus Cole or Simon Flexner.

QO: No, it was Dr. Peyton Rous. Could you tell me about Peyton Rous and his position in the Rockefeller Institute when you first

came in 1922? ,

Rivers: Before I answer your question, just let me say that I don’t think there would have been any heartburning about the MillerAndrewes article. Tillett and I knew all about the work that was going on in Swift’s department on rheumatic fever, and in particular about Andrewes’ search for a rheumatic fever virus. As a matter of fact, as I mentioned earlier, Andrewes and Swift to a certain extent helped save Bill Tillett and me from sticking out our necks too far on

Virus III. Of course, Rous didn’t know all this when he read that paper, and the letter he wrote was a natural thing for him to do as

editor of the Journal of Experimental Medicine. If you want to know what kind of a portrait Peyton Rous presented to me in 1922, I don’t mind telling you that it is the same kind of a

portrait he presents to me today. Rous is one of those people who | never change very much in their physical appearance, and it is only within the last year or two—and he is in his eighties—that he has begun to show some of the effects of age. He is still the same kind of a person, namely, one who has taken his pleasures in life from his work, reading, and writing. He is not much given to athletics, hunting or fishing. He and I are completely different people—it’s nothing against him, and it may not mean anything against me. When I first came to the Institute in 1922, Dr. Rous had already made his mark as a scien-

tist. In 1911 Dr. Rous demonstrated the existence of the virus of ' chicken sarcoma and helped prove that it was transmissible. I don’t know how to stress the importance of that work other than to say that it was an important watershed in cancer as well as virus research. It was quite a discovery, and anyone who works in these two areas today

| owes much to Peyton Rous. Yet, I don’t know whether he capitalized *’ Peyton Rous to Simon Flexner, August 15, 1924 (Flexner papers).

Rockefeller Institute for Medical Research—1922 87 on this discovery as much as he could have; otherwise I think that he

would have won a Nobel prize. I know that several times his name } has been put up for the prize, and rumor has it that on one particular occasion it boiled down to Rous and one other fellow, and the other fellow got it—I am not going to mention his name. I personally think

that Rous should have had it. It’s not too late yet. Right now the virologists, particularly those down at the National Institutes of

Health, are hell bent on proving that a virus is the cause of cancer in | man. I am not so sure that they are going to get away with all ‘of this,

but if they are successful I think that Rous will come into his own. Then there’ll probably be a joint Nobel prize for Rous and the fellow who proves the thing in human beings.

QO: Was Dr. Rous engaged in virus research when you came to the Institute?

Rivers: By the time I had come to the Institute, Dr. Rous had moved away from the study of viruses. During World War I, he had become interested in problems relating to the preservation of blood and from that field moved over to the study of the function of the ~ liver. He didn’t move back to the study of viruses until Dick Shope came up with his very nice rabbit papilloma. It’s funny to talk about tumors as being nice, especially when everybody knows they are not, but an experimenter may think they are beautiful or nice because they help him find answers to problems that bother him. In 1933 Dick Shope discovered a natural papilloma occurring in the wild North American rabbit. The interesting thing about this particular tumor was that it was virus-induced. If you ground and filtered these tumors, you could transmit like tumors to other rabbits. The tumors generally were benign. However, Rous discovered that after a long period of time they could become malignant and metastasize. The interesting thing was that these new highly malignant tumors still had the virus that was originally present in the Shope papilloma. ‘There was a ques-

tion in Rous’s mind, as well as others, whether the virus and the malignant tumor had any relation to one another—when, lo and be-

hold, the Shope papilloma virus disappeared from the tumor and Rous was just left with a highly malignant tumor. Originally, if you

88 , Chapter 3 got rid of the virus, you got rid of the tumor; now you could get rid of

| the virus and still have a highly malignant tumor, which you could transfer from animal to animal. ‘This is where the matter now stands. Rous’s shift in fields is rather interesting and shows that, although he . worked on problems of the blood and liver for over 15 years, when a

real opportunity presented itself for him to make new and original observations in a field he left years before, he boldly made the most of it. I would like to say this, however. Rous has always been a lot more interested in what his virus did than in what it was. ‘To my mind, he

is not a virologist; he is still a pathologist, and the irony is that he

, could have been the virologist of the United States and the world, if he had so desired. It doesn’t bother him; he didn’t want it, he didn’t desire to be that, and he is perfectly happy about the whole thing.

You know, at the time I started to study viruses, to be a good virologist, one had to be a good pathologist as well as a good clinician,

because you could only study viruses by the pathological or clinical picture they presented. ‘Today we deal with viruses on a biochemical level—we purify and crystallize them, we grow them in tissue cultures, we examine the nucleic acid, and what not. That’s fine—but a lot of virologists today wouldn’t recognize a patient infected with a virus any more than a newborn baby would—I think they miss a lot of the fun by not knowing what these damn things do in humans; they miss a hell of a lot of fun.

QO: Dr. Rivers, you mentioned Dr. Rous as editor of the Journal of Experimental Medicine, and I wonder if you would speak of the position of the Journal vis-a-vis research.

Rivers: I think that the Journal of Experimental Medicine was and is probably the best journal that is put out covering research work in the medical sciences. Every youngster and every oldster, particularly youngster, doesn’t feel that he has arrived until he has had one of his papers published in the Journal. I know that this was true in my day,

and I think that it still holds. For years, Dr. Rous and his secretary took care of getting out the Journal alone. Of course, when Rous got hold of a paper that he didn’t understand, he would call on somebody in the institute or hospital—since they covered nearly all the essen-

Rockefeller Institute for Medical Research—1922 89 tial fields in medical science—to help him out. ‘Today the Journal of

Experimental Medicine has a board of editors: medical research has | broadened to such an extent that running the Journal is beyond the powers of one man. I should add that, although Rous has long been retired from the Institute, he still acts as editor-in-chief of the Journal." Rous was, and I suppose still is, a stickler for the right kind of Eng-

lish, and I know that he used to edit papers quite severely. He had certain pet peeves that you could never get by. One of them—and I think he was correct—was that he would never allow an author to speak of an animal except by means of the neuter pronoun, it. For example, a lot of doctors using chimpanzees while studying polio would refer to a he or she chimpanzee. When Rous saw this, he would always hit the ceiling and make them change it to it. He always reminded me of Dr. Howland’s rule on the use of the pronoun, it, in relation to infants. Howland always spoke of an infant as it. One day,

I asked him why, and he said, “When you are looking at an infant that’s fully clothed, you don’t know, you can’t know whether it’s a he or a she, and, if you say he and it’s a she, the mother doesn’t like it. But if you say it, the mother doesn’t take offense. You are always right when you say it.” The Journal always had a severe restriction on the number of pages you could submit, and very rarely did an article run over twenty pages. At such times as an article did exceed the limits, the author, if he was a member of the Institute, had to pay for the excess pages out of his

budget. If he wasn’t a member, the extra payment came out of his pocket. ‘There was also a limitation on the amount of illustration you could have for an article, and unless it was an exceptional article the

author again had to pay for the extra illustrations. In spite of these limitations, most researchers wanted to have their articles published in the Journal.

When I first came to the Rockefeller Hospital, Dr. Cole used to 4 George Corner, historian of the Rockefeller Institute, makes this observation concerning the direction of the Journal of Experimental Medicine. “For fifteen years Flexner was active as chief editor, assisted by Opie, 1904-1910, and Benjamin Terry, 19111912. In 1921 Peyton Rous was appointed coeditor. Assuming practically the whole task, he was effective editor for thirty-six years, although Flexner’s name continued to

be carried on the title page even after his retirement and until his death in 1946... . Herbert S. Gasser became joint editor in 1935, René J. Dubos in 1946, and Vincent P. Dole, Jr., in 1953.”’—G. W. Corner, op. cit., p. 63.

90 Chapter 3 rag me about my writing. He thought I couldn’t write, and one day to underline the point wrote a special version of a paper I was going to submit to the Journal. ““Take them both over to Rous,” he said, “he will tell you which paper is better.” Well, I went over to Rous with both papers, and although I didn’t want to stay he insisted that I stay until he had completed reading both papers. When he got through, he had a great big grin on his face. “Rivers,” he said, “it’s very easy to

know who wrote the better of the two papers. There is so much difference between them that it is almost a shame even to discuss it.” He kept waving a paper in his hand. Finally, I said, “Which paper are

you talking about, Dr. Rous?” “Here’s the paper that Dr. Cole wrote,” he said. “Anybody would know that Cole wrote this.” I looked at it. “Dr. Rous,” I said, “that’s the paper I wrote. I didn’t tell you which paper was written by whom. The paper you are. holding is the paper I wrote.’”’ Rous’s face turned crimson, and he got rid of me as fast as he could. Later my paper was published just as I wrote it. It was the last time that either Cole or Rous ever bothered me about my writing.

A lot of the boys at the Institute had things like this happen to them, because Dr. Flexner, Dr. Cole, and Dr. Rous were of the opinion that medical school graduates did not know how to write articles. I don’t want to give the impression that only youngsters were handled roughly by Dr. Rous’s editorial pencil—he made little distinction between young and old, famous and nonfamous. If a paper didn’t come up to the standards in English that Dr. Rous set, it was rewritten; it

didn’t matter if it was a young doc in the hospital or Karl Landsteiner.

QO: Dr. Rivers, didn’t you and Karl Landsteiner come to the Institute in the same year?

Rivers: Yes, we were both appointed the same year. Just let me say very quickly that I think that Karl Landsteiner was probably one of the greatest members that the Rockefeller Institute ever had. It must be remembered that he had made a name for himself long before he came to the Institute in 1922. In 1901 Dr. Landsteiner discovered that there was more than one blood group and opened the way for

Rockefeller Institute for Medical Research—1922 9] successful blood transfusions, a discovery for which he won the Nobel

prize in 1930. In 1909, in concert with Dr. Erwin Popper, he produced poliomyelitis in monkeys, an experiment that you might say was the beginning of the laboratory attack on that disease. I can’t be-

gin to detail the work in immunochemistry that came from Karl Landsteiner’s laboratory in all the years he was at the Institute, save to say that in 1939 it culminated in the elucidation of the Rh factor in the blood, which has been so important for human childbearing

and for the great impetus it has given to the study of genetics.” Actually, I am surprised that Dr. Landsteiner didn’t get the Nobel prize a second time. He certainly deserved it.

Landsteiner was short on words either spoken or written. His reports to the Board of Scientific Directors of the Institute were rarely ever more than two or three pages; they were succinct and clear, with little attempt to pretty them up. It used to be the custom at the Institute that members on Friday afternoons would speak about the work they were doing. Landsteiner rarely ever spoke at these Friday afternoon meetings. ‘That was true of Dr. Avery as well. However, Avery would talk to you freely in his laboratory, while Landsteiner just didn’t want to talk to you about what he was doing. There was another difference between Landsteiner and Avery. While Avery turned out a great many experimenters and teachers, Landsteiner practically turned out none, with one exception, Dr. Merrill Chase, who is now at the Institute. Dr. Chase worked with Landsteiner until the day he died, and you might say that Merrill Chase arrived on his

own in spite of Landsteiner. The fact is that Dr. Landsteiner wouldn’t allow his boys to plan an experiment on their own. He’d call them in and give them the protocol, and they would have to carry out

the experiment the way he set it out. There was reason for this. A long time before Landsteiner came to this country, he was fooled by one of his Dieners. The Diener happened to know what Landsteiner was attempting to prove by his experiments and arranged things to come out as Landsteiner hoped they would. Landsteiner went into . print and a short time later discovered what his Diener had done and had to retract everything he said about this particular work. He never 2 An excellent brief evaluation of Landsteiner’s career is contained in P. Rous, “Karl Landsteiner 1868-1943,”’ Obit. Notices Fellows Roy. Soc., vol. 5:295 (1947).

92 Chapter 3 got over it. Never. From that time forward, he suspected everybody, if

: you ask me, even himself, when it came to experimental results. Dr. Landsteiner was a hard customer, and he demanded more work and longer hours of his workers than was usually demanded of workers by other people at the Institute. He had little thought for any activity except experimentation that would lead to new knowledge. I

think that that attitude is best exemplified by a fight I had with Landsteiner over Clara Nigg, who was one of Dr. Landsteinetr’s assis-

tants. At one time Hans Zinsser reported the growth of typhus rickettsia in tissue culture, and Landsteiner decided to do certain experiments using rickettsia grown in this fashion and put Dr. Nigg to

work on it. I think that none of us at that time knew how easily typhus fever rickettsia could pass from tissue cultures to the persons working with them. I know I didn’t realize it. Well, to make a long story short, Clara Nigg developed typhus fever and became my patient on Ward One at the Rockefeller Hospital. She was pretty sick. Most anybody that has typhus fever is sick. I can’t remember that any of us felt that she was going to die, but we realized that she was doggone sick. In the course of her disease she developed certain sequelae that worried us, but in time she became better. I kept her on the ward as long as I could, and if I had known

what was going to happen I would have kept her longer. But I thought that she could go home and rest there without burdening a hospital bed, and so I let her go. Doggone it, no sooner did she get out of the hospital than Dr. Landsteiner put her to work as if she had never been sick. God almighty, he worked that girl eight and ten hours a day. When I found out about it, I went to see Landsteiner. I want to tell you the old boy didn’t think much of my coming to him about it. He made it plain that he thought that I was monkeying with his business and that I should let him run his lab in the way he saw fit. I differed with him—TI told him that Clara Nigg was still my patient and it made no difference whether she was back in his lab or not, and that until her health was back to normal she was going to do what I said, no matter what he thought. Knowing Landsteiner, you can know that this upset the old gentle-

man, and he argued with me, but I stuck to my guns. Finally I told

Rockefeller Institute for Medical Research—1922 93 him, “Dr. Landsteiner, if you don’t play ball with me I am going to take Clara away from here, and you are not going to see hide nor hair of her for the next six months. I don’t mind having Clara work for you a certain amount of time each day, but you aren’t going to work her to death.” He looked at me and said, “I am going to call Dr. Flexner and Dr. Cole.” “Dr. Landsteiner,” I said, “you won’t get Dr. Cole or Dr. Flexner to change my mind because they can’t: I am Clara Nigg’s doctor, and you ain’t going to get to first base.” Well, I was firm and he finally understood. In the end, he did cut Clara Nigg’s work down until I discharged her as normal.

I think this story prepares one for what happened when Landsteiner received the Nobel prize. He was working in the lab when news that he had won the prize came to him. He kept on working as if nothing had happened. When he came home that evening, he discovered that his wife had already gone to bed, but he never awakened her, and he didn’t tell his wife he had received the prize until the next morning. Landsteiner was simply devoted to his work, a condition that existed to his dying day. After he retired from the Institute, he still maintained his lab and continued to work regularly. One day he simply collapsed at his desk in the lab and was brought to the hospital in bad shape. It was obvious that he had had a coronary, but the old man just wouldn’t accept it and tried to return to the lab. If we hadn’t restrained him, he would have. A few hours later he lapsed into a delirium, and all he spoke of was how he had to get back to his

laboratory. Over and over he said, “I have got to get to my laboratory. 7 I have experiments going that must be carried on.” He spoke that way until he died.

Not everyone at the Rockefeller Institute was cast in the mold of Landsteiner, and there were a lot of people who had great world-wide

Hideyo Noguchi. | reputations who I think little deserved them. One such person was

Noguchi was a very colorful person, small in stature and typically Japanese in appearance. He came to the Institute because of his association with Dr. Simon Flexner, and that is a story in itself. As I told

you before, in 1899 Dr. Flexner went out to the Philippines as a member of a medical commission to study dysentery in the islands.

94 Chapter 3 After his work was done, he went on a sightseeing trip to Japan, and while on this trip he apparently met Noguchi.” I say apparently because, from the stories Dr. Flexner later told, he did not remember seeing Noguchi on this occasion. Later, not too much later, when Dr. Flexner got back to his laboratories at the University of Pennsylvania

—he was at that time professor of pathology at the University of Pennsylvania Medical School—Noguchi showed up. He bowed and formally presented Dr. Flexner with a small gift and announced, “Dr. Flexner I have come to work with you.” Well, this just about bowled Dr. Flexner over. He didn’t know who his visitor was—he couldn’t remember him—and here he was saying, “I have come to work with you.” I have heard any number of tales as to what was subsequently said

and done, but the important thing is that Dr. Flexner kept him and. put him to work. Noguchi did creditable work on snake venom while

at Pennsylvania, and when Dr. Flexner moved to the Institute he brought Noguchi with him. Actually, I don’t think that he had any choice, because, if Flexner hadn’t taken him, I think that Noguchi would have taken the train from Philadelphia and come anyway. By the time I came to the Institute, Noguchi had a world-wide reputation for his work on the spirochete Treponema pallidum, the various media he prepared for the growth of bacteria, and the claim that he and Dr. Flexner had isolated the cause of poliomyelitis, and that it was small globoid bodies that would grow in nonliving media. I will have much to say about these claims later; for the present let me say that, when I later asked Noguchi about these claims, he wouldn’t answer me and would only say that a man who had done research work for a long time had scars that he could never get rid of.”* | *8 Rivers has mistaken the itinerary taken by Flexner and the expedition. The first ‘stop was in Japan where Flexner and Lewellys Barker had important conversations with Dr. Shibasaburu Kitasato and Dr. Kiyoshi Shiga. Later they proceeded to Hong Kong and finally to the Philippines. See S. Flexner and L. F’. Barker, “Report upon an expedition sent by Johns Hopkins University to investigate prevalent diseases in the Philippines,” Johns Hopkins Hosp. Bull., vol. 11:37 (1900). * Tt is very unlikely that this conversation took place. Noguchi died in May of 1928, at least two years before the first serious scientific attack on the concept of “globoid bodies,”’ by Peter Olitsky and his associates. Even after Olitsky’s article appeared, Simon Flexner, reminiscing about Noguchi in the privacy of his diary (1931), still thought well enough of the concept to claim that the idea of the globoid bodies was really his and not Noguchi’s. It seems highly improbable, therefore, that Noguchi would act as

Rockefeller Institute for Medical Research—1922 95 I was always on amicable terms with Noguchi, and when I first came to the Institute it was Noguchi who supplied me with the first batch of vaccine virus that I worked with. It was an interesting batch.

Originally Noguchi got his strain from the Board of Health of the City of New York, and passed it through a number of generations of rabbits by intratesticular inoculation, with the idea of making a bacteria-free vaccine virus for human use. Just let me say that this virus went beautifully in rabbits by intratesticular passage, and that it was freed of its bacterial contaminants, but I found, when I used it, that it would not produce encephalitis in rabbits. ‘That was a rather

unusual situation, and so I sent down a request to the Board of Health for some more of the original strain sent to Noguchi. I carried this new batch intratesticularly in rabbits and freed it of its bacterial contaminants. However, when I injected it into the brains of rabbits I was still able to cause an intense encephalitis. ‘The difference in the results lay in the fact that Noguchi’s batch had passed through rab-

bits’ testicles for a longer period than mine did, and in the process had mutated. This work was the beginning of an attempt which I later made to cultivate vaccine virus in tissue culture suitable for Jennerian prophylaxis in man.

I must say that, after I got to know Noguchi better, I did not consider him a great scientist. For one thing, his general attitude disturbed me. For example, when I discovered that Virus III was not a chickenpox virus, I told Noguchi about it, and his answer ruined him as far as I was concerned. “Oh, why worry about that,” he said. “Dr. Noguchi,” I said, “I want to be the first one to retract and to say that

I have made an error and tell why.” “Oh,” he said, “I’d never do that. , It'll take them fifteen years to find out you are wrong.”’ Well, a scientist just doesn’t say things like that, at least a reputable one doesn’t.

This was Noguchi. I don’t think that he was honest.” Now, I am if he were in error about the globoid bodies before serious criticism had been heard. See P.H. Long, P. K. Olitsky, and C. P. Rhoads, “Survival and multiplication of the virus of poliomyelitis in vitro,” J. Exptl. Med., vol. 52:361 (1930). Diary of Simon Flexner: Entry, February 28, 1931, Palermo (Flexner papers). * Peter Olitsky, a contemporary of Noguchi’s at the Rockefeller Institute, takes sharp exception here to Rivers’ evaluation of Noguchi. I am amazed at what Dr. Rivers states here about Noguchi’s alleged duplicity. I had been very friendly with Noguchi but never heard from him such words or thoughts. He had great difficulty with English as a spoken language. His method was to translate the

96 Chapter 3 being perfectly frank. Noguchi has long had a public reputation for his work on yellow fever. The fact is, he knew nothing about the pathology of yellow fever and wouldn’t know a case of yellow fever if it hit him in the face. Someone in South America once sent him material from a case of what purported to be yellow fever, and Noguchi isolated a spirochete from the material, which he called Leptospira icteroides.

Well, as you know, Weil’s disease clinically can look very much like yellow fever and is caused by a spirochete called Leptospira icterohemorrhagie. | don’t blame Noguchi for drawing a spirochete out of the material which was sent him, but when he claimed that the organism that he got was serologically different from the spirochete

that causes Weil’s disease, why then I do hold him responsible. Noguchi was working in a field that he was supposed to be expert in, and he should have been able to tell the difference, or rather the similarity between the organism that he called Leptospira icteroides and the Leptospira icterohemorrhagie. Plenty of other people were able

to show that Noguchi’s spirochete was one and the same with that which caused Weil’s disease.

On the basis of Noguchi’s claims, a vaccine was prepared against Leptospira icteroides and given experimentally to part of the Brazilian army. Later an article even came out in the Journal of the American Medical Association purporting to show that the vaccine was helpful against yellow fever. I have no explanation for how these results were obtained, but I will say that for a while many people believed it, with the possible exception of Hans Zinsser and several others who would | English he thought he heard, back to German which he knew better, then to Japanese; to respond in English the process was reversed, Japanese to German to English. The result was confusion and a jargon only he understood. Perhaps he wished to amuse Dr. Rivers with a Japanese type of jocularity rather than an antinomianism (private communication). Dr. Peyton Rous, the doyen of American virologists writes in a similar vein.

I came to know Noguchi well during the years from 1909, when I came to the Institute, until he left for Africa. In 1909 his reputation was already so great from what he had done that he was pressured to do still larger things, not only by his fellow scientists, but by foundations and the lay public; yet he remained a modest, honest, and immensely serious scientist. It was as such that, wishing to check the findings of the Englishman Stokes about the cause of yellow fever, he went to Africa, though ailing, and risked and lost his life. A false person would never have acted in this way (private communication).

Rockefeller Institute for Medical Research—1922 97 never accept the spirochete as a cause of yellow fever. In 1927 Adrian

Stokes, Johannes Bauer, and Paul Hudson went over to Africa to combat a yellow fever epidemic on behalf of the Rockefeller Foundation, and their initial reports cast doubt on the Leptospira icteroides

as a cause of yellow fever.'® Noguchi at the time thought that the yellow fever in Africa was entirely different from that which he found in South America and, supported by the Rockefeller Foundation, prepared to go on an expedition to West Africa to test his ideas. A week

or two before he left, | met him in the illustration department of the Institute. He was getting some pictures taken of what looked like tissue cultures and he asked me at that time if I would accompany

him to Africa. Well, knowing what I knew, I was very polite to Noguchi, thanked him for the invitation, and told him that I had a lot of things going that I couldn't leave, and that I couldn’t go. It was on this expedition to Africa that Noguchi developed yellow fever and died. However, before he contracted the fever, he sent a long cable to Dr. Flexner, claiming that he had discovered the cause of yellow fever in Africa, and that it was a large positive spore-bearing bacillus. (I

never saw the cable, but Francis Blake, who was on the Board of Scientific Directors told me about it.) When Noguchi’s cultures were examined later, they contained nothing more than B-cereus, something you find most everywhere. Obviously Noguchi was still cockeyed as hell about yellow fever.

QO: Dr. Rivers, what you have told me is a savage.indictment of Dr. Noguchi. Didn’t he do some rather nice work on Bartonella?

Rivers: I didn’t mean to imply by what I said that everything that Noguchi did was wrong or dishonest. As a matter of fact, you are quite right, his work on Oroya fever and Verruga peruana has stood the test of time and is a nice solid piece of work. It is when you weigh *°In 1925 a yellow-fever commission, under the leadership of Dr. Henry Beeuwkes, was sent to West Africa. ‘There, work on 67 cases of yellow fever failed to reveal the Noguchi leptospira. In 1927 A. F. Mahaffy, a member of this commission, was first to transmit the disease to an animal (rhesus monkey) other than man. In 1927 the writers mentioned here by Rivers were first to confirm that the causative agent of yellow fever was a virus. For further information, see W.A. Sawyer, “A history of the activities of the Rockefeller Foundation in the investigation and control of yellow fever,’ Amer. ]. Trop. Med., vol. 17:35 (1937).

98 Chapter 3 his accomplishments against his failings that you find him wanting. I don’t think that Noguchi was an honest scientist, and I don’t think

that he was a great scientist, although his name was great at that time, and I will bet you right now that scientists all over the world will feel that I have been disrespectful in speaking of my elders in the way I have. But this is the way I felt, this is the way Hans Zinsser felt,

and this is the way a number of other scientists in the world felt about Noguchi."*

QO: We have spoken now at some length about several of your colleagues at the Institute but little has been said of your colleagues at

the hospital. Rivers: When you speak of the hospital, almost the first name that comes to my mind is that of Oswald T’. Avery. As I mentioned before,

I first met Dr. Avery when I joined the Pneumonia Board during World War I to investigate an outbreak of pneumonia following a measles epidemic. Even at that time, Dr. Avery was one of the acknowledged experts on pneumonia in the United States. He was one of those who took a lead in typing pneumonia, and as early as 1913 had

helped develop a serum therapy for treatment of pneumonia type 1.

Dr. Avery worked at the Rockefeller Hospital and was directly re sponsible to Dr. Cole, who was also interested in pneumonia. As a matter of fact, one of the chief endeavors of the Rockefeller Hospital for the first thirty years of its existence was research in the field of pneumonia. Many of the early momentous discoveries in this field came from Avery’s laboratory. In 1930, for example, Dr. Avery, in conjunction with one of his young workers, Dr. René Dubos, discovered a bacillus from the soil of a cranberry bog in New Jersey which was capable of dissolving the capsular polysaccharide surrounding the pneumococcus, thereby making it susceptible to phagocytosis.

It was a discovery that not only revealed an important factor in the pathogenicity of pneumonia but also helped initiate one of the significant advances in pneumonia therapy prior to the advent of anti-

biotics. Actually it was Dubos’s later work with tyrothricin and 7 For another recent critical appraisal of Noguchi, see P. F. Clark, “Hideyo Noguchi 1876-1928,” Bull. Hist. Med., vol. 33:1 (1959).

Rockefeller Institute for Medical Research—1922 99 gramicidin which helped lay the groundwork for the great breakthrough in antibiotics that came in the early forties. Avery was one of the nicest people I ever knew, but he was rather shy and retiring. He was small of stature, and a lot of people seeing him for the first time might call him a sissy. He certainly had the outward marks of a sissy because he was small, gentle, and considerate.

But if anyone pushed him, they would have found anything but a sissy. Avery was tough, or rather I should say, tough-minded, and you

had to be pretty damned good to get anything by him. Actually I would say that he was not entirely familiar with what went on in other parts of the Institute. He only knew or cared about what was going on in his particular field. You couldn’t sit with Avery for 15 * minutes (and I don’t care what you were talking about) but what he would have you talking about your own work as it related to the pneumococcus. Avery spoke and wrote beautifully, and his youngsters found that he wouldn’t pass a paper for publication unless it met his standards of expression. He was peculiar in the way he conducted his

department. If a man came to work in his department, he just left him alone for about two years, and the fellow just had to figure out his own reading and what experiments to do. It was only after the fel-

low was around for a year or two that Avery would begin to speak with him. Now, that kind of behavior was pretty tough on a youngster, but if he stuck it out it usually paid off. It was sink or swim, but

it divided the good from the bad, the men from the boys. It was through this technique that Avery helped develop some of the leading

bacteriologists and immunochemists in this country, among them Tommy Francis, Colin MacLeod, Walther Goebel and René Dubos. QO: Some of your early papers have footnotes telling of the kindness of Dr. Avery in supplying material for given experiments.

Rivers: I was and am not a timid soul, and I have never been accused of that. If I needed any information that I thought Dr. Avery had, I never hesitated to ask him, and I was never turned away. Avery would give of his knowledge freely, and any material he had that was

handy and that he didn’t need himself he would gladly give me. Avery was just that kind of a person.

100 Chapter 3 To me, Dr. Avery was one of the great men that I came in contact with at the Institute; yet I was never close to him—never—even after I became director of the hospital in 1937. I guess a lot of people at the Institute never became close friends with Avery, but the ones who knew him and had the privilege of being close to him were extremely fortunate, because he saw problems in a big way.

QO: Dr. Rivers, were workers at the Rockefeller Hospital only concerned with bacterial and virus diseases?

Rivers: Hell, no. ‘There were workers at the hospital who had little or nothing to do with viral and bacterial diseases. For example, at the

time I came to the Rockefeller Hospital, Donald Van Slyke was already hard at work on problems relating to kidney physiology. Carl Binger, who today has a reputation as a psychiatrist, was in those far off days interested in the physiology of the lungs and heart. ‘The hospital, in addition, had a department that was solely devoted to problems of cardiology. ‘hat department was run by Dr. Alfred Cohn. Dr. Cohn, was, in fact, one of the pioneers in this country on heart research. Before coming to the Rockefeller Institute, he had studied with Sir James MacKenzie and Sir ‘Thomas Lewis in England (two of England’s great cardiologists of the early twentieth century), and as early as 1909 had helped Sir ‘Thomas set up a string galvanometer for the purpose of taking electrocardiograms at University Hospital in London. Cohn always used to stress that the use of the string galvanometer for taking electrocardiograms was first developed in Eint-

hoven’s laboratory in Leiden. As a matter of fact, when Cohn returned to the United States in the fall of 1909, he brought an Einthoven string galvanometer with him and set it up at the Mt. Sinai Hospital in New York. Strange as it may seem, he once told me

that he wasn’t the first in this country to publish on the use of the string galvanometer for electrocardiograms, and that that honor fell to Dr. Horatio B. Williams and Dr. Walter James of the College of Physicians and Surgeons at Columbia, who published the first paper on this subject in the American Journal of Medical Science in 1910. By the time I took over the hospital in 1937, Cohn was still a member of the Rockefeller Institute although he was no longer en-

Rockefeller Institute for Medical Research—1922 101 gaged in serious cardiological research. He had at this time actually become a philosopher and not a bad one at that. He was an extraordi- narily well informed man, well read in a variety of fields, and with a passion for collecting rare books. His personal library was large and had books in it ranging from medicine to music. I know because Dr.

Cohn left his library to the Institute, and today it is housed ina special room in the administration building for the benefit of Institute members and students. Still, all of this doesn’t tell you what kind of a guy Cohn was. For me the spirit of Alfred Cohn is contained in a let-

ter he once wrote to Dr. Flexner criticizing Dr. Francis Peabody of the Harvard Medical School. It was an exchange that came about as the result of a long letter that Dr. Peabody had written to Warfield Longcope, who at that time was chairman of the Board of Scientific Directors of the Rockefeller Institute. ‘The letters in themselves are interesting because they are part and parcel of a debate that is still going on in American medicine relating to the role of research and clinical instruction. Because they are lengthy, I am going to read parts of them verbatim, so that in the future one can judge for himself the spirit of these two men. Before I do, I should perhaps say a few words about Francis Peabody. Dr. Peabody has been dead a long time now—if memory doesn’t fail me, I believe, he died sometime during the late spring of 1928— but I want to tell you that they still remember and talk about. him in Boston today. ‘To my mind, and I know that this is going to rile some people I know in Boston, Dr. Peabody more than either Harvey Cushing or Henry Christian, was the spirit of medicine in the Boston of his day. Originally he was a graduate of the Harvard Medical School, but

after graduation he went to the Hopkins and worked with Dr. William ‘Thayer. I don’t know how long he spent at the Hopkins, but from there he went to Friedrich Muller’s laboratory at Munich, and subsequently came to the Rockefeller Hospital in 1911. His work at the hospital was mainly concerned with pneumonia and poliomyelitis, and as a matter of fact in 1912, together with George Draper and Alphonse Dochez he wrote a monograph on poliomyelitis that to this day ranks as one of the best clinical descriptions of the disease. Dr. Peabody’s stay at the Rockefeller Hospital was relatively brief, and in

1914 he returned to Boston to take a post at the then newly opened

102 Chapter 3

school. . Peter Bent Brigham Hospital. He was a superb clinician and teacher and quickly rose to be professor of medicine at the Harvard Medical

When the ‘Thorndike laboratory was opened at the Boston City Hospital in 1922, Dr. Peabody was made its first director. Given the _ politics of Boston and Boston medicine, I don’t think that anyone except Francis Peabody could have made that unit function in the wonderful way that it has. Peabody had everything going for him when he developed a cancer. Those boys at Harvard went wild trying to do something for him. Every possibility was explored. Dochez, a close friend of Peabody's, once told me that, when Dr. Blair Bell in England developed a so-called cure for cancer through use of lead therapy, Dr. Channing Frothingham dropped what he was doing and hopped a boat to England to investigate its possibilities. Needless to say, he re-

turned empty handed and frustrated. Dr. Peabody carried himself well in that last illness, and in spite of great pain gave himself wholeheartedly to an examination of problems in medical education. Before he died, he gave a talk to assembled physicians and students of the Harvard Medical School on the role of the doctor. It was a masterpiece and was later reprinted in the Journal of the American Medical Association. ‘The letter that he subsequently wrote to Dr. Longcope was a detailed exposition of his position. Later the letter was mimeo-

graphed and sent around to various people for comment. I believe that in this way it came to the attention of Dr. Cohn.

My dear Warfield: , Thank you so much for your good letter. Of course you are altogether too kind in what you say about the Clinic at the Boston City Hospital and the part I have played in its development, but you set me up and stimulate me to write you at some length about the problems that many of us who are teaching Clinical Medicine have on our minds,—whither are we tend-

ing and what ought our aim to be? I have tried recently, without much success, to formulate a very brief statement as to the type of Clinic I wanted to develop at the Boston City Hospital and I am glad to be encouraged to try my hand at the subject rather more in detail. First of all | do not think we can or should all aim at having the same type of Medical Clinic. This must depend in part on local conditions,—thus you, in a Unversity Hospital, completely under your own control, have a very different problem and will produce something quite different from what I, a cog in a

Rockefeller Institute for Medical Research—1922 103 great Municipal Hospital, can produce. Each has its advantages and its dis-

) advantages. In part, moreover, the type of Clinic will reflect the personality and interests of the Chief, and the whole character of the Clinic may alter when a new Chief is put in charge of it. . . . I believe that the primary function of a Department of Medicine is to teach students those things that will enable them to practice the best contemporary medicine and will give them a foundation on which to superimpose the advances that will come during their professional life. ‘They must be taught medicine as a vital expanding subject, and must be stimu-

lated to keep abreast of its growth. If it be true that preparation of students for a career in Clinical Medicine, and more specifically for the prac-

tice of medicine, is the first duty of a Department of Medicine, then it seems clear to me that the backbone of the Clinic is the General Ward and the Out Patient Department, for it is here that one finds or can readily create conditions which most closely resemble those which are found in

actual practice... . If the General Ward is the back-bone of the Clinic, then the Head of the Clinic must be close to it,—indeed it ought to be directly under him! The importance of the General Ward, and what it stands for as representing the general practice of medicine can only be impressed on the younger

members of the Staff and on the students if the relation of the Chief to the ward is real and not fictitious. ‘he whole atmosphere of the General Ward, and thus the attitude of the future practitioners to the profession of medicine is here set by the Chief of the Clinic for it must always be remembered that standards of thought, as well as of action, are set from

above. ...

What is to be expected of the Chief in the way of research? One hears a

great deal about research ability as a qualification for the Professor of Medicine and about the necessity of his carrying on research personally while he occupies the position. Capacity for high grade research is so rare a quality in itself that it will always be almost impossible to find it combined with the other qualifications demanded of a Professor of Medicine. Ability to do good, conscientious, independent work, interest in stimulating and

assisting others to carry on research, and an appreciation of the role that research plays in the Medical Clinic are more important than great personal research genius. The Professor must keep in close touch with the work of his Staff, guiding where he can, suggesting and encouraging, and he should always try to keep up some independent work if only for his own intellectual satisfaction so that he may set an example to the Staff and may have some little field in which he excels his assistants. Even if he had great

ability as an investigator he could not expect to accomplish much as the multifarious demands on his time make it almost impossible to obtain the sense of leisure which thoughtful work requires. Indeed, I am inclined to

104 Chapter 3 feel that if a man really has this rare gift he ought not to be the Head of a Department of Medicine lest his talent be wasted. One may reasonably question whether the large proportion of the bud-

get of the Department of Medicine that is devoted to research and the great stress that has been laid on research ability in the selection of teachers is entirely justified when one considers that much of the research out: put is of a routine nature and that really significant research is unusual. My personal feeling is that it is justified, although I think the pendulum has swung too far in the matter of choice of Professors. Here there ‘is a very unfortunate tendency to pay too little attention to broad clinical experience, something that is acquired only by many years of hard work, and too much attention to research ability, or what is worse, to the possible development of research ability in some promising young man. The publication of a number of good papers does not really indicate any marked capacity for investigation and such papers certainly offer limited evidence of ability to run a Department of Medicine. Even in the preclinical laboratories and Research Institutes the proportion of research that is very noteworthy is not always particularly high, and when one considers all the other functions required of the men in the Department of Medicine, I think that on the whole, we may be rather proud of what they are accomplishing.

, There is a common tendency to attempt to select Assistants in a Department of Medicine whose training represents the different preclinical sciences, physiology, organic chemistry, physical chemistry, physics, bacteriology, etc.,—so that one may have a well rounded Clinic. ‘There is obviously much to be said in favor of such a plan as it helps to bring together an experienced group of “scientists”, but there is also an inherent practical danger which I am sure we all have observed and to which more attention

should be paid. These men, thoroughly trained in one direction, quite naturally look for their research problems in the fields in which they are trained. They seek the problems to suit their particular tools. ‘This must necessarily be the attitude of workers in a fundamental science when they attempt to study a clinical problem, and this may explain why they often are not more successful in formulating and working out problems involving a knowledge of disease in man. ‘The approach of the Internist to the study of disease in man should be quite different. He is, first of all, absorbed by

an interest in the problem and then seeks the type of tools necessary to solve it. This is the intellectual, rather than the technical, method of approach. Once given an absorbing passion for the solution of a clinical problem, the man who has a good general scientific training can usually acquire in a few months or in a year or so, enough of any of the fundamental sciences to enable him to tackle it. The Clinical Investigator, with his knowl-

edge of disease in man, thus finds the problem first and determines the practical way to study it, turning to his colleagues in the fundamental sci-

Rockefeller Institute for Medical Research—1922 105 ence especially for technical experience. We often discuss what the difference is between the function and opportunity of the man who is primarily a “scientist” working on a clinical investigation, and the man who is primarily an “Internist” using methods of exactly the same highly refined nature, and also working on the same general type of investigation. ‘The real difference is, I think, to be found in the point of view of approach. The Medical Clinic should encourage its staff to use methods of any sort, no matter how difficult or specialized, that are needed for the solution of their immediate problems, but their first interest should center about the general subject of disease in man. ‘The first interest of the “scientist”, on the

other hand, is and should be in the development of his own particular _ field. ach has his proper and legitimate role, but in the Medical Clinic it is better to have an inspired “internist” than a skilled “chemist”... . In the last analysis, the whole problem resolves itself into what kind of men you select for the Hospital Staff. If they do the type of work they are expected to do, they can never see more than a very few private patients— fewer, indeed, than come now to the Private Wards of some “full-time” Clinics. If they want to see more patients they must be transferred to the Clinical Staff. Practically, the issue has seemed to me to solve itself without presenting any great difhculties and without resorting to an overorganization that limits the freedom of the individual. What we want is less of the system and law that kills and more of the Spirit that gives life.1®

If the patient was the center of Peabody’s medical universe, research was the heart of Cohn’s world. It’s an argument that still goes

on in medicine today and perhaps with a little more intensity. The letter that follows is Dr. Cohn’s criticism of Peabody’s argument.’® August Ist, 1928. Dear Doctor Flexner,

It was not my intention to permit so long a time to pass before replying to your letter of May 7th, 1928, concerning the opinion you formed on rereading Francis Peabody’s long communication on the subject of the medical clinic. I too have reread it and have come to the conclusion that it is likely to remain harmful, not so much because it is actually harmful in itself, but because the close scrutiny of ideas is not an American habit. If thinking were as active and prevalent a function of the national character as action, the amount of damage that might be done would depend on the 8 Francis Peabody to Warfield Longcope (undated mimeographed copy in unmarked folder, Rivers papers). This letter and two articles that Peabody wrote on the relationship of the physician to the patient appeared posthumously as a small book. F. W. Peabody, Doctor and Patient. Macmillan, New York, 1930. * Alfred Cohn to Simon Flexner, August 1, 1928 (Flexner papers).

106 Chapter 3 regard in which his opinions are held. And now his memory is a myth, and myths have influence. Recently an interesting side light on this episode has come to my attention. Governor Smith and certain of his advisers have become dissatished with the support of the Editorial page of the New York World, [This is naturally not tor publication.| Its qualified, understanding attitude of certain crucial aspects of the political and social situation have inclined them to wonder whether their cause might not be better served if

the World went over wholly to Mr. Hoover; its opinions then would be much easier to meet—without equivocation and without embarrassment. A political situation like this which requires immediate action, requires the immediate development of an attitude; people care; the meaning of the World’s Editorials sinks in. But the meaning of Peabody’s letter may on account of the national habit of indolence in the domain of reason escape analysis.

I thought at first that it would be profitable to analyze each of the thirteen or more points in “The Soul of the Clinic.” ‘That can in point of fact be done. ‘The result would however be unsatisfactory and unclear because it would fail to be informed by the motives and ideas which underlie his letter as well as by those which are opposed to it. Sharper contrast between the two positions can be developed than simple statements which seem to disclose no stiiking differences. Pain and fever and glycosuria may exist for instance for more than one reason—it is not always by their fruits that you know them. It is the underlying ideas which are crucial. ‘The difference between whether this life is the matter of main concern or some other one, is after all the real difference between the Renaissance and the Middle Ages. The difference between Peabody and me is that to him the center of interest in medicine is practise and the care of the sick; to me it is the enlargement of the confines of Knowledge. His is not an unworthy object. But its center of gravity is not one which places the medical clinic in the heart of a University. His might be a preparatory or an apprentice school. It makes of the Professor the father of his children and of knowledge a decoration. But in a University knowledge is not a decoration but a passion and indeed life itself. ‘The University does not neglect the care of the sick nor ignore teaching how this end may be accomplished—it has a function here just as it has assumed one in respect to engineering. At the same time though it cares for mathematics and physics. But to care only for engineering is to erect a Stevens Institute; to be concerned only or principally with the care of the sick is to found a school like the College of Physicians and Surgeons of the year of grace 1900. Very good objects these, but not the one to which I thought I was devoting my life. Perhaps I have been in error in believing that the meaning of our activities was not even remotely directed to making the Professor feel more comfortable and intimate with his patient when he had established a relation with him on the basis of the coin of the realm. Or has the doctrine of materialism so taken possession of

Rockefeller Institute for Medical Research—1922 107 the puritan tradition that the meaning of noblesse oblige has completely departed from the belief of our society. But this is a trifling matter. It points however to an interest in action and in human relations rather than to one in knowing and in science. ‘This is the interest which lies at the basis of Peabody’s position. You suggest that if the system cannot stand the criticism to which it has been subjected it must be either too young or too weak to survive. It is not

so much that the system can or cannot stand criticism as that the system which is under criticism is not the system we are proposing. If there is any slaying to be done it makes a difference whether the victim is a goat or a sheep. ‘Their swan songs sound different and may make a different appeal.

It seems unnecessary to analyze Peabody’s letter in great detail. ‘The error, foreseen by many of us at the beginning and still uncorrected, concerning the functions and choice of professors is an error of judgment, only of historical interest; it does not cut to the root of the issue nor invalidate our proper aims. ‘Time and a deeper insight may be counted on to correct ‘it—provided loyalty to the initial aims remains. The wards are not “the backbone of the clinic” —at least of a University

clinic. They represent merely one of the vertebrae. Whatever part of the argument depends on this assumption must go the way of all syllogisms based on incorrect premises. ‘The description of “the head of the clinic’ is trivial. ‘This conception of the professor is more like that of a Y.M.C.A. secretary than of a person with vital purposes in life. I can find little compensation for intellectua] curiosity in the excellence of his proposed manners or in his sartorial perfection. Much may be said of the other qualifications

predicated of Peabody’s professor, but I find it unprofitable to take what

he says seriously when the image and example of personalities like Nothnagel come to my mind, unless it is necessary to admit that Europeans when transplanted to America become trivial. On the subject of research it is possible to say much but in order to do so, Peabody’s conception of research itself requires analysis for he does not seem to regard it as an integral function of the good society nor to comprehend its essential nature. But I must stop. If I escape boring you I may be impaling myself on the other horn of the dilemma by being annoying. I wish an enemy rather than a friend had written that letter. We send you our greetings, the more cordial now that we are cooled. Sincerely yours, ALFRED FE, COHN

Dr. Simon Flexner | South West Harbour Maine

108 Chapter 3 Rivers: I think that this letter tells you more about the kind of guy Alfred Cohn was than anything I could say. He wrote beautifully, and he loved to argue either from the privacy of his study or at the lunch table at the Institute. ‘To sit with Cohn at lunch was always an experience because the youngsters at the Institute have no respect for age and when Cohn threw rocks he always got some thrown back at him. Which is just the way I would have it—you bang at ideas and people as long as you are able to. When folks get too old to stand or do this they should quit.

QO: Dr. Osler said that scientists after the age of 40 had little to contribute.

Rivers: Osler was too tough. I know plenty of guys who were fruitful long after the retirement age of 65. Plenty of guys.

CHAPTER 4 .

Virology and Virologists— 1926 Nicely to observe the History of Diseases, in all their Changes and Circumstances, is a Work of Time, Accurateness, Attention and Judgment; and wherein, if Men through Prepossession or Oscitancy, mistake, they

may be convinced of their Error by unerring Nature and Matter of

act. .. “se John Locke to Thomas Molyneux, January 20, 1692/3

QO: Dr. Rivers, I wonder if you could give me some notion of how your work day began.

Rivers: When I first came to the Institute, I used to get up very early in the morning and walk a mile from my house to catch a street . car, which at that time ran from Forest Hills along Queens Boulevard

to the foot of the 59th Street bridge in mid-Manhattan. It was my custom to walk from the bridge to the Institute, which then as now was at 66th Street and York Avenue. I did this every day, seven days a

week. I was usually the first one into my laboratory and the last to leave, and my day rarely ended before 10 o’clock in the evening. When I first came to the Institute, my wife saw very little of me, and

she used to complain that some of our neighbors in Forest Hills doubted that she was married, because they never saw her husband. Eventually they did get to see me and realized that my wife was an honest woman.

For some reason or other, I have never been able to produce or do anything without working hard at it. I suppose there are some people who have had the good fortune to be able to turn out good research results without working too hard, but they are rare, and I am certainly 109

110 . Chapter 4 not in that category. I will admit that some great discoveries have been stumbled on by accident; but remember, you don’t stumble unless you are walking. The fellow who stumbles on a discovery in science certainly has to be working. There is no substitute for work in science, and I have always regarded results without work as a fairy tale.

O: Could you tell me the circumstance that led to your first compendious review of viruses?

Rivers: In 1926, I was asked by the Society of American Bacteriologists to help organize a symposium on viruses for their annual meeting, which by custom took place during Christmas week. This particular year it was held in Philadelphia. The paper I prepared was a review of what was known of viruses to that time—it was very general and dealt with such subjects as the various diseases caused by viruses, their size, filterability, and problems of immunity and cultivation. The problem of cultivation of viruses was a particularly ticklish one for me to handle, because the views I held on this subject were diametrically opposed to those held by Dr. Flexner. The issue, moreover, was crucial because it involved a basic postulate or definition of

- what a virus actually was. Both Dr. Flexner and Dr. Noguchi had long claimed that they had isolated the causative agent of poliomyelitis from the poliovirus, and that it was in fact a globoid body that was capable of being grown on lifeless media. My own view of the cultivation of viruses was quite

different, and I didn’t mince any words. Quoting from the paper which I gave at this meeting, I said: In general it can be said that . . . no worker has proved that any one of the etiological agents of the diseases [shown] in ‘Table I down to mumps are susceptible of cultivation in the absence of living cells. A satisfactory explanation of the difficulty experienced in cultivating the viruses on artificial media is not easily found. Their small size alone should not necessarily make them insusceptible to cultivation. Nor does it seem to be a question of delicacy or sensitiveness, because many of them are extremely resistant to chemical and physical agents. Furthermore, no viruses have been found multiplying free in nature. Therefore, the viruses appear to be obltgate parasites in the sense that their reproduction is dependent upon living

Virology and Virologists—1926 Ii] cells, Whether this reproduction occurs intra- or extra-cellularly is a debated question.1

Before I went down to Philadelphia, I made an appointment to see Dr. Flexner to show him my paper. I did this because I didn’t think

that it was proper for me to speak against the views of my boss, with- | out letting him know ahead of time that I was going to-do so. After he finished reading it, I asked him if he thought it was right or wrong, or if he had any objections to my making the speech. Dr. Flexner looked me square in the eye—and | think that the old boy was sincere. “Rivers,” he said, “every man has a right to his own opinion.” He didn’t say that he agreed or disagreed with me; all he said was, “Every man has a right to his own opinion,” meaning that I could go ahead, and I did. I could never tell whether the old guy—and he was a smart old devil—had his tongue in cheek or not. He certainly gave

me every opportunity to do what I wanted to do. Whether he believed what I believed, I don’t know. But I will say this: “he did a lot more for me than my immediate boss, Dr. Cole, would have done. Cole was a wonderful person, but he was not as bold or courageous as Dr. Flexner. Dr. Flexner would stick his neck out. Dr. Cole was very careful not to. And Dr. Flexner stuck his neck out for me quite a bit. For instance, when the psittacosis virus came along, I told Dr. Flexner I needed more money. I was careful not to say how much, and

without batting an eye the old fellow handed me $10,000. I don’t have to tell you that in the early thirties that was a lot of money. Flexner would do such things, although he wouldn’t admit a mistake if he could get out of it.

QO: Dr. Flexner wasn’t the only one at the Institute who held the view that viruses could be grown on lifeless media. Didn’t Dr. Peter Olitsky at this time publish a paper on the growth of tobacco mosaic virus on lifeless media? ?

Rivers: ‘Through the years, Peter and I have fought about a lot of things, and sometimes I was right and sometimes he was right, and | *'T. M. Rivers, “Filterable viruses: A critical review,” ]. Bacteriol., vol. 14:228 (1927). *P.K. Olitsky, “Experiments on the cultivation of the active agent of mosaic disease in tobacco and tomato plants,” J. Exptl. Med., vol. 41:129 (1925).

112 Chapter 4 will admit that on some occasions he has made me sit up and take notice. I will tell you of some of those times later; for now, let me tell

you one little story. For a long time, I and a lot of other virologists had an article of faith, namely, if you spotted intranuclear inclusion bodies in a cell, it meant that that cell was infected by a virus. Well, one day the little devil invited me to his laboratory to look at some cells. He got me to swear that the intranuclear inclusion bodies that I saw were virus produced, and then with great glee proved that he could produce like bodies through use of aluminum hydroxide. I am awful fond of Peter, awful fond of him, and I think I should tell you a little more about him. Peter is a graduate of the Cornell Medical School and got his early training in medical research at the laboratories of the Department of

Health in the City of New York and the Mt. Sinai Hospital. He is a small and gentle person, and I have always found it remarkable that such a mild little fellow had all the adventures that he has had. In 1916, Peter went to the Sierra Madre Mountains in Mexico as part of a commission to investigate a typhus epidemic. Several years before,

on just such a mission, Howard Taylor Ricketts had contracted typhus fever and died. Peter also had the misfortune to contract typhus—he was terribly 11]—and I understand that they shipped him out of Mexico in a box car to die, but he survived to join the Rockefeller Institute in 1917. During World War I, the Rockefeller Institute worked very closely with the army, acting as a laboratory and training school for doctors

to learn various bacteriological’ techniques. Peter was one of the teachers in this school, and later, when a series of meningitis epidemics broke out in various army camps, he and a number of other people were sent into the field to help bring them under control. Actually, because of Simon Flexner’s early work in the preparation of an effective serum against meningitis, the Institute was often called

upon for advice in how to deal with this disease. When a cerebrospinal meningitis epidemic hit Hong Kong in the spring of 1918, the British government asked the Institute to send an expert to help bring

the epidemic under control. Dr. Flexner sent Peter out to the Far East to instruct the British in the preparation of an antimeningococcus serum.

Virology and Virologists—1926 113 After the war, Peter returned to the Institute, and, together with Dr. Fred Gates, settled down to a study of influenza. In 1922, they iso-

lated some pleuropneumonia-like organisms from influenza cases, which they called Bacterium pneumosintes. In the manner of scien-

tists everywhere, they ruminated about the organisms they had isolated and very tentatively suggested that they might be the inciting cause for influenza. Hells bells, when the newspapers got hold of the

story, they blew it up into something like “Rockefeller Institute savants find cause of influenza.” ‘There was a great deal of excitement, because influenza was a topic of wide public interest—people still remembered the epidemic of 1918 with some terror—but the only trouble was that Bacterium pneumosintes was no more the cause of influ-

enza than Pfeiffer’s bacillus—and you remember the claims that Blake and I made for that bacillus. I guess Peter has since learned not to speculate out loud, because through the years he has been forced to deny claims that he never made in the first place.

In 1925, the U.S. Department of Agriculture borrowed Peter to help European scientists study foot-and-mouth disease, which, as you know, is virus induced. It’s a terrible disease, and we in this country have only had it on two occasions, once in ‘Texas and once in Califor-

nia. I want to tell you that, when it showed up, farmers or ranchers didn’t wait to examine which cattle had it and which cattle didn’t; they just dug trenches, marched all their cattle to it, killed them, and buried them. Only by such drastic treatment were they able to halt the

disease and keep it from getting established. It is such a terrible disease that no one in the country outside of the scientific laboratories on Plum Island is allowed to work with the virus. However, you can work with the virus of vesicular stomatitis, a disease of horses which in some ways is like the virus of foot-and-mouth disease. Peter made some interesting epidemiological findings about the virus, but little of it had immediate import for control of the disease.* * Olitsky was part of a special commission which was formed by the Bureau of Animal Industry of the U.S. Department of Agriculture to study foot-and-mouth disease in 1925, In addition to Olitsky, the commission contained Harry W. Schoening, of the Bureau

of Animal Industry, and Jacob Traum, of the University of California. In Europe it . worked in close cooperation with Louis Boéz, of the Institute of Hygiene in Strasbourg. For details on the work of this commission, see Report of the Commission to Study Foot and Mouth Disease. U.S. Department of Agriculture, Bureau of Animal Industry, Technical Bulletin 76, 1928. Rivers is not entirely fair in his evaluation of Olitsky’s

114 Chapter 4 A lot of Peter’s early work was good, but certainly not as arresting as his later work on the encephalitides and poliovirus. (Il talk about

that work later.) I don’t think he will be sore at me if I say that he wasn’t iri Landsteiner’s class as an investigator—few people were. But

Peter had one quality that Landsteiner and others at the Institute never had, and that was his quality as a teacher and a person who creates interest. Peter was and still is, although he is retired, a crackajack

teacher, and I am not kidding when I say that some of the best virologists in the country have come out of his laboratory. Herald Cox, Jerry Syverton, Albert Sabin, Isabel Morgan, Jordi Casals, and Walter Schlesinger among others, all worked with him. I suppose the

fellows I have left out will be sore at me. I say this because the virologists that Peter trained are intensely loyal to him. Do you know that when he retired, they wrote a letter of commendation of him to the Board of Scientific Directors of the Institute. ‘That in itself, I expect, is not remarkable; what makes this particular letter exceptional is that, when you read it, you think it’s children speaking about their fathers, instead of workers talking about their boss.

It’s a long introduction, and now I just want to say that Peter’s claim for growing tobacco mosaic virus in lifeless media was all wrong. Actually, at that time I think that Peter knew very little about plant pathology and virology. Louis Kunkel had not yet come to the Institute, and I don’t think there was anyone around who could have given Peter cogent advice about tobacco mosaic virus. I expect that Peter undertook this work because Dr. Flexner told him to. Flexner had a habit in those days of asking Peter to do things, and often he was hard on him when he didn’t deserve it. Peter, being a mild gentleman, took all of this; if it had been me, I would have talked back and been fired.

QO: To get back, Dr. Rivers, how did the symposium turn out? work. At least one immediate import for the control of the disease was Olitsky’s finding that sodium hydroxide in 1% solution killed the virus within a minute, a discovery that saved many barns from being burnt to the ground. Another important result of Olitsky’s research was the discovery of methods of diagnosis of vesicular stomatitis of horses and its separation and differentiation from foot-and-mouth infection. See P. K. Olitsky, “Virus diseases of mammals as exemplified by foot-and-mouth disease and vesicular stomatitis,”

in T.M. Rivers (ed.), Filterable Viruses. Williams & Wilkins, Baltimore, 1928, pp. 205-232.

Virology and Virologists—1926 115 Rivers: ‘The symposium was very successful. As a matter of fact, after it was over, I was asked by the people at Williams and Wilkins to edit a book for them on viruses. I agreed and asked several of the people who had participated in the symposium to submit extended versions of their papers for publication. However, I didn’t limit my choice to those who were at the conference, and I also invited several people who were expert in virology, whose fields I felt should be represented in a general volume on viruses. I will admit I wasn’t highminded in all my choices. For instance, in one case I chose a fellow for his name value and not because he had anything in particular to contribute. ‘That was Alexis Carrel. I am not particularly proud oi that choice, but the others I think met the test. ‘They included Lloyd Aycock, Harold Amoss, Jacques Bronfenbrenner, Edmund Cowdry, Rudolph Glaser, Ernest Goodpasture, Louis Kunkel, Peter Olitsky,

and Stuart Mudd. One choice at least marked the beginning of a long and friendly relationship.

When I was asked to put the volume together, I thought it would be nice to have a section on plant viruses, a subject about which I unhappily knew nothing. One day at lunch I mentioned my dilemma to Edric Smith, the business manager of the Institute, and he told me that, if I went up to the Boyce ‘Thompson Institute in Yonkers and talked to L. O. Kunkel, I would find the kind of a man I wanted to take part in my enterprise. I took his advice and discovered what others before me had also found, namely, a superb plant pathologist and virologist, one of the greatest this country has ever had. Kunkel at that time had already done superb work on the viruses that attacked sugar cane and pineapples, and within a year after our meeting he was

to come to the Institute to start up its Division of Plant Pathology. Kunkel was an amiable but tight-mouthed individual, but in all the years that I knew him we had only one battle. It was a continuing one

although quietly fought. He never pushed me, and I never pushed him, but we both certainly had firm convictions on the subject. . Kunkel always believed that the honor of being the father of virology belonged to the Russian Dimitri Iwanowsky, because he showed that the agent that caused tobacco mosaic disease passed through a filter.

He did this work in 1892. My own choice for that honor was the Dutch plant pathologist, Martinus Beijerinck, who in 1898 repeated

116 Chapter 4 Iwanowsky’s experiments with tobacco mosaic disease but went one

step further and passed the disease by filtrates to healthy plants. There is no doubt that Iwanowsky made the first observations; the difference for me lay in the fact that, while Iwanowsky always believed that the agent that went through the filter was a little bacter1um, Beijerinck realized that it was a new agent and put his neck out by calling it a living contagious fluid. You know, I was never able to persuade Kunkel to my belief. QO: Dr. Rivers, your volume is titled Filterable Viruses; today most books dealing with the subject are simply titled Viruses. Could you tell me why you used the word filterable and what importance it had, if any?

Rivers: First off, let me say that there was a row about how to spell the word “filterable.” Up until the time I published my book, just about everybody spelled it “filterable.”’ ‘Then someone with nothing better to do investigated the root of the word, found that it went back to the latin filtr and claimed therefore that the adjective ought to be spelled filtrable. Some scientists always want to be right and began to spell it that way. I think that sometimes usage makes the spelling of a

word right, even though we later find out that it is wrong. This proved to be the case with regard to spelling “filterable’; I and the British people working on viruses decided that we would keep on spelling according to usage. ‘Today only the purists spell it filtrable. You know, usage is a great thing. I come from a part of the world where everybody uses the word ain’t. ‘The old saw says ain’t ain’t in the dictionary, but like filterable it persists, and like filterable I think it’s here to stay.

In the early days of virology, filterability was rather important because it was the only way that workers had of differentiating the socalled viruses from bacteria. Even at the time that I began my work,

there were people who thought that viruses were no different from bacteria. Hideyo Noguchi, for example, thought that they were small

bacteria that were merely a little bit difficult to grow on regular media. He felt that all you had to do was find the right medium and you could grow any virus. He wasn’t the only one who believed that.

Virology and Virologists—1926 117 Dr. Earl Baldwin McKinley, who was professor of bacteriology at the

George Washington University Medical School in Washington, D.C., had the same belief and spent a great deal of time trying to prove it. Later, while collecting air samples to find what bacteria if any were to be found in the upper atmosphere, McKinley died. The plane he was on disappeared and everybody aboard was lost. Although

McKinley believed that you could grow viruses on artificial lifeless media, his death was a great loss to virology. It is my opinion that if he had lived he would have contributed a great deal to virology, because he was active in the laboratory and possessed a keen imagina-

tion. |

In the early days, filterability was important from still another point of view, in that it could give us a rough approximation of the size of the virus. Generally speaking, three types of porcelain filters were used in laboratories. One type was labeled V. ‘This was a coarse filter with relatively large pores and would let organisms of the size of from 8 to 10 microns through. The second was called N or normal. Here the pores were slightly finer and would allow organisms of 5 to 7

microns through. The third was called W or wenig (the German for

little), and organisms of the order of 3 to 4 microns would go through. Practically all the viruses that we know will pass through filters of these three types. I should add here very quickly that this is not a foolproof standard, because there are some organisms like the pleuropneumonia-like group that will pass filters and are not viruses

at all. Some virologists in fact have been wanting to eliminate trachoma and psittacosis from the virus list (they go through large filters with a little difficulty), because they respond to chemotherapy and most viruses do not. I personally consider them viruses and have kept identifying them as such in the volume I later edited

on Viral and Rickettsial Infections of Man. ) QO: Dr. Rivers was there any particular reason for dedicating your volume on Filterable Viruses to Dr. Charles E.. Simon.

Rivers: Yes. Dr. Simon was a professor at the School of Public Health of the Johns Hopkins Medical School whom I had known for some years before I came to the Rockefeller Institute. I was always

118 Chapter 4 friendly with him; however, I didn’t dedicate the volume to him merely out of friendship. I dedicated it to him because he got away with murder. Although Dr. Simon was an elderly man, he was one of those who

in the United States very early appreciated the future of virus research. It was through his efforts, for example, that the first laboratory

devoted exclusively to the study of the viruses in the United States was established at the School of Public Health at Johns Hopkins. Sometime during the early twenties, Dr. Simon went to Europe and brought back a load of viruses—many of which should never have been brought back into the country. (He must have looked pretty innocent, because he got them through customs without being held up.) One of those viruses was fowl plague. Fowl plague is a devastat-

ing disease of poultry which is not present in this country, and the Department of Agriculture, I might add, has very stringent regulations about bringing it in—I know because on several occasions I tried to get a strain for Karl Landsteiner with no success. As I say, Simon smuggled a strain in, and his lab began to work with it. A technician

whose name I have forgotten was assigned the chore of keeping it going in chickens and he did his job well—that is, until he was faced with the dilemma of doing his job and going on vacation. He solved it by taking his infected chickens along with him on vacation, to a farm in southern Maryland. Damned if the plague didn’t get loose among

the chickens of that farm. All hell broke loose, and there was one heck of a time keeping fowl plague from spreading throughout Mary-

land. If that disease had become established, it would have been an economic calamity. I am not exaggerating when I say it would have cost the poultry industry millions. They probably would have hung poor Charles Simon. Luckily for him and the chickens of the United States, fowl plague didn’t get established, and I had the privilege of dedicating my book to him—it’s not often that a man with foresight gets away with murder.

O: Dr. Rivers, I would like to quote to you some remarks that you

made on the nature of immunity in your volume on Filterable Viruses: Another interesting feature concerning the immunity to virus diseases is the fact that only active virus protects against a second inoculation of the

Virology and Virologists—1926 119 same virus. In other words, it is doubtful with a few exceptions whether an injection of a virus completely inactivated leads to a protection against the same virus in an active state.*

Rivers: First, I would ask you to keep in mind that the statement was made in 1928 and made on the basis of information existing at that time. I did not discard that notion for some years, and I will tell you later under what circumstances I came to change my mind. _ The problem of immunity in virus diseases was, and for that matter still remains, a knotty one. For instance, in 1928 we knew that, with few exceptions, persons who had recovered from diseases caused by so-

called filterable viruses had lasting immunity. What we didn’t know, and still don’t know, is why that immunity persisted. Some investigators were of the opinion that lasting immunity was due to repeated

infections that were so mild that only the first infection attracted attention. Others claimed that lasting immunity was the result of the persistence of the virus in the once-infected individual. I must say, in

all candor, that I inchned to the latter view, because there were plenty of examples in the literature relating to viral infections of animals that supported it. For example, Sir Arnold Theiler’s laboratory

in Praetoria, South Africa, followed a horse with a virus-induced South African horse sickness for 14 years, and, although the horse was immune to the disease, virus was recovered from the blood regularly

throughout the entire period.® Gillies de Kock, another South African investigator, made observations of another disease in horses known as swamp fever, or infectious anemia, and obtained virus regularly from seemingly recovered ani-

mals. His work gave considerable support to the theory that a prolonged infection can persist for a long time in a host which is refractory to reinfection. It is for this reason that any horse that has ever had a history of swamp fever is not used for the making of serum for human beings.®

Closer to ‘home, in 1927 Dr. Rufus Cole and Dr. Ann Kuttner of *'T. M. Rivers (ed.), op. cit., p. 9. °A. Theiler, African Horse Sickness. Union of South Africa, Department of Agricul-

ture, Scientific Bulletin No. 19. Praetoria, 1921. | . *°G.v.d.W. DeKock, A Contribution to the Study of the Virus, Haematology, and Pathology of Infectious Anemia of Equines under South African Conditions. Union of | South Africa, Department of Agriculture Scientific Bulletin, 9th and 10th Report. Praetoria, 1924.

120 Chapter 4 the Rockefeller Hospital discovered that, once guinea pigs were infected with salivary gland disease, they also carried the virus with them

throughout life and remained immune to reinfection.’ Indeed, once an adult guinea pig was infected with the virus, you couldn’t reinfect

it, even if you injected the virus into the brain. However, if you caught a young guinea pig and separated it from its mother very early, you could cause or produce a beautiful encephalitis by injecting the

virus into the brain. ‘The reason for this was that guinea pigs were born free of the disease and only contracted it when exposed to the contaminated feces of their parents. Later, Dr. Kuttner demonstrated that the salivary glands were not necessary for the persistence of the virus. Although the virus is usually found in the salivary glands, when

Dr. Kuttner removed these glands experimentally, she found that the virus moved to the parotid. It was as if the virus had a mind of its own and could think. Of course, it didn’t—the point is that it per-

sisted, and if its usual home was missing or unavailable it quickly found another.

Some years later, some virus diseases that occur in humans gave evidence which, for me, buttressed the notion of the persistence of virus in immune people. In 1931, for example, Dr. Wilbur Sawyer discovered circulating antibodies against yellow fever virus in a human case who had been exposed 75 years before and who, since that time, had lived outside the yellow ‘fever zone.* Eighteen years later,

| Dr. John Paul of Yale made similar observations of the persistence of circulating antibodies against type | and 2 poliovirus. In 1949, while examining the E'skimos of semi-isolated Barrow Village in Northern Alaska, Dr. Paul discovered that none of the inhabitants in the village under the age of 19 had neutralizing antibodies against type 2 polio, while over 80 per cent of the population above this age possessed such antibodies. Further study revealed that most of the population above

the age of 40 had neutralizing antibodies against type 1. The data gathered correlated very well with information of polio epidemics in the region in 1905 and 1930. Now, I don’t know how to explain the presence of Sawyers and Paul’s circulating antibodies unless there is 7R. Cole and A. G. Kuttner, “A filterable virus present in the submaxillary glands of guinea pigs,” J. Exptl. Med., vol. 44:855 (1926). °'W. A. Sawyer, “Persistence of yellow fever immunity,” J. Prevent. Med., vol. 5:413 (1931).

Virology and Virologists—1926 12] some persistence of the virus. I should hasten to add that not all virologists would agree with my conclusions; in fact, I know some that would heartily disagree.®

Q: Dr. Rivers, while you seem willing to debate with one and all on * the problem of the cultivation of viruses, immunity, and so forth, there is one problem that you go out of your way to avoid, and that is the interesting problem of whether viruses are living or nonliving organisms.

Rivers: I won't deny that this particular problem was interesting. | will, however, say that I thought discussion of this problem with the amount of knowledge we had at hand in 1927-28 sterile, and I was not and am not particularly given to sterile metaphysical exercises. First, let me point out that no two scientists in 1928 could agree on tests to act as criteria for the presence of life. Then again, we knew little about the cell and its relation to viruses. ‘Today, we confidently speak of the role of nucleic acid in the process of replication and infectivity of viruses; what we tend to forget is that the work that this knowledge is based on is comparatively recent. Please keep in mind that the work of the Schramms, Fraenkel-Conrats, and Commoners was about a quarter of a century away in 1928. What, for example, did we know of cell types in relation to virus reproduction in 1928? Let me just quote what I said on this subject at that time: In view of the fact that viruses’ apparently multiply only in the presence of living cells, it is advisable to ascertain what kinds of living cells promote their reproduction best, and what effect upon the cells is induced by this reproduction. Species Specificity—-A remarkable species specificity is exhibited by many viruses. Rous’ sarcoma grows only in chickens. Sanarelli’s virus of infectious

myxomatosis and Virus III are active only in rabbits. The salivary-gland virus described by Cole and Kuttner apparently affects only guinea pigs. A wilt virus that attacks one kind of caterpillar is innocuous for other caterpillars. The virus of poliomyelitis is active only in man and the monkey." ®7J.R. Paul and J.R. Riordan, “Observations on serological epidemiology,” Amer. J. Hyg., vol. 52:201 (1950).

TM. Rivers (ed.), op. cit., pp. 13-14.

122 Chapter 4 As you can see, we didn’t know a hell of a lot; actually it would be more honest to say that we knew damned little. Take the specificity of poliovirus; we literally didn’t get to home on this problem until 1959, when Jerry Syverton and his boys at the University of Minne‘sota published a wonderful series of papers in the Journal of Experimental Medicine. ‘Vhis work is very important and bears some further comment. In 1958, Dr. Syverton and two of his associates, Dr. John Holland and Dr. Leroy MacLaurin, discovered that the limitation of poliovirus infectivity to primate cells was governed by the specific interaction between the protein coat of the virus and the cell surface receptors. A short time later, they showed that if they took only the

viral ribonucleic acid (without its protein coat) and exposed it to usually insusceptible nonprimate cells (in vivo and in vitro) those cells would produce infectious poliovirus, protein coat and all.1’ Now

, we couldn’t have done a piece of work like that in 1928 if our lives depended on it, and all the metaphysical debate on whether viruses were living or nonliving wouldn’t have helped us one whit. I still don’t think much of the interesting problems you speak of, but today I think I could give you a definition of life that would make viruses “living organisms,” whereas in 1928 I couldn’t. “Life,” we might say,

“as the process that goes on due to the activity of enzymes and coworking substances under the direction of nucleic acid.’”’ Or you can

shorten it into “Life is a continuum directed by nucleic acid.” QO: Dr. Rivers, while we have spoken of several of your colleagues at the Rockefeller Institute in some detail, we have only spoken of Dr.

Flexner peripherally, and, since he was the director of the Institute for the first twelve years of your tenure, I wonder if you would tell me of your relations with him when you first came to New York.

Rivers: I worked in the Department of the Hospital, and Dr. Cole, as director of the hospital, was my immediate boss. Dr. Flexner and Dr. “J.J. Holland, L.C. McLaren, and J.'T. Syverton, “The mammalian cell-virus relationship. I. Attachment of poliovirus to cultivated cells of primate and nonprimate origin; II. Adsorption, reception and eclipse of poliovirus by HeLa cells.” J. Exptl. Med., vol. 109:475, 487 (1959); “III. Poliovirus production by nonprimate cells exposed to poliovirus ribonucleic acid,” Proc. Soc. Exptl. Biol., vol. 100:843 (1959); “IV. Infection of naturally insusceptible cells with enterovirus nbonucleic acid,” J. Exptl. Med., vol. 110:65 (1959).

Virology and Virologists—1926 123 Cole did not bother each other about what went on in the hospital; yet I probably saw as much of Dr. Flexner as I did of Dr. Cole, because Flexner was interested in viruses. He was at that time one of the leaders in the United States in polio research and deeply interested in other virus diseases, notably encephalitis. I was rather surprised to find that Dr. Flexner was interested to the extent that he would send me notice of articles on viruses. For example, he would look through the Journal of the AMA, the back of which was devoted

to abstracts of current literature, and frequently he’d cut out these abstracts and place them on a card—I suppose his secretary did it— and send them over to me, if he thought they were things that I should read. On occasion, when he had read an article on viruses that he liked, or questioned, he would call me over to his office and would

want to know if I had seen it. If I had, we would then sit down to discuss it.

My relations with Dr. Flexner were very happy, and we got along exceedingly well together. At times he was very complimentary, and I should add that, generally speaking, he was not a man given to profuse compliments. I remember that, shortly after my book on Filterable Viruses came out in 1928, he gave a luncheon for some distinguished scientists and invited me. I was probably the youngest man at this particular luncheon, and Dr. Flexner, in introducing me to these people, some of whom I’d never met before, made the remark that I was the author of a recent best seller, a book on filterable viruses.

Well, I’d never considered that my book could be called a “best seller,” but these are exactly the words that Flexner used. He did this on several other occasions, and I thought he went out of his way to do it. Most people were intimidated by him. You take as relatively easygoing a fellow as Dochez—when Dochez first came to the Institute, he had the opportunity of working with Dr. Flexner, and Dochez just wouldn’t work with him. As he once put it to me, “I was afraid of the Old Man.” I don’t know that I would have worked with him either. Not because I didn’t respect him, but because he and I didn’t see eye

to eye on the nature of viruses, and I’m sure that we would have busted each other’s brains out, because we were pretty much the same kind of specimen. It’s not wise for fellows too much alike to be too close together. But Dr. Flexner and I got along, even though he knew

124 Chapter 4 I didn’t always agree with him. I wasn’t scared of him, not the least bit scared of ‘him.

When I first came to the Institute, I came as an associate, and at the end of two years I was increased in rank and became an associate member, and they increased my salary a little bit—the salaries were not large. I spent the next three years as an associate member. In the spring of 1927, five years after I had come to the Institute, the board met and reappointed me for another three years as an associate member and, if I remember correctly, gave me a slight raise in salary upon reappointment. A short time afterward, Francis Blake and Milton Winternitz from Yale came down to see me, and offered me the professorship of pediatrics at Yale at $4000 a year more than I was getting at the Institute.

Dr. Howland had died, and Ned Park, who was a professor of pediatrics at Yale, went down to Hopkins to take Howland’s place. That left the chair of pediatrics open at Yale. It was early in the week, and Blake and Winternitz—I knew both of them very well—asked me if I could give them an answer by Friday, because it was getting to be late in the year, and they wanted to get a professor to fill the opening. I told them I’d try to reach a decision by the end of the week.

I went to see Dr. Flexner and told him about the offer I had received from Yale. Well, Flexner talked to me for about a half an hour

about how well I had done at the Rockefeller Institute in the previous five years, and what a bright future I had ahead of me at the Institute if I kept on doing as well in the future as I had done in the past. He was extremely nice.

After he’d talked to me about a half hour, he stood up. We all knew that, when Dr. Flexner stood up, it meant that the interview was over. I got up and said good-bye to him. I got over to the door,

turned the door knob, and was just getting ready to pull the door open, when Dr. Flexner said, “‘Come back here, Rivers. Come back here, Rivers. You haven’t told me what you are going to do.”

I said, “Well, Dr. Flexner, you didn’t ask me what I was going to do.” He said, “I’m asking you now.”

I said, “All nght, Pll tell you. If ’m not made a member of the Rockefeller Institute, ’m going to Yale. You say I’m good, that I

Virology and Virologists—1926 125 know how to do research, and that I’ve got a good future at the Institute, but you've only offered me security for three years. The boys at Yale don’t know whether I can teach pediatrics or not, because I have never had a teaching job. ‘They’re gambling on me. I may be a bum teacher, I may run a rotten department of pediatrics, but they’re giving me $4000 a year more than you are, and security for life, and you ain't giving me anything except a promise!” I said, “If I am not made a member, I am going to Yale.” He said, “Well, look, Rivers, I can’t do anything about it now, the board has already met.” I said, “Dr. Flexner, did you ever hear of the telegraph office? All

the people on the board know me. You can get an answer as to whether or not they want me as a member of the Rockefeller Institute very quickly. If you don’t make me a member of the Rockefeller Institute before Friday morning, I’m going to Yale.” And I walked out of the office.

I didn’t hear anything more, but Friday morning, when I got to my office, Exdric Smith, the business manager of the Rockefeller Institute, was sitting in my office waiting to tell me that I’d been made a member of the Rockefeller Institute. PII tell you one thing: the Institute was still a little bit stingy. Although they'd given me a slight raise when they reappointed me as an associate member, when I was made a member it was without any further increase in my salary. In those days they were like that. Dr. Flexner used to say, “If we gave enough money to attract a man here because of the salary, then we’d get the wrong kind of people. We keep our salaries down, so if a person comes here and lives on it we

know he wants to do research.” That attitude obtained even when Dr. Gasser and I took over, after Dr. Flexner and Dr. Cole had left. We didn’t blow the salaries up very high. We raised them a little bit, because they were pretty tight. But it’s true that, if you give a large salary, you have all kinds of people coming in and wanting to do research. Research is something that ought to be done by people who want to do it so bad they'll sacrifice a little bit.

QO: Dr. Rivers, did Dr. Flexner ever restrict your activities outside the Institute?

126 Chapter 4 Rivers: I think that it would be fair to say that on many occasions Dr. Flexner urged me not to get mixed up in things that would keep me from the laboratory. For instance, in the spring of 1928, Dr. Rudolf Kraus of Berlin invited me to be editor of an international journal of virology which he was trying to establish, and Dr. Flexner

very quickly put a damper on the project. I still have the letter he wrote to me on that occasion and will quote a portion of it. . .. [have yet another reason for your keeping yourself free. I should hate you to put your valuable time into editorial work and especially editorial work of an international nature. Still another point is that Europeans are used to publishing long papers. They can do this because the publisher charges so much for so many pages constituting a volume and issues volumes irregularly. ‘I’o carry on this kind

of business a business organization is required; it does not exist in the United States. I believe, too, European contributors expect pay for papers based on their length. All this you see would make the publishing of an international journal in the United States expensive and extremely bothersome and time consuming. I do not see how you could undertake the responsibility.1

Flexner, of course, was quite right. I should also add that, even if he had given his blessings, I would have turned Dr. Kraus down, because I was of the firm belief at that time that virology was too young to be considered a separate discipline. ‘T’oday there is a very fine jour-

nal in the United States, which is specifically dedicated to problems in virology, and is edited by Dr. George Hirst of the Public Health Research Institute of New York. In 1928, such a journal would have

been premature. : }

Now what I said just now doesn’t mean that Dr. Flexner turned

down everything; as a matter of fact, there were times when he urged me to take on certain chores. In 1937 Mayor Fiorello La Guardia invited me to join the Board of Health, and Dr. Flexner kept after me until I did. He always said that there were certain things that people at the Rockefeller Institute should do as a civic duty, and he made it plain to me that, with my knowledge of infectious diseases, I should feel proud to serve on the Board of Health. I gave my time and energy to the board for 18 years, and to this day, I am a member emeritus. 2 Simon Flexner to Thomas Rivers, July 15, 1928 (Flexner papers).

Virology and Virologists—1926 127 Sometimes it was time consuming to go to meetings, but, hell, I enjoyed it; don’t you for one minute think that I didn’t. I must have, because it cost me money to be on the board. Members received no pay; however, when a new member was sworn in, it was necessary for him to sign a special registry. ‘The fee for signing that registry was four

cents—money that La Guardia never returned to me—so you see I can rightfully claim that joining the Board of Health cost me. O: Dr. Rivers, did Dr. Flexner ever ask you to assume clinical duties

outside the Rockefeller Hospital?

Rivers: On occasion he did, but since I was a clinician—and for that matter still am—I never objected to such requests. As a matter of fact, as head of the infectious disease ward at the Rockefeller Hospital, I was frequently asked by doctors who had no connection with the Institute to see people on consultation. I did this without charge because I was on full time at the Institute and considered it as one of

the obligations of my post. |

I think that Dr. Flexner’s requests to me to see people shed light on one part of his personality that he was very careful to keep hidden. Frequently, he is presented as being cold and austere. I am not saying that he wasn’t tough or that he couldn’t be mean—he could, believe me—but he also was tender with people, and often with people who

had no claim on him. Once, when he was in Washington, someone took him to see a boy who had muscular dystrophy. ‘The boy’s parents

were plain people and were visibly disappointed when Flexner explained that he was a pathologist and could really not give them the expert clinical advice they sought. He, of course, knew that the boy

had muscular dystrophy and that nothing could be done, but, to make them easier in their mind, he promised to send someone from : the hospital to examine the boy and eventually asked me to go. It was no great imposition, because I was about to attend a scientific convention in Washington anyway, and when I arrived in the capital I went to see this family. The poor lad had an unmistakable case of

muscular dystrophy, and I had the unpleasant job of telling his mother and father that the disease had no known cure, and that the inevitable outcome was death at some future time. I explained that

128 Chapter 4 doctors couldn’t give the exact time the boy had, because it varied from case to case.

They seemed to accept this knowledge quietly. I suppose they had been told this previously, so it didn’t come to them as a shock or a surprise. However, it was plain that they were looking for some happier news. They thought that, since I came from the Rockefeller Insti-

tute, I would tell them that it wasn’t muscular dystrophy, or that, even if it were, the Institute had worked out a cure. I don’t know why

people had that view of the Institute, but some people did. They looked on the Institute as the home of miracle workers. It is too bad they didn’t know us as we actually were; then they would have known that we were just common ordinary everyday folk. Occasionally my hospital duties took me into private homes. The purpose of these visits was twofold: first, to see whether the hospital should admit the patient, and, second, to get permission to do autopsies. It must be remembered that the Rockefeller Hospital was a research hospital, and the only patients who were admitted were those whose condition had particular interest for the staff. I remember that

| I once went down to Elizabeth, New Jersey, to look at a patient who, I.had been told, had eastern equine encephalitis. A careful examination, however, revealed that the poor fellow had lethargic encephalitis. He was over the hump of the original infection but, like so many of the victims of that disease, he had been left with permanent injury,

and I had to tell the family, as gently as I could, that the patient would be better off in a hospital for chronic diseases.

Getting an autopsy is, of course, very important for every doctor and hospital, because it is the place that you go to for final judgments on the medical knowledge you possess, and the care you are furnishing your patients. here is no appeal from the autopsy table. Actually, every patient that came into the Rockefeller Hospital—either personally or some responsible member of the family—signed a slip giv-

ing permission for an autopsy in case of death. The truth is that those signed slips had no legal validity; however, only in a few cases was the hospital ever denied autopsy. It was a precious and valued privilege and extraordinarily helpful to us in performance of our clinical duties and research.

Virology and Virologists—1926 129 O: Correspondence in Dr. Flexner’s letter files reveals that, during the period 1927-1931, you and Dr. Cole frequently fought over the question of extra laboratory help.*®

Rivers: During my early tenure at the Rockefeller Institute, I _ learned very quickly that, if I was to run my laboratory efficiently and well, my animal keepers would have to be extraordinarily careful in handling the infected monkeys, rabbits, and mice that I worked with,

and that my technicians would have to use faultless aseptic technique. I’o accomplish these things, it was plain that I would need more help. Well, it took me a long time to persuade Dr. Flexner and Dr. Cole to this point of view. The first impression that was made on them came when Wilbur Sawyer, Paul Hudson, and Stuart Kitchin returned from Africa and began to work with yellow fever virus and monkeys in the Rockefeller Foundation laboratories, which were then located at the Institute. ‘The animal house where those infected monkeys were kept can only be described as a disgrace. Moreover, the laboratory space allotted to Sawyer and his group was entirely inade- quate. Anyone with half a grain of sense could have predicted what was going to happen, and it did. Within a very brief time Dr. Sawyer, Dr. Hudson, Dr. Kitchin, and two of the technicians contracted yellow fever and became my patients on Ward One. They were damned sick, and I was sore because it could have easily been prevented. At that time, Dr. Cole was one of the scientific advisors to the International Health Board of the Rockefeller Foundation, and when I complained about conditions he decided to make an inspection. He took one look at the animal house and laboratories and got madder than hell, and I want to tell you that in short order the Institute got new facilities for the boys working with yellow fever.

However, it was still not easy to persuade Dr. Cole or Dr. Flexner that my labs also needed the same treatment because I was working with highly infectious psittacosis virus. My labs were then in Founders Hall, and they couldn’t have been more centrally located. If you * Rufus Cole to Simon Flexner, December 10, 1928, February 4, 1930, June 20, 1930

_ (Flexner papers). In fairness to Cole, it should be pointed out that he was primarily concerned that Rivers was attempting too much and that this tendency was dangerous for the development of his career.

130 Chapter 4 went to the lunch room you had to pass them, if you went to the business office you had to pass them, if you went to the ladies’ room you had to pass them, or if you went to the library you had to pass them. ‘To complicate matters, a short narrow alleyway was all that separated the windows of my labs and the windows of the library.

Well, neither Dr. Cole nor Dr. Flexner ever wanted to understand why I wanted dustproof doors and windows installed in my labs.** I don’t think that it was penury on their parts; rather [ think that it was a habit of mind of investigators who had been brought up in an age of bacteriology. For example, after the yellow fever laboratories had been cleaned up, Dr. Frederick Russell, who was director of the

International Health Board, came over to make an inspection. He looked around and said, “I don’t like a clean laboratory. Whenever I see a laboratory like this, I feel like taking a bottle of ink, putting it on a string, and swinging it around my head until it is empty.” Older bacteriological workers felt that a working laboratory should be dirty; a clean one was a personal affront to them. It took them a long time to realize how clean and careful you had to be when you worked with viruses. For instance, I found that it was almost impossible to work with more than one virus when I worked with vaccinia. It made no difference how careful I was, or what techniques I used; in the end, all of the animals in our laboratory became infected. I don’t ** Rivers here is unfair to Dr. Cole. Cole well understood the dangers involved and wrote strongly in Rivers’ behalf to Simon Flexner. Rivers and Berry are working with psittacosis. Rivers came to me yesterday a little disturbed about the working facilities so I went over the whole matter with him and Mr. Smith. The experiences in Baltimore, Washington, and now in Park’s laboratory, make the situation a bit disturbing. Three of the women who have been working with Park and Krumwiede have come down with what they think is psittacosis, and Park telephoned me yesterday that they were going to stop their work and would send all their material up to Rivers. You know of course about the death of Anderson in Washington ‘and Stokes in Baltimore. Rivers is very anxious to continue with his work and I feel that this is a great opportunity for him. I wish, however, that he might have better facilities than are afforded by the dark room in which they are working. Should not men working on easily transmissible diseases, such as yellow fever and psittacosis, have large light rooms in which every precaution to avoid infection can be taken? I think Mr. Smith is writing you today about

what may possibly be done. The only space we have in the hospital is that which Binger . used. That could be cleaned out and would be suitable, but I don’t think it would be advisable to bring that work into the hospital. I doubt if there would be any danger of the virus getting out of the laboratory, but if any cases should arise I fear we would be open to criticism.—Rufus Cole to Simon Flexner, March 6, 1930 (Flexner papers).

Virology and Virologists—1926 3) want to blame only bacteriologists; sometimes even experienced virologists don’t understand how careful you have to be. As late as five

years ago, some of the world’s best virologists had to relearn this lesson. If it weren’t for Jerry Syverton, they still wouldn’t know how easy it is for HeLa cells to contaminate tissue cultures.?®

Q: Dr. Rivers, what about Dr. Cole’s complaint to Dr. Flexner that you stole Dr. Muckenfuss from Bronfenbrenner’s laboratory? 1°

Rivers: I think that Dr. Cole misunderstood this particular situation. In my early days at the Institute, a lot of the things that I did were misunderstood because I respected no boundaries. It is true that I proselytized for virology among young investigators, and that I did try to get people in the Institute laboratories, as opposed to the hospital laboratories, to work on things I was interested in. I did this on the general theory that, if they did it, I wouldn’t have to. But I never stole anyone, and I surely didn’t steal Ralph Muckenfuss.

Muckenfuss, who was an M.D., was at that time working with Jacques Bronfenbrenner in the Institute laboratories on bacteriophage. You know, in the early days of virus research, very few investigators regarded phage as a virus. Felix d’Herrelle, one of the

discoverers of phage, certainly believed that it was a virus, and demonstrated his belief by calling it Protista. Bronfenbrenner and | shared this belief, and if you look at my book on Filterable Viruses you will find that Chapter 9—which was written by. Bronfenbrenner —is devoted to this subject.

Muckenfuss stayed for a short while with Bronfenbrenner—I believe no more than two years—but in that period they did several very nice papers together. I still remember that in one paper they showed that phage in the absence of bacteria did not respire. Some investigators at the time claimed that, because phage did not respire, it was not alive. However, respiration is not the sole indication of life or death, and an investigator named Ohga at the Boyce Thompson Institute very dramatically demonstrated that lotus seeds that had

been buried for hundreds of years in India—and which certainly * Rivers’ reference here is to discussion at a conference on nonprimate cells susceptible to polioviruses which was held in New York, November 27, 1957. *° Rufus Cole to Simon Flexner, January 12, 1928 (Flexner papers).

132 Chapter 4 didn’t respire very much during this period—began to sprout when put under proper environmental conditions.*”

I think that it was Muckenfuss’s general interest in viruses, rather than my proselytizing, that brought him to my laboratory. | know that Bronfenbrenner was glad to have him come and certainly never raised any objections. If it had been a steal, he would have raised the roof. Looking back, I would say that Muckenfuss benefited from his stay with me. In 1929 he was appointed assistant professor of bacteriology at the’ Washington University Medical School in St. Louis,

and in 1937, after the retirement of Dr. William H. Park, he was hired to take charge of the laboratories of the New York City Board of Health. I might add that he got both jobs because, in addition to being a first-rate bacteriologist, he knew something about viruses.

In fairness to Dr. Cole, I must admit that I was a handful, because I did do my damnedest to expand my laboratory and get new workers. But that was no secret; everybody knew it, including Dr. Flexner, and on one occasion he even helped me get an assistant. In 1929 a young German investigator from the Koch Institute named Eugen Haagen came to the Rockefeller Hospital. Originally, he was supposed to work with Alexis Carrel; however, he was so nationalistic that Carrel refused to take him. Dr. Flexner didn’t order me to take

him, but he made it obvious that he would be pleased if I did. I grabbed Haagen, not because he knew anything about virology, but because he was expert in working with tissue culture, and I wanted very much to undertake some experiments with vaccinia using tissueculture techniques. Haagen later proved to be very helpful in that work.

Actually, all the youngsters who came to work with me in those early years worked out well—with one notable exception—a young Chinese named Dr. Chen P. Li. In 1928, Dr. Carl tenBroeck of the Division of Animal Pathology of the Institute went to China as visiting professor of bacteriology at the Peking Union Medical College. While in China, Dr. tenBroeck worked with Dr. Li and, although they only worked with bacteria, he was sufficiently impressed with Li's abilities to recommend him to 71, Ohga, “The germination of century-old and recently harvested Indian lotus fruits, with reference to the effect of oxygen supply,” Contribs. Boyce ‘Thompson Inst. Plant

Res. vol. 1:289 (1926).

Virology and Virologists—1926 133 me. I accepted him, and the Rockefeller Foundation gave him a fellowship to come to America to work with me. Li had wonderful technical ability, and the first year he was with me he worked out the cultivation of vaccinia in minced chick-embryo tissue and ‘Tyrode’s solu-

tion. It was done very well, and at the end of the year I approved renewal of his fellowship without hesitation.

I wanted him to continue his work on the cultivation of viruses in

tissue culture, but for some reason or other Li decided that that wasn't what he wanted to do. I do not now remember the proposal he __ made, but I do remember telling him that it wouldn’t be rewarding. Pll be damned if he didn’t put on a sit-down strike. Half the times I wanted him, I couldn’t find him, the other half he spent in the library reading. I just couldn’t get him to do any work. It wasn’t ugly, no harsh words were spoken; it was just a sit-down strike.

I took it for about two months, and finally I called the Rockefeller Foundation and asked them to send him back home. I guess he never expected that I would take such drastic action, and I know it came asa shock to him. It was a terrible loss of face, and face, as you know, means a great deal to people in that part of the world. He returned to China and on several subsequent occasions tried to patch up relations with me. During World War II, Li became a general in the Chinese Nationalist army and was in charge of preparing all the vaccine virus for the army. He did a bang-up job; however, when it became appar-

ent to him after the war that Chiang would not hold against the Communists, he emigrated to the United States. (I forgot to say that one of his children was born in the United States.) In time he got a

job with the U.S. Public Health Service and was assigned to the laboratories they maintain in Montgomery, Alabama. ‘The head of the laboratory at that time was Dr. Morris Schaeffer. Schaeffer is a good virologist and knows how to run things, and fortunately he and Li hit it off. Together, they established type 1 polio in the brains of mice by intraspinal inoculation and got an excellent attenuated strain, — which is now known as the Li-Schaeffer strain. So, in spite of every-

thing, Li has turned out all right. I don’t hold his sit-down strike against him, and I guess that by now he understands that if you are running a laboratory you can’t have too many viruses going at the

same time or you get tied up. }

134 Chapter 4 QO: I would like to discuss now some of the studies that you undertook between 1926 and 1930. I find it particularly interesting that in the midst of your work on viruses you returned to study the growth requirements of bacilli, a problem you hadn’t been concerned with in years.*®

Rivers: Before I came to the Rockefeller Institute, it is true that I had done much work on the growth requirements of influenza bacilli _ of the hemolytic and nonhemolytic varieties. However, when I arrived at the Institute, Dr. Cole told me that I had best drop that work because Dr. Ernest Stillman at the hospital was already working on a like problem and that he didn’t want the two of us to get tangled up.

Now, that attitude was general throughout the Institute. For instance, it was understood that no one in the Institute laboratories would work on the pneumococcus, because the pneumococcus was reserved for Dr. Avery and his boys at the hospital. I never saw much in

that rule, but I went along with Dr. Cole and stopped work on the influenza bacilli. However, I kept my organisms and passed them. There was good reason for this. At that time, we had no typed culture collection, and after one had worked up organisms like the ones I had

and knew their growth requirements, why, it was the better part of wisdom to keep them going, and I did. Today, of course, things are a lot easier. If a laboratory needs a particular culture, let us say, for teaching purposes, there is no necessity of passing the organisms every few weeks throughout the year; all you have to do is send some money

to the typed culture collection and buy what you want or need. If it had been up to me, the chances are that I wouldn’t have done another thing with these bacilli, but in 1926 a very bright young Eng-

lishman named F.C.O. Valentine came to work with me at the hospital. He didn’t look particularly English; he was dark, with very black hair and dark eyes, and I always like to speculate that some _ Spaniard of the Spanish Armada did make it to shore and made a private conquest. Valentine wasn’t particularly interested in viruses, but he had a first-rate mind, and one day he came to see me. “Dr. Rivers,” he said, “I have been thinking about the growth requirements of in*F.C.O. Valentine and T.M. Rivers, “Further observations concerning growth requirements of hemophilic bacilli,” J. Exptl. Med., vol. 45:993 (1927).

Virology and Virologists—1926 135 fluenza bacilli. According to Avery, the true influenza bacillus requires both *X’ and ‘V,’ parainfluenza bacillus Rivers requires only ‘V,’ and

hemoglobinophilus canis only ‘X.’ If you take a medium which has neither “X’ nor “V,’ and put all three strains in, they ought to multiply. It seems very likely that the bacilli that need “V’ must make ‘X,’

and vice versa.” }

It was a very nice supposition for a youngster to make, and when

we put Valentine’s idea to the test—and it was his idea and not mine—we found that it worked out in precisely the way he imagined it would.

O: Dr. Rivers, together with Dr. Valentine and Dr. Eldridge, you also did some work on experimental measles during this period, and I wonder if you would give me some of the background of those experiments.*°

Rivers: Before I came to the Institute, Francis Blake and James Trask had reported that measles was caused by a filterable virus, and that by obtaining the virus from the blood and nasal pharyngeal washings of human patients they could, through intratracheal and intraperitoneal inoculation, produce experimental measles in monkeys.

However, they were unable to propagate the virus indefinitely in monkeys. During the twenties, two very good and respected workers,

Ruth Tunnicliffe and Newell S. Ferry, attacked Blake and Trask’s work, and claimed that measles was the result of a streptococcus infection. It was this state of affairs that led me to start my own experiments on measles.”° *® Report of Thomas Rivers to the Board of Scientific Directors of the Rockefeller Institute for Medical Research, 1927.

» See further F.G. Blake and J.D. Trask, “Studies on measles. Susceptibility of monkeys to the virus of measles,” J. Exptl. Med., vol. 33:385 (1921); R. Tunnicliffe, “The cultivation of a micrococcus from blood in pre-eruptive and eruptive stages of measles,” J. Amer. Med. Assoc., vol. 68:1028 (1917); “Further studies on a diplococcus in measles. A measles skin reaction,” J. Infect. Diseases, vol. 37:193 (1925); R. ‘Tunnicliffe and A. L. Hoyne, “Further studies on a diplococcus from measles. Prevention of measels by immune goat serum,” ]. Infect. Diseases, vol. 38:48 (1926), and N.S. Ferry and L. W. Fisher, “Measles toxin. Its preparation and application as a skin test, as an immunizing agent, and for the production of an anti-toxin,’ J. Amer. Med. Assoc., vol. 86:932 (1926).

136 Chapter 4 O: How did you set up your experiments? What questions did you attempt to answer?

Rivers: I had no reason to doubt Blake and T'rask’s claims, and | began with the proposition that measles was a virus infection. My initial experiments were designed to answer such questions as:

When can one be reasonably certain that the virus of measles is in the blood stream in amounts sufficient for experimental work? Is the virus in the rash present in amounts suitable for experimental work? If so, how long does it remain active in the rash? Can one obtain the virus from the lesions in the skin after it has disappeared from the blood? Is there some way of preserving the virus in the blood or in some organ so that it retains sufficient activity over a long enough period of time to permit of its filtration and use for prophylaxis? ?1

Let me say here that I very quickly confirmed the work that ‘Trask and Blake had done. For example, I was able to demonstrate that the virus of measles was in the blood for about 48 hours prior to the appearance of the rash. I got a particular kick out of being able to show that the active agent was present in skin lesions, and that if you took

affected bits of skin very early, macerated them, and injected the material intracerebrally or intratesticularly in monkeys, you could produce experimental measles. However, before you begin patting me

on the back, let me say that there was one thing that I couldn't do, and that was to pass measles from one monkey to another. Today, | understand what happened, but in those days it was a great frustrating mystery. ‘The fact is that monkeys pick up measles virus very easily and carry it, and many of my monkeys developed an immunity before

they even reached my laboratory. If they didn’t get infected on the way to the lab, they had plenty of opportunity to pick up the virus in the animal house. I kept all of my experimental monkeys in the same room—those that I had already artificially inoculated and those that I hoped to infect in the future—and while it is true that I kept them in separate cages it made no difference, because my animal keeper, in the performance of his daily tasks, unwittingly carried the virus from cage to cage. I am not surprised now that we couldn't pass the virus from monkey to monkey, and that we didn’t always get a take. 1 These questions quoted by Rivers from miscellaneous notes in folder marked Measles (Rivers papers).

Virology and Virologists—1926 137 I never wrote a paper on experimental measles because I didn’t think that I had anything really to add to the literature. Why should I waste people’s time by making them read such a paper? But this 1s not to say that the research was a waste. It wasn’t—I had a lot of fun, and I did learn a hell of a lot. QO: Dr. Rivers, how do you explain Dr. Tunnicliffe’s findings?

Rivers: I don’t know. I can’t account for the results claimed to have been attained in many scientific experiments. Some scientists see

what they want to see. I remember that around 1926 Dr. Yves Kermorgant of the Pasteur Institute claimed to have isolated a spirochete from a mumps patient,” and Pll be damned if some of my medical brethren didn’t begin treating patients with neoarsphenamine. Some even claimed to have gotten excellent therapeutic re-

sults. Some docs are just plain unadulterated uneducated experimenters, and they don’t know what they have to do experimentally to _

prove whether a thing is true or not. I feel sorry for them, but I can’t accuse them of being dishonest—there’s a difference. Occasionally

you will find a smart scientist that fudges and he knows he’s fudging , —but thank God, there are not many of those. I knew Dr. Tunnicliffe and knew her very well. She was a good and respected worker, but on several occasions she was able to get strep viridans out of the throats and conjunctival fluid of measles patients and became convinced that they were the inciting cause of measles. The thing she apparently forgot was that you could get strep viridans out of practically anybody’s throat. I think that Dr. ‘Tunnicliffe was

just about the only person in my time who believed that strep . viridans was the cause of measles; nearly everybody believed that it was caused by a virus.

QO: Dr. Rivers, there were any number of virus diseases which were

thought to be caused by strep. Didn’t Dr. Edward Rosenow of the Mayo Clinic contend that poliomyelitis was caused by a strep? #8 2°Y. Kermorgant, “Contribution a l'étude de Vétiologie des oreillons,’ Ann. Inst. Pasteur, 39:565 (1925); “Sur l’étiologie des oreillons,”” Ann. Med. Paris, vol. 19:301 aE. C. Rosenow, “Streptococci in spinal fluid in acute poliomyelitis,” J. Amer. Med. Assoc., vol. 91:1594 (1928).

138 Chapter 4 Rivers: He did indeed, and he kept to that belief from before World War I to the day he died. I knew Dr. Rosenow, and in many respects I considered him a first-rate bacteriologist. He was a sincere man and sincere about his work, but he didn’t know anything about viruses. It was his contention that he got strep viridans out of the spinal Huid of patients with polio, and that he could produce polio in rabbits by injecting them with strep. To save my soul, I don’t know how he did all of this. Of course, he was one-hundred-per-cent wrong. Actually, as far as the virus of polio is concerned, it is practically never

found in the spinal fluid. If Rosenow was looking for the virus of polio, the spinal fluid was just about the sorriest place to look—I _ think that it probably turns up there maybe once in a thousand times. Dr. Flexner had a running battle with Rosenow on this problem for over a quarter of a century, and I had one run-in with him at a meeting held before the Association for Research in Nervous and Mental Disease during Christmas week in 1931. I was pretty savage with him. Do you think that helped? Hell no, if you ask me for my candid opinion, I think that most of the audience present believed Rosenow. It

took a long time to educate doctors to understand the nature of viruses,*#

| QO: Dr. Rivers, one of the viruses you studied at this time was fowlpox virus. Could you tell me what led you to study this virus? *

Rivers: Looking back, I would say there were two major reasons. The first related to the virus itself. Fowl pox, as you know, is a common disease of the barnyard, and it recurs in epidemic form in many * Olitsky adds this note.

While Dr. Flexner and Dr. Rivers had verbal “running” battles at meetings with Dr. Rosenow, I was delegated by Dr. Flexner to experiment with the problem of streptococcus as the possible causal agent of experimental poliomyelitis in monkeys, and of herpes

febrilis. In these tests I was associated with Drs. P. H. Long and C. P. Rhoads. We could find no evidence to warrant a conclusion that streptococcus was the cause of either infection, as stated by Rosenow. But the latter resented our statements in publications, and at many meetings (which I did not attend) Rosenow in histrionic addresses leveled

devastating criticisms against me, personally, for daring to report such findings. (private communication ).

Cf. P.K. Olitsky, C.P. Rhoads, and P.H. Long, “Relation of streptococci to spinal fluid in experimental poliomyelitis,” J. Amer. Med. Assoc., vol. 92:1725 (1929). * Report of Thomas Rivers to the Board of Scientific Directors of the Rockefeller Institute for Medical Research, 1928.

Virology and Virologists—1926 139 countries. As a rule, it is not fatal; however, it is a disease which leads to great economic loss because it affects the egg-laying activity of all

infected fowl. In 1928 it presented an interesting problem because, although virologists had long been able to transmit fowl pox by direct inoculation, its rapid spread under natural conditions in the barnyard remained a mystery. Ernest Goodpasture—who was a great investiga-

tor, by the way—pointed out about that time that, even if you put infected fowl together in the same cage with healthy fowl and let them pick at one another, the pox did not spread very readily. He had expected the reverse to happen. Well, Goodpasture’s finding intrigued

me, and, as I read through the literature, it became apparent that farmers as well as some scientists were of the opinion that insects, flies or mosquitoes were instrumental in the spread of the disease. However, no one put the idea to the test. I therefore decided to undertake experiments to ascertain whether mosquitoes were of any significance in the spread of fowl pox.

The probability is that I would not have undertaken this series of experiments if it hadn’t been for the particular people I then had working with me in the laboratory. In addition to Dr. Muckenfuss and Dr. Haagen, whom I have spoken of before, I had a visitor in my lab for several months, named Israel Kligler. Dr. Kligler was a bacteri-

ologist who had previously worked for the Rockefeller Foundation and had done some very handsome work on malaria and mosquitoes.

It was an ideal situation; I had two fellows who knew something | about viruses and another who knew something about mosquitoes but nothing about viruses. I just put one and two together and got a very neat experiment. ‘T’oo often people think that beginning an experi-

ment depends on only one lab. It doesn’t. You not only have to depend on the work that others do before you; you also are dependent on material in their possession. | was able to get my experiments under way when Dr. Howard Andervont, who had previously worked on fowl pox, very kindly sent me some pox to work with. Actually, the experiment was not difficult to do. We took a mosquito, placed it in a

test tube, and then placed the tube over an infected wattle or comb. When we were sure that the mosquito had fed on the lesion, we took him and let him feed on a perfectly healthy hen. ‘There was no doubt-

ing the evidence that the mosquito was the culprit in transmitting |

140 Chapter 4 fowl pox in nature. In the beginning, I thought that nobody paid much attention to this work. A number of years afterward, I was at a

convention in San Francisco listening to Sir Frank MacFarlane Burnet—he wasn’t a sir then, just plain Frank Burnet—talking about the spread of infectious myxomatosis from rabbit to rabbit by mosquito. I sat listening with my mouth wide open, because it was my fowl pox experiment done over in rabbits. Well, you know me, after the meeting was over I asked Burnet if he had ever seen my paper on fowl pox. He smiled and nonchalantly said, “Why sure, Dr. Rivers, that’s where we got the idea.”

_ Q: Dr. Rivers, for me, one of the most interesting pieces of research engaged in during your early tenure at the Institute was growing vaccine virus in tissue culture. Were you the first to grow vaccine virus in

tissue culture? |

Rivers: I don’t want to disappoint you again; you historian fellows are always looking for a first, and I can unequivocally say that I was not the first even to attempt the growth of vaccine virus in tissue culture. I believe the credit for that belongs to Constantin Levaditi °® of the Pasteur Institute. If I remember correctly, Dr. Levaditi infected an animal with vaccine virus and then took a nerve cell from that animal and put it in a hanging-drop tissue-culture setup and after a certain number of days demonstrated that the virus was still present. So

far as I can remember, there was no proof that the virus had multiplied in that setup; at most, I think all one could say was that it survived. *6 Tissue-culture work in the United States began under the auspices of Leo Loeb and Ross Harrison. It should be borne in mind that the question put to Rivers was not about tissue-culture work in general but the cultivation of vaccine virus in tissue culture. His remembrance of Levaditi’s investigation is undoubtedly an outgrowth of his collaboration with Alexis Carrel, for Levaditi’s work is the first one cited in the paper they later prepared. Although Levaditi tried to cultivate viruses in tissue culture, he did not work with vaccine virus, but initially used poliovirus. C. Levaditi, “Symbiose entre le virus de la poliomyélite et les cellules ganglions spinaux, a l’état de vie prolongée in vitro,” Compt. rend. soc. biol., vol. 74:1179 (1913). I later discovered that the first report of the cultivation of vaccine virus in tissue culture was made by E. Steinhardt, C. Israeli, and R. A. Lambert, “Studies on the cultivation of the virus of vaccinia,” J. Infect. Diseases, vol. 13:294 (1913).

Virology and Virologists—1926 14] The next investigators to try this were headed by Robert Nye and Frederick Parker, Jr., at Harvard, and, if memory doesn’t fail me, they passed vaccinia through several cultures of rabbit testicular tissue and got a multiplication of virus.?’ Still later, Alexis Carrel and I did

a little piece of work at my request to see whether we could get a multiplication of virus in plasma clot medium. I don’t think very much of that work, but it did look as if we too had some multiplication of the virus.

In 1928 Dr. Hugh B. Maitland and his wife, of the Department of Bacteriology of the University of Manchester in England, concocted a medium that consisted of minced chicken kidney suspended in a mixture of chicken serum—lI believe, one part—and Tyrode’s solution— two parts. hey claimed that after three days there was no detectable growth of cells in that culture and that, when vaccine virus was added

to it, it multiplied.*8 Now the Maitlands were both experienced investigators—you might even say superb investigators—and there was no doubt in my mind that the virus multiplied. What bothered me was the claim that the virus grew in the absence of living cells. I just couldn't swallow that. Hell, it hit at my fondest beliefs. I decided therefore to test the Maitlands’ findings. I repeated their experiments as carefully as I could, and, like them,

discovered that vaccine virus indeed did multiply in a medium of ) normal fresh kidney cells plus ‘Tyrode’s solution and chicken serum. However, whereas the Maitlands believed that their medium was not a tissue culture and actually thought autolysis of cells to be complete © in three days, I demonstrated that many cells remained viable for as long as five days, and that in such instances their medium was capable at times of supporting multiplication of virus. It was definite that the vaccine virus did not multiply in the absence of living cells. But let me just point out that, in spite of my findings, the work of the Mait-

lands was most important for the study of viruses, because they found a medium for the easy cultivation in vitro of vaccine virus and other infectious agents of a viral nature. 7 R.F. Parker, Jr., and R.N. Nye, “Studies on filterable viruses. I. Cultivation of

vaccine virus,” Amer, J. Pathol., vol. 1:325 (1925). ;

8 T1.B. Maitland and M.C. Maitland, “Cultivation of vaccinia virus without tissue culture,” Lancet, vol. 2:596 (1928). )

142 Chapter 4 O: Weren’t there other attempts at that time to see if you could get viruses to grow or multiply outside of the living cell?

Rivers: Just what are you referring to?

QO: I have particular reference to the work of Dr. Olitsky and Dr. MacCartney testing the survival of rickettsia separated from living host cells by collodion membranes.”®

Rivers: I remember that. When the question came up of whether viruses could exist or multiply in the absence of living host cells, some investigators, among them Dr. Olitsky and Dr. MacCartney, decided

to test that idea by implanting collodion membranes containing rickettsia in the peritoneal cavities of experimental animals. As I remember it, Olitsky and MacCartney later reported that the rickettsia survived approximately thirty-one days. I objected to these experiments, because I felt that the collodion sacs with their contents acted as foreign bodies, and, instead of the rickettsia being brought into close relation with normal host cells, they were brought into indirect contact with the fibrous capsule, by which the bags had become surrounded.

With the help of Ralph Muckenfuss—and I should add here that he did all the work—I put vaccine virus in a cell-free mixture of serum and ‘T’yrode’s solution, placed it in a collodion sac, in dialyzing apparatus, outside of which there was a preparation of living kidney cells in serum and Tyrode’s solution. We soon discovered that under such

conditions the virus retained its activity. It appeared to me then that the living cells had something which was capable of reaching the virus

through diffusion of the semipermeable membrane. I didn’t know what it was; nobody knew. * The implication of the question asked here by the interviewer is deceptive. Olitsky and McCartney did not use collodion capsules as a way of maintaining rickettsia free from living cells. The object of the experiment was to supply oxygen to the organisms under such conditions as to extend their survival time. P. K. Olitsky and J. E. McCartney, “Experimental studies on the etiology of typhus fever: V. Survival of the virus in. collodion: sacs implanted intra-abdominally in guinea pigs,” J. Exptl. Med., vol. 38:691 (1928).

Virology and Virologists—1926 143 QO: Dr. Rivers, I don’t want to press you, but how do you explain the persistence of the belief that it was possible to grow viruses on

nonliving media? During the early thirties, for example, several notable claims were made that it was possible to cultivate vaccine virus on lifeless media. ‘The work I have in mind is that by Dr. Arthur Kendall in America and Dr. George H. Eagles in England.

Rivers: Let’s talk about Kendall first. Dr. Kendall was a bacteriologist and a good one. During World War IJ, he had done some very good work on intestinal bacteria, and during the twenties made significant contribution to our understanding of bacterial metabolism. He knew little or nothing about viruses; however, in 1931 he pub-

lished an article in Science, in which he claimed to have grown vaccine virus on a lifeless medium of his own concoction known as K medium. Previously, he had had some success growing typhoid bacilli

on this medium, and his claims began to attract attention. I didn’t take Kendall’s claims very seriously, and they didn’t concern me until Dr. Thomas Futcher, who was one of my teachers at the Hopkins, invited Kendall to give the annual guest lecture before the Association

of American Physicians. Futcher, who was a wonderful clinician, knew very little about bacteriology and virology, and, after it became generally known that he had invited Kendall, a number of his friends who were conversant with Kendall’s work urged him to withdraw this

invitation. Futcher was a gentleman and refused to do so, but as a concession asked Hans Zinsser and myself to attend the meeting and

discuss Kendall’s paper.

I hadn’t intended to test Kendall’s work but, when Dr. Futcher asked me to discuss the paper, I repeated the experiments. I gave it an honest whirl but, as you might suspect, I got no proofs of Kendall’s claim. But I did come armed for the discussion. After Kendall gave

his paper, Futcher called on me. I was a much younger man than Kendall, and I was also a younger man than most of the people in the Association of American Physicians, because I hadn’t been a member very long. So I got up and, in a very temperate manner, called the fel-

low a liar. Not in so many words. Actually, all I said was that I couldn’t repeat the experiment and I therefore didn’t believe his findings were true (see Appendix A).

144 Chapter 4 J was very temperate about it, but Zinsser wasn’t. When I got through, Dr. Futcher called on Hans. He was standing in the back of the hall, and he did his trick. ‘he moment he was called on, he began

to talk, and he talked all the way down the aisle to the platform. Every eye was on him, and nobody missed a word that he said. You know, this was characteristic of Hans. I saw him do it at Harvard. He would stand in the back of the classroom—they are steeply banked— and talk all the way down to the desk and never lose a student. Well, Hans did this down there, and he just gave Kendall bloody hell. I’d never seen Hans so hot in all my life. I had to agree with everything he said—but I really felt sorry for poor old Kendall—he

just sat there and took it. I will never forget that, when Hans sat down, Popsy Welch felt so bad for Kendall that he got up and said, “You know, you folks shouldn’t be so tough on Dr. Kendall. After all,

he might be right. I don’t know whether he is or not—but you oughtn’t to be so hard.” Hans was tough, but this time he had every right to be.

QO: Dr. Rivers, while one can accept the fact that Dr. Kendall as a bacteriologist knew little about viruses, that stricture surely cannot be used against Dr. Eagles.

Rivers: Eagles’ papers on the growth of vaccine virus in lifeless media cost me two years’ work—yet I don’t blame him entirely. The person I hold most responsible is Hideyo Noguchi. Noguchi had a tremendous influence on scientists throughout the world, and at one time most of them believed that you could cultivate just about anything in the Noguchi medium. All you needed was his long narrow test tube, a bit of rabbit testicle or kidney, a deep layer of broth, and the virus or bacteria you were working with, and you were in business.2° Now, this belief was not restricted to beginners; respected and

*° Olitsky writes: .

The medium described here by Dr. Rivers was first devised by Theobald Smith in 1899 and could be considered as an historical forerunner of the Maitland type. Its chief ingredients were a fragment of kidney (rabbit, later monkey or rabbit) plus fresh, unheated ascitic fluid collected under sterile conditions from human beings, generally cases of hepatic cirrhosis. The fluid contained cells, and the presumption was that they and the cells from the tissue could have been viable for several days at least. The medium became

Virology and Virologists—1926 145 experienced investigators believed it too. Bill MacCallum, professor of bacteriology at the Hopkins believed it and John Ledingham, later sir John Ledingham, director of the Lister Institute, believed it. As a matter of fact, Ledingham came all the way from England to learn from Noguchi personally about his special medium, and I am sure that it was Ledingham who spread the gospel to other investigators at the Lister Institute, like Eagles and McClean.

About 1932 Eagles and one of his associates, Dr. McClean, reported that they had successfully cultivated vaccine virus in a “cell free” medium.*! What they did was to take an extract of rabbit kidney, suspend it in a mixture of serum and Tyrode’s solution, and ground and centrifuged it at high speed to get rid of as many cells as possible. ‘The material was then frozen (in a mixture of alcohol and ice) and thawed repeatedly, and, when virus was added to such extracts, it was claimed that it multiplied. Well, Sylvia Ward, who was then my technician, and I very methodically and carefully repeated

the work of Dr. Eagles, and I want to tell you that in no instance

were we able to show that vaccine virus multiplied in a “cell-free” . medium. We did discover that grinding and repeated freezing and thawing of Eagles’ medium did not in every case get rid of all the cells, and in some instances cells not only remained alive but proliferated. In such cases, the virus multiplied. Some years later, Dr. AIbert Sabin, who worked at the Lister Institute during this period, told

me that the technique used in Eagles’ laboratory was not exactly faultless, and that in several instances virus multiplication occurred because the pipettes used in culture transfers were not sterilized prop-

erly.

I think that Eagles’ experiments were the last gasp of folks who

said you could grow viruses on nonliving media. So far as I know, no one has done it yet. However, this doesn’t mean that they won't. Up to now, it seems that the living cell is the only thing that can provide

the factor that’s necessary for the growth and multiplication of a virus. But I can easily imagine the day when somebody will come known as the Noguchi medium from his use of it in 191] and later. Dr. Fred Gates and I renamed it Smith-Noguchi, for Noguchi only added some modification (private communication ).

*1G.H. Eagles and D. McClean, “The cultivation of vaccine virus in a cell free medium,” Brit. ]. Exptl. Pathol., vol. 12:97 (1931).

146 Chapter 4 along and put the necessary chemical components together to have a virus made in a test tube—shake it—and create a virus in the absence of the living cell. Until now, nobody has been able to perform this trick, and it’s still safe to hold that viruses multiply or are multiplied

by the living cell. 3

In the early days of virology, I had to defend that theory pretty vigorously, although the evidence supporting my position was present in the literature. For the life of me, I don’t see why it was so hard for me to convince people. The only reasonable explanation I can find at this late date is that sometimes science is held up because people of great renown hold on to their ideas and refuse to give them up. Some

years ago, I expressed that notion at some length in a paper I gave before the American Philosophical Society on polio research in the United States. Progress in poliomyelitis research [I said] has not been continuous. In fact, at times we have gone backward instead of forward, and, when we have gone forward, it has been by fits and starts instead of in a smooth, steady manner. At the roots of progress in poliomyelitis research, as in all research, lie proper concepts and adequate techniques. ‘These have been acquired more slowly in relation to poliomyelitis than is the case regarding other viruses. Because of this, many errors have been made and workers

have taken part in many wild goose chases. ‘Those who have made the errors, unless they refuse to admit them and to give up false concepts, should not be held in low repute, for not infrequently their mistakes, if recognized, make easier the paths of other investigators. ‘There are times, however, when workers of great scientific repute continue to misconstrue the meaning of their data or will not admit inadequacies in the techniques employed by them. When this happens, progress may be materially impeded and much effort must be expended in tearing down the false edifice before a true one can be built. Thus, “no one has the right to encumber science with premature assertions,” for “an erroneous afhrmation which has taken a day to construct requires sometimes twenty years to overthrow.” ®2

Several weeks after that article appeared in the Proceedings of the American Philosophical Society, I received a note from Justice Felix Frankfurter of the United States Supreme Court. He apparently had read the article—although for the life of me I don’t know why—and *'T.M. Rivers, “The story of research on poliomyelitis,” Proc. Amer. Phil. Soc., vol. 98:254 (1954).

Virology and Virologists—1926 147 wanted to know where I got the quotation I used in the paragraph I just quoted. I told him that I got it from a book by Charles Richet called The Natural History of a Savant and advised him that if he wanted to have many laughs to read it. I advise you to do the same— it’s a wonderful wise and witty book. In 1931 when I gave a talk to the Pacific Northwest Medical Association in Butte, Montana, I quoted extensively from that book. I remember that old Ajax Carlson of the University of Chicago was in the audience. He was the only one in the entire hall who wasn’t wearing a tuxedo. He had his chair tilted back against a post and an old cap pulled down over his eyes. I thought the old son-of-a-gun was asleep, but he wasn’t. He listened to every word I said, and when I got through he got up and spanked hell

out of me. He made it plain that he didn’t think much of me for quoting from a book written by a man who in later life became a spir-

itualist and translated by another who did the same. It made no difference to him that Richet won the Nobel prize for his work on anaphylaxis and that Sir Oliver Lodge had been an eminent scientist.

The fact that they had both embraced spiritualism in later life was

enough for old Ajax to condemn them to hell and me along with them for quoting the book. I didn’t care what they believed in their old age. Hell, if Carlson had argued that the Nobel prize committee made a mistake in giving the prize to Richet for work on anaphylaxis, why then I might have gone along with him. I have always believed that the prize for that work should have gone to Theobald Smith.

O: Dr. Rivers, I’d like now to turn to a consideration of your work on growing vaccine virus in tissue culture. For example, the strain of virus that you work with is of historical interest, and although you mentioned something of this before in passing I wonder if you would begin by telling me how you came to work with it.

Rivers: As I mentioned before, Hideyo Noguchi had passed a strain of vaccine virus that he had received from the New York City Board of Health through a number of generations of rabbits by intratesticular inoculation, with the idea of making a bacteria-free vaccine virus for human use. He was successful; however, in the process his virus

mutated and no longer produced an encephalitis in rabbits. Well,

148 Chapter 4 that aroused my interest and I sent to the Board of Health for another batch of the original strain sent to Noguchi. I was particularly interested in the original source of the virus. At that time Charles Tyler of the Board of Health wrote me the following note: Regarding the history of our strain of vaccine virus: the following statement appears in the Yearly Report of the New York City Board of Health for 1874-75:

“We began vaccinating with virus of the same stock as that which had been supplied by the late Dr. Loines of the Eastern Dispensary and myself

for about 5 years and which had been used and sold by him for about twenty years previously. ‘This virus was originally obtained from England

by Dr. Loines and in all probability was descended from the stock furnished by Jenner. As it always developed characteristic Jennerian vesicles and as it always thoroughly protected from small pox those upon whom it was used, Dr. Loines never thought favorably of employing any other.”

The same strain of virus has been in use since the time of this report. The virus has been “humanized” at various times, usually from one to

three times yearly.3? .

; I think the evidence is pretty straightforward, enough for me to claim that I was working with an historic strain.

O: Were there any other reasons for cultivating vaccine virus in tissue culture?

Rivers: Yes. About that time, there were many reports claiming that encephalitis followed vaccination against smallpox. Actually, there

were such cases and, while they were more numerous in Europe than in the United States, the antivivisectionists and antivaccinationists in this country used the occasion as pretext for vigorous attacks on the medical profession in general and those engaged in experimental medicine in particular. I didn’t think that polemical debate with such people would be fruitful. As a matter of fact, I thought it more likely that such debate would merely add fuel to a fire already kindled. In-

stead, I thought that the best method of combatting such attacks against vaccination would be the preparation of a better and cleaner 8 Quoted from T. M. Rivers, “Cultivation of vaccine virus for Jennerian prophylaxis in man,” J. Exptl. Med. vol. 54:453 (1931).

_ Virology and Virologists—1926 149 vaccine virus. It seemed logical to me that, if I cultivated the virus in

: tissue culture that I would get what I was looking for. Together with Dr. Li, I worked out a nice technique for growing the virus on minced chick embryo suspended in Tyrode’s solution. I mention this because

I found that other media permitted the entry of unknown virus into the cultures as contaminants. There is nothing more to be said about this except that the actual work for cultivating a virus in tissue culture

suitable for purposes of vaccination in man was done with Sylvia Ward. I was gratified to learn that, although the virus was propagated in cultures for a considerable time, it seemed to have lost none of its characteristics—enough to encourage me to ask Dr. Alfred Hess, who was a very well-known pediatrician, if I could inoculate some of the

kids whom he had medical charge of in an orphan asylum with my | vaccine. He agreed, because those kids had to be vaccinated anyway. I

did, and I want to tell you I was not pleased with the results I got, because they were just as ugly as one would get with the straight virus furnished by the Board of Health, if not more so. At that time, I gave up any idea of using the virus in human beings. However, as I cultivated it in generation after generation in tissue culture, I noticed that it became less and less virulent for rabbits generally. On several occa-

sions, | pepped it up by putting it back into the testicles of rabbits; eventually, however, I got a strain that I couldn't rejuvenate. Yet that strain, given intradermally into children, produced very little if any

, reaction—usually a red spot, slight induration—but the tissue would not break down and the children were not sick. When I subsequently tested those children, they were pretty much immune to the city vaccine virus.

I was pleased as punch. I thought it would be a nice way to vaccinate people, since they would not have ugly scars and were not

likely to get an encephalitis after vaccination, as they sometimes would after the use of more virulent strains. Six months later, when I re-inoculated the children, I thought they had much more reaction to the Board of Health vaccine than they should have had. Well, Sylvia Ward and I studied this problem very carefully and finally came to the conclusion that the kids were not as thoroughly protected as they should have been, and I gave up trying to get the Board of Health to

150 Chapter 4 use my attenuated vaccine virus. You know, even with the vaccine that the city uses now, you don’t get lifelong immunity, and if you go

abroad you can’t get back into the country unless you’ve been

value.

vaccinated within the last three years. In sum, you might say that I discovered some interesting things about getting an attenuated strain of virus by using tissue culture, but nothing that was of real practical

CHAPTER 5

The Process of Virus Research—1930 But what created mind can comprehend Their number, or the wisdom infinite That brought them forth, but hid their causes deep. John Milton, Paradise Lost

O: Dr. Rivers, as a physician and investigator, were you bound to the hospital and laboratory? Did you ever get a chance to see what

_ was happening in the world outside the Institute? | Rivers: I most certainly did. In 1930 I attended the First Microbiological Congress in Paris as one of the representatives of the Rockefeller Institute. Before I went, Dr. Flexner urged me to speak on the problem of poliomyelitis but I refused. Although I was quite familiar with what was going on in polio research, the truth is that I had never

, worked with the virus, and I felt I shouldn’t meet my peers talking about a subject in which I had no personal experience. Instead I decided to report on psittacosis. | was then working with psittacosis virus and knew much about it, but even more important almost every virus laboratory throughout the world at that time was interested in the disease. T’he paper I prepared was very brief, and I don’t think it ran more than 800 words. If you look through the proceedings, you will find that, with small exception, speakers had no more than 800 words at their disposal.

Given this state of affairs, it should come as no surprise when I tell you that I didn’t hear anything particularly new about viruses at the 15]

152 Chapter 5 congress, and that I got very little out of the papers as they were given in, the meeting hall. However, this was the first time I ever saw

a certain thing happen. A fellow got up to give a talk and he, like other speakers was limited to 800 words. Well, what can you say in 800 words? You can hardly get started. ‘he chairman was understanding and let the speaker go over his time, and on he went. A short

time later when the chairman tried to call a halt, he found that the speaker would not stop. ‘The words kept pouring out until, at the chairman’s suggestion, three people in the front row of the audience got up and bodily removed the speaker from the room. I had never seen this done before and several years later, at the Sec-

ond International Poliomyelitis Conference held in Copenhagen, | was faced with a like problem. I was chairman at an introductory session which was devoted to virus research in general. Prior to the conference the National Foundation had invited the Russians to participate in the sessions but had never received any reply to their invitation. Assuming that the Russians were not coming, the sessions were

planned accordingly. Well, a day or two before the conference opened, a small group of Russians appeared and declared that they

were ready to participate in the sessions. We were sore but we |. | maneuvered the program so as to allow the Russian delegation a speaker at this preliminary session. I will never forget him—he was a queer little fellow with a beard down to his upper chest. His talk was just as queer, because he kept insisting that all the pioneer work in polio had first been done in Russia. ‘That didn’t bother anybody, but what was annoying was that he gave no indication that he was ever

going to stop talking. Had I let him, I think he would have spoken into the night. Finally, some people in the audience got up and toted him away. Nine years later at the Fifth International Poliomyelitis Conference, held in Copenhagen, Russian behavior changed marked-

ly. This time they replied to their invitations and sent an excellent

delegation composed of Dr. Anatoli Smorodintsev, Dr. Mikail Chumakov, Dr. Valentin Soloviev and Dr. Marina Voroshilova who contributed knowledgeably and helpfully to the discussions.

To get back to the First Microbiological Congress in Paris, I do want to say that the congress gave me the opportunity to meet and see people I had heard and read about. For example, I heard Serge

Process of Virus Research—1930 153 Winogradsky, one of the pioneer soil microbiologists in the world, give a paper, I saw the distinguished clinician, Dr. Arnold Netter, and

I spoke to old Dr. Emile Roux who you may remember followed Louis Pasteur as director of the Pasteur Institute.* During the conference I made a special effort to see the room at the Pasteur Institute that is dedicated as a memorial to Pasteur. It was something to see. You know, the French have a way of doing such things for their distinguished citizens, whether they are generals or scientists. I think that they pay more tribute to their scientists than we do. Our scientists never get much from the public except an occasional bawling out. On the last day of the congress Dr. Harry: Plotz of the Pasteur In-

stitute put Dr. Thorvald Madsden of Denmark, Dr. Jules Bordet, and me in a taxicab and took us to a top notch club for dinner. I should add that it wasn’t the kind of a club that scientists usually go to, but by the same token I want to say that we didn’t need any instructions on how to enjoy ourselves. We had a hell of a good time. My trip to Paris in 1930 was not the only jaunt that I made out of the country during my early years at the Institute. In the fall of 1934 I was invited to attend a medical congress in Argentina, and I took advantage of the opportunity to visit Brazil as well. It was the first trip that I made to Latin America since my stay of 18 months as a second year medical student in Panama back in 1912. In those days few people traveled by air, and traveling to Europe or South America was usually by ship. It was a nice way of going because it gave you a chance to rest and meet people. I remember that on this particular trip I ran into Yandell Henderson, the physiologist from Yale, and he _ proved to be a most interesting shipboard companion.

We landed in Rio de Janeiro and before I had a chance to find out if I was lost, Fred Soper of the Rockefeller Foundation met me and

took me in hand. It was through Dr. Soper that I met Dr. Carlos Chagas, who at that time was director of the Oswaldo Cruz Institute, who showed me the first cases I had ever seen of Chagas disease. Dr. 1The succession to Pasteur’s post as director of the Pasteur Institute was slightly different. Upon Pasteur’s death, Emile Duclaux was appointed director of the Pasteur Institute, while Dr. Emile Roux took the post of associate director. When Duclaux died in 1904. Roux succeeded to the directorship. W.R. Bulloch, A History of Bacteriology.

Oxford University Press, London, 1938, pp. 362, 393.

154 Chapter 5 Soper and one of his associates, John Kerr, then took a lot of time to brief me on the research work that the Rockefeller Foundation was doing on yellow fever in Brazil. ‘The thing that still sits in my mind after all these years is not the people I met, but an experiment I saw

going on in one of the laboratories. A young doctor who was the brother of Dr. Miguel Ozorio, the minister of Health and Hygiene, was trying to treat cancer by means of increased oxygen tension. He found, for example, that if he subjected his animals to increased oxygen tension they usually died. However, if he took the precaution of starving them for several days before the experiment, they lived and, in some, cases of sarcoma were cured.

I believe that, at most, I spent three days in Brazil and then left for Argentina. ‘The congress was held in a place called Rosario. Looking back I would say that it was much like the AMA conventions held in

this country. In one week’s time, approximately 1500 papers and communications were read. I myself gave two papers—one was a general review of virology, the other a review of research on psittacosis. Some of the conferees gave as many as ten papers. I don’t think that many were particularly distinguished, but people sat and listened and later commented on them.

In my free time, I visited the medical school attached to the University at Rosario. ‘The buildings and laboratories seemed to be well equipped, but I couldn't for the life of me tell whether it was adequate for the student body. I say this because the equipment and rooms I saw would be adequate for 50 students in a class, but many of

my informants told me that some classes had between 250 and 300

students. I could never judge for myself, because at the time of my visit the medical students were out on strike, and all I could count | were the soldiers who surrounded the University.

Thirty years ago, medicine in Argentina followed the model provided by French medicine, the texts used were largely French, and when students finished school they sometimes went to France for postgraduate work. I would say that the Argentina of that day had many good physicians and surgeons, but it also had a good many serious deficiencies. For instance, nursing was extraordinarily bad and, outside of Dr. Angel Roffo’s Institute for the Study and Treatment of Cancer, there were few facilities for training nurses. In part, that situ-

Process of Virus Research—1930 155 ation stemmed from the public attitude toward women, which incidentally frowned upon proper wellborn women doing nursing. Medical research was pretty much in the same category, and outside of the work done by Bernardo Houssay at the Physiological Institute in Buenos Aires, there was little in Argentine medicine that could be dignified by calling it research. I remember that in the lecture room of the large Maternity and Gynecological Hospital run by Dr. A. Peralto Ramos the motto, “Medicine is Art not Science,” was displayed very prominently. Still, if you searched you could find a tradition of experi-

mentation. While in Rosario, I found a rare volume on viruela— smallpox—by José Penna, who has been called the Jenner of South

America. I tried to purchase it, only to be told by the owner, Dr.

Recaldo Cuestas, that it was not for sale. Before I left he very

graciously gave it to me as a gift. | Q: Dr. Rivers, I would like to turn your attention to the research you did in those years. Could you tell me how you came to do work with the psittacosis virus?

Rivers: In 1929 and again in 1930, there were serious outbreaks of psittacosis or parrot fever in California and New York. ‘The death rate was fairly high, and a number of laboratories, particularly the Public Health Service Laboratory in Washington, D.C., and the laboratories of the New York City Board of Health began to work on the disease. Within a very short period of time, investigators as well as technicians in these laboratories started to come down with the pneumonias that

were typical of psittacosis. The laboratories that were doing the research were no amateurs. In Washington, for example, Charles Armstrong, one of my classmates at the Hopkins, ran the show. Well, it made no difference because 16 people came down with psittacosis. What made it embarrassing was that some of the people weren’t even

in Armstrong’s laboratory and worked on a different floor. In New York, two technicians in Dr. Charles Krumwiede’s laboratory came down and it was the latter event which helped bring the virus to my laboratory. Let me say that Dr. Krumwiede was an extraordinarily gifted worker and the fact that two of his technicians came down with a disease under investigation would, under ordinary circum-

156 Chapter 5 stances, not have deterred him from pursuing his research. The fact is that, just about the time Krumwiede started his work on psittacosis, the poor devil discovered that he had a carcinoma of the bladder, and it was this which decided him to give up working with the virus and led him to offer it to the Rockefeller Institute. Dr. Flexner accepted the virus and then called me over and told me to work on it. Actually I began my research on psittacosis about a year after it be-

came a public health problem in the United States. Soon after I started my research, all of the laboratories in the United States, save my own at the Rockefeller Hospital, stopped working on the disease, and for a period of approximately two years, material from every patient in the United States who came down with psittacosis was sent to my laboratory for diagnosis.

QO: Was there much difficulty in differentiating a pneumococcal pneumonia from the respiratory infection caused by psittacosis?

Rivers: In the beginning I believe that many general practitioners had such difficulty. However, there was no difficulty in the laboratory

in differentiating between the lesions caused by a virus and a bacterium. At one point in my investigations, I described quite clearly the microscopic changes that one would find in lungs which were in-

vaded by psittacosis virus. ‘here was, however, a debate among virologists as to what constituted portal of entry for the virus.

Both Dr. Karl Meyer in this country and Dr. Samuel P. Bedson in England claimed that the virus was transmitted by the bite of an infected bird. It is true that many people who fed their parakeets by

mouth were bitten, and there were cases where parrots became annoyed with people and bit them on the hand. It was thought that the virus entered the bloodstream in this fashion. I didn’t think much of this theory for several reasons. First and foremost was the fact that the pathology of psittacosis in man and the monkey was in the lungs, and, when I injected my experimental monkeys intraperitoneally or intracerebrally with the virus, I could make them sick or kill them, but I could never produce a pathological lesion in the lung. ‘The only time I could get a pathological sign in the lung was when I inoculated them intratracheally. Secondly, I always found it odd that most of the

Process of Virus Research—1930 157 16 cases that came down with psittacosis in the laboratories of the Public Health Service in Washington never even saw a parrot or para-

keet. When- Charley Armstrong demonstrated the virus in fecal droppings of parrots, what happened in Washington became clear. Armstrong’s experimental parrots were kept in the basement of the old Hygienic Laboratories in Washington. It was an old red brick building, and the only thing hygienic about it was its name. I want to tell you that the basement where those birds were kept wouldn’t win any medal for cleanliness. When parrots relieve themselves, they have a way of standing on the side of the cage, and instead of putting their

feces and urine in the cage, they usually put it on the floor of the room in which they are kept. Armstrong’s birds carpeted the floor of that basement with feces and urine, and the cockroaches that infested the building completed the job by transporting the virus to the desks of workers throughout the building. You know I argued the problem of transmission of psittacosis virus for over 20 years with Karl Meyer, and I couldn’t get the son-of-a-gun to admit he was wrong until a general conference on psittacosis which was held in honor of ‘“Red” Beaudette in the mid-fifties.?

Q: Dr. Rivers, you mention a debate on portal of entry of the virus. Wasn't there also one on diagnosis?

Rivers: If there was a debate, I don’t think it was much of one. Dr. Bedson—and by the way he was a very careful and good worker— claimed that he could demonstrate the virus of psittacosis by taking blood from an infected patient and injecting it into a parakeet or a lovebird. Well, to put the matter bluntly, I didn’t think much of this work. In the first place, one might not always find the virus in the blood, and secondly Karl Meyer had previously demonstrated that many parakeets were already naturally infected. My own ideas for diagnosis came from some of the work that Krumwiede did. Krumwiede early demonstrated that the mouse was susceptible to psittacosis, and that encouraged me to experiment with the white mouse. 2 Rivers here has reference to a conference called by Dr. F.R. Beaudette to discuss the problems of diagnosis, epidemiology, and control of psittacosis in 1956. A similar conference was held in 1953 but was not attended by Rivers.

158 Chapter 5 I'd like to point out that for a long time the Rockefeller Hospital had used the white mouse to make diagnoses of lobar pneumonia. These particular mice were beautiful to work with, they were highly susceptible to the virulent type 1, 2, and 3 pneumonias, and they handled the nonvirulent ones with ease. We soon discovered that, if we took

the sputum of an infected patient and put it intraperitoneally into our white mice, that within a few days they would come down with psittacosis. , Now, telling whether or not our mice had psittacosis was not a hit or miss affair. Although the pathological lesions of psittacosis in the human host were always in the lungs, in mice the lungs were rarely affected; instead the most constant and characteristic changes were to be found in the liver and spleen. In 1930 a German worker by the name of Walther Levinthal demonstrated that, if you took a smear of a liver infected by psittacosis, you invariably found clusters of bodies —almost like a little colony—growing in the cytoplasm of the cells of the liver. When you saw these “minute” bodies your diagnosis was just about 100 per cent.’

What makes all of this ironic is that, today, nobody ever makes a diagnosis of psittacosis any more than they make a diagnosis of lobar

pneumonia. The moment a patient has any signs in the lungs and . runs a high fever, the doctor gives him an antibiotic. It doesn’t mean that we don’t have the disease, ‘because we still have it. It’s present in

| parrots from Brazil, turkeys from Texas, and ducks from Long Island. °'W. Levinthal, “Die Atiologie der Psittakosis,” Klin. Wochschr., vol. 9:654 (1930). * Peter Olitsky adds this note on Levinthal: Walther Levinthal came to the Rockefeller Institute in 1925 and remained about four months observing the methods that we used in my laboratory. He was a member of the staff of the Robert Koch Institute at Dahlem, then under the direction of Fred Neufeld, the discoverer of different'types of pneumococci. Dr. Neufeld held the highest opinion of young Levinthal’s character and capability. My impression also was that he was a remarkable worker with great potentialities and deserving of encouragement and facilities

to be able to express his superior talents. He returned to the Robert Koch Institute in 1926 and continued to study the pneumococcus and Jater psittacosis. In 1930 he reported what is known in the literature as the “Levinthal bodies,” as the causal agents of psittacosis. . . . In 1933 with the accession of Hitler to power, Levinthal was compelled to leave his country. He sought a position at the Rockefeller Institute through me; however, on referring the matter to Dr. Flexner, [I learned that] his application could not be granted, since a large number of talented Germans were ahead of him and no place could be found. He settled in England, and the last I heard from others was that he was practicing medicine in the provinces there (private communication).

Process of Virus Research—1930 159 Some investigators have even found the virus in chickens. But we just don’t make any diagnosis. People are filled with antibiotics, and that’s it.

QO: Sir MacFarlane Burnet says that anyone working with psittacosis

usually has some good stories to tell. Could you favor me with some? *

Rivers: I don’t know whether the stories I could tell would be interesting. The only thing that I can promise is that they will have some relationship to the work that I did. During the outbreak of psittacosis in New York in 1930, a girl came into the Rockefeller Hospital with what seemed to be a virulent pneumonia. We ran the usual tests on her and soon discovered that she didn’t have a pneumonia at all but was infected with psittacosis. What made this particular case interesting was the fact that the patient had not been near a parrot or para-

keet. Well, we talked to her and talked to her until she finally remembered that some time before, while walking through Central Park, she and her mother came upon a sick pigeon on one of the paths. They felt so sorry for the bird that they picked it up and took it

home to care for it. However, in spite of their efforts it soon died. I began to wonder why the mother wasn’t sick when sure enough she too showed up with a virulent pneumonia. ‘These two ladies were the first patients the Rockefeller Hospital had from whom we were able to recover psittacosis virus. Just about that time Dr. Karl Meyer of the

Hooper Foundation published a paper in which he claimed to have isolated the psittacosis virus in racing pigeons. ‘There is no doubt that

the honor of pointing this out first belongs to Karl. However, the work we did at the Rockefeller Hospital nailed it down.

These two ladies were not the only confirmation we got of the widespread distribution of psittacosis virus in birds. A short time after they left the hospital, a barber from Brooklyn showed up with a case of psittacosis. He too never saw a parrot or a parakeet, but he did have a pet troopial. In case you don’t have a book on ornithology handy, troopials belong to the mockingbird family. ‘This particular troopial was a wonderful bird—it sang well—and was the picture of health, ‘F.M. Burnet, Viruses and Man. Pelican Books, London, 1953, p. 153.

160 Chapter 5 and I hated like hell to destroy it but I did. I felt bad about it until I discovered that the bird was just full of psittacosis virus. You know, Meyer didn’t call it psittacosis. He had to call it ornithosis. Psittacosis means a disease you get from psittacine birds while ornithosis means a disease you get from birds. ‘Today the word ornithosis has pretty well

dropped out of the picture. I think we all know that what a lot of these birds have is a form of psittacosis.

Q: Dr. Rivers, while you were working with psittacosis, wasn’t a virus discovered that was similar to psittacosis yet markedly distinct from it? °

Rivers: Yes, that particular virus was found by Dr. Geneserio Pacheco and some of his coworkers in Brazil. Originally, he claimed

that it was psittacosis. However, some of the descriptions in his papers bothered me, and I asked him to send me some of the virus so that I might investigate further. Pacheco was very kind and sent me all the virus I wanted. Soon after I began my experiments, it became obvious that Pacheco’s virus was not psittacosis. For one thing, I could not carry it in mice or for that matter in any other lab animal that I tried. Actually, initially the only way I could successfully carry it was from parakeet to parakeet. Later I discovered that I could pass it from one embryonated egg to another. Occasionally a chick would be born from an embryonated egg that had been infected with this virus, and for about a day or two you could find inclusion bodies in the chick. On one or two other rare occasions, we took a day-old chick and injected large amounts of the Pacheco virus and found that we could get a very mild infection.

By and large, however, Pacheco’s virus limited its activities to psittacine birds. I doubt very much whether it would bother a human being. I could almost swear that it wouldn’t. It differed from psittacosis virus in one other respect—while the psittacosis virus invariably caused colonies of elementary bodies to show up in the cytoplasm of liver cells, Pacheco’s virus had the beautiful characteristic of producing intranuclear inclusions in aftected cells, much like the bodies produced by herpes and pseudo rabies. ‘The differences in host range and >'T. M. Rivers and F. F. Schwentker, “A virus disease of parrots and parakeets differing

from psittacosis,” J. Exptl. Med., vol. 55:911 (1932).

Process of Virus Research—1930 16] in intracellular pathology were sufficient to differentiate between psittacosis and Pacheco’s virus. ‘Today, I am almost embarrassed to say that I don’t know what finally became of the Pacheco virus, because I didn’t keep it in my laboratory. If you look at the back of one of the first experimental papers I did on psittacosis ° you will find a picture of George Berry dressed up like

a Ku Kluxer with a parrot on his arm. He is wearing long rubber gloves, a rubber apron, and a special mask fitted into a hood going over his head. ‘That was just Berry’s way of protecting himself while working with psittacosis. Paul de Kruif made fun of that picture because he had the unique and outlandish notion that it wasn’t right for

a man who was working with highly infectious material to protect himself. Paul, I guess, has always believed in heroics. Well, protection

or not, poor George came down with psittacosis. It’s ironic. I never became infected, although I never even wore a gown in the laboratory. ‘The reason I didn’t wear protection was not that I was a hero— far from it—I didn’t wear anything because I was more comfortable working with my sleeves rolled up. I always figured that if I was careful not to have anything touch my clothes I was safe. The trouble with gowns, masks, and gloves, was that they gave you a false sense of

security and you were less careful while working. Hell, if you touch psittacosis virus with a damp gown, the virus will go night through that gown and get on your clothes, and before you know it you are contaminated.

Q: Dr. Rivers, looking through your papers on psittacosis, I notice

that some of the animals you worked with that recovered from psittacosis didn’t necessarily gain immunity. While your rabbits and parakeets did, your mice and monkeys didn’t. Did this cause you any difficulty? 7

Rivers: You know, I never really did make up my mind about the question of immunity to psittacosis. Parrots are birds of long life and live in many instances from fifty to seventy years. There is reason to °'T’. M. Rivers, G. P. Berry, and D. Sprunt, “Psittacosis: Experimentally induced infections in parrots,” J. Exptl. Med., vol. 54:91 (1931). 7 See especially ‘T’. M. Rivers, G. P. Berry, and C. P. Rhoads, “Psittacosis, observations concerning the experimental disease in parrots, mice, rabbits, guinea pigs and monkeys,” J. Amer. Med. Assoc., vol. 95:579 (1930).

162 Chapter 5 believe that certain parrots, once infected with the virus, can remain infected from twenty to thirty years without giving any outward sign of infection. In my own experience, I have examined several birds that were at least fifty years old that seemed perfectly healthy; yet after we killed them we were able to recover virus from them without any difficulty.

Some of my patients who had psittacosis, like Dr. Berry, had very few, if any, neutralizing antibodies in the blood. ‘To be sure they had complement-fixing antibodies, but complement-fixing antibodies have very little if anything to do with immunity to virus infection. At one time, you know, I devised a method for vaccinating man against the disease. First | experimented with monkeys and discovered that those who had recovered from psittacosis were more refractory to reinfection by the intratracheal route than my normal controls. Later I admunistered large amounts of active psittacosis virus intramuscularly to monkeys and learned not only that they would not come down with serious infection, but that such vaccinated monkeys had neutralizing antibodies in their sera and were again more refractory to the disease than my control animals. It was these results which encouraged me to try my hand at human vaccination. I used a live virus which previously had been passed through the brains of mice, and actually I was the first to take it. The first dose, I remember, was large enough to kill

10,000 mice. However, I had very little reaction to it. I felt a little lackadaisical for a day, and my temperature went up to a hundred, but nothing much happened. Subsequently I took several more doses, the last one large enough to kill ten million mice, but again nothing happened. Of course, it was impossible to test my refractory state by intratracheal inoculation; however Francis Schwentker worked out a tricky neutralization test which, when conducted with sera taken before, during, and after vaccination, clearly indicated that after vaccination | had an increase of neutralizing antibodies in my sera.

I will admit that there weren’t a hell of a lot of neutralizing antibodies, and the amount present wasn’t very striking—but you could read it. Subsequently, I immunized a number of people who were working with me in the laboratory, on the general theory that a little protection was better than none. However, nothing much came out of this particular phase of my work, and my techniques for vaccina-

Process of Virus Research—1930 163 tion were thrown into the ashcan when it was discovered that an antibiotic could very handily take care of a psittacosis infection. About the only thing that did happen was that I was elected to the Walter Reed Society—its membership, as you know, is made up of scientists who have experimented on themselves.

O: Dr. Rivers, in looking over your published papers I am struck by the fact that you do not concentrate your efforts on investigating one particular virus, but rather study several seemingly dissimilar viruses. In 1932-33, for example, you worked with Rift Valley fever virus.® Could you tell me how you came to investigate this virus?

Rivers: It never made any difference to me what virus I worked with—the important thing was the question I wanted answered. In the early days of virology, we knew relatively little about the general nature of viruses, and any virus investigated turned up new and useful information. I would like to add that I never went out of my way to study this or that virus; sometimes it was just chance that would lead to particular experiments. Rift Valley fever, for example, is a natural disease of sheep found in Africa. I didn’t go to Africa to study this virus—it came to New York. Originally the virus was investigated by English workers, and it was an Englishman named Dr. George M. Findlay who brought it to the United States. Nobody as far as I know ever asked Findlay to bring it, and I still don’t know why he did, but I

do know that early in the fall of 1932 he showed up with it at the Rockefeller Institute and gave a sample to the yellow fever laboratory of the Rockefeller Foundation. He also gave a sample of the virus to a

the virus. 7 young Canadian worker in Dr. Flexner’s laboratory named Ronald Saddington, and it was through Saddington that I came to investigate

Several weeks after receiving his sample, Dr. Saddington came

down with what seemed to be an infection. He had chills, fever, sore throat, and a general aching all over. ‘The symptoms certainly were nothing to be alarmed about, and Saddington, being the kind of fella he was, tried to carry on in the lab. ‘This went on for a day or two, and

vol. 59:305 (1934). |

. FF. Schwentker and T.M. Rivers, “Rift Valley fever in man,” J. Exptl. Med.,

164 Chapter 5 finally he came into the hopital and became my patient on Ward One. Because he had been working with Rift Valley fever, I naturally suspected that he might have it, and after I eliminated the possibility of

strep and other bacterial infections, I drew some of Saddington’s blood and made several intraperitoneal injections in mice. Mice as you know are very susceptible to Rift Valley fever, and within 48 hours they came down with an illness which by proper pathological technique was shown to be the disease. At the time Dr. Saddington came into the hospital as a patient, his

blood had no antibodies against Rift Valley fever virus. Later, however, he did develop antibodies, so we were further assured that our diagnosis was correct. At no time was I concerned about Saddington’s recovery, because Rift Valley fever in man is usually not fatal. Saddington was recovering rapidly when he began to complain of pain in the calf of one of his legs—Pve forgotten now which leg. An examination revealed that he had developed a thrombophlebitis, or a clot, in the vein of his lower leg. He was immediately put to bed, his leg was elevated, and he was given instruction not to move around. It was the usual treatment for such a condition, but 1t didn’t seem to do

much good. When Saddington began to complain that the pain seemed to be traveling up the leg, I decided to have a surgeon over to discuss the feasibility of putting a ligature on the femoral vein. After much discussion and debate, I concluded not to do it and it was, J am sorry to say, probably the wrong conclusion to draw.

Saddington was kept quiet and for several days he seemed to get better. Then one day he suddenly began to develop severe pains in his

chest. The thrombosis in his legs began to break up, and when the clots reached the lung they caused pulmonary infarcts. The next several days were very stormy. I don’t remember how many infarcts he

. had but he was very sick. ‘Then the attacks subsided. The poor devil had had a rough time—but he seemed to be over the hump. I remember that he began to plan a trip to the West Indies for his convales-

cence. One morning at five o'clock I received a phone call from Francis Schwentker at the hospital who told me that Saddington was

dead. We later did an autopsy and found a huge clot in the heart. Saddington had obviously died immediately. Saddington’s case, I sup-

pose, is the only human case of Rift Valley fever that ever ended fatally, although, strictly speaking, he didn’t die of Rift Valley fever

Process of Virus Research—1930 165 at all, but of a thrombophlebitis brought on by the disease. After Saddington’s death I stopped working with the virus. I froze and dried it and put it away in an icebox. I also cléaned up the places where we had kept mice that were infected. A year later, several workers in another laboratory came down with Rift Valley fever. One was

Thomas Francis, Jr., who today is a professor at the University of Michigan. The other was a technician named Sal Spatola, who still works at the Institute. For the life of me, I still don’t know how they contracted the disease. I am positive they weren’t working with the -virus, and the virus which I had frozen, dried, sealed, and put away in the icebox was still in its place untouched.® ® Dr. Olitsky makes this comment on Dr. Rivers’ implied criticism of Dr. Findlay: I must come to the defense of Brigadier General G. M. Findlay, RAMC. I am sure that he did not give the Rift Valley virus sample to Saddington, as Dr. Rivers says, since he did not know him at the time. It is more likely that Dr. Findlay, a scholar and gentleman, presented it to the director, Dr. Flexner, following custom. Dr. Saddington was then attached to Dr. Flexner’s laboratory and the latter would have turned this material over to Dr. Saddington to keep or work with since Dr. Flexner was busy with executive

duties. More important, at the time that Dr. Findlay presented this gift, it was not known here how invasive the virus was for laboratory personnel. After Saddington’s death,

that became common knowledge, and the Rift Valley virus was placed with typhus fever rickettsiae and other agents as dangerous to workers, even to those not directly handling the material (private communication ). It is interesting to compare Dr. Olitsky’s comments with a letter that Dr. Rivers wrote to Rufus Cole two years after Dr. Saddington’s death.

February 18, 1935 Dear Dr. Cole: The following is a record, complete as far as my knowledge is concerned, of Rift Valley fever virus since its introduction into this country by Dr. G. M. Findlay. Dr. G. M. Findlay without being requested to do so brought into this country Rift Valley fever virus September 2, 1932. A sample was given to the Yellow Fever Laboratories of the Rockefeller Foundation. While Dr. Findlay was here, Dr. R. Saddington, working in Dr. Flexner’s laboratory, obtained directly from Findlay a sample of the virus. Dr. Saddington developed Rift Valley fever December 2, 1932. I recovered Rift Valley fever virus from his blood. This was the source of the virus with which I have worked and which I now have. No one in my laboratory has handled the virus except Dr. Schwentker and myself. All animals were thoroughly isolated in my “psittacosis room.’”’ We fed the animals and cleaned the cages ourselves. , In August 1933, two monkeys were immunized against the virus in order to have a source of diagnostic serum. These animals were isolated during the process of immunization. After it was completed they were returned to the main animal house and are now in Room A 11. We have seen no indications that they are carriers. Late in the spring of 1934 Dr. Schwentker and I carried out a few experiments with

166 Chapter 5 QO: Dr. Rivers, didn’t you also work with another virus disease of sheep at this time called louping-ill? *°

Rivers: Yes. However, please keep in mind that the virus that causes louping-ill is quite different from the one that causes Rift Valley fever. Louping-ill is a disease of sheep found in northern England

and Scotland and, although it has been known for a long time, its viral nature was only established about 1930. I should add that it is also found in sheep in Russia and the Middle East. I was once told—I don’t know how accurately—that the word louping comes from the Scotch for leaping. When sheep get the disease it affects their central nervous system, and they begin to leap in a characteristic fashion. Be the virus in mice. The last experiment was finished June 18, 1934. The mice were destroyed and we cleaned up the containers and the room housing the animals. On May 22, 1934, we stored some dried virus. I still have it and so far as I know none of it has disappeared. During the latter part of August and most of September 1934, E. Hayes and F. Com-

polier (my laboratory boys) were cleaning and painting the “isolation room’ or “psittacosis room.”

E.. Hayes was sick from October 5th to October 16th, 1934. Dr. Parker thought he had influenza and obtained “washings” for Dr. Francis. From these washings Dr. Francis obtained Rift Valley fever virus. Hayes did not come into the hospital. The Bureau of Animal Industry knows that I have the virus in my laboratory and has not requested me to destroy it. I have letters on file regarding this matter. So much for the history of the virus in my laboratory. Now I shall relate the story, as far as I know it, of the virus in the Yellow Fever Laboratory. Dr. S.F. Kitchin was its custodian in that laboratory and did some experiments with it. On February 21, 1933, T.W.N. came down with Rift Valley fever. On September 6, 1933, V.G. came down

with Rift Valley fever. On October 9, 1933, G.W.M. came down with Rift Valley fever. On October 19, 1933, Dr. Sawyer had a talk with Dr. Flexner and between October 19, 1933, and November 2, 1933, all the virus in the Yellow Fever Laboratory was destroyed. According to Dr. Sawyer, their laboratory has been without virus since

November 2, 1933. |

Unless Hayes contracted the disease from dust (the virus must have been at least several months old in the dust of the room at the time he painted the isolation room) or unless there are carriers of the virus, I cannot explain how Hayes contracted the infection. Dr. Francis and Sal most likely caught the disease from the animals infected with Hayes’ virus. Sincerely yours,

Dr. Rufus Cole .

Tuomas M. Rivers

The Rockefeller Hospital

FF. Schwentker, T.M. Rivers, and M.H. Finkelstein, “Observations on the immunological relation of poliomyelitis to louping-ill,” J. Exptl. Med., vol. 57:955 (1933).

Process of Virus Research—1930 167 that as it may, let me say that I received my strain of louping-ill virus

in the fall of 1932 from Dr. G. Mackie of the University of Edinburgh. Actually it was given to me personally by a young South Afri-

can scientist named M. H. Finklestein, who came to this country in 1932 as a fellow of the British Medical Research Council, and who for a brief period was a volunteer worker in my laboratory.

A short time before I received the virus, Dr. E. Weston Hurst in England pointed out that louping-ill was capable of producing in monkeys a disease which pathologically seemed to be quite similar to

poliomyelitis. These findings interested me, and I thought that I _ should try to find out whether there was in fact an immunological relationship between the two viruses. In the back of my mind was the possibility that, if the two viruses were immunologically related, I might try to use louping-ill virus for immunization against polio much like we used vaccinia against smallpox. There was no problem about experimental animals since it had already been shown that louping-ill

~ could be transmitted experimentally to mice, monkeys, and swine. We were much aided in our work by Dr. Flexner who supplied us with monkeys who were immune to polio. I should add here that I use the word we because Dr. Finklestein did most of the work although it was done under my direction. He was a smart hombre and I will admit that he annoyed me because he knew that he was smart, but he worked well. After we devised a method of immunizing monkeys to louping-ill, we inoculated one set of louping-ill immunized monkeys with polio, and another set of monkeys immunized to polio with louping-ill, and found nothing to indicate that the two viruses were even remotely related immunologically. I suppose you might say that you could guess the outcome of these experiments, but in science

you don’t guess; someone has to do the job. Later, when we discovered that white mice contract louping-ill when the virus 1s dropped into the nose, Dr. Leslie Webster and I decided to investigate the pathogenesis of the disease in mice, and in particular to learn whether serum therapy had any value.

O: Dr. Rivers, before you rush on, I wish you would stop to tell me something about Dr. Webster and the nature of his work. Save for an obituary notice in Science, and a warm dedication in John Paul’s re-

168 Chapter 5 cent volume on Clinical Epidemiology, there is little personal data

about Webster in historical literature.

Rivers: I knew Leslie Webster very well, and as a matter of fact Jordi Casals and I wrote the obituary notice in Science that you mentioned. Webster was a graduate of the Johns Hopkins Medical School and after graduation spent a year in the Department of Pathology. In 1920 Harold Amoss persuaded Dr. Flexner to invite Webster to the Rockefeller Institute. Dr. Flexner did, and Webster remained at the

Institute until his death in 1943. Webster was a man of great intelligence and vision, but he had a great deal of difficulty in expressing himself verbally, because he stuttered very badly. The interesting thing about his stuttering was that it didn’t hamper him when he sang. Webster played the piano and when he would sit down to the piano he could sing a song without stuttering one bit. It was, however, painful to try to carry on a conversation with him, but that didn’t interfere with his intelligence.

Up to the time that Webster first came to the Institute, the epidemiology of disease had been studied largely in human populations. The obvious difficulty here was that it was impossible to control conditions so that one could examine epidemiological problems ex-

perimentally. Webster, on the other hand, decided to study the spread of typhoid in mouse populations. Before anybody begins shoot-

ing, just let me say very quickly that Webster was not the only one who had that idea; and that several English workers, among them William W. Topley, Graham S. Wilson, and Major Greenwood had the same notion. I don’t know who was first. Actually, I think that they developed their ideas simultaneously and independently.” I do know that they later disagreed on the meaning of their findings. Both “'T. M. Rivers and J. Casals, “Leslie T. Webster,’ Science, vol. 98:167 (1943); J. Paul, Clinical Epidemiology. University of Chicago Press, Chicago, 1956; P. K. Olitsky,

“Leslie T. Webster,” Arch. Pathol., vol. 36:536 (1943). “There can be little doubt that in this instance the English investigators had priority. In 1919 Flexner had observed the early work of William Topley and his associates in experimental epidemiology and was so impressed with its possibilities that, upon his return to the Rockefeller Institute, he began similar experiments in collaboration with Harold Amoss. When Amoss left the Institute in 1922 for another post, Leslie Webster took over the work in experimental epidemiology and developed it independently. Cf. G. W. Corner, op. cit., pp. 197-200.

Process of Virus Research—1930 169 Webster and his English counterparts quickly learned that, when B. enteritidis (mouse typhoid) was introduced into a population of susceptible mice, an epidemic ensued which, while fatal to many, always left some survivors. ‘They also found that when they added immigrants to such populations they could maintain the infection indefinitely. However, in spite of this, a certain number of mice always resisted the infection. I believe that Topley, Wilson, and Greenwood . felt that the survivors had become immunized, and they contended that the constituents of the uninfected population were alike with re-

- gard to their initial resistance to an infection. Webster, on the other : hand was convinced that individual mice in the population were innately resistant to typhoid infection at the outset, and that indeed various individuals in the population might differ widely in their initial resistance to infection. Very early, I would say about 1922, Dr.

Webster began selective breeding experiments with mice to determine not only whether unexposed mice were all alike in their resistance to infectious agents, but more important whether mouse strains of uniform susceptibility or resistance could be developed. At one point in his work he did develop a strain of mice, 95 per cent of whom were highly susceptible to mouse typhoid, and another line, 95 per cent of whom were resistant to mouse typhoid infection. I watched Webster’s work with great interest, and pretty soon I got the idea that it might be nice if Webster would attack the problem of »

- the epidemiology of virus disease in mice. Well, that was easier said | than done, but I persisted, and when the louping-ill virus came along I finally convinced Webster that he ought to study the pathogenesis

of the disease in mice, and in particular to investigate the value of serum therapy. I must say that Webster’s work was beautiful—it was well thought out and well executed. He quickly demonstrated that, if you put louping-ill virus into the nose of a mouse, it traveled up the olfactory lobes into the brain and eventually down the cord. Now, what I am about to say is strictly from memory and might

not be 100 per cent accurate, but I seem to remember that he was able to show that lesions were present in the cord at least 24 hours before the animal showed any visible sign of illness. Now, this finding was in accordance with the belief that I had, namely, that, once a person was infected with a virus, it was very difficult to influence that in-

170 Chapter 5 fection by the use of serum. Now, there are exceptions. For example, in measles it is about ten or eleven days from the time of exposure to the appearance of Koplik spots in the mouth and, from then, another two or three days before a rash appears on the body. Well it has been known for some time now that, if you give convalescent serum during the first six days after a known exposure, you can prevent the disease. From six days until Koplik spots begin to appear in the mouth, most

physicians think that you can influence the severity of the disease if you give serum. However it’s pretty definite that once Koplik spots appear in the mouth, it makes no difference how much serum you give; you just cannot influence the severity of the disease, either feverwise or as to the amount of rash you have. Now, measles happens to

be a disease with a long incubation period. In a disease like yellow fever, where the incubation period is much shorter, it would be very dificult to demonstrate any effect of convalescent immune serum.” Today of course very little serum is used for the treatment of virus diseases, but that has not always been so, and up until the early nineteen thirties the tendency was in the other direction. Actually, serum - from animals or from convalescent human beings was used to treat a wide variety of viral infections. For example, for a very long time, convalescent human serum was used prophylactically and therapeutically in polio cases. It used to be that doctors would draw off a lot of spinal fluid and inject quite a bit of convalescent serum intrathecally for the treatment of polio. ‘his went on for years, until the New York — Academy of Medicine around 1931-32 put on an experiment to test the efficacy of serum therapy for polio and discovered that it was no use at all. Since that experiment, so far as I know, few if any doctors have ever worried about the serum therapy for polio. Let me tell you, however, that it was just harder than all outdoors to make doctors be-

lieve this initially. Hell, they had been using diphtheria antitoxin against diphtheria and it worked, they had been using antipneumococ-

cal serum against type 1 pneumonia and it worked, so why should they believe that it wouldn’t work against viruses? Everybody just believed that it had to work. Trying to sell a new idea in medicine is like 8 The principles stated by Rivers, based chiefly on clinical observation, are also applicable to experimental viral infections. See P.K. Olitsky and A.C. Saenz, ‘Serum treatment of western equine encephalitis in mice determined by the course of viral infection,” Proc. Soc. Exptl. Biol. Med., vol 68:200 (1948).

Process of Virus Research—1930 17] trying to elect a completely unknown man to be president of the

United States. It takes a lot of doing. ~ I would like to add here that before I finished my work with louping-ill, I found myself in a hassle with the government. Shortly after Dr. Webster began working with louping-ill, he and two of his technicians came down with the virus and became my patients in the hospital. After they were discharged, Dr. Schwentker and I wrote a brief paper on louping-ill in man, and all hell broke loose. Someone in Washington, by one of those strange coincidences, read that paper and the one I had previously written on Rift Valley fever in man and wanted to know how in the name of goodness I came to be working with two viruses that were prohibited from coming into the country. They made it plain that in their view I had broken the law, and they were going to throw the book at me. I just wrote back and told them that they had the wrong fellow, that I didn’t bring the viruses into

the country, and had in fact gotten them from my patients at the Rockefeller Hospital. I said that I saw no reason why I shouldn’t get

such viruses out of a patient I-was caring for. But if the truth is known, I was whistling, and I thank goodness they didn’t press me. I suppose they could have given me the works. Perhaps they decided that what I had learned was worth the nsk. I don’t know but I’d like

to think that. In the end they left me alone, but I want to tell you they put a tight clamp on those two viruses’ moving around the coun-

try. At the present time, so far as I know, nobody is working with

those viruses. :

QO: Dr. Rivers, was it very difficult in those early years to differenti-

ate between the various virus diseases? For example, between St. Louis encephalitis and louping-ill?

Rivers: ‘The answer to that question rested in large part on how well a virologist knew his pathology. For instance, St. Louis encephalitis and louping-ill both go in monkeys, and if you knew anything about _ the brain and cord you could differentiate between these two viruses pathologically. Louping-ill in the monkey does peculiar things, the _ animal can become paralyzed, but invariably the most marked clinical symptom is ataxia. ‘The reason for this is that the louping-ill virus pri-

172 Chapter 5 marily hits the Purkinje cells in the cerebellum. Don’t misunderstand me, other parts of the cerebellum are involved, but the salient cells that are affected are the Purkinje cells. Subsequently I used sections from the cerebellum of monkeys infected with louping-ill to illustrate that infection and destruction of cells are primary phenomena in virus disease, and that inflammatory reactions are secondary. You know, I could kill a monkey infected with louping-ill, and if I caught him at the right time, every Purkinje cell would be gone. It was as if somebody had taken a forceps and picked out the cells leaving, little holes in their place. There would never be any evidence of inflammation. The only thing you could notice was that the tissues seemed to be a

bit more watery. Inflammation came later, and it could easily be shown that it was due to the products of the dead cells, which are very irritating and cause inflammation.

In 1939, when I gave the Lane Lectures at Stanford University, I used pictures of the cerebellum of monkeys infected with louping-ill to underline this point. I assure you it was very dramatic to see every Purkinje cell missing from what seemed to be a normal cerebellum. Actually at that time you couldn’t attract the average doctor unless you produced something dramatic. Like everything else, I suppose, when you have got to learn something that you didn’t know before, or you have to alter your ideas, you don’t do it easily. You have to be hit over the head. I used these pictures as my club.

QO: Dr. Rivers, I wonder if we could shift the focus of our examination from viruses per se, and take up a peripheral but important piece of research you did on allergic encephalitis in 1933.4

Rivers: In 1922 and for several years thereafter, in England, Holland, and other European countries it had been noticed that, following vaccination against smallpox, quite a number of people developed

encephalitis. ‘his postvaccinal encephalitis, as it came to be called, was far more prevalent abroad than it was in this country, although

we did have our share of cases. Why there was such an outbreak at that time, I don’t think anyone will ever know. Some of those *'T. M. Rivers, D. H. Sprunt, and G. P. Berry, “Observations on attempts to produce acute disseminated encephalomyelitis in monkeys,” J. Exptl. Med., vol. 58:39 (1933).

Process of Virus Research—1930 173 aftected died, most recovered; however, in some cases there were unfortunate aftereffects. Now it had been noticed that, following certain diseases like measles, chickenpox, and influenza, and certainly following vaccination against rabies, that similar kinds of illnesses occurred. _ Some investigators in England and Europe were of the opinion that the condition arose because of the direct action of the virus on the brain, and that postvaccinal encephalitis was really a viral encephalitis.

I couldn’t agree with this point of view, because I thought that the pathological signs that were found in postvaccinal encephalitis were definitely different from that found in an encephalitis produced, let us say by St. Louis encephalitis virus. In the latter case, where there is a direct action of the virus on the brain, the neurones in the gray matter are attacked, they die, and you have an inflammation around the dead cells. In postvaccinal encephalitis, the pathological picture is strikingly different. Here the white matter is attacked, and there is a distinct and startling demyelination around the blood vessels, particularly the small veins. ‘There was one man in England at that time who agreed with me. His name was E..Weston Hurst. Dr. Hurst pointed out that in distemper in dogs (a virus disease) you actually could get two kinds of encephalitis, one that came early in the disease and an-

other that came several weeks later, sometimes after the dog had about gotten over his original infection. He too was able to show that the pathological picture in such cases was markedly different. The problem still remained, as to how the postvaccinal encephalitis occurred, Well, like many another before me, I began to study the liter-

ature and I soon discovered that the question was not as new as | thought, and that it had come up earlier with rabies therapy. I learned 7 that, in the early days of the use of the Pasteur rabies vaccine, some patients did come down with a peculiar demyelinating encephalitis, and that even in those days there was a big row as to whether this was due to the direct action of a virus that might have stayed alive in the vaccine or whether it had come about through the injection of foreign

brain tissue into human beings. The more I read the literature the | more fascinated I became, and I finally decided to see what would : happen if [ injected brain tissue into monkeys. I killed perfectly normal rabbits, ground up their brains and began

174 | Chapter 5 to inject monkeys. I honestly didn’t know how long I was going to do this, but for the next several months I injected about 1 cc of an emulsion of such brain tissue into monkeys twice a week. I figured I would just keep on doing this until something happened, or until I got dissusted and quit. ‘This went on for approximately six months until one day Francis Schwentker, who was working with me, came in and said, “Tom, there is something the matter with those monkeys.” I said, “For Pete’s sake, let’s go over and have a look.” Sure enough,

one or two of the monkeys were slightly ataxic and looked kind of seedy. A day or two later they began to tremble and became weak in the legs, and very shortly thereafter they became so ataxic that they couldn’t get around the cage. At this point I killed them. When I examined them, I found to my astonishment a remarkable change in the cord and brain. It was a demyelinating encephalitis. I must say that it didn’t exactly look like the postvaccinal encephalitis that we saw in human beings, nor the kind described following rabies. But there was destruction of brain tissue, there was demyelination, and a lot of the lesions were around blood vessels, particularly veins.

It was extraordinary to learn that it was possible to kill an animal by repeatedly injecting it with some other animal’s tissue. While Dr. Schwentker and I had not used the monkey’s own brain we had no reason to believe that it couldn’t be done. Later we showed that rabbit brain would do it in rabbits, and still later Dr. Elvin A. Kabat and Dr. Abner Wolf at Columbia University proved that it could be done in monkeys. ‘hey operated on a monkey, took out its frontal lobe, and. froze and stored it on ice while the monkey recovered. ‘They then

took the lobe that they had stored, ground it up, added Freund’s adjuvant, and injected the emulsion into the same monkey. ‘That monkey got sick from its own frontal lobe, and I want to tell you that Kabat and Wolf didn’t have to wait for their results six months like Schwentker and I had to.

To me, it’s a profound biological phenomenon to learn that the tissues of a person or animal can create antibodies that will result in _ disease or the death of that person or animal. In the recent past, Dr. Ernest Witebsky in Buffalo, New York, and some English workers simultaneously demonstrated that Hashimoto’s disease (acute thyroiditis ) was caused by antibodies against the thyroid. Many workers

Process of Virus Research—1930 175 are now entertaining the idea that rheumatoid arthritis is due to autoantibodies and are even suggesting that many of the chronic diseases

: that we call degenerative are caused in a like manner. Herein [ think lies a lot for the future. The work I did on demyelinating encephalitis is probably the nicest piece of work I ever did, and it wasn’t in virology. ‘To be sure, I was trying to get an answer to what might follow an infection of viruses, but it turned out to be a whole new field. ‘Today a lot of people talk a great deal about allergic encephalitis, and the ironic part is that they

don’t connect me with it at all.

Q: Dr. Rivers, in previous conversation you have mentioned that pathologists know very well when a virus is infecting the brain. However, unless they should find particular inclusion bodies, it is difficult to differentiate one encephalitis from another. What do you do when

_ you are presented with a new virus, let us say, the one that causes lymphocytic choriomeningitis?

Rivers: I remember that, sometime during the winter of 1934, Dick Shope of the Division of Animal Pathology of the Rockefeller Institute and Bill Edwards, a house painter at the Institute both showed up on my ward with complaints that suggested involvement of the meninges and possible involvement of the brain. Dr. Thomas McNair Scott, who is now professor of experimental pediatrics at the Univer-

sity of Pennsylvania Medical School, was working with me at that time, and I put him in charge of both cases. Tom took spinal fluid from the patients, put it intracerebrally and intraperitoneally in mice and began to watch the mice. After two or three days the mice that had received the inoculations began to show certain peculiarities, and Tom called me in to look at them. We did nothing at that time, but a day or two later, when the mice were obviously sick, we killed them and isolated a medium sized virus.. After making a series of transfers in mice, we became confident that the virus we had found truly came

from the patient’s spinal fluid and not from the animals we were working with; it was unlike any virus I had worked with before, and I thought we had discovered a new virus. However, after talking around and searching the literature I discov-

176 Chapter 5 ered that this was not so. It'turned out that Charley Armstrong of the

National Institutes of Health had isolated a similar virus several months before. As I remember it, Charley isolated his virus from a patient who was originally diagnosed as having St. Louis encephalitis. Well, this poor fellow died, and Charley began to pass material taken from him to monkeys. In the first passage, the clinical picture fitted

with that generally found in St. Louis encephalitis; however, after several passages, the clinical picture began to change, and when Char-

~ ley made a pathological examination of the monkey he not only found lesions that were usually observed in viral encephalitides, but he also found a marked involvement of the meninges, ependyma,

and the choroid plexus. Given these findings, Charley named it lymphocytic choriomeningitis. I’d like to add that at that time there had never been any autopsy on human beings for this condition—it’s a relatively mild disease in humans—and that the disease was named for a condition found in monkeys and mice. About the same time this was going on, Eric ‘Traub of the Division of Animal Pathology of the Rockefeller Institute at Princeton was trying to produce hog cholera in mice. He was injecting hog cholera material into the brains of white Swiss mice when, lo and behold, a good

many of them came down with an encephalitis. At first he thought that he had adapted hog cholera to mice, but then he noticed that his control mice, which had received sterile normal broth, also came down with the same kind of disease. A careful examination revealed

that practically all of the mice in the Princeton laboratories were carrying this virus in a latent form, and that it was passed from

| mother to offspring. Se When Tom Scott and I found our virus, it.didn’t immediately occur to us that our virus was the same as that found by Armstrong and Traub. I do not remember now who suggested that we compare our viruses, but someone did and, on comparison, it turned out that

they were identical. ,

I can understand how Dick Shope got his infection. He was working with Princeton mice and they were loaded with the virus. But for the life of me, I don’t know where Bill Edwards got his. I know that none of the white mice that we were using at the Institute were infected, because if they had been they never would have shown any-

Process of Virus Research—1930 177 thing when we inoculated them with Shope’s and Edwards’ spinal fluid—so they were clean. The origin of Bill Edwards’ infection re-

mains a mystery to me. |

It can be said that the virus was discovered independently in three separate laboratories almost simultaneously. The honor for naming the disease goes to Armstrong. In the middle thirties we saw quite a bit of lymphocytic choriomeningitis in human beings and it seemed

that people all over the country were showing up with this queer disease. And you know, by gosh, even before I stopped working on viruses the disease seemed to disappear. ‘Today you practically never hear of anyone being infected with lymphocytic choriomeningitis.

QO: Dr. Rivers, with the continuing identification of new viruses,

was there a tendency on the part of general practitioners to ascribe ' unknown infections to viruses? How many laboratories were set up to do routine diagnostic work of viral infections?

Rivers: ‘To be sure, there was a tendency on the part of some practitioners to ascribe all unknown disease to virus infection, and I might add that there is such tendency now. If a doc can’t readily find the cause of a disease, he sometimes says to the patient, “You are infected with virus X.” Whatever X may mean, it means he doesn’t know. On

the whole, I would say that doctors during the thirties could quite readily differentiate a viral from a bacterial infection. In cases of meningitis, an examination of the spinal fluid could readily show if. the pa-

tient had a viral or a bacterial meningitis. If it was ‘bacterial, the spinal fluid was usually cloudy (although it is true that in tuberculous meningitis the fluid can be fairly clear) and microscopic smears would _ turn up meningococci, strep, or other bacteria, while if it was viral the spinal fluid was clear.

In my day, when a physician got a case that presented meningeal signs like lymphocytic choriomeningitis he looked to see if it satisfied the criteria ° laid down by the Swedish pediatrician Arvid Wallgren, 45 Sudden onset of meningeal symptoms associated with a slight or moderate increase in the number of cells, especially lymphocytes, in a bacteria-free spinal fluid; a benign course with no complications; the absence of a focus of acute or chronic infection in the vicinity of the brain, for example sinusitis; and the absence from the community

178 Chapter 5 and if it did he called it acute aseptic meningitis. Wallgren considered this condition as a clinical entity and that bothered me. It was

| plain that there were many different kinds of infections of the central nervous system that would fall under Wallgren’s description of aseptic meningitis, and it was almost impossible to differentiate, by clinical means alone, a case of acute aseptic meningitis caused by the virus of lymphocytic choriomeningitis from those produced by an-

other agent. I later wrote a paper attacking Wallgren, but let me make plain that that didn’t make him any less a great man. He was a great pediatrician, and in my view, although I later attacked him he

made an important contribution through his use of the term, acute aseptic meningitis. Keep in mind that he was out in front of the boys. During the thirties there were few laboratories that were set up to do routine virus diagnostic work. In New York, for example, if a general practitioner turned up what he thought was a case of psittacosis

or lymphocytic choriomeningitis, he would send me the patient’s blood or spinal fluid for examination. He did this, because he knew I was working on these diseases. In other parts of the country doctors might call on Ernest Goodpasture or Karl Meyer or Lloyd Aycock. Today a certain number of cities and states have set up virus diagnostic laboratories that can with a reasonable amount of speed and not too much expense give the general practitioner an accurate diagnosis. For instance, Werner Henle’s laboratory at the University of Pennsylvania is supported by the state to do routine diagnostic work for viral diseases in Pennsylvania. It’s an example that can be multiplied , several times over. In my day, such laboratories were lacking.

~ Q: Dr. Rivers, I would like to shift the focus of our attention from viruses that you worked with in the laboratory to a virus that you didn’t work with, but one whose effects absorbed your attention, namely, the virus of poliomyelitis. In 1936, for example, you became associated with the President’s Birthday Ball Commission, which was then one of the major agencies in the United States directing the battle against poliomyelitis. I would like to begin with a discussion of the of diseases known to be capable of producing irritation of the meninges. Cf. R.D. Baird and T.M. Rivers, “Relation of lymphocytic choriomeningitis to acute aseptic meningitis (Wallgren),’’ Amer. J. Public Health, vol. 28:47 (1938).

Process of Virus Research—1930 179 members of the commission and the circumstances that led to your joining.

Rivers: Let me say that in the beginning I did not know any of the members of the Birthday Ball Commission, like Basil O'Connor, Keith Morgan, Jeremiah Milbank, Edsel Ford, or the others who were concerned with raising funds. I did know the members of the advisory committee who were charged with the responsibility of distributing the funds collected by the Birthday Balls for research. At that time 70

per cent of all the money collected remained in the local areas and was largely used in makeshift local care programs, while 30 per cent went to the national office and was used for administrative cost and an over-all research program. ‘he committee in charge of planning the research program was composed of Dr. Max Peet, Dr. Donald Armstrong, Dr. George McCoy and Dr. Paul de Kruif. I would say that, while the committee had distinguished people on it, it wasn’t particularly prepared to deal with the problems presented by the virus of poliomyelitis.*®

Max Peet was a neurosurgeon and a good one. He was an honest, straightforward, and upright person. I liked him, but he didn’t know anything about viruses.*’ [ could never see why he was on the committee, except that he was a friend of Paul de Kruif’s, and anything that Paul wanted to do, Max said yes to. Dr. Donald Armstrong was a third vice president of the Metropolitan Life Insurance Company, in charge of medical affairs. He was clear minded and knew much about problems of public health, but knew little about virus research. About the only fellow on the committee who knew anything about viruses

was Dr. George McCoy. Dr. McCoy was in charge of the Hygienic Laboratory of the U.S. Public Health Service in Washington. Early in his career he had done very nice bacteriological research and later was 1° The first Birthday Ball to raise funds for Georgia Warm Springs Foundation was held January 30, 1934. Subsequently, from 1935 to 1938, this nationwide celebration of the President’s birthday became the principal method of raising money to fight infantile paralysis. On December 15, 1934, a special Birthday Ball Commission of fifteen prominent people was organized to administer the funds raised by the birthday balls. To aid the commission in its work, a special scientific advisory committee was formed early in 1935 and began making grants to medical investigators on May 28, 1935. The first sixteen grants made totaled $241,000. “In 1937, Max Peet helped isolate Lansing type 2 poliovirus.

180 | Chapter 5 the boss of such excellent experimentalists as Dr. Joseph Goldberger and Dr. Charles Armstrong. I would say that Dr. McCoy had more scientific knowledge about viruses than anyone else on the commit-

tee. However, he had very little to say about what was to be done. Without a doubt, the most important member of the advisory committee was Paul de Kruif. Paul de Kruif was and is an interesting man. Originally he took his

Ph.D. in bacteriology at the University of Michigan under the tutelage of Frederick G. Novy, one of the great bacteriologists in the United States at the beginning of this century. After he got his Ph.D. he came to the Rockefeller Institute and worked in the laboratories. I want to tell you that de Kruif did excellent work. Together with John Northrup, he described the rough and smooth colonies of salmonella.

I don’t think I am exaggerating when I say that de Kruif and Northrup had within their grasp one of the most important phenomena in bacteriology, but unfortunately they were never able to exploit it. Later when the English bacteriologist Dr. Joseph A. Arkwright pointed out that the rough colonies were nonpathogenic and the smooth colonies were pathogenic, he was knighted.'* In the thirties the same phenomena was shown to be true with pneumococci as well. de Kruif had the makings of a great scientist. I know him well and, even though I know that he doesn’t like me, I can’t refuse to say

that at one time he had these great possibilities. He never got a chance to develop them at the Institute because Dr. Flexner fired him. Around 1922 de Kruif wrote an anonymous attack on the Institute in a popular magazine which he signed M.D. When Flexner discovered that it was de Kruif who wrote the piece he fired him. Now I - want to make it clear that de Kruif was not fired for writing the article. He was fired—in Flexner’s words to me as well as to de Kruif—for

not signing the article. I don’t think that de Kruif would have been fired if he had signed the article. Dr. Flexner put great store on having the courage of one’s convictions and standing up and taking responsibility for one’s thought and

actions. For instance, I informed Dr. Flexner that I was going to at18 The implication of Rivers’ statement is misleading. Arkwright’s research on bacterial variation started several years before de Kruif began his own experiments and was carried on independently of de Kruif. Arkwright’s knighthood was conferred for a broad range of bacteriological research. See C.J. Martin, “Joseph Arthur Arkwright, 18641944,” Obit. Notices Fellows Roy. Soc., vol. 5:127 (1945).

Process of Virus Research—1930 18] tack him publicly at a meeting of the Society of American Bacteriolo-

gists on one of. his fondest scientific beliefs, the globoid bodies of poliomyelitis, and nothing ever happened. He didn’t try to stop me

and he didn’t fre me. When Dr. Olitsky and Dr. Long presented scientific proof controverting Flexner and Noguchi’s theory, the article was printed with Flexner’s blessing in the Journal of Experimental Medicine. Flexner was like that.

Paul de Kruif’s rupture with the Institute was complete, and soon after he took.a great public revenge. Sinclair Lewis was at that time preparing to write his novel Arrowsmith, and de Kruif became his advisor on scientific problems. ‘The McGurk Institute so beautifully satirized in the novel is the Rockefeller Institute. Most of the members of the Institute found their way into the novel, Jacques Loeb, John Northrup, Peyton Rous, Simon Flexner, and others. ‘hey were recognizable although never identified by name. Some of those portraits were etched in acid, and the book * remained a topic of conversation at the Institute for a long time. * Paul de Kruif’s autobiography also contains an account of his stay and separation from the Rockefeller’ Institute. While his version contains substantially the same facts as are related by Rivers, the nuances de Kruif gives these facts make for another interpretation. See P. de Kruif, The Sweeping Wind. Harcourt, Brace & World, New York, 1962, pp. 16-51. Peter Olitsky, another contemporary of de Kruif’s at the Rockefeller Institute, offers these observations on de Kruif’s relations with the Institute and with Flexner:

I had been Paul’s next-door neighbor at the Rockefeller Institute during a considerable period of his stay at the Institute (1919-1922). We learnt a great deal about each other and were quite friendly; there was always something of interest to hear in his laboratory—talk of shop and gossip—and he had a captivating way in which he entertained his visitor. Many persons thought as I did; consequently his laboratory was usually the scene of much sociability. On the day he was dismissed from the Institute by Dr. Flexner, I met Paul on his way out; he was deeply aroused and excited and said that he had a “waspish pen” and would settle accounts with Flexner in a way to get his revenge for this dismissal. I tried to dissuade him from such action but was turned down.

Dr. Flexner felt that the lay articles, papers, and books published by de Kruif, whether anonymously or not, had the appearance of having the approval of the Rockefeller Institute (as advertised by Hearst’s International Magazine, for example), and that the responsibility for his publications was therefore forced on the Institute without any editorial consent for de Kruif’s literary work, in advance of publicaion. Flexner thus jus-

tified his stand on [de Kruif’s] dismissal. On the other hand, de Kruif’s colleagues at the Institute regarded his microbiologic

work as superior and excellent, strikingly original and obviously important, and himself as a young genius of great possibilities. They expressed amazement by his divagation into the field of journalistic writing and tended to blame Mencken and others of the Smart Set—a contemporary magazine of the avant-garde of the early twentieth century,

182 Chapter 5 Later de Kruif demonstrated that he had great possibilities as a writer. I don’t exaggerate when I say that his books, Microbe Hunters and Hunger Fighters, were read by hundreds of thousands. He had a style that had never been seen before in popular scientific writing and it caught on—to such an extent that other writers tried to copy him. I suppose that that is the final accolade for a writer. ‘The tragedy is that, although Paul has been a successful writer, he has never realized his potential as a writer. I suppose that during the thirties Paul de Kruif was probably the world’s leading writer in the field of medicine and science, and [ suspect it was this preeminence which brought him on the advisory committee of the Birthday Ball Commission.

QO: Dr. Rivers, if you examine the grants made by the Birthday Ball

Commission, it appears that very little of the funds was expended for learning about the fundamental nature of polio virus.

Rivers: If my memory doesn’t play me false, Louis Weed, Joe Stokes, Howard Howe, and Lloyd Aycock all received grants which allowed them to pursue questions relating to the fundamental nature of the virus. But you are right when you imply that most of the relong since defunct—for the loss of de Kruif to science: they believed that these editors

of the Smart Set had taken de Kruif from the straight and narrow and well-defined road of science and steered him onto the winding, wide, and unmarked way of journalism. In this, Norman Hapgood of Hearst’s International Magazine also had a definite, directive hand. Mencken is described in the Columbia Encyclopedia as writing “pungent, iconoclastic criticism, aimed chiefly at all complacent attitudes.” The editors believed that there was a field for their kind of writing in science, even though science is never complacent. I endeavored to discuss these matters with my neighbor, but he believed me timid and reactionary. After his establishment as a going concern in journalism, he lost his zest for laboratory investigation, for Professor Elser of Cornell told me he kept a place open for him for a long time without any success in trying to get him back to his original aptitude for microbiology. One must say, however, that he made a brilliant success, not only of his short experience in scientific research, but also of his writing for the lay reader. Indeed, even Dr. Flexner acknowledged the excellence of his Microbe Hunters, I must add here that . . . Albert Sabin, when he was my associate, related how he had completely abandoned his course in dentistry and changed over to study medicine, for

after reading [Microbe Hunters] he became imbued with, and carried away by, the idea of wearing the shining armor of a microbe hunter (private communication). For those interested in examining further the role of de Kruif in the writing of Sinclair Lewis’s Arrowsmith, see M. Schorer, Sinclair Lewis, An American Life. McGraw-Hill Book Co., New York, 1961; C. Rosenberg, ‘Martin Arrowsmith, the scientist as hero,” Amer. Quarterly, vol. 15:448 (1963).

Process of Virus Research—1930 183 search funds went toward developing a vaccine. As a matter of fact, Dr. William H. Park received a great deal of money from the Birthday Ball Commission for just such a purpose.

Q: Did the Rockefeller Institute get such help? After all, the Institute pioneered in the field of polio research in the United States.

Rivers: As I mentioned earlier, de Kruif and Flexner didn’t get along, and it should come as no surprise that the Institute didn’t get any money from the Birthday Ball Commission. I doubt whether the Institute would have taken it even if it had been offered, first, because Mr. John D. Rockefeller, Jr., did not allow anyone from outside— either government or private agencies—at that time to contribute to the support of the Institute research projects, and, second, because Dr. Flexner did not think that it was possible to make a practical vaccine against polio at that time. Paul de Kruif did know William H. Park and considered him a very distinguished scientist and one certainly worthy of support. Let me add that Dr. Park in his heyday was a great. He was an original and had made important contribution to our understanding of diphtheria, influenza, and measles. In the late twenties Park became interested in polio and tried to develop a horse serum against the disease. As might be suspected, the serum he developed didn’t work, Park, and for that matter other workers at that time, didn’t know that there were three types of polio, and even if the antiserum Dr. Park made in a horse had worked it would only have been good against one type of polio. Dr. Flexner was pretty acid about this work and I suppose part of it went back to the fact that there was no love lost between the two men. Now what I am going to tell you is rumor, gossip, hearsay—call it what you will—but it was common talk among the bacteriologists of my day.

You may remember that I told you earlier that Flexner, Park, and Lewellys Barker in 1899 were part of a commission to investigate dysentery in the Philippine Islands. During the course of that expedition, a new dysentery organism was discovered. ‘The honor of that dis-

covery went to Dr. Flexner and the organism was named after him.

The story goes that Dr. Park always felt that he was the true dis-

184 Chapter 5 coverer of the bacillus and that it should have been named after him. Now, I don’t know who discovered the bacillus. I don’t care to know if Flexner did or Park did. ‘This was gossip that went the rounds and was used in explanation of why Flexner and Park were not friends.”° Be that as it may, I want to tell you that, if Dr. Park ever needed polio material for experimentation, he always sent to Dr. Flexner for virus, and his request was always filled and promptly. That was one of

Dr. Flexner’s attributes, and it still is one of the attributes of the Institute. If we have something at the Institute that other people want, other people usually get it.

In the early thirties Park teamed with a young Canadian bacteriologist named Maurice Brodie to produce a formalinized inactivated vaccine against polio. Dr. Brodie had trained at McGill. Early in 1930 he showed up at the Institute with a letter from one of his professors saying that he wished to learn about poliovirus. Dr. Flexner was very nice, took him to his laboratory, and turned him over to Peter Haselbauer. Peter is what I would call a very high-class technician. He came to the Institute when he was a young boy—just out of high school, I believe—and Dr. Flexner trained him as a technician. He spent his entire life at the Institute and became in fact Dr. Flexner’s technician. He was associated with Dr. Flexner in polio research almost from the beginning of Dr. Flexner’s own researches in 1909, and so he knew a great deal about the MV virus used at the Institute. Peter was a pretty smart hombre and, although he didn’t have formal collegiate training, he was good. Flexner would write out

the protocol for the experiment, and Peter would do it. Peter, of course, was in no position to form an opinion as to whether the old man was right or wrong about a given experiment, because he didn’t » There is no doubt that there was a great antipathy between Dr. Park and Dr. F'lexner. In this respect, what Dr. Rivers says above is true. The reasons that Rivers ascribes for that antipathy are, however, a complete myth. Dr. Park was not a member of the Philippine expedition, and there was never any debate between Dr. Flexner and Dr. Park over the discovery of Shigella flexneri. ‘The bad feeling between the two scientists stemmed from Dr. Park’s public attack on the efficacy of Dr. Flexner’s serum treatment of meningitis before the Harlem Medical Society and in the public press (see New York Evening Post, January 16, 1912). Later when Dr. Flexner’s treatment was proved effective, Dr. Park took the position that Dr. Flexner had merely copied the ideas of the German physician, Dr. Georg Jochmann (see correspondence in folder marked Meningitis Serum, Flexner papers). The myth here created is, however, revealing of Rivers.

Process of Virus Research—1930 185 have the background, but, as I say, he was a superb technician and Flexner could rely on him. Peter taught Brodie about the MV virus for about a month or six weeks, and then Brodie returned to McGill. After that I didn’t hear about Brodie for several years. Actually, I didn’t hear of him again until he came to New York University as assistant professor of bacteriology in the Medical School and had

joined forces with Dr. Park to try to produce an inactivated formalinized vaccine against polio.

At the time Dr. Brodie came to work with Dr. Park, Park was failing, and as a matter of fact he later became very senile. On several occasions Brodie came to see me at the Institute to discuss problems related to making an inactivated vaccine and while I listened to what he had to say I said very little in reply, because I didn’t want to hurt Dr. Park’s feelings. By 1935 Dr. Brodie claimed that he had an inactivated formalinized vaccine that was capable of inducing immunity in

monkeys and humans. Among other things, he maintained that he had developed a minimal completely paralyzing dose of virus. He carried out his titrations to five and six decimal places. Don’t ask me how

he got such titrations because I don’t know. I do know that I didn’t believe them. Later Brodie took a lot of people, bled them, and did antibody titers. Many adults, as you know, have antibodies against type 2 polio. Brodie claimed that, when he gave them formalinized suspensions of virus, he could demonstrate a rise in antibodies. Well, while the amount of stuff he injected might have acted to cause an increase of antibodies, I seriously doubt whether it could have induced the antibodies to come to the point where he could demonstrate them.**

Everything, as I say, came out just night, and Brodie and Park per-

suaded public health officials in California to allow them to immunize about 7000 children with their vaccine. Dr. Ralph Muckenfuss who had earlier worked with me at the Rockefeller Institute, was at this time associated with Dr. Park, and he told me—and you might confirm my remarks with him to see if I have unintentionally dis-

torted what I am about to say—that the vaccine was made in the most incredible sloppy manner. 1 On this particular point, see also M. Schaeffer and R.S. Muckenfuss, Experimental Poliomyelitis, The National Foundation, New York, 1940, pp. 80-82.

186 Chapter 5 The question we now come to is whether any of the children who received the Park-Brodie vaccine came down with polio as a result of using the vaccine. Dr. Norman Topping, who was with the U.S. Pub-

lic Health Service in California at that time, has maintained that some of the children who received the Park-Brodie vaccine could have

come down with polio as a result of the vaccine, because they came down within the proper incubation period after having received the vaccine. However this, as far as I know, has never been proved. It is unquestionable, however, that some of the children who received the Kolmer live-virus vaccine at that time did come down with polio.

O: Dr. Rivers, in retrospect, there are a number of disquieting aspects to the Park-Brodie vaccine incident. Isn’t it true that, long before immunization with the Park-Brodie vaccine took place in Cali-

fornia, workers at the Rockefeller Institute were skeptical of Dr. Brodie’s and Dr. Park’s findings?

Rivers: ‘That is true. Dr. Flexner was very skeptical of this work, and I believe he asked Peter Olitsky to see if he could repeat Dr. Brodie’s experiments. Dr. Olitsky, with the assistance of Dr. Albert Sabin and Dr. Perrin H. Long, then tried to see if they could immunize monkeys following Brodie’s procedures and had no success at all. I watched

them. They did a nice job, but they found it impossible to repeat

Brodie’s work.”

} Dr. Olitsky disputes Rivers here. Dr. Rivers’ memory is somewhat dim here. What happened was that I had started in 1935 on this work of reexamination of Kolmer and Brodie’s experiments, employing ricinoleate (Kolmer) and formalin (Brodie) as virucidal agents, adding tannin for control and untreated virus (infected monkey brain) as another control, to note whether an effective vaccine could thereby be produced for use in monkeys. I later requested my associate, Herald Cox (Drs. Sabin and Long were not available then) to join me in this work. I had great respect for his ability and skill and desired to continue work on the polio problem. The virucidal agents were used in the dosages prescribed by Kolmer and Brodie. We found that, in general, if these chemicals did not act a sufficient time, the vaccine by itself could produce polio in monkeys; if they were applied over longer periods of time and killed the virus, no immunity, except rarely, was induced to a test dose of virus given

into the brain of vaccinees, but antibody could be found in the blood. Also, it was difficult to find an end point for formalin; ricinoleate was generally ineffective. Dr. Cox did well in this work and this was the beginning of his researches on polio, which he

Process of Virus Research—1930 187 O: If that is true, why didn’t the Institute make an attempt to halt the immunization program projected by Dr. Park and Dr. Brodie? Rivers: Well, California is a long way from New York, and I expect that the people in California were much more cognizant of Dr. Park than they were of Dr. Flexner. Park’s name was awfully well known the world over.

QO: Come now, Dr. Rivers, Dr. Flexner was surely as well known as Dr. Park. Even if what you say is true for California, how do you explain the fact that the U.S. Public Health Service allowed vaccination with the Park-Brodie vaccine in North Carolina and Virginia? They surely had as much respect for Dr. Flexner’s name ‘as for Dr. Park’s

name. |

Rivers: Well, all I can say is, it’s against the law to do many things, but the law winks when a reputable man wants to do a scientific expe-

riment. For example, the criminal code of the City of New York holds that it is a felony to inject a person with infectious material. Well, I tested out live yellow fever vaccine right on my ward in the Rockefeller Hospital. It was no secret, and I assure you that the peo-

ple in the New York City Department of Health knew that it was | being done. ‘Then again, the statutes of the City of New York plainly say, if there are cases of yellow fever in the city a yellow flag should

be flown in the harbor for all to see. I don’t know whether anyone saw such a flag flying when I had several yellow fever cases on my ward in 1931.

Unless the law winks occasionally, you have no progress in medi-

cine. For instance, it was plainly against the law for people at the. Sloan-Kettering Institute and the Memorial Hospital several years ago to inject people with what they thought were oncolytic viruses.

: The Department of Health and the lawyers running the city knew

munication ).

about it but again they did nothing. They cooperated. Actually, you continued after his departure from my laboratory with brilliant success (private com-

For further detail of this work, see P. K. Olitsky and H. R. Cox, “Experiments on active immunization against experimental poliomyelitis,’ J. Exptl. Med., vol. 63:109 (1936).

188 Chapter 5 have such laws to keep unprincipled people from taking advantage of an unsuspecting public. Remember that Dr. Park, Dr. Brodie, and Dr.

Kolmer were well-known scientists. For instance, John Kolmer’s name was known all over the United States, because of the excellent

book he had written on serological techniques. I don’t think that there was a laboratory in the country that didn’t make use of that book. ‘They were not penny ante fellows.

O: Dr. Rivers, apparently there were a number of people who did have second thoughts about both the Park-Brodie and Kolmer vaccines. Wasn’t a meeting arranged by the American Public Health Association in October 1935 to discuss the safety of the Park-Brodie and Kolmer vaccines? **

Rivers: Indeed, there was such a meeting, and I was asked to go out to Milwaukee and be the hatchetman. I kind of dreaded the job because I liked Dr. Park, but believe me I didn’t mind jumping on Dr. Brodie and Dr. Kolmer. ‘The meeting was much like any other meeting run by the Public Health Association. Brodie and Kolmer had been asked to prepare papers and I was asked to discuss them. While I remember the substance of my remarks, I don’t remember the detail

, and I would like to submit here a typewritten copy of the remarks | prepared for that meeting. You can insert it later. [See Appendix B.| I remember that there was subsequent discussion of my paper by Brodie, Park, and Kolmer, but I don’t think that anything conclusive

happened. After the meeting Dr. Foard McGinnes asked me if | would join another symposium on poliomyelitis to be held at the meet-

ing of the southern branch of the American Public Health Association in St. Louis the following month.** This time I was asked to prepare a formal paper on immunity in virus diseases with particular reference to poliomyelitis. Dr. Brodie, Dr. Park, and Dr. Kolmer were again asked to prepare papers describing their work on polio immuni-

zation, and in addition Dr. Robert Onstott and Dr. Alexander Gilliam of the U.S. Public Health Service, who were associated with field *8 Meeting of the American Public Health Association, Milwaukee, Wisconsin, October 8, 1935. * Dr. Rivers’ reference here is to the Fourth Annual Meeting of the Southern Branch of the American Public Health Association, held on November 19, 1935, in St. Louis.

Process of Virus Research—1930 189 studies of polio vaccination in North Carolina, were also asked to prepare papers. The paper I presented was later published in the American Journal

of Public Health,’ and if you examine it I think you will find that while I made more extensive remarks about the nature of immunization to virus diseases in general, the substance of my remarks about

the Park-Brodie and Komer vaccines was the same as those I had made a month before. But I want to tell you that the meeting in St. Louis was very different from the one held in Milwaukee—the difference was James P. Leake of the U.S. Public Health Service. Dr. Leake was a very distinguished field officer who had had a long experience with polio, dating back to the epidemic of 1916. He was in charge of the immunization program in North Carolina and had followed very closely the polio cases that appeared after use of the Kolmer live-virus vaccine. Because Dr. Onstott and Dr. Gilliam were officially giving papers on behalf of the U.S. Public Health Service, Leake was not at the meeting in an official capacity. However, just as soon as I finished giving my paper (mine was the last in this particular session) and the floor was open to discussion, Leake was on his feet. I want to tell you, he was hot under the collar. He presented the clinical evidence to the

effect that the Kolmer live-virus vaccine caused several deaths in children and then point-blank accused Kolmer of being a murderer. All hell broke loose, and it seemed as if everybody was trying to talk at the same time. A little later Dr. Brodie got up and said, “It looks as though, according to Dr. Rivers, my vaccine is no good, and, according to Dr. Leake, Dr. Kolmer’s is dangerous.’”” He sat down and Dr. Kol-

mer got up. He didn’t refer to me at all. He just said, “Gentlemen,

then sat down. )

this is one time I wish the floor would open up and swallow me.” He

Jimmy Leake used the strongest language that I have ever heard used at a scientific meeting and when he got through speaking both vaccines were dead. It took something like Jimmy Leake’s statement to put an end to the vaccines. When you say somebody is committing murder, people usually stop and think. I believe that the vaccines would have died a natural death within a year, but Leake killed them *'T’. M. Rivers, “Immunity in virus diseases with particular reference to poliomyelitis.” | Amer. J. Public Health, vol. 26:136 (1936).

190 Chapter 5 then and there—you didn’t have to wait twenty-four hours. ‘The vac-

cines were dead and so were careers. Within a very short period of time, Brodie was fired from his post at New York University, and _ Kolmer and Park retired.”* It was because of the Park-Brodie vaccine that I was asked to come on the advisory board of the Birthday Ball Commission.

QO: Could you explain the last statement a little more fully?

Rivers: Yes. Paul de Kruif and the rest of the boys on the Birthday Ball advisory board were afraid to tell Dr. Park that he couldn't get any more research funds. ‘They had to have somebody like me—a rough-neck—to get the job done. After I came on the commission, Dr. Park never got another cent. For the life of me, I couldn’t see why he got all that money in the first place. I would have been in favor of giving some of those funds to Lloyd Aycock of the Harvard Medical School and David Kramer of the Long Island Medical School. Now

that is not hindsight. Both Dr. Aycock and Dr. Kramer had had a long experience with polio through their association with the Harvard Infantile Paralysis Commission and knew polio from the clinical as well as experimental side. Aycock and Kramer ironically did receive some money from the Birthday Ball Commission, to test the results of the Park-Brodie vaccine immunizations in North Carolina. Later when the National Foundation came into existence, Dr. Kramer, who

by that time had moved to the Department of Health of the state of Michigan, received several grants and did interesting work developing ** The printed record of the discussion at this meeting in the American Journal of Public Health does not contain the harsh language that Rivers claims was used by Leake.

Here Leake is pictured as saying, “I beg you, Dr. Kolmer, to desist from the human use of this vaccine.” It is very probable, however, that Leake used stronger language, and the editor of the American Journal of Public Health later altered it for purposes of publication. Soon after my interviews with Rivers I had occasion to speak with Leake about this point, and he told me that, while he didn’t remember the exact words he used at the meeting, he did remember that he had used some very harsh language. Cf. “Discussion of poliomyelitis papers,’ Amer. J. Public Health, vol. 26:148 (1936). Rivers’ account in one respect misconveys the outcome of the failure of the vaccines. The burden for that failure was publicly borne by Dr. Brodie. Dr. Park was retired with honors, Dr. Kolmer continued a useful and productive career as a professor of medicine at Temple University School of Medicine until his retirement in 1957. Only Brodie

was fired and disgraced. |

Process of Virus Research—1930 19] a killed vaccine against polio. If I am not mistaken he got very sugges-

tive results in mice—but again no one took them very seriously. : QO: Dr. Rivers, live-virus and inactivated-virus vaccines were not the only ways thought of by doctors to protect against polio. Didn’t some

investigators like Dr. E. W. Schultz attempt to prevent infection through intranasal irrigations with various chemical agents such as tannic acid, zinc sulphate, and picric acid? 7

Rivers: Dr. Schultz was not the only one who tried this. Peter Olitsky and Albert Sabin at the Institute tried it, and so did Charley Armstrong of the U.S. Public Health Service. I believe they all used different chemicals, but the general idea was to see if, by treating the: olfactory nerves with chemical solutions, they could prevent the virus from traveling along the olfactory nerves to the brain. At that time . Dr. Flexner thought that the virus traveled in lymph channels around

the nerve to the brain but later W. E. Le Gros Clark in England proved that it traveled along the nerves themselves.?* The experi_ mental work with sprays in animals was suggestive, and in 1936 Dr. Armstrong tried using picric acid and alum sprays on children in Alabama. Armstrong was never able to prove whether the children whose noses he had sprayed were protected against polio. Actually, he never got a chance to run the controlled experiment he needed, because “The interviewer here was not as precise as he might have been in posing the question. ‘There is no doubt that as early as 1934 Peter Olitsky and Herald Cox had demonstrated that a dilute tannic acid solution put into the nostrils of white mice served to protect them transiently against an intranasal installation of equine encephalitis virus. Subsequently this technique was independently and almost simultaneously adopted by Charles Armstrong, Edwin Schultz and Peter Olitsky in their experimental poliomyelitis

research. See P. K. Olitsky and H.R. Cox, Science, vol. 80:566 (1934); C.A. Armstrong and W.'T’. Harrison, “Prevention of intranasally inoculated poliomyelitis of mon-

keys by the installation of alum into the nostrils,” Public Health Rept., vol. 50:725 (1935); E.W. Schultz and L.P. Gebhardt, “Prevention of intranasally inoculated poliomyelitis in monkeys by previous intranasal irrigation of chemical agents,” Proc. Soc.

Exptl. Biol. Med., vol. 34:133 (1936); A.B. Sabin, P.K. Olitsky, and H.R. Cox, “Protective action of certain chemicals against infection of monkeys’ infection of monkeys with nasally instilled poliomyelitis virus,” Abstract, J. Bacteriol., vol. 31:35 (1936); article later printed in full, J. Exptl. Med., vol. 63:877 (1936). ** Rivers has reference here to W. E. Le Gros Clark, Anatomical Investigation into the

- Routes by Which Infections May Pass from Nasal Cavities into the Brain. Ministry of Health Reports on Public Health and Medical Subjects, No. 54 H.M. Stationery Office, London, 1929.

192 Chapter 5 parents in Alabama started to spray children on their own and the kids he did spray resisted so much that he never knew whether he had in fact thoroughly applied the spray in the nasal vault. Later the spray idea was given an extended test in Toronto, and the doctors there concluded that the spray would not protect because you couldn’t apply it properly without putting the child on his back and

lowering his head in such a manner that he would receive the full effect of the spray in the nose. It certainly wasn’t a procedure that could be used for spraying large populations of children. Max Peet. tried to devise a practical technique for spraying large groups of children but never came up with a practical solution. ‘The sprays were not without danger—some of the people who received the spray lost their sense of smell. One such person was Dr. Donald Fraser of the Con-

naught Laboratories. He never regained it to the time he died. He told me once that the only objection he had to this loss was that he couldn’t enjoy his sherry anymore. You know, you smell sherry instead of tasting it. Given these results, spraying of the nose with zinc

sulphate, picric acid, or what have you fell into disuse. However, when the National Foundation came into being in 1938 people still spoke of sprays and the Foundation was quite prepared to support such a program if someone came up with a decent testing plan. No such plan was ever presented, and the sprays also died a natural death.

QO: Dr. Rivers, I still can’t understand why the major research support of the Birthday Ball Commission was directed to problems of immunity, rather than dealing with basic problems relating to the poliovirus per se—for instance, trying to type the virus. .

Rivers: I am not sure I understand all of this myself. You know, when the St. Louis encephalitis virus was discovered, in very short order it was differentiated from other encephalitic viruses like Japanese B, western equine, eastern equine, Venezuela, and so on. ‘That never happened with poliovirus, largely, I believe, because Dr. Flex-

_ ner and Dr. Noguchi kind of overpowered people, even people of great repute. While they never outright said so, they acted as if there were only one poliovirus, and if Noguchi and Flexner felt that there was only one poliovirus, why in hell should a young investigator just

Process of Virus Research—1930 — 193 out of Podunk question them and try to type viruses? I think this also

held true for the question of portal of entry for the virus, although here I believe chance played a role as well.

Dr. Constantin Levaditi of the Pasteur Institute early claimed that he could bring down monkeys by feeding them poliovirus by mouth. Dr. Flexner, on the other hand, always disputed those findings because he couldn’t infect his monkeys using this technique, although he could infect them readily enough by dropping the virus into the nose. Dr. Flexner worked with the Macacus rhesus, and he was abso-

, lutely right—you can’t bring the rhesus down by feeding it virus. Levaditi on the other hand was working with the cynomolgous monkey, which can be brought down by feeding. If Flexner had used the

cynomolgous in his experiments,?? he would have found out that monkeys can be brought down by feeding. It so happens that the mouth is the portal of entry for the poliovirus in humans. I don’t know low many years were used up in debating whether the portal of

entry was the nose or mouth. Progress was held up purely by chance . because a big man like Flexner was using the rhesus monkey. If Flex-

ner had used the cynomolgous monkey, the chances are that we might have had a vaccine that much sooner. | QO: Dr. Rivers, how would you characterize the research accomplishments of the President’s Birthday Ball Commission? —

Rivers: Minus. If you take the good things that they did, and subtract the bad things that they did, you get a minus. It doesn’t mean — that everything they did was rotten or useless. It means that when you add and subtract you get a minus. That’s all. 7° Rivers overlooks here that, soon after Dr. Flexner learned that Dr. Levaditi in cooperation with Carl Kling had reported experimental infection of cynomolgous monkeys by the feeding of poliovirus, he undertook to restudy the whole question of the mode of infection. The particular feeding experiments he undertook were not successful, and he concluded that the gastrointestinal tract played no considerable part as a portal of entry of the virus in man or monkey. See the report of Simon Flexner to the Board of Scientific Directors of the Rockefeller Institute, 1932, and S. Flexner, “Respiratory vs. gastrointestinal infection in poliomyelitis,” J. Exptl. Med., vol. 63:209 (1936).

CHAPTER 6

The Rockefeller Institute Hospital —1937 ... In my laboratory . . . we work with and think of tobacco mosaic virus much as we would with simple organic molecules. Dr. Wendell Stanley, Some Chemical, Medical, and Philosophical Aspects of Viruses: An Address, 1941

QO: Dr. Rivers, on July 1, 1937 you took over the duties of director of the Rockefeller Institute Hospital—did appointment to this post come as a surprise to you?

Rivers: ‘The answer to that question is yes and no, and I am sorry to give you such a tentative reply. Dr. Flexner had retired as director of

the Institute in 1935 and was succeeded by Dr. Herbert Gasser. Everybody knew that Dr. Cole was reaching the age of 65 and would retire as director of the hospital in 1937, so there was reason to believe that a new director of the hospital would be appointed. There were many people in the country who could have been chosen to fill the post, and I have since heard that certain good people were consid-

ered. I won’t mention their names, but I will say that they were equally as good as I was and in one or two cases even better. I think the reason I got the job was that by 1937 the Board of Scientific Directors of the Institute knew me very well, and even more important the new director of the Institute, Dr. Gasser knew me. Gasser had been a classmate of mine at the Hopkins, and in the two years he had

been director of the Institute he had a chance to renew his acquaintance with me and to relearn things about me. 194

Rockefeller Institute Hospital—1937 195 Gasser didn’t know a thing about viruses, and I guess that made us even because I sure as hell didn’t know anything about his work. He was a neurophysiologist and a good one. Good enough, I might add, to win a Nobel prize. In 1944 Gasser and Joseph Erlanger, of Wash-

ington University in St. Louis, shared the prize for their earlier pioneer work in tracing the passage of electric impulses along nerves. That work was enormously complicated, and to this day it amazes me.

I still can’t honestly say that I thoroughly understand it. I suspect that Gasser felt the same way about viruses and for that reason perhaps saw me as a useful teammate. He knew that we could work together without any difficulty, and I have always felt that it was his de-

sire to have me in charge of the hospital that was the determining factor that in the end brought me the directorship.

_ Q: Dr. Rivers, I wonder whether the growing preeminence of virology played a role in your selection as director.

Rivers: I don’t know how to answer that question. When I first came to the Institute in 1922, virus research was a brand-new discipline and, in spite of the fact that Dr. Rous and Dr. Flexner, among others, had already made significant contributions to the field, there were but a handful of people at the Institute who were interested in virology per se. By 1937 that picture had changed radically: virology as a discipline was well rooted at the Institute, and some of the best virologists in the world were to be found there. ‘These included people

like Wendell Stanley, Peter Olitsky, Louis Kunkel, and Dick Shope. A new generation of virologists like Albert Sabin, Jerry Syverton, Joe Smadel, and Herald Cox were finishing their apprenticeship and were just about ready to take command of their own laboratories. As a matter of fact, you could find virologists anywhere you looked at the Institute—in the Division of Laboratories, the hospital, the Division

of Animal Pathology, or the Division of Plant Pathology. I don’t think that I am far from the mark when I say that there were some members of the Board of Scientific Directors who were afraid that, if things kept ‘going the way they were, the Rockefeller Institute would

become a virus institute. I believe that one of the reasons that Dr. _ Gasser was chosen to head the Institute was that it was felt that he

196 Chapter 6 would keep the Institute from becoming too narrowly concerned with viruses and infectious disease. Dr. Gasser subsequently did much to

develop basic physical and chemical research at the Institute, and I might add that I stopped proselytizing for virus research and got other

things under way at the hospital. Make no mistake, to this day the Institute has its share of superb virologists—people like Dick Shope

and Igor Tamm are proof of this—but today the Institute does not have as many virologists as we had in 1937. Today the best virus laboratories in the world are to be found in Tiibingen, Germany, while Wendell Stanley’s laboratories at the University of California run them a close second.

QO: Dr. Rivers, one of the implications of your remarks is that there was a rivalry between M.D.’s and Ph.D.’s at the Institute, or put an-

other way between medicine and the basic sciences. | Rivers: In my day there was not much conflict between the M.D.’s and the Ph.D.’s at the Institute, although there always was a bit of looking down the nose between the two groups. The M.D.’s looked down their noses at the Ph.D.’s and vice versa. For the life of me I

} never could understand why a Ph.D. should look down his nose at an M.D. Most M.D.’s take a four-year college education and then follow it with four more years at medical school. Afterward they have from

three to four more years of interneship and residency. By the time most M.D.’s came to the Institute, they had been through this mill and you would think that they had had enough education to command the respect of the Ph.D.’s. But it really never was a matter of education: the bald fact is that the Ph.D.’s never felt that the M.D.’s were scientists. Just recently I heard a young doc at the hospital com-

plain to one of the old Ph.D.’s at lunch that all the M.D.’s went around trying to pass themselves off as Ph.D.’s, and he wondered if it

had always been so at the Institute. “No,” replied the old Ph.D. “Thirty years ago I tried to pass myself off as an M.D. Then they were the kingpins around here, you know.” Now I personally never felt that way, what with people like Don-

ald Van Slyke, Wendell Stanley, L.O. Kunkel, and Moses Kunitz around. However, there was justice to his remarks. It is true to say that in my day the people who rode the saddle were M.D.’s. The first

Rockefeller Institute Hospital—1937 197 director of the Institute, Simon Flexner, was an M.D. ‘The first direc-

_ tor of the hospital, Rufus Cole, was an M.D. The Institute was the Rockefeller Institute for Medical Research and its most preeminent figures—like Rous, Landsteiner, Avery, and Cohn—were also M.D.’s.

When Dr. Flexner and Dr. Cole retired, they were replaced by M.D.’s. Today this is no longer true. The Institute has become a postgraduate institution in the basic sciences, and while the hospital still exists it no longer plays the important role it once played in Instttute affairs. Detlev Bronk, the current director, is a Ph.D. who has Ilittle interest in medical problems per se, and God knows he has no inferiority complex as far as M.D.’s are concerned. I will speak more of this change later.

O: Dr. Rivers, to whom were you responsible as director of the hospital?

Rivers: I was immediately responsible to Dr. Gasser who ran the entire Institute. Ultimately, I suppose I was responsible to the Corporation of the Institute, which was composed of two separate bodies, a Board of Trustees and a Board of Scientific Directors. ‘The ‘Trustees were largely concerned with financial matters, like maintenance of In-

stitute property, investment of endowment funds, taxation, and so forth. In matters of scientific policy, everybody deferred to the Board of Scientific Directors. ‘This board was invariably composed of distinguished medical scientists and at one time or another included such

figures as William Welch, Theobald Smith, Warfield Longcope, Walter Cannon, and Hermann Biggs. ‘The director of the Institute was always a member of the Board of Scientific Directors. However, the same did not hold true for the director of the hospital. In Dr. Flexner’s time, Dr. Cole was not made a member of the Board of Scientific Directors. However, when Dr. Gasser was appointed, he recognized this policy as a fallacy and made a place for the director of the

hospital on the board. When I was appointed director of the hospital I took a place on the Board of Scientific Directors, but I never served with the ‘Trustees.

O: Dr. Rivers, many of the members of the Board of Scientific Directors had full careers and some were even engaged in their own re-

198 Chapter 6 search. How did they keep tabs on the work in progress at the Institute? Rivers: Almost from the beginning of his tenure, Dr. Flexner established a unique system of reporting at the Institute. Each spring, the

heads of the various departments in the Division of the Laboratories, the hospital, and the Division of Animal Pathology were required to write a technical report of their work in progress to the Board of Scientific Directors. Nobody ever told them how long to make their reports, and the length of reports varied from scientist to scientist. In my own case, the reports I submitted were rarely less than twenty pages and frequently more than forty pages, while Dr. Landsteiner’s reports were rarely more than five pages and frequently less than three pages. In the fall of each year, a similar report in nontechnical Janguage was prepared for the Board of ‘Trustees.

The reports were never sent directly to the Board of Scientific Directors, and in the first instance always came to the director of the Institute and the director of the hospital. Each year, Dr. Gasser and | would read these reports and prepare an hout’s talk for the Board of Scientific Directors on the significance of the research in progress. We, of course, stressed the things we believed to be important. However, the board could always make up its own mind by studying the original reports. I want to tell you that the Scientific Directors read those reports, and some members like Warfield Longcope even made a point of visiting various laboratories.

QO: Did the Board of Scientific Directors ever try to direct research?

Rivers: JI should say not. No. And for that matter, neither did I or Dr. Gasser. Oh, from time to time we might tell a fellow, “Gee, why don’t you try this?” If the guy wanted to he could, and if he didn’t that was all right too. Let me say here that the minute a director of a first-class research institute begins to direct research in that institute he should be fired. If he is allowed to do it, and the workers in that institute accept such direction, they should be fired, because you can take it from me, they are not worth the salt they eat. It’s either one or the other—you just can’t go fooling around with the independence of

Rockefeller Institute Hospital—1937 199 research workers. ‘he time to make a decision about a researcher is when you hire him; once you are sure that he knows how to do research, you leave him alone.

Between us, Dr. Gasser and I could make appointments to assistants’ jobs in the laboratories or the hospital, but any job beyond the level of an assistant, either a primary appointment or a promotion from assistant to the next higher grade or rank, had to be passed upon

by the Board of Scientific Directors. Any time we wanted to raise somebody’s rank, particularly if we wanted to make him a member, we might have to talk an hour or so to the Board of Scientific Directors in explanation of why we thought Dr. So-and-So should be made a member. On one occasion in Dr. Flexner’s time the board refused “to honor a promotion. I won’t tell you the man’s name. You may find it sooner or later—if you do, all right, but I don’t want to be the one to give it away. I will say this, that several years later the same board turned around and made this man a member. Back in the old days, a

membership in the Rockefeller Institute was far hetter than a professorship in a university. You had to work hard to get it, and it was hard to come by, because the Board of Scientific Directors deliberately made it that way. Boy, you had to be something.

QO: Dr. Rivers, what were your duties when you took over the hospital?

Rivers: When I took over the directorship of the hospital, I had two titles, I was director of the hospital and I was a member of the , Institute. I still had my laboratory. It functioned and had good men in it. However, I could devote less time to research because of the press of my administrative duties. I don’t know that I can get away .

Slyke. : with all this. Let me add that my administrative duties were not very

burdensome, because the heads of the various departments in the

hospital were old hands like Swift, Van Slyke, Cohn, and Avery. ‘They

knew what they were about and certainly didn’t need me butting in. About the only member that caused me any difficulty was Dr. Van

Van Slyke was a Ph.D.—but what a Ph.D. I don’t think that the

Rockefeller Hospital will soon see his like again. Although Van Slyke

200 Chapter 6 was a Ph.D., he had charge of all the kidney cases in the hospital, and over the years I must say that he was a better physician as far as his handling of nephritis and nephrosis was concerned than most M.D.’s. Because Van Slyke was a Ph.D., he couldn’t sign orders in the order book for medicine and drugs, nor could he order tests. However, most of the orders carried out by M.D.’s on the service were usually done at

Van Slykes’ suggestion. Hell, the only people in the country who equaled him in knowledge about the kidney were Homer Smith, the expert in renal physiology at Bellevue—Homer was also a Ph.D.—and A. N. Richards at the University of Pennsylvania. As far as I am concerned, no one in the United States has done as much as Donald Van Slyke to unravel the nddles regarding the physiology and diseases of the kidney. Now, why did I have trouble with Van Slyke? I'll tell you why and you can judge for yourself. For years Van Slyke and his boys followed all the cases of nephritis and nephrosis that came into the Rockefeller Hospital. ‘They followed them meticulously, sometimes for periods of

twenty years or more, often until death intervened, and when that happened they frequently got autopsies. In the end, they collected between six and seven hundred cases. ‘he material cried to be written up. In my estimation, if that had happened it would have been one of the outstanding contributions ever made by the Rockefeller Hospital,

but Pl be damned if I could ever get Van to write them up. I tried and tried and tried. One time I even persuaded Harry Eider of the Cornell Medical School to help Van Slyke with this chore. Do ‘you : think that helped? Hell, no. It never got done, and it’s really the only thing I have against Van. In 1948 Van Slyke retired from the Rockefeller Institute and went

, out to the atomic energy laboratories at Brookhaven, Long Island. You know they have built a little Rockefeller Hospital out there and Lee Farr, who worked with Homer Swift at the Institute on rheumatic fever, runs the operation. He and his associates, many of whom are Institute alumni, study patients as thoroughly as they ever did, perhaps more so, because today they have the benefit of isotopes created by atomic energy which are so useful in the laboratory.

O: Dr. Rivers, when senior members like Dr. Avery, Dr. Swift, Dr. Van Slyke and Dr. Cohn retired whom did you get to replace them?

Rockefeller Institute Hospital—1937 201 Rjvers: When a member retired from the Institute or hospital, he was not necessarily replaced, nor was his work necessarily carried on. Traditionally, the laboratory just folded up. When Landsteiner died

this happened; when Phoebus Levene retired this happened, and when Alfred Cohn retired this happened. ‘Today, the Rockefeller Hospital does not have in the true sense of the word a straight cardiologist like Dr. Cohn. In Dr. Ahrens, for example, they have a man who is interested in one phase of cardiology—that is, arteriosclerosis and coronary thrombosis—but there is no one who is actually replacing Cohn’s department as such. To be sure, you can always replace a distinguished person in one field by another distinguished person in the same field. However, I myself didn’t do this; instead I chose to take young people and gamble on them and let them develop into people who had the stature of Avery and Swift. If there are any boners about the present members of the Institute that work in the hospital, I am the fellow who is responsible, because I appointed them. Making an appointment wasn’t always an easy matter. For example, when Dr. Van Slyke retired, I wanted to get a doc who knew something about chemistry and who would carry on in his tradition. Such people are hard to find, and I finally settled on Dr. Reginald Archibald. Archibald was an M.D. and an excellent chemist. In the beginning of his career he had worked with Van Slyke; however, when Dr. Elmer MacCollum retired from the Hopkins, Archibald left the Institute and took his place as professor of biochemistry in the School of Public Health. Archibald had all the qualifications, but one thing bothered me. When he was with Van Slyke I could never

get him to see patients, because he loved the laboratory. It didn’t make any difference how much I bawled him out. When I say bawled out, I mean in parentheses—you don’t bawl out a fellow like Archibald—I mean I talked to him. It didn’t make any difference, because he spent the bulk of his time in the lab. Dr. Gasser knew about this, and when I put up Archibald’s name he said, ““T’om, if you bring him back, he is going to spend all his time in the lab, and he is never going to look at a patient.” Well, I kicked it around awhile and finally decided to gamble on Archibald.

Do you shoot craps? Gasser told me I was going to throw a three—I shot an eleven. From the moment Archibald returned to the hospi- |

202 Chapter 6 tal, he quit going to the lab. All he did was see patients. ‘Today he has the biggest outpatient department of endocrine disorders in children in the City of New York, and he has become one of the leading experts in the United States on such abnormalities in children. I.don’t

: have to tell you that the kids and their parents love Archibald because he is devoted to them. ‘The only thing I regret is that he is not connected with a teaching institution, because the kinds of abnormal children who find their way to the Rockefeller dispensary should be seen by medical students, and those medical students should have the benefit of an expert like Archibald to instruct them. Now, I never thought I’d make a mistake as big as that.

QO: Dr. Rivers, you surely must have had some administrative problems.

Rivers: I don’t want to give the impression that everything went free and easy. It didn’t. There is always something coming up in a hospital on a day-to-day basis. When I became the director of the hospital, I in effect became responsible for the welfare of each and every patient that we had and I made it my business to go around and see them. My nurses and residents might not have liked that, because if I found anything that wasn’t exactly the way it ought to have been _ they heard from me, loud and clear. I want to make it plain, however, that I didn’t go around only because of a sense of duty; it so happened that I just liked to see patients.

My biggest administrative problem was the superintendent of nurses, Nancy Ellicott. Miss Ellicott hated me and, brother, I wasn’t too fond of her. It wasn’t a short-term affair and began almost from

the day I came to the Rockefeller Hospital. When I first came to New York, Miss Ellicott gave me an earful of what a heavenly place

the Rockefeller Hospital was, that the nursing setup was incomparable, that everything was this, that, and the other. ‘To hear her tell it, everything was perfect. Handling of children, particularly infants, is very different from handling adults. Most hospitals had recognized that and gave their nursing staffs special training. So far as I was concerned, the nurses at the Rockefeller Hospital had had no such training, or if they had they gave every indication

Rockefeller Institute Hospital—1937 203 that they had forgotten it. For instance, soon after I took charge of Ward 1, I made rounds and found a child of about three years of age alone in isolation in an adult bed. ‘The nurse had placed the child on a

bedpan in the middle of the bed and then for some reason or other left it alone. Well the child used the bedpan, and when it tried to get off it-tipped it over, spilling everything all over the bed. Well, that little kid somehow got off the bed and went over to get a towel next to the sink in the room, spreading joy as it went. Feces—I never saw so many feces in my life, the room was full of it. I got hot under the collar and went to get Miss Ellicott and my resident, Hugh Morgan, who later became a professor of medicine in Nashville. “Miss Ellicott,” I said, “is this an example of your good nursing?” I can tell you, she didn’t like that. On another occasion, I entered a room and found a baby lying in a cradle where the floor of the bed had been raised over the sides. Raising the floor of the bed in this manner was standard practice and was

done so the nurse would not have to work down in the hole of the crib, What wasn’t standard practice was that the baby was lying on its stomach on top of the crib all alone, three feet off the ground, with a

thermometer up its behind. God, did I raise hell about that one. A broken thermometer up the behind is one of the bugbears of the practice of pediatrics. You just don't leave a thermometer up the behind of a baby without keeping your hand on it. When I got through, Miss Ellicott never forgot that rule, and neither did the nurse. Another time, I went into a room and found a nurse bathing a baby in a pan in the middle of the floor. ‘I’o keep the child from crying, the nurse had given it a small open box of talcum powder. When I came into the room the kid had the box in its mouth. “What in the name

of God do you mean giving a child a box of talcum powder to play : with?” I asked. “Don’t you know that if any of that powder is inhaled and it gets into the kid’s lung there is a very good chance that it will get pneumonia?” When I finished with her, I went over and raised hell with Miss Ellicott. She didn’t take kindly to my lecture and went over to complain to Dr. Cole. Cole then called me in. “Dr. Rivers,” he said, “I don’t believe talcum powder will cause pneumonia.” “Dr. Cole,” I replied, “You’re the expert on pneumococcal pneumonia,

but I want to tell you right now that you don’t know a damn thing

204 Chapter 6 about the kinds of pneumonia kids can get. I’ll bring you a dozen articles on pneumonia caused in children by talcum powder. Once that

stuff gets in the lungs and gets wet, you are going to have the damnedest pneumonia.” In this case I was a prophet, because that kid did get a pneumonia and was sick, real sick. From these stories I think you can see that I wasn’t very diplomatic

as far as Miss Ellicott was concerned. Don’t you for one moment think that I was like Dr. Cole. Dr. Cole was a very nice person, and he didn’t like to fuss and fight with ladies. He didn’t like to fuss and fight, period. Actually, he would go out of his way to dodge a fight,

and in the hospital that meant that Miss Ellicott kind of had her way. I was different, and don’t think that I didn’t like fighting with Miss Ellicott. I enjoyed it, and I just looked for a fight on all and every occasion. If she hadn’t been so ornery, I probably would have been much easier on her. As it was, I looked close, and every time I caught her off base she heard about it.

Our last hassle came about a year before her retirement and concerned her replacement. Miss Ellicott was a graduate of the Johns Hopkins Nursing School, and Hopkins nurses were in my day always considered something special. ‘Ihe Hopkins, for example, was the first nursing school that required its girls to have a college education be-

fore they went into nursing training. ‘The Hopkins nurses were thought to be super duper, and as far as I was concerned they were super duper, super duper on paper work, and super duper in trying to

avoid taking care of sick patients. When the question of the new superintendent came up, Miss Ellicott made it plain that she wanted Stella Hoffmann, the head nurse on Ward 3 and a Hopkins graduate, to get the post. She also told me in no uncertain fashion that it was

her feeling that the housekeeper should have a place in the front office of the hospital. I couldn’t see all this, and I suggested to the Board of Scientific Directors that Alice Lockie who had been the head nurse on my ward (Ward 1) be made superintendent. Miss Lockie was Canadian—about a third of the nurses at the Rockefeller were Canadian—and they were a different breed from the Hopkins." *For another and perhaps more balanced view of Hopkins nurses, see E. Johns and B. Pfefferkorn, The Johns Hopkins Hospital School of Nursing, 1887-1949, ‘The Johns Hopkins Press, Baltimore, 1954.

Rockefeller Institute Hospital—1937 205 They didn’t know much about paper work, but they sure did know about how to take care of a sick patient. For assistant superintendent, I nominated another Canadian nurse named Georgianna Drew. Miss . Drew had previously been in charge of the diet kitchen. And finally I proposed Miss Hoffmann as supervisor of nurses. I didn’t pay any attention to Miss Ellicott’s suggestion about putting the housekeeper in the front office—housekeeping in the hospital is usually done by people who live below the stairs, and it made no sense to me to put them

in the front office. That’s the way it went. I must say that I subsequently didn’t have many administrative problems, because Miss. Lockie and Miss Drew took care of everything, and they are still taking care of that hospital. This doesn’t mean that on occasion I didn’t bawl them out—lI did—but it was always friendly.

O: Dr. Rivers, you mentioned before in passing that getting the d1rectorship of the hospital meant a diminution in your lab work. How did you feel about this?

Rivers: I felt bad. I don’t know why, but in this country people always take someone who has been successful in the laboratory and make him an administrator. For instance, Conrad Elvehjem was probably one of the best researchers in the field of nutrition in the country before they took him out of the laboratory and made him president of the University of Wisconsin. To be sure, he is making them a wonderful president, but the fact is there are other people who could make the University of Wisconsin a good president. How many Elvehjem’s can you find to put in the laboratory? ‘his is characteristic of what happens in science in this country. Mind you, I ain't complaining. I would be lying if I told you I didn’t like being made

director of the hospital. Actually, the Board of Scientific Directors gambled quite a bit on me, because up to the time I became director | had not administered anything of any size. I still ran my lab, but the actual work was done by people like Bob Parker, Joe Smadel, and Charley Hoagland.

Q: Dr. Rivers, much of the work in your laboratory since 1936 has to do with the elementary bodies of vaccinia virus and I wondered

206 Chapter 6 what impact Dr. Wendell Stanley’s crystallization of tobacco mosaic virus had on this particular work.’

Rivers: I don’t know how to measure the exact impact of Wendell Stanley’s work on my own research, but it was important, and perhaps

I should say a few words about him. Dr. Stanley is a chemist, and at the time he crystallized tobacco mosaic virus he was working in John Northrup’s setup in Princeton.*? Now that is a fact of extraordinary importance. Northrup is a biochemist and in his day was one hell of a

scientist. I put it this way because he is now in retirement. Dr. Northrup’s laboratory was one of the most productive at the Institute, and I don’t mind telling you that at one time the Institute came close to losing him to Yale. Northrup hated living in New York and around 1926 or so went to Dr. Flexner to complain. “Dr. Flexner,” he said, “I can’t live in New York and, if you don’t let me work outside the city Iam going to Yale.” Dr. Flexner didn’t want to lose this brilliant worker and in the end allowed him to move his laboratories to Princeton. At that time, the

Division of Animal Pathology and Plant Pathology of the Institute also maintained laboratories in Princeton. Although Northrup’s lab was separate from those run by Dr. tenBroeck and Dr. Kunkel, they benefited from being close together, and I suspect there was always a

great interchange of ideas between those units. Dr. Northrup at that , time was working on the crystallization and purification of enzymes and his laboratory always attracted unusual people—one of those was Moses Kunitz. Dr. Kunitz, a Russian by birth, is an odd and brilliant person who to this day doesn’t speak English very well. At least, I have always found it dificult to understand him. He just ain’t a talker, but God,

he is good in the lab. Dr. Kunitz has never received the amount of public recognition he has deserved for his work on the purification of enzymes, largely because he is the kind of guy he is. Do you know he can be in a room and nobody will ever see him or know he is there? I 2 W.M. Stanley, “Isolation of a crystalline protein possessing the properties of tobacco mosaic virus,’ Science, vol. 81:644 (1935). * This is a slip of the tongue. Dr. Stanley was a member of Dr. Louis O. Kunkel’s laboratory. However, he did have association with Dr. Northrup and his colleagues during his stay in the plant pathology laboratories in Princeton.

Rockefeller Institute Hospital—1937 207 tell you all of this, because it is my belief that Stanley in his work benefited from his association with people like Kunkel, Northrup, and Kunitz. ‘This in no way should detract from Dr. Stanley’s accom-

plishment—believe me, crystallizing tobacco mosaic virus was quite | an achievement.

In 1935, through steps I cannot now recapitulate, Stanley found what he called a protein substance that possessed the properties of tobacco mosaic virus. Protein chemistry at that time was relatively new, and in the beginning Stanley didn’t trust his findings. I want to

tell you that he redissolved and recrystallized his substance many times, but each time he found that it acted just like the virus. I don’t know how many times he tested the effects of various chemical reagents on the infectivity of tobacco mosaic virus. When he finally published his note that tobacco mosaic virus was an autocatalytic agent which was protein in character and readily obtainable in a crystalline form, people sat up and took notice.* ‘This didn’t mean that

everybody agreed with him or even accepted his work night off. For instance, Kunkel, who was probably the leading expert on tobacco mosaic virus at that time, remained skeptical of his achievement. Let

me read part of a report he made to the Board of Trustees of the Rockefeller Institute at that time. . . . Last year Dr. Stanley isolated from the juice of mosaic diseased tobacco plants a crystalline material such as is shown in the photograph. His report that the material is a protein possessing the properties of tobacco mosaic virus has aroused great interest, because the work indicates that this virus may be a chemical compound.

The crystalline protein has a molecular weight of about 17 million, a value considerably larger than that of any other known protein. It is over one hundred times more active than the suspension made by grinding diseased tobacco leaves. Dr. Stanley has not been able to separate virus activity from the high molecular weight protein by filtration through collodion membranes, by centrifugation at the isoelectric point, by centrifugation of positively or negatively charged protein in solution or by centrifugation of

the protein from solutions containing other proteins. The same, or a closely related, high molecular weight protein has been isolated from tomato, spinach, and other phlox plants affected by tobacco mosaic disease. . * This was true for the general public as well as the world of science. See editorial, ‘A crystalline protein having the property of a virus,” J. Amer. Med. Assoc., vol. 50:37] (1935); and the editorial, “Life in the making,” The New York Times, June 29, 1935.

208 | Chapter 6 Spinach and phlox do not belong to the tobacco family, and it is quite evi-

dent that the protein being studied is characteristic of mosaic diseased plants. . . . It is difficult to prove either that the high molecular weight protein is the virus or that it is not the virus. Dr. Stanley is engaged in accumulating further evidence bearing on this important point.®

Dr. Kunkel’s note will give you some notion of the skepticism that a scientist has to satisfy before a new finding is accepted, and I must say that subsequently Stanley worked hard in gathering the necessary evidence to prove his achievement. I also want to make it clear that | too was one of the skeptics, and I wasn’t exactly gentle with Stanley. One of the reasons was that Stanley and some other scientists wanted to believe nght away that all viruses could be crystallized and that they were all alike. On this point, I was certain that he was wrong. It was clear to me that viruses were not all alike and that they differed in size and complexity. Shortly thereafter, Bob Parker and I were able to show that dry elementary bodies of vaccinia virus were composed of ash, fat, protein, and some carbohydrate, not protein alone, as Stanley claimed.

As a matter of fact, an important emendation was made of Stanley’s findings within a year of publication by two British virologists. Originally, Stanley claimed that tobacco mosaic virus was a rather large protein; however, Frederick C. Bawden and Norman W. Pirie, two English virologists, demonstrated that it was, in fact, a nucleoprotein.* Now when I say this I am not running Stanley down; such corrections happen every day in science—it’s nothing new. What Stanley did was new, and in 1946 he shared a Nobel prize with James B. Sumner and John H. Northrup. Dr. Sumner got one half the prize for crystallizing urease and Dr. Northrup and Stanley shared the other

half, Northrup for crystallizing pepsin and trypsin, and Stanley for crystallizing tobacco mosaic virus.’ In 1948 Dr. Stanley left the Institute and went to the University of * Report of Louis O. Kunkel to the Board of Trustees of the Rockefeller Institute for Medical Research, 1936.

°F. C, Bawden and N. W. Pine, “The isolation and some properties of liquid crystalline substances from solanaceous plants infected with strains of tobacco mosaic virus,”

Proc. Roy. Soc. London, Ser. B, vol. 123:274 (1937). “Dr. Rivers’ appraisal here is similar to one that he made of Dr. Stanley’s work twenty years earlier. See T. M. Rivers, “The infinitely small in biology,” Science, vol. 93:143 (1941).

Rockefeller Institute Hospital—1937 209 California in Berkeley. Here he demonstrated another quality, that of a scientific organizer. ‘Today I would say that Stanley’s laboratory is one of the great virus laboratories in the world. While he himself now does little work with his own hands, he has succeeded in attracting

such workers as Heinz Fraenkel-Conrat, Frederick Schaffer, and Carleton Schwerdt, and I want to tell you that these boys turn out damned fine work. Well, I chalk that up to Stanley. There is an art in

getting people to work for you, and by so doing Stanley has done much for virology in this country.

Q: Dr. Rivers, can you recapitulate for me the events that led to your work with elementary bodies of vaccinia virus?

Rivers: As I mentioned before, following Dr. Stanley’s work, a number of investigators became firmly convinced that viruses, partic-

ularly small ones, were of the same order of magnitude as that of a large protein molecule, and that in essence they were inanimate substances fabricated by autocatalysis in diseased hosts. Other investigators, myself included, were equally convinced that some viruses notably large ones, in spite of their obligate parasitism were autonomous living agents.

I turned my attention to vaccinia virus, because it had long been used as a prophylactic against smallpox, and much was known about it. Secondly, it was a rather large virus possessing a diameter of between 150 and 200 millimicrons. In 1906 a German worker, Enrique Paschen, observed small bodies in tissues infected with vaccine virus which he called elementary bodies. Actually, I believe elementary bodies were first seen by a British worker,* but certainly no one paid much attention to that British work until later. In science you can always go back and find somebody who did something before the guy everybody else says is first. ‘he point is, such people rarely make their findings stick. Paschen did and he deserves credit, but for many years the importance of his observation was overlooked. ‘The reason for this is relatively simple. The elementary bodies, when dried and stained * Dr. Rivers here undoubtedly has reference to John Biust. See M. Gordon, “Virus bodies. John Biust and the elementary bodies of vaccinia,” Edinburgh Med. J., vol. 44:

65 (1939).

210 Chapter 6 properly, could be seen by means of ordinary light and a good microscope. ‘I'he only trouble was that there were other small bodies which also took the stain, and it was difficult to differentiate them from the elementary bodies themselves.

In 193] Dr. John Ledingham and in 1932 Dr. James Craigie demonstrated methods by which one could obtain elementary bodies of vaccinia in a relatively pure state. It was an important step because without considerable amounts of elementary bodies in this state, it was Just impossible to do any chemical, serological, or immunological testing. This work opened the door. By means of differential centrifugation in horizontal and angled centrifuges, Bob Parker and I were able to repeat Dr. Ledingham’s and Dr. Craigie’s work. I should add

that our preparations of elementary bodies exhibited an extremely high titer of vaccine virus, and we became convinced that the elementary bodies were associated with the virus. Following this, we made

chemical analyses of the bodies and, as I mentioned before, discovered that they were composed of protein, fat, carbohydrate, and ash. In all of this work Bob Parker played an important if not primary role.

O: Dr. Rivers, how did Dr. Parker come to work with you?

Rivers: I don’t now remember the immediate circumstances that brought Bob Parker to the Rockefeller Institute, although I can tell you that Dr. Gasser had a hand in it. Bob received his training at the Washington University Medical School in St. Louis and as a student attracted Dr. Gasser’s attention. Gasser considered him to be very

bright, and with that as a recommendation I took him on. By the way, he was in the same class as Joe Smadel, who later also came to work with me. Parker was a tall, lanky individual, possessed of great patience, and

I quickly found him capable of doing excellent work, particularly where great accuracy was required. For example, when we were working on the elementary bodies of vaccinia, we decided we would do a

statistical study of the relation of elementary bodies to infection and agglutination. After the elementary bodies had been prepared, the number of bodies in a particular suspension had to be counted, the

Rockefeller Institute Hospital—1937 211 density of the suspension had to be measured, and finally a correlation had to be made between the number of elementary bodies in the suspension and its infective titer. Well, counting elementary bodies by direct observation was not exactly easy and required, to say the least, patience. Bob did the counting, using a Petroff-Hausser counting chamber under a microscope with dark-field illumination. Between each count it was necessary to cleanse the chamber. You can see that it wasn’t very edifying close work. In the end, we found that the correlation between the number of elementary bodies in a suspension determined by direct count and the infectious titer of the suspension was pretty close, and we took our findings to mean that in all probability one elementary body would infect. I am this tentative because there were a great many variables. For example, you could never be sure that all of the elementary bodies that you saw were active, and

in addition you couldn’t be absolutely sure that every particle that you saw was in fact an elementary body. ‘here was only an 80-percent chance of it being so. As I say, Bob was largely responsible for this work. In 1938, after three years in my laboratory, Bob went to Western Reserve University and today is a professor of medicine at that institution.

O: Dr. Rivers, would you say that it was your work with the elementary bodies of vaccinia that focused your attention on an inactive approach to virus immunity?

Rivers: Well, no. Not by itself. QO: I raise the point because in 1928 you made the statement that it was highly doubtful that an inactivated virus could lead to protection against the same virus in an active state.

Rivers: I made such a statement in 1928 and I was incorrect. At that time I was of the impression that you could never get a vaccine that would protect against a virus disease unless it was active. I even believed rabies vaccine, which was supposed to be inactive, had some active particles in it. I was fortified in this belief by Dr. Leslie Webster. It was never bruited about, but Webster once showed that a lot

212 Chapter 6 of the rabies vaccines that he got from commercial houses that were supposed to be inactive were in fact active. But damn it all, you know I could never immunize rabbits against smallpox with massive doses of inactive vaccinia virus. Heck, I could give them 50 cc of concentrated elementary bodies that had been inactivated by heat, formaldehyde, or ultrasonic methods, I could get antibodies against the L and

S soluble substances, but I could never get any neutralizing antibodies, nor could I get much of an immunity. ‘This is true to this day. Smallpox happens to be a disease that you cannot immunize against with a killed vaccine. Yellow fever is another. Believe me when I say

that Max Theiler has tried and tried and tried. It just can’t be done; live yellow fever vaccine is the only way you can immunize against yellow fever.

The thing that really made me change my mind about immunization with inactivated viruses was when Peter Olitsky and his boys at the Rockefeller Institute demonstrated that they were able

to immunize guinea pigs against encephalitis with an inactivated virus. ‘That work really bowled me over—lI just couldn’t get around

it—and that was the time I began to eat the words I had written in 1928.9 Later, Ei Lilly and Company, on the basis of Olitsky’s work, ° Dr. Olitsky writes of Dr. Rivers’ comments as follows: What Dr. Rivers refers to here is the work done with Dr. H.R. Cox, which began

as soon as he came to my laboratory at the Rockefeller Institute in 1932. What we sought then was a model for work on the poliovirus problem—another virus which attacked the central nervous system and to which mice were susceptible. At that time only monkeys were susceptible to the available strains in the laboratory. Monkeys were dificult to get and to handle, and the pressure for something to be done was high. We obtained a sample of equine encephalitis virus, western strain, from Dr. K. F. Meyer, of the Hooper Laboratory at the University of California, and worked chiefly on prob-

lems of immunity for the next four years. We used infected brain tissue and tissueculture virus in active form or inactivated by different methods, and various routes of injection of mice with varying quantities of virus, and finally came up with the principles underlying the development of immunity in mice: for example, how much vaccine to use to produce the required amount of resistance or differing degrees of immunity.

We felt complimented when our neighbor, Dr. L.T. Webster, used our methods for working out the immunology of rabies in mice. In spite of our showing that a solid immunity could be obtained readily in mice with completely inactivated virus, Dr. Rivers, as he states here, was not convinced at the beginning but with time, as he says, he was “bowled over’ by our results. This statement by Dr. Rivers is the first public notice by others than ourselves of our work—now 30 years since its inception; hence I must add some explicatory remarks: In the first place Dr. Rivers is too generous to give us so much credit when our work was chiefly on the principles underlying induced immunity in mice. Successful immu-

Rockefeller Institute Hospital—1937 213 began to manufacture an inactivated vaccine for immunizing horses

against encephalitis. But please remember that when I made that statement in 1928 I had good reasons for making it. I think that, if I had my life to live over and I were faced with the same facts, I would probably make the same mistake. There is no disgrace in having to eat your words occasionally; the only disgrace comes when you have to

eat them all the time. I think that the best scientists, and this includes people like Pasteur, make mistakes. Sure, if you read Vallery-

Radot’s biography of Pasteur he comes out like a cross between a saint and an IBM machine—pure and perfect. But remember that René Vallery-Radot was a relative—what do you expect? Pasteur, the working scientist, was a different man; not all of his experiments and results were perfect, and he wasn’t an angel to work with. ‘This doesn’t

make him less great—it only makes him human. René Dubos doesn’t gloss over these points in his biography of Pasteur, and for the

first time you can get to understand Pasteur the scientist. I think Dubos’s biography is infinitely superior to the one written by Vallery-

Radot. I stress the point because I know of no scientist who hasn’t made a mistake. ‘he only guy in research who hasn’t made a mistake is the guy who has never done anything.

O: Dr. Rivers, I wonder if you really waited for Dr. Olitsky’s results. Didn’t you say at one point when you were working with the elementary bodies of vaccinia, “It’s apparent from our data that the repeated injections in rabbits of large quantities of elementary bodies of vaccine virus inactivated by small amounts of formaldehyde led to the

appearance in the serum of specific agglutinans, precipitants, and nization of horses was secured by M.S. Shahan and L. T. Giltner of the U.S. Bureau

of Animal Industry (1934-1936) and by ].W. Beard of Duke University and by R.W.G. Wyckoff of the National Institutes of Health and their associates (1938), the former group using infected brain tissue inactivated by formalin and the latter group using tissue cultures of the virus also similarly inactivated. The “Lederle Laboratories in Pearl River, N. Y., also received permission to prepare commercial vaccines that were first used in 1938 on horses, which were suffering many serious epidemics at that ... time. The vaccines were freely used then and with considerable success, for the incidence of the disease among equine animals . . . was reduced 90 per cent the first year the vaccination was carried out, but not all equine animals were injected. The vaccine is not available as yet for human beings. At the moment, a more efficacious way of handling an epidemic in man is by abatement, or eradication (if possible), of mosquitos, which are the carriers of the virus (private communication).

214 Chapter 6 neutralizing antibodies as well as the development in the animals of a certain degree of resistance to an infection with vaccinia’? 1°

Rivers: Yes. What you have quoted is exactly what I found. I hated to have to say the neutralizing antibodies, but I did. ‘They were there. The others wouldn’t have made any difference. But the resistance to infection was minimal, and you could not use such a substance to

immunize the human population against smallpox. It instilled a doubt, but Olitsky’s work nailed it down.

QO: Iam sorry to have thrown you a curve ball.

Rivers: You are not bringing up anything new. I have known about this for years, and so has everybody else. ‘There is nothing wrong with

making a mistake; if you don’t learn from it, why then it’s another matter.

QO: Dr. Rivers, you earlier mentioned the name of Dr. Joseph Smadel. I know that in the period between 1937 and 1942 he played a singularly active part in the research on elementary bodies of vaccinia virus. However, before we discuss his specific contributions I wonder if you could tell me something of his background and how he came to work with you.

Rivers: Joe Smadel was born in Vincennes, Indiana, and after a secondary education in the schools of that city attended the University

of Pennsylvania. I don’t know the circumstances that led him to choose medicine as a career, but after college he went on to the Washington University Medical School in St. Louis and in 193] sraduated with his M.D. degree. Subsequently he took an interneship and residency at the Barnes General Hospital in St. Louis and in 1934 joined Homer Swift’s department in the Rockefeller Hospital as an

assistant. Originally, I believe that Dr. Smadel started to work on streptococci, but the thing that brought him to my attention was his 10R,F. Parker and T. M. Rivers, “Immunological and chemical investigations of vaccine virus: Response of rabbits to inactive elementary bodies of vaccinia and to virus free extracts of vaccine virus,” J. Exptl. Med., vol. 63:90 (1936).

Rockefeller Institute Hospital—1937 215 work on nephrotoxic serum. Actually he did this work in collaboration with Lee Farr, who at that time was also working in Swift’s department. Briefly, what they did was to take rat kidney and inject it into ducks, hens, and rabbits to produce-an immune serum. Subsequently they took the serum and injected it into rats, producing the most beautiful nephrotoxic nephritis you ever saw. I should add that Dr. Smadel and Dr. Farr were not the first to do this trick and were preceded by a Japanese investigator named Masugi. Nevertheless it was Smadel’s and Farr’s work that put nephrotoxic nephritis on the map because it was so beautifully and carefully done.”

QO: Dr. Rivers, that sounds very much like the work you were doing in allergic encephalitis.

Rivers: Yes. Actually I think that that was one of the reasons that Joe later wanted to come to work with me. Another was that by 1937 he had become interested in viruses. He knew about the work I was doing on elementary bodies of vaccinia virus from Bob Parker, who was a former classmate of his, and then again I wasn’t shy in telling youngsters at the hospital about my work. I didn’t have to wean him away from Dr. Swift. I think it’s fair to say that he wanted to come with me on his own. For my part, I was happy to get him. Joe was one of the hardest workers I ever had. I never told him to do anything; I didn’t have to. If you look at the bibliography of my laboratory in the years between 1937 and 1942 you will find my name on a lot of papers with Joe. Properly speaking, my name shouldn’t be on those papers at all. ‘They were Joe’s ideas. All I did was to let him go ahead. I think that Joe is the best man I ever had to work with in my laboratory—he just was blessed with the imaginative qualities that are so essential for a man to make a success in research. As a person, I would say that he hasn’t changed a bit. I don’t think ™ Rivers has reference here to M. Masugi, “Uber das Wesen der spezifischen Verdnderungen der Niere und der Leber durch das Nephrotoxin bzw. das Hepatotoxin. Zugleich ein Beitrag zur Pathogenese der Glomerulonephritis und der eklamptischen Leberkrankung,” Beitr. pathol. Anat. allgem. Pathol., vol. 91:82 (1933); J. E. Smadel, “Experimental nephritis in rats induced by injections of anti-kidney serum preparation and immunological studies of nephrotoxin,” J. Exptl. Med., vol. 64:921 (1936); J. E. Smadel and L. E. Farr, “Experimental nephritis in rats induced by injection of anti-kidney serum. II. Clinical and functional studies,” J. Exptl. Med., vol. 65:527 (1937).

216 Chapter 6 that he ever will. He’s a man who acts naturally under all conditions. It makes no difference where he is or whom he is with. For example, if he wants to say son of a bitch, he’ll say son of a bitch. I remember that once I was speaking with a distinguished visitor in my office in the hospital. My office door opened onto the hall, and I usually kept it open. ‘That day for some reason Joe got hot under the collar in the laboratory and came storming into the office. He walked around the room several times looking at me and my visitor not saying a word.

Suddenly he exploded, “That God damn son of a bitch,” and with that left the room. I want to tell you, my visitor was shaken. “Tom,”

| he said, “what’s wrong with that guy?” “There ain’t nothing wrong with him,” I said. “He just came in to blow off a little steam. He knew it was better to blow it off here than in the laboratory. It’s his way of cooling off.”

This is Joe. When World War II broke out Joe wanted to join my navy unit but the navy wouldn’t take him because he couldn’t meet their physical requirements. He joined the army instead. After the war he ran the Virus and Rickettsial Disease Laboratories at the Walter Reed Hospital, and in 1956 switched to the U.S. Public Health Service as associate director of NIH. In time he got tired of administrative work and in 1960 returned to the laboratory. Today he is chief of the Virus and Rickettsial Laboratories at NIH. Such change takes courage, but again it’s absolutely characteristic of Joe. Hell, he’d work for nothing as long as he is able to do what he wants to do. If you ask

me, I would say that, without question, Joe Smadel today is one of the most knowledgeable all-round virologists in the country—far better than I was in my heyday. He’s right in there working today, and sitting here, reminiscing at this desk, doing nothing, I know that I am missing something.

QO: Dr. Rivers, I would like now to turn to an examination of Dr. Smadel’s work on the elementary bodies of vaccinia virus. ‘The published papers indicate that that work involved the use of sophisticated biochemical techniques including the use of equipment like Tiselius apparatus and the ultracentrifuge. When, for example, did you begin using the ultracentrifuge in your laboratory?

Rockefeller Institute Hospital—1937 217 Rivers: The people in my laboratory first began to use the ultracentrifuge late in 1937 or early 1938. At that time it was a relatively new piece of hardware and was little used in virus work. During the late twenties Dr. ‘The Svedberg in Sweden, with the financial assistance of the Rockefeller Foundation, developed the first ultracentri* fuge. The original model was a huge piece of equipment and had to be housed in a special building. While its use for experimental biological work was immediately perceived, it took a team of highly skilled workers to run it, and that plus its original cost made it prohibitive to use. “‘T’he ultracentrifuge my people used was a model that was developed in the laboratories of the Rockefeller Foundation—then housed

on the top floor of Theobald Smith Hall—by Edward C. Pickels, a young physicist who had trained with Dr. Jesse Beams at the University of Virginia. Dr. Pickels’ centrifuge got its energy from compressed

air, and, while it needed a special foundation and setup for the compressed air, it was a much smaller machine than the one developed by Svedberg. In the beginning there was no commercial production of this machine, and people at the Institute who wished to use an ultracentrifuge had to use the one housed in the Rockefeller Foundation laboratories. Actually it was a matter of courtesy that Dr. Pickels and the Rockefeller Foundation labs let my people use the ultracentrifuge. They were, of course, anxious to learn what their machine could do, and we wanted to learn more about the elementary bodies of vaccinia. I want to make it clear that I myself had nothing to do with this work, and that it was carried out by Dr. Smadel with the assistance and collaboration of Dr. Pickels and Dr. Theodore Shedlovsky. OQ: Dr. Rivers, can you tell me what they did?

Rivers: I can tell you the problem they wanted to solve and what they found, but don’t ask me how they did it because I don’t remember. Basically, I would say that Smadel and Shedlovsky wanted to find

out in a more precise fashion the size and density of elementary bodies of vaccinia, and to learn to what extent they responded to osmotic influences. It was, I must say, a good problem. At that time the values for the size and density of elementary bodies of vaccinia

218 Chapter 6 virus varied from investigator to investigator. Dr. William Elford and Dr. Christopher Andrewes, for example, determined size by means of filtration through collodian membranes, and on that basis estimated the diameter of such bodies at from 160 to 170 millimicrons. Using the ultracentrifuge and ultraviolet photography, Smadel and Shedlovsky were able to measure the sedimentation rates of different particles * of vaccinia suspended in media of different densities and soon discovered that in general there was an underestimation of the size of

these bodies, and that their diameter varied between 236 and 252 millimicrons. During the course of that work, Smadel and Shedlovsky noticed that the size and density of elementary bodies were affected by the type of suspending fluids that they used. ‘They thereupon de-

cided to vary the osmotic pressure and specific gravity of their aqueous solutions, and if memory doesn’t fail me I believe they used sucrose, glycerol, and urea to accomplish these ends. ‘They quickly learned that in the modified solutions the elementary bodies changed their density and size. Interestingly enough, however, these physical changes were of a reversible nature, and when the elementary bodies were resuspended in dilute buffer solutions the normal rate of sedimentation obtained. It was very nice physical-chemical work and as | say I had little to do with it—it was all Smadel and Shedlovsky. Later Shedlovsky and Smadel collaborated on a handsome piece of work related to the LS soluble antigen of vaccinia. Around 1934 Dr. James Craigie demonstrated that specific soluble substances could be separated from elementary bodies of vaccinia, and that these in turn would react with an immune serum and give a precipitate. It was an interesting finding because, years earlier, Dr. Dochez and Dr. Avery had shown that the capsule that surrounded the pneumococcus also had a specific soluble substance (a polysaccharide) which gave a nice

precipitate with antipneumococcal serum. Craigie actually maintained that there were two substances, that one was heat labile and the other heat stable, and he called them, respectively, L and S. In 1942 Shedlovsky and Smadel, using electrophoretic techniques, showed that under ordinary conditions the L antigen was not found free of the S reacting substance. Indeed they showed that both L and S immunological activities were to be found in a single protein mole-

Rockefeller Institute Hospital—1937 219 cule.” Subsequently they demonstrated that either of the two distinct antigenic properties could be altered selectively by means of heat and alkali, which left the stable antigen intact, or by crystalline chymotrypsin, which destroyed the stable component and left the labile antigen intact. Today all of these things seem commonplace to the young, but they weren’t then. I get sore as hell at people who ask me, why are you so thrilled by this? It’s the kind of question put by folks who have never really known the joy of discovery, or who were not active workers 25 years ago.

QO: Dr. Rivers, was Dr. Shedlovsky a member of your department? Rivers: No. Dr. Shedlovsky is a physical chemist and at that time he

was actually a member of Dr. Duncan MaclInnes and Dr. Lewis Longsworth’s department. He is a member of the Institute. However, throughout his career at the Institute, he has worked with all sorts of people in various departments. It’s my impression that at one time or another just about everybody at the Institute has called upon Shedlovsky for help. It’s good sense because he is quite a fellow. I am very fond of him. Do you know that, if he had a different kind of personal-

ity he would probably be one of the best-known scientists in the world. But he is not that kind—the truth is, he just doesn’t give a damn. In all the years that I have known Shedlovsky, I think that the best time to meet him is when he has had a couple of drinks. ‘T'wo whiskey glasses make him unbend a little—that’s true. As a matter of fact, whiskey is a good thing to have when you want to find out about a guy. What is it that Shakespeare says, makes a man stand to, etc., and take off his false face, etc., etc.? Liquor. It can certainly take the veneer off a guy in a hurry, and you can see him for real.

QO: Dr. Rivers, doesn’t that procedure have pitfalls—after all there is always the chance of forgetting what you have seen after a bender? ™yJ. Cragie and F.O. Wishart, “Studies on the soluble precipitable substances of vaccinia. I. The dissociation in vitro of soluble precipitable substances from elementary bodies.of vaccinia,” J. Exptl. Med., vol. 64:803 (1936); “Studies on the soluble precipitable substances of dermal filtrate,” J. Exptl. Med., vol. 64:819 (1936); J. E. Smadel and 'T’. Shedlovsky, “The LS antigen of vaccinia. IT. Isolation of a single substance containing both L- and S- activity,” J. Exptl. Med., vol. 75:165 (1942).

220 Chapter 6 Rivers: I never forgot. There is only one time in my entire life that I have ever been so tight that I didn’t remember. If that had been the habit with me, I don’t think that I would have taken much liquor because I knew too much and I would probably have been hung or shot. QO: Dr. Rivers, in your previous answers to my questions you indicated the new and important role of physics and chemistry in virus research, more particularly the use of such techniques as electrophoresis and such equipment as the ultracentrifuge. Did you have occasion to use the electron microscope as well?

Rivers: We did use the electron microscope in our work with elementary bodies of vaccinia, but that did not take place until 1942. Actually, I believe that the first use of the electron microscope for virus work took place in Germany around 1938, when Bodo von Borries and Ernest Ruska, using a machine manufactured by Siemens,

made an electron micrograph of one of the large viruses.’* It was a damn good picture and I can still see it in my mind’s eye, but | don’t remember whether the virus was a vaccinia virus, molluscum contagiosum, or myxoma virus. Shortly after that Dr. Salvador Luria succeeded in making some wonderful pictures of bacteriophage in process of invading a bacterium. ‘The technique promised much, and

in 1941 Dr. Stanley with the aid of Dr. Thomas Anderson of the RCA laboratories in Camden, N.J., made a series of pictures of tobacco-mosaic-virus particles which showed them to be rodlike in character and of varying length. After Stanley reported his work, I began to get after my boys to get some pictures of the elementary bodies of vaccinia virus, but, for some reason that I still can’t fathom, they were reluctant to do this. Perhaps they just didn’t want to take the trip to New Jersey. In the early 1940’s the electron microscope was still a rather unique instrument and most research institutions didn’t own one. The Rockefeller Institute, for example, did not buy an electron microscope until 1944, and most of the early electron microscopy carried on at the Institute was done in collaboration with the RCA laboratories in Camden. I kept after the boys and finally persuaded *B. von Borries, E. Ruska, and H. Ruska, “Bacterium und Virus in tibermikroskopischer Aufnahme,” Klin. Wochschr., vol. 17:94 (1938),

Rockefeller Institute Hospital—1937 221 Joe Smadel and Dr. Robert Green, who at that time was a postdoctoral fellow of the National Research Council, to make the pictures I wanted. ‘The work, of course, was highly technical and required great skill, and it’s taking nothing away from Smadel and Green to make

particular mention of the contribution of Tom Anderson to this work. I want to tell you, the pictures those boys got of elementary bodies of vaccinia virus made everybody sit up. Everybody expected

those ‘bodies to be spherical—instead the electron micrographs showed that they were roughly brick-shaped. Best of all was Smadel’s

demonstration that the elementary bodies had an internal structure and a limiting membrane, and were in fact morphologically closer to bacteria than to plant viruses like tobacco mosaic virus."* O: Dr. Rivers, given the growing importance of physical-chemical techniques in virus research by the end of the thirties, did it become necessary for you to recruit workers for your laboratory with particular background in chemistry or physics, or was the M.D. enough?

Rivers: Actually there was little need to look for people with the particular skills that you mention. If I needed a person with skill, let us say in physical chemistry, I looked for him at the Institute in other departments. I could always find such a person. Dr. Shedlovsky is a case in point. But Shedlovsky was not the only one; another person who collaborated with my department during this period was Dr. George Lavin. Lavin didn’t know much about viruses, but he did know a great deal about ultraviolet light, and that knowledge was of great help to my people. I remember that at one. point he collaborated with Charles Hoagland and devised a way of taking a photo-

micrograph of muscle tissue using ultraviolet light, which later allowed Hoagland to correlate the morphological and physiological changes in that tissue. Dr. Lavin was a good collaborator; however, sometime later he left the Institute because of personal difficulties, and his relationship to my laboratory ended. Although I could always find people with particular or unique skills at the Institute, it is true that in later years when I recruited people 4R.H. Green, T.F. Anderson, and J. E. Smadel, “Morphological structure of the virus of vaccinia,” J. Exptl. Med., vol. 75:657 (1942)

222 Chapter 6 for my laboratory I made a special effort to get people who were well trained in chemistry. Sometimes I went after people directly. Other times they came to work with me by chance. Dr. Charles Hoagland

and Dr. Wayne Woolley are two cases in point. Let me talk about Dr. Hoagland fist. Hoagland was an extraordinary and unusual person. He was born somewhere in the midwest, either Nebraska or Kansas. I don’t think that Hoagland ever knew, because he never knew who his parents were. He was brought up as a foundling and later had the good fortune to be adopted by a kindly lawyer. I have forgotten his name, but let me tell you he treated Charley as a son, gave him a fine education, and saw him through medical school.” In 1935 Hoagland was graduated with a brilliant record from the Washington University Medical

School in St. Louis, and after serving his interneship joined Dr. Avery’s laboratory at the Rockefeller Hospital. It was at this time that I first came to know him. | recognized him as a rather unusual person and let him know that I wanted him to stay on. Unfortunately, however, before Hoagland had left St. Louis he had promised Dr. David

Barr, the professor of medicine there, that he would return to St. Louis after his year at the Institute. Well, it has always been my pollicy never to interfere in such arrangements, and I let him return. But

that didn’t keep me from trying to get him the following year—I thought that it was fair game to do that—and when I made him an offer to join my laboratory in the hospital he came. Although I realized that much of the future work in virology was going to develop on a chemical level, I never looked for a straight chemist. I wanted a fellow who could not only think chemically but, even more important, one who would have an appreciation of the role of infectious agents in disease. ‘The thing that attracted me to Hoagland was that he was an M.D. who could think chemically. To tell the truth, Hoagland was never very much interested in viruses; his basic interest was to apply his biochemical knowledge to a study of metabolic disorders of various kinds. Just before World War II he shifted part of his research to muscular dystrophy and later concentrated his efforts on diseases of the liver. ‘That’s running ahead of the * Hoagland was adopted by A. W. McCawley, at one time a senator in the Missouri legislature. Cf. G. W. Corner, of. cit., p. 477.

Rockefeller Institute Hospital—1937 223 story. For now, just let me say that when Hoagland joined my labora-

tory he did his work and did it handsomely. Sometimes working alone, at other times collaborating with Smadel and Shedlovsky, Hoagland in a relatively brief period helped delineate the chemical nature of elementary bodies of vaccinia and, more particularly, the enzymes associated with them. In 1942 that work culminated in the discovery of DNA in vaccinia. To this day I don’t know why that work didn’t create more of a furor.

It was just about this time that Hoagland discovered that he had a malignant hypertension. Neither the army nor the navy would take him, and he continued his work without letup at the hospital, shifting as I mentioned before to the study of muscular dystrophy and later of liver disease. He never really got a chance to develop these interests—by 1945 his hypertension was out of hand and early in 1946 he died. Hoagland is the case of what might have been—Woolley is the case that became. Unlike Hoagland whom I deliberately chose, Woolley came to my laboratory by chance.

He was trained as a biochemist and prior to coming to the Rockefeller Institute had worked with Conrad Elvehjem at Wisconsin on nicotinic acid and problems relating to nutrition. His work was outstanding, and Elvehjem recommended him to Dr. Gasser. Originally, Woolley was supposed to come to the laboratories, but that year Dr. Gasser unfortunately had no vacancy or salary for a new worker, and

he asked me if I would take Woolley on at the hospital until he could make arrangements for him in the laboratories. Dr. Gasser didn’t have to twist my arm; I had a vacancy in my laboratories; more important, I had followed Elvehjem’s work very carefully through my

association with the Virus Committee of the National Foundation, and was very much impressed with Woolley’s work demonstrating the chemical nature of pantothenic acid. Hell, the fact that he came with Elvehjem’s recommendation was enough to sell him to me. I didn’t try to get him to work on viruses; as a matter of fact, I let him alone and he continued his experimental work on pantothenic acid. ‘The year was a fruitful one. Almost the first thing that he did was to discover a new growth factor—the hydroxy acid fragment of pantothenic acid—as essential for the life and activity of hemolytic

streptococci. Soon afterward he demonstrated that rats not only

224 Chapter 6 needed pantothenic acid as a growth factor but also needed a hitherto unrecognized substance found in liver concentrates. His work was excellent and when the year was up I hated to see him leave.*®

Soon after his transfer, Woolley came to the hospital as a patient. Ever since his boyhood he had suffered with diabetes. In the pre-

insulin era, that was a death sentence. However, by good fortune Woolley managed to stay alive until insulin came in. If insulin had not been discovered in 1923, Woolley would have long since been dead. I can truthfully say that, coming when it did, it has saved for humanity and civilization the continued activity of a brilliant brain, and that, I might add, is more than saving a life. Now I knew that Woolley had diabetes when I took him on at the Rockefeller Hospital; what I didn’t know was that he was blind in one eye with a retinitis caused by vascular troubles induced by dia-

betes. I didn’t ask him and he didn’t volunteer the information. When Woolley turned into the hospital, we discovered that his other eye had become affected and that he was in fact totally blind. There was absolutely nothing that we could do for him except to calibrate the amount of insulin he had to take.

QO: Was there any question of his continuing at the Institute? Rivers: I should say there was. Dr. Gasser was faced with a problem that would have stumped a Solomon. Although Dr. Woolley at that time was not yet a member of the Institute, he was running an independent laboratory and there was risk in letting him continue. ‘There was a physical risk of his being injured in the laboratory, and there was a risk as to whether he could continue to work fruitfully in the laboratory. In the end, Dr. Gasser decided to gamble on Woolley, and I must say that it turned out extremely well. As far as Woolley was

concerned, I don’t think that he ever had the intention of quitting and just assumed that he would continue working as he had before. God, he is an independent cuss. Once we tried to get a seeing-eye dog for him, and he just wouldn’t hear of it. Another time we tried to * 1D. W. Woolley, “Biological responses to the constituent parts of pantothenic acid,”

]. Biol. Chem., vol. 130:417 (1939); “Observations on the multiple nature of the rat filtrate factor,” Proc. Soc. Exptl. Biol. Med., vol. 43:352 (1940).

Rockefeller Institute Hospital—1937 225 get him to read Braille, and he would have nothing to do with that. Instead he paid students to come and read scientific articles to him. It makes no difference to him what language they are in—French, German, or what have you—he remembers them all and he can cite refer-

ences almost by page and line. He has a most remarkable memory. Before he married he traveled around by himself, and at one time actually made a trip to Cuba alone. Today, of course, his wife accompanies him to and from the Institute, but every now and then he gets

impatient and walks home alone. Don’t ask me how he does it because I don’t know. I don’t know how he continues to work in the lab but he does and, I might add, works efficiently and brilliantly. I have

seen him set up the most intricate chemical apparatus by himself ° with no help other than that of someone reading directions to him. Since his blindness, Dr. Woolley has become one of the most active researchers in the field of antimetabolites. Antimetabolites are, as you know, substances that are almost like the essential metabolites of

the body. If they are fed, let us say, to a small animal they will be picked up and fit into the chemistry of the body; yet they do not perform the functions that metabolites carry out. Yet in given circumstance they can prevent metabolites from carrying out their functions and have thus become useful in producing a number of experimental deficiency diseases.

For his work in developing this field and his earlier work on pantothenic acid, Dr. Woolley was elected in 1953 to the National Academy of Sciences.?? © * Dr. Olitsky adds this comment on Dr. Woolley.

The dramatic story related by Dr. Rivers can be said to be restrained, for it is my belief that Woolley will become a legendary hero in the future annals of the history of medical research. I have had the pleasure of a temporary association with him on a problem which was on the effect of nutrition on the susceptibility of mice to a virus infection. In this I was helped by my associate, Walter Schlesinger. The work, after several months, came to nothing, owing chiefly, I must confess, to my lack of knowledge of the subject at that time. It was then that I realized the amazing characteristics of his capabilities despite his complete lack of sight. Dr. Rivers mentions his “remarkable” memory. His memory was even more than remarkable: it was a substitute for sight in experimental work. For example, in a test involving numbers, say, 10 sets of mice, each set receiving different dilutions of virus and treated by varying dosages of, say, vitamins, arranged by sighted persons in a “checkerboard” paradigm, he could tell the fate of each of his experimental subjects on any day in the course of the experiment. He palpated the mouse and his questions were answered by an attendant, but in the end he fufilled all the requirements of a perfect test (private communication).

CHAPTER |

The National Foundation tor Infantile Paralysis: Early Research Programs—

Part 1 Rivers believes it is now time for the Research Committee to survey the field, not of knowledge, but of what we do not know of poliomyelitis.

Rivers believes that when this is done, the Committee should then attempt to block out the problems....... When this is accomplished, men and institutions should be sought to carry out the broad aims which have been defined by the Research Committee. Minutes, Scientific Research Committee of The National Foundation for Infantile Paralysis, November 9, 1938

QO: Dr. Rivers, when ‘The National Foundation for Infantile Paralysis was founded in 1938, did you expect, because of your previous connection with the President’s Birthday Ball Commission, to serve with the Foundation? *

Rivers: I had no idea that I would be called on again. At that time I did not know Mr. O’Connor, the president of the Foundation, and I am sure that he didn’t know me. One night soon after the National Foundation was formed in 1938, Paul de Kruif came to visit me at the * The Certificate of Incorporation of The National Foundation for Infantile Paralysis was filed on January 3, 1938. See “Certificate of Incorporation of The National Foundation for Infantile Paralysis Inc. Pursuant to Membership Corporation Law.” Undated, 6 pp. (Organizational files, National Foundation Archives.)

226

National Foundation: Early Research Programs—Part | 227 Rockefeller Hospital. He always took a great deal of pleasure in visit-

ing me whenever he was in New York and cramming what he was doing down my throat. I don’t think that he had anything against me personally; I suspect that he did this because he didn’t like the Institute. Paul either likes you or he doesn’t. If you differ with him a little bit, you just belong to the other clan—that’s all there is to it. And I don’t deny that I belonged to the Institute clan. On this particular occasion Paul was a little tight, and he told me that I was going to be invited to join the Scientific Research Commit-

tee of the National Foundation. I hadn’t at that time been formally notified of my appointment, and I have always suspected that Paul had a lot to do with making me a member of that committee. Later I learned that, after the Foundation was created, Mr. O’Connor had suggested to Paul that he arrange the formation of a number of committees to advise the Foundation on medical problems. Several such committees were formed: there was a General Advisory Committee, a

Scientific Research Committee, a Committee on Public Health and Epidemics, and a Committee on Care and After Treatment. Later other committees were added. Each committee had its own members, and if I remember correctly not all of the committees began their life

at the same time. I am almost certain, however, that the Scientific Research Committee was the first one to go into business.” Q: Dr. Rivers, do you remember who served on this committee? Rivers: Indeed I do. Initially the committee was composed of Paul de Kruif, Dr. Donald Armstrong, Dr. Charles Armstrong, Dr. George McCoy, Dr. Karl Meyer, and myself. 1 remember, because they did me the honor of electing me chairman, a position I then held for the next seventeen years. Actually, this committee had several members who had previously served on the Scientific Advisory Committee of * The Committee on Scientific Research was initially organized on July 6, 1938. It was subsequently reorganized several times with accompanying name changes reflecting

new functions and responsibilities. On May 13, 1940, it became the Committee on Virus Research; on September 30, 1947, the Committee on Virus Research and Epidemiology; on April 8, 1959, the Committee on Research; and on October 5, 1959, the Committee on Research in the Basic Sciences. In speaking of the work of this committee, Rivers often uses the titles of the various committees interchangeably.

228 Chapter 7 the President’s Birthday Ball Commission. Unlike that committee, this one had three working virologists, Charles Armstrong, Karl Meyer, and myself. I have mentioned some of Charley Armstrong’s work before, but I have said little about Karl Meyer. I have known Karl Meyer for many years and I can say unequivocally that he is a superb virologist. He is a Schweizer by birth and was originally trained as a Doctor of Veterinary Medicine. About 1910 he

migrated to the United States and took a job as professor of bacteriology and pathology at the University of Pennsylvania. His work very quickly began to attract attention, and just before World War I he was invited to become professor of bacteriology at the University of California. A short time later he joined the Hooper Foundation for Medical Research and from that time has been associated with them.

The Hooper Foundation in many respects is the analogue of the Rockefeller Institute, with one important difference: throughout its existence the Rockefeller Institute has had no connection with any medical school. However, the Hooper Foundation has always been closely connected with the Medical School of the University of Calli-

fornia. I can’t now begin to detail Dr. Meyer's scientific contributions; just let me say that he has made lasting contribution to our understanding of sylvatic plague, western equine encephalitis, and psittacosis. Physically, Karl is a big man with a big voice and on the west coast

he has long been known to his colleagues as King Karl. It’s not too much to say that, as far as bacteriology and virology went, he ruled things on the west coast. Dr. Meyer was a valuable acquisition to the Scientific Research Committee. Before the National Foundation began its operations it was difficult to find people who were interested in or even knew very much about problems of polio. One of the reasons

for this state of affairs was that the field had been more or less usurped by Dr. Flexner and the Rockefeller Institute. You could count the laboratories who could do research in this field on the fingers of your hands. ‘he Hooper Foundation was one of those places.

If I am not mistaken, it had worked on polio problems for over a quarter of a century before the National Foundation opened shop, and Dr. Meyer as its director was fully conversant with the problems presented by polio research.

National Foundation: Early Research Programs—Part 1 229 O: Did the Scientific Research Committee develop a program for the Foundation, or did you depend on receiving applications from individual investigators?

Rivers: Almost the first problem the Scientific Research Committee faced was regularizing the manner in which applications for grants were made and passed upon. During the life of the President’s Birth-

day Ball Commission, such applications went directly to Paul de Kruif, many of which the Scientific Advisory Committee never saw. It would have been nice to see them all, but the committee never got to see them. As secretary to the Scientific Research Committee of The National Foundation for Infantile Paralysis, Paul was in the same position when the new foundation got under way in 1938. Now, nothing

much passes Mr. O’Connor. Being an orderly man, an orderly thinker, running an orderly law office, devoted to everything being run in an orderly manner, you can guess that he wasn’t going to put up with the hit-or-miss of what had gone before—and he didn’t. At the first formal meeting of the Scientific Research Committee, which was held in joint session with the Public Health and Epidemic Committee, it was urged that a formal application blank be adopted. At Morris Fishbein’s suggestion, the committee adopted the application blank for grants in aid of research used by the American Medical Association. Now, on the surface, that doesn’t seem like much, but please remember that, before such a procedure was adopted, all a fellow had to do was to write a letter or note to de Kruif for consideration for a grant. It was, to say the least, a slipshod way of doing business, and it was done away with.

That first meeting was very important and, as I remember, most of

it was given over to a discussion of the nature of the principal unsolved problems of poliomyelitis. Rather than trust my memory on what was said, I would like to insert here a portion of the minutes of that first meeting. Some of these problems agreed by all present to be important and fundamental, were: (1) What is poliomyelitis? Is the disease a clearly defined

entity? Is there more than one form of the virus? If so, are these forms clearly separable and identifiable? (2) Is the pathology of the disease in humans adequately worked out? No. (Much more knowledge is needed of

230 Chapter 7 monkey disease pathology.) (3) Is the portal of entry known certainly for humans? Not certainly. But for major epidemics, it is still presumptive that the portal of entry is by way of the olfactory area. But work should continue. (4) Axonal transmission? ‘This appears highly probable. But is it propagated in the body by this route? Should be settled if possible. Work should continue. (5) Chemical blockade? ‘This is certainly the most promising of known methods of prophylaxis, which may be tried in the field. Work in this field should certainly continue, in an effort to find chemicals as effective as zinc sulphate, but less irritating. (6) Basic research should continue on attempts to alter the virus with the hope of making a vaccine. There are precedents for this. Yellow fever, horse encephalomyelitis, etc. (7) ‘The relation of polio to constitution. Rivers. occupied somewhat lone wolf position here, believing that this inquiry should be prosecuted. (8) nature of the virus. Bearing in mind the crystallization of mosaic viruses, and the new physical methods of concentrating and separating viruses,

effort should be concentrated on developing this inquiry on multiple fronts. ... (9) ‘The possibility of setting up a travelling fellowship was discussed. (10) Chemotherapy of the acute disease. This should be pushed. (11) Collection of strains of viruses during epidemic emergency. Grantees should be contacted to find out if they would serve in the field in this capacity.®

It was, I think, a fruitful discussion and after the meeting Paul de Kruif asked Dr. David Kramer to compile a dossier on what was not known about polio. As I mentioned before, Kramer was one of the early investigators in the field of polio and had done much clinical and experimental work with Lloyd Aycock on the Harvard Infantile Paralysis Committee. By 1938 Kramer had taken a post at Long Island University Medical School, and through de Kruif was given a

minor administrative position in the Foundation. He was a good choice for the job that de Kruif had in mind, but at that particular time he was busy with his own research and paid little attention to the request made of him. If he forgot, Mr. O’Connor didn’t. In the early days, the Scientific Research Committee met in his law office at 120 Broadway, and he attended each meeting faithfully. I might add here that he still does.

Mr. O’Connor thought de Kruif’s idea for a survey a good one and kept pressing the matter. When he realized that Dr. Kramer wasn’t going to do anything, he called me at the hospital and asked me to 3’ Minutes of the Committee on Scientific Research, National Foundation for Infantile Paralysis, July 6, 1938.

National Foundation: Early Research Programs—Part | 23] take responsibility for compiling the dossier. I wasn’t enthusiastic about taking on the job, but I realized that it was something that had to be done. I'll tell you why. During the first year of the National Foundation’s existence, the Scientific Research Committee received any number of applications for grants from individual investigators, and, while many were worthwhile in themselves, together they didn’t seem to be going anywhere. They were too haphazard for my taste, and I thought that the Foundation would be better served if the committee surveyed the field of polio research and blocked out problems that needed solution. With such a guide in hand, I felt that the committee should seek out the men and institutions capable of handling such problems and support them with grants. I don’t know whether Mr. O’Connor had such a program in mind when he asked me to take over Dr. Kramer’s chore; however, I do know that when I submitted

such a program to the Scientific Research Committee in the fall of 1938, I was asked by Mr. O’Connor to draw up a memorandum embodying the details of such a program. I worked on that memorandum throughout the winter of 1938, and when I thought I had a representative list of the major research problems in polio, I circularized the members of the committee and asked them to rank the problems in terms of their relative importance, and

to state who in their opinion was best qualified to investigate these problems. Now I want to make one thing clear. Although I initially drew up the list of research problems, I had nothing to do with puting them in the order in which they finally appeared: that ranking was the result of a consensus of the entire committee. In this final form it became the eleven-point program which guided the National Foundation in its grant policy until the appearance of the Salk-Sabin

vaccines. | Q: Was there any opposition to your proposals?

Rivers: Indeed there was. Several members of the committee didn’t like my idea, among them George McCoy and Charles Armstrong. They felt that the Foundation would be better advised if it simply continued to give grants to competent investigators of accredited in* Ibid., November 9, 1938.

232 Chapter 7 stitutions who voluntarily expressed their wish to do research into the

causes and prevention of polio. However, I will say this: when the eleven-point program came up for a vote they did not oppose it. Q: Dr. Rivers, could you give me the substance of the eleven-point program?

Rivers: Ill do better than that. I will read the eleven-point program as it appears in the minutes of the Scientific Research Committee. The averaging of the ratings of each problem brought it about that the eleven problems listed by Dr. Rivers were rated in the following order of importance:

1. Pathology of poliomyelitis in human beings 2. Portal of entry and exit of virus 3. Purification and concentration of the virus

4. What is to be called poliomyelitis? : 5. Mode of transmission of virus from man to man? 6. Transmission of virus along the nerves [Questions 4, 5, 6 received identical average ratings]

7. Further attempts to establish poliomyelitis in small laboratory animals

8. Settlement of the question of chemical blockade 9. Chemotherapy of poliomyelitis 10. Relation of constitution to susceptibility I1. Production of a good vaccine ®

I suppose that some people will want to know why the committee designated the pathology of poliomyelitis in human beings as the first large research problem to be tackled by the Foundation. First let me say that by 1938, while there was a good deal in the literature on the pathology of polio in monkeys, we actually knew very little about the pathology of polio in human beings.

QO: Dr. Rivers, were there any pathologists on the Scientific Research Committee?

Rivers: No. But as I mentioned before, if you were a virologist in those days (not necessarily today) you had to know pathology, be° Ibid., April 18, 1939.

National Foundation: Early Research Programs—Part 1 233 cause the only way you could study viruses at that time was to discover its effects on human beings or animals. By gosh, whether you wanted to or not, if you worked in virology you sooner or later developed into a pretty good pathologist. So it’s fair to say that, although the committee had no pathologists, the virologists on the committee did have an appreciation of the significance of pathology for an understanding of polio. If you look at the early literature of polio you frequently find it referred to as Heine-Medin disease. Heine and Medin are the names of two doctors. Jacob von Heine was a German physician who as early as

1840 made shrewd observations on the nature of polio, while Oscar | Medin, a Swedish physician later in the 19th century, helped clarify the

picture with good clinical descriptions of the disease during an epidemic. The interesting thing about Heine’s observations was that he assumed, on the basis of his clinical observations, that the primary lesion of polio would be found in the anterior horn cells of the cord. It was he who called polio spinal infantile paralysis—and it always

gives me a kick that he did this, because he never had a chance to study any post-mortem cases of polio.®

In time doctors began to disregard Heine’s observations, and when I was a young doctor it became fashionable to speak about a perivascular infiltration as being characteristic of polio. As I began to learn

about viruses, I thought less and less of that particular idea. It just couldn’t be—not if my idea that viruses were obligate parasites that could only grow and multiply in the presence of living susceptible cells was correct. Actually there was enough in the literature for us to question the notion of a perivascular infiltration. For instance, some-

time around 1929 or 1930, E. Weston Hurst demonstrated that the primary attack of polio in the nervous system was on susceptible neurons, and that the inflammatory reaction that pathologists found was the result of this neuronal damage. He maintained that it was the death of these cells which led to an infiltration of the tissues with polymorphonuclear leucocytes. Dr. Albert Sabin at the Rockefeller Institute was another investigator who very early helped clarify the pathological picture of polio. *'The early history of poliomyelitis is described in P.H. Romer, Epidemic Infantile

- Paralysis, William Wood, New York, 1913; International Committee for the Study of . Infantile Paralysis, Poliomyelitis, Williams & Wilkins, Baltimore, 1932.

234 Chapter 7 QO: Dr. Rivers, you have mentioned Dr. Sabin earlier. Before you de-

scribe his pathological work can you tell me how you first came to meet him?

Rivers: I first came to know Albert Sabin when he worked with William H. Park at the New York City Health Laboratories down at the foot of Fifteenth Street on the east side of Manhattan. Dr. Park at that time, among other things, was working on problems of polio

and had as one of his assistants an attractive and bright young Canadian investigator named William Brebner. One day Dr. Brebner was bitten on the hand by one of the monkeys being used in an experiment. People had been bitten by monkeys before, and Dr. Brebner paid the bite little mind. About a week or ten days later he noticed that his hand was becoming weak, and soon after it became paralyzed. Within a few days the paralysis spread to his respiratory center and brain and he died.

Dr. Sabin had worked with Dr. Brebner and at the autopsy got ; some material for examination. I believe he got a portion of the brain,

although I am not sure, and after very careful work isolate a Virus.

At the same time, Frederick Gay, a professor of bacteriology at the College of Physicians and Surgeons of Columbia, also got some mate-

rial from the autopsy and, with the help of one of his assistants, a young lady named Holden, also isolated a virus. Dr. Gay and Miss Holden contended that the virus they had isolated was herpes simplex virus; Dr. Sabin on the other hand argued that.it was a new virus, and in honor of Bill Brebner called it B virus. A first-class hassle developed. Well, Sabin was never bashful, and he came up to the Institute to tell me about his fight with Gay and to show me his work. I went over his work more than once and finally became convinced that he was right, and so I supported him in his fight with Gay. Dr. Gay himself never talked to me personally about this question. No matter. In the end Sabin won out and most investigators accepted B virus as a new virus. Subsequently several other workers were bitten by monkeys and died, and this same virus was recovered. An examination of

the blood of the implicated monkeys revealed that they had antibodies against the virus—in other words, they had previously had a viral infection but had recovered. Today it is established that B virus

National Foundation: Early Research Programs—Part 1 235 is a virus disease of monkeys, and while it is not necessarily fatal to monkeys it is practically 100-per-cent fatal to rabbits. In 1933 Sabin received a fellowship and went to England to work at the Lister Institute. Here he had the benefit of working with such virologists and bacteriologists as Sir John Ledingham, E. Weston Hurst, and G. H. Eagles and, as I mentioned before, he later put me on the track of why Eagles was getting positive results growing vacCinia virus in the presence of nonliving cells. We corresponded some during this period, and when Sabin got ready to return to the United States he wrote me and told me he was looking for a job. I went to see Dr. Flexner. “Look, Dr. Flexner,” I said, “Here is a nice young Jewish boy who is as smart as all outdoors. He has worked with Dr. Park, and at the Lister Institute and knows a great deal about viruses. I think we ought to give him a job.” Well, Dr. Flexner listened and later asked Peter Olitsky if he would take him on. Olitsky agreed and when Sabin returned from England he came to work at the Institute. God, he was a sight when he arrived. He wore tweed jackets and fancy

vests and smoked a pipe. He was the most elegant dresser in the entire Institute, but, more important, he quickly showed that he was also capable of doing elegant work in the laboratory.’ 7 Dr. Peter Olitsky, who was Albert Sabin’s chief at the Rockefeller Institute, gives this account of the hiring of Dr. Sabin: Albert Sabin when he came to the Rockefeller Institute was less than 30 years of age;

this may explain some youthful display of dress which amused Dr. Rivers. He was appointed during the autumn of 1934 as assistant but began his work in January 1935. He was advanced to associate in 1937 and left the institute in the autumn of 1939 to take on duties as associate professor of pediatrics at the University of Cincinnati. Thus he spent something less than 5 years in my laboratory. A month or two before his arrival I was warned by several well-meaning persons, 1

presume, including certain ones in favor with the Lord and with men, that it was a mistake for me to accept him. The reasons given were nonsensical: one said he would appropriate for his use all the monkeys in the place! (What superiority over those who spend so much laboratory time on cross-word puzzles!) Others, including Dr. Rivers, pointed to personality problems, but none denigrated his work (except one who knew nothing about it). I had, however, my own opinion on his amazing genius, and having worked successfully with geniuses before, I was anxious to have him as an associate. The next few years showed the justification of my action, for what he produced was not just

superior but brilliant (“elegant,” Dr. Rivers says): working with infinite patience and most careful technique, precise planning, detailed and elaborate recording of observations, accurate measurements and, especially, an incisive analysis of a problem (and its

corollaries) and skillful tests with rigid controls. Perhaps there was one answer for the belief of his critics: he could see much further than they and could see whatever he looked at more thoroughly and clearly, and thus could promptly relate the significance of a problem to the world at large. In his forth-

236 Chapter 7 Dr. Olitsky’s laboratory at that time was working on problems related to local and general immunity in virus infections and paid par-

ticular attention to poliovirus and the viruses of equine encephalomyelitis. Sabin had had previous experience with viruses, and quickly became a productive member of Olitsky’s team. Together with Olitsky, he worked on such problems as preventing polio infection in monkeys by chemical treatment of their nasal mucous membranes, and examining whether structural host factors in the peripheral and central nervous system of mice and guinea pigs influenced the invasiveness of certain neurotropic viruses. For instance, Olitsky

and Sabin had found that, when they took a neurotropic virus and instilled it in the noses of young mice, that it progressed along the olfactory nerve to the olfactory region of the brain, giving rise in the end to a fatal encephalomyelitis. When they conducted like experiments with older mice, they found that the virus never went beyond the olfactory region of the brain, and was in fact blocked from pro-

ceeding further. ‘hese older animals, as far as I remember, never showed any clinical signs of disease. Sabin and Olitsky reasoned that the virus was arrested because of certain physiological and structural host factors, and that these factors varied with age and the species of animal infected. It was a nice piece of work and typical, I think, of the wide variety of work that went on in Dr. Olitsky’s laboratory at this time. The work I remember best of this early period was Dr. Sabin’s and Dr. Olitsky’s in vitro cultivation of poliovirus. I remember it because

it was beautifully done and because it demonstrates again the role that chance plays in science.* Sometime in 1935 or thereabouts, Dr. Olitsky’s laboratory obtained

from one of the New York hospitals a three- or four-month-old human embryo taken from a Caesarian section. Using tissue from the brain, cord, kidney, lungs, and liver of the embryo, Sabin and Olitsky prepared several different tissue cultures and inoculated them with a filtrate of the Institute’s MV virus. ‘They soon discovered that, while right, confident manner, he would explain to them and, man being what he is, they would resent being given the answer by a tyro much younger than they (private communication ). ® A.B. Sabin and P. K. Olitsky, “Cultivation of poliomyelitis virus in vitro in human

embryonic nervous tissue,” Proc. Soc. Exptl. Biol. Med., vol. 34:357 (1936).

National Foundation: Early Research Programs—Part |] 237 the virus multiplied readily enough in nervous tissue, it would not grow in the presence of nonnervous tissue. ‘hat work was so meticulously done that I believed it was absolutely correct. Hell, 1t was correct, and every working virologist that I know believed it, with the possible exception of John Enders at Harvard. To this day, I don’t know why John didn’t believe that work. I suppose it’s his nature. He is a great old skeptic who never believes any-

one right off, and I expect he just didn’t take this work as proved. In 1949 John made everybody sit up when he reported that he was able to grow poliovirus in nonnervous tissue. (I believe that he used the foreskins obtained from circumcision in his initial experiments.) I'll discuss John Enders’ work at length later; for now, let me say that | read his paper over and over looking for a flaw. In the end I had to believe he was right. It wasn’t easy, because I damn well knew that Olitsky and Sabin were also right. Hell, I saw their work with my own eyes—I watched them—and yet both couldn’t be right.

By this time Sabin had moved to the Children’s Hospital in Cincinnati, and so I went to Olitsky. “Look, Peter,” I said, “I believe you and Sabin, but I can’t disbelieve John Enders’ results. ‘There must be a reason for his findings. ‘The only way I can figure it out is that the MV virus that you used in your experiments has mutated and become neurotropic. Why don’t you find out if this is so?”

It wasn’t a profound thought; it had occurred to other workers at the Institute and was discussed quite freely at lunch and elsewhere. In the end, Sabin, I believe, did investigate this problem and discov_ ered that the MV virus, because of the very large number of intercerebral passages in monkeys, had become a variant that lacked the property of multiplication in nonnervous tissue. Now this is an example of the role that chance plays in science. If Olitsky and Sabin had worked with another strain of poliovirus, the

chances are that they would have been able to grow the virus in nonnervous tissue, and we would have had a breakthrough of major proportions in making a vaccine. As it turned out, we had to wait fourteen years for this particular breakthrough.

pathology of polio? QO: Dr. Rivers, can you now tell me about Dr. Sabin’s work on the

238 Chapter 7 Rivers: Yes. Actually Sabin did several very nice pieces of work on the pathology of polio, and all of them have one thing in common: they grew out of work that went on in Peter Olitsky’s laboratory at the Rockefeller Institute. Let me begin by repeating that Dr. Simon Flexner had very early demonstrated that, when poliovirus was instilled nasally in rhesus monkeys, it entered the central nervous system by way of the olfactory nerves and bulbs. That experiment was

accepted as conclusive, and it quickly became an article of faith among polio investigators, many of whom then assumed that the nose and respiratory tract were the portal of entry for the virus in man. Not

everybody accepted this notion. Dr. Olitsky and a number of other investigators remained skeptical, skeptical enough to devise experiments to test the hypothesis. In 1937 Dr. Olitsky and Dr. Sabin discovered, after a series of ex-

periments performed in monkeys, that when polio invaded the central nervous system by pathways other than by the nose there were no pathological changes or lesions in the olfactory bulbs; they suggested that an examination of olfactory bulbs in human cases might resolve the problem of whether the virus had its portal of entry via the olfactory nerve.® In 1939 Sabin did an experiment which fortified him in the belief that the olfactory bulb was not necessarily the portal of entry for poliovirus in animals. A number of investigators, among them

Lloyd Aycock of Harvard, had reported that, following tonsillectomies, several cases of bulbar polio had developed. Since little experimental work had previously been done on the tonsils and pharynx as a route of polio infection, Sabin decided to investigate this possibility

experimentally. He soon found that, if he injected poliovirus into monkeys via the tonsillopharyngeal route, they came down with bulbar polio; however, in no such case was he ever able to detect poliovirus in the olfactory bulbs.*°

Now, before I go on, I want to make a number of things clear. First, I want to underline the fact that it was unusual in most post mortems of human polio to examine the olfactory bulbs. ‘They are not easily accessible in the skull and most pathologists overlooked them. ° A.B. Sabin and P.K. Olitsky, “The olfactory bulbs in experimental poliomyelitis,” J. Amer. Med. Assoc., vol. 108:21 (1937). *° A.B. Sabin, “Experimental poliomyelitis by the tonsillopharyngeal route,” J. Amer. Med. Assoc., vol 111:605 (1938)

National Foundation: Early Research Programs—Part |] 239 Second, several years before Dr. Sabin examined the olfactory bulbs in human polio, one or two other investigators in the United States attempted such examination, but their findings were not conclusive. Indeed, if I am not mistaken, a year or so before Sabin published the results of his findings on olfactory bulbs in human polio, two Australian investigators, Dr. Charles Swan and Dr. Graeme-Robertson did a very careful study of the olfactory bulbs taken from polio victims of the 1937 epidemics in Australia.* They found that the olfactory bulbs were free from pathological changes and reached the conclusion that infection by the olfactory route in man was less common than had been previously thought. So far as I know, Sabin worked independently of the Australians and the fact that he did what others were doing should not take away from his accomplishment. ‘The fact remains that he did his work beautifully and, after he published it, it became perfectly clear that the theory that the olfactory pathway was

the usual portal of entry of the virus in man would have to be discarded.**

Sabin did one other piece of pathological work on polio which I think deserves to be mentioned because it too served as corroboration

in ruling out the olfactory bulbs and respiratory tract as a portal of entry for the virus. When Sabin was at the Rockefeller Institute, he

and Dr. Olitsky undertook to determine the pathways taken by | neurotropic viruses within the central nervous system. It required meticulous pathological work and afforded good training for Sabin. In

1941, a little more than a year after Sabin moved to the Children’s Hospital in Cincinnati, he determined to undertake a similar piece of work in relation to poliovirus. With the help of Dr. Robert Ward he began to trace the distribution of poliovirus in nervous and nonnervous tissue, chiefly I suspect as a way of determining the site from which the virus invaded the central nervous system and its mode of spread within that system. Using various tissues taken from the autopsies of polio victims, Sabin and Ward discovered that, next to the 44, Swan, “The anatomical distribution and character of the lesions of poliomyelitis,” Australian ]. Exptl. Biol. Med. Sci., vol. 17:345 (1930); E.G. Robertson, “An examination of the olfactory bulbs in fatal cases of poliomyelitis during the Victoria epidemic

of 1937-38,” Med. J. Australia, vol. 1:156 (1940). 2 A.B. Sabin, “The olfactory bulbs in human poliomyelitis,” Amer J. Diseases Children, vol. 60:1313 (1940).

240 Chapter 7 central nervous system, poliovirus was to be found predominantly in the alimentary tract.** I don’t want to give the idea that Dr. Sabin was the only person at this time who did good work on the pathology of polio. As a matter of

fact, we didn’t get a complete picture of the pathology of polio in human beings until Howard Howe and David Bodian at Johns Hopkins completed their now classic work on the neuropathology of polio in the early 1940's.

Q: Dr. Rivers, didn’t the National Foundation also support the work of Dr. Howe and Dr. Bodian?

Rivers: Yes they did, but you know it took several years before the Foundation was able to get them in the fold, and I am afraid that I was partly to blame for that state of affairs. Perhaps I ought to explain that last statement a little more fully. I believe that the first agency to

support the work of Dr. Howe was the President’s Birthday Ball Commission. In 1937, before the Commission shut up shop, Dr. Lester Evans, of the Commonwealth Fund, came to see me at the Rockefeller Hospital. ““T'om,” he said, “the President’s Birthday Ball Commission is going out of business, and I think that we would like to take over one or two of their grantees—whom would you support?” I

told him that if I were in his shoes I would go after Dr. Howe and Dr. Aycock—I may have mentioned somebody else but I don’t remember now. Lester took my advice and for the next five years the

Commonwealth Fund supported the researches of these people. When the Scientific Research Committee began to search for people to do research on the pathology of polio, my recommendation came home to roost, because we soon discovered that two of the best people.in the country qualified to pursue such research were being supported by the Commonwealth Fund and had no need of a grant from us. Do you know what is most important in making a grant? I can tell you now that it is not only money; what’s more important is having people who are capable of having ideas and doing the job. Hell, if it wasn’t for the grant which the Foundation made to Johns Hopkins * A.B. Sabin and R. Ward, “Natural history of human poliomyelitis; distribution of virus in nervous and non-nervous tissues,” J. Exptl. Med., vol. 73:771 (1941).

National Foundation: Early Research Programs—Part 1 241 University in 1942, Dr. Bodian and Dr. Howe would probably still be supported by the Commonwealth Fund.

Q: Dr. Rivers, could you tell me about the genesis of the grant to Johns Hopkins University?

Rivers: I can, but before I do I think that I ought to clarify one thing—the grant went to the School of Public Health and Hygiene at Johns Hopkins and not to the Johns Hopkins Medical School. To my

mind the person primarily responsible for the grant was Kenneth Maxcy.

QO: Dr. Rivers, before you tell me about the purpose of the grant I wish you would take a moment or two to tell me about Dr. Maxcy.

Rivers: Maxcy was in my class at the Johns Hopkins Medical School in 1915 and, as I mentioned earlier, he and I were assistant residents together on Dr. Howland’s service way back im 1917. We were old friends and for that matter still are. After World War I, Dr. Maxcy joined the U.S. Public Health Service and soon made an inter-

national reputation by his work on murine typhus. In 1929 while studying an outbreak of typhus in South Carolina and Georgia, Maxcy came to the conclusion that the reservoir of the disease would probably be found in rats and mice and was probably spread to the human population by means of fleas or mites. The thing that stands out in my mind about this work is that Maxcy reached his conclusions on the basis of reasoning from the epidemiological data.** He himself did not mention the reservoir or vector. Later Hans Zinsser, while investigating an outbreak of typhus in Mexico, showed that the red flea

was responsible for the spread of this separate variety of typhus. Maxcy’s work paved the way and it was a classic. As a matter of fact,

it is one instance where a single piece of work resulted in a man’s

(1929). .

being elected to the National Academy of Sciences.

In 1929 Maxcy left the Public Health Service and became a professor of preventive medicine at the University of Virginia. I don’t “K. F. Maxcy, “Typhus fever in the United States,” Public Health Rep., vol. 41:1735

242 Chapter 7 know how long he remained there—I believe that he moved out to Minnesota for a while—but in 1938 he joined the School of Public Health and Hygiene at Johns Hopkins as professor of epidemiology. It was in this capacity that he approached the National Foundation for a grant sometime during the fall of 1941.

Q: Dr. Rivers, can you give me the substance of Dr. Maxcy’s proposals to the Foundation?

Rivers: Maxcy felt very strongly that, if a dent was ever to be made on the polio problem, it would be necessary to plan a comprehensive program which would not only study the spread of the virus in the human body but would study its distribution in the community as well. ‘To achieve this end, he wanted to establish a permanent research center at the School of Public Health and Hygiene at Johns Hopkins that would devote itself to the study of polio and other virus diseases. ‘The key to his plan was to gather a nucleus of research work-

ers in pathology, anatomy, virology, and epidemiology and later, as the situation demanded, to add people from such collateral fields as biochemistry and physics. Maxcy was astute enough to recognize that, to get and keep such people, he would have to get enough funds to establish his center for a period of not less than five years. ‘Today, in the era of large grants, it is hardly any news if a researcher asks for a half a million dollars for five years, but back in 1941 research grants

were made on a year-to-year basis and were far more modest. It took courage for Ken to ask for a whopping grant on a five-year basis.

I might add that it took just as much courage on the part of the National Foundation to give it to him. It certainly wasn’t the style of giving grants for medical research at that time.

QO: Dr. Rivers, I have a host of questions to ask you. First, did Dr. Maxcy discuss these plans with you personally?

Rivers: You are damn right he did. Ken is no fool. He knew that eventually the proposal would come before the Virus Research Committee, and it was no secret that I was the chairman of that committee. There was and is nothing wrong with discussing ideas—it is one

National Foundation: Early Research Programs—Part |] 243 way that people have of clarifying thought—but I can tell you now that I could give him no indication of what would happen to his grant once it reached the committee. I could only speak for myself, and the important thing to remember is that the final decision for making or not making a grant did not rest with me. I talked with Ken about his grant proposal, and I didn’t keep these talks secret from the Foundation. You can bet your sweet life that I kept them informed. I am

sure that Ken did the same. :

O: How did the Johns Hopkins Medical School react to Dr. Maxcy’s proposals?

Rivers: As I remember it, Louis Weed, who was then the director of the Medical School, and Lowell Reed who was dean of the School of Public Health and Hygiene, both thought highly of Maxcy’s plan.

The only snag in the beginning came from some of the Medical School faculty who were sore at the Foundation for discontinuing a grant which had previously been made to one of the orthopedists at the Medical School. I don’t know why that grant was discontinued, because it was made by a different committee at the Foundation. | will say that it was one of those matters that was raised and then for-

gotten—it never really interfered in the negotiations between the Foundation and the University. QO: Dr. Rivers, what was the reaction of the Foundation to the proposals?

Rivers: I think that it would be fair to say that from the beginning, Maxcy received a sympathetic hearing from various officials of the Foundation, particularly Mr. O’Connor. The biggest problem that Maxcy faced was in recruiting personnel or, to put it a different way, persuading the Foundation to give him a long term grant so that he could get the personnel he wanted. I would say that, from the outset, that Dr. Maxcy regarded Thomas Turner, Howard Howe, and David Bodian as the nucleus of his staff. There is no doubt in my mind that

Ken felt that initially he and Tommy Turner would pursue the epidemiological problems relating to polio, while Bodian and Howe

244 Chapter 7 would concentrate on problems relating to the pathology of polio in the laboratory. It was a nice division of labor and a nice team.

QO: Dr. Rivers, can you give me some biographical data about the team?

Rivers: Well, let me tell you about Tommy Turner first. Tommy took his medical training at the Medical School of the University of Maryland, and very early in his career joined Johns Hopkins as an instructor in the Department of Medicine. [ don’t know how it happened, but he developed an interest in syphilology and early in the

1930’s took a job with the International Health Division of the Rockefeller Foundation to study syphilis and yaws in the West Indies. I believe that he did a great deal of work among the Carib Indians. You know, some authorities maintain that the Carib Indians infected Columbus’s crew with syphilis, and that was the way the disease was introduced into Europe. I don’t know how accurate that the-

ory is—I have my doubts—but let me say that when European settlers later reached North America, they sure as hell reintroduced the disease.

After completing his work with the Rockefeller Foundation, Tommy joined the School of Public Health and Hygiene at Johns Hopkins as a professor of bacteriology. I would say that Turner offered no problem to Dr. Maxcy since he was already a member of the School of Public Health and Hygiene. Actually at that time Dr. Turner was already under grant by the National Foundation to doa study of the distribution of polioviruses and their neutralizing antibodies in the population of the Eastern Health District of Baltimore. That area in Baltimore was an excellent place to do such research; for years it had served as a proving ground for public health problems for the School of Public Health and Hygiene, and its residents were accustomed to having medical investigators show up to take bloods and detailed medical histories. The war interrupted Dr. Turner’s work, but you know eventually he showed that a very high percentage of the population in the Eastern Health District had neutralizing antibodies against the Lansing strain of poliovirus (type 2). I don’t think we

realized the meaning of that finding at that time, because we still

National Foundation: Early Research Programs—Part 1 245 didn’t know how many types of poliovirus there were—although some investigators were beginning to suspect that there was more than one immunological type.

The real personnel problem Dr. Maxcy faced was in obtaining the services of Dr. Howe and Dr. Bodian. Dr. Howe at the time was an associdte in anatomy at the Johns Hopkins Medical School, and had for a period of years prior to Maxcy’s request done very creditable work in pursuing a neuroanatomical approach to problems of polio. In 1939 that approach bore splendid fruit when he joined forces with David Bodian. Howe is about nine or ten years older than Bodian, and I would like to say a few words here about the younger man, who is a most unusual scientist. Although I am going to say complimentary things about Bodian, I don’t want anyone to get the idea that that means that Dr. Bodian and I haven’t had our battles. Hell, we have had some dingdong fights, although I must say that, by nature, Bodian is a gentleman and not given to fighting the way I am. Bodian was originally trained as an anatomist and took a doctorate in that field. After receiving his Ph.D. he went on to take an M.D. as

well. His ability was very early recognized and the dean of neurologists in the United States, Dr. L. Judson Herrick, on more than one occasion in the thirties told me that, as far as he was concerned, Dave

Bodian was the best neurologist of his age in the country. I am skipping ahead, but I don’t think you would get any argument if you added that today there is no one in this country—or for that matter anywhere else—who knows more about the pathology of polio than Dave Bodian.

In 1939 Bodian came to Johns Hopkins as a research fellow and teamed up with Dr. Howe. Within two years they did a number of neuroanatomical and pathological studies of polio that established them as one of the important polio research teams in the country. For example, they helped work out the rate of progression of poliovirus in the sciatic nerve, and later discovered that axonal section was sufhcient to make two different groups of highly susceptible nerve cells

refractory to destruction by poliovirus. Some of their pathological studies were just as arresting. It was they who found that nonparalytic

cases of polio could have as severe pathological involvement as paralytic cases, the difference being that in nonparalytic cases the de-

246 Chapter 7 stroyed motor neurones in the spinal cord were too scattered to involve a single functional muscle group sufficient to produce a noticeable functional loss. Perhaps one of the prettiest pieces of pathological work that they did was on the portal-of-entry problem in human polio. Here they confirmed Sabin’s observations on olfactory bulbs

and helped establish the alimentary tract as the region of virus proliferation, adding at the same time to our knowledge of the distribution of pathologic lesions in the motor cortex. J don’t know why I am telling you all this—all you have to do is to

pick up their volume on Neural Mechanisms in Poliomyelitis and read for yourself.*® It is a classic piece of work. My only regret is that miuch of this early wonderful work of Dr. Howe and Dr. Bodian was done under the auspices of the Commonwealth Fund—but please be-

lieve me when I say that they had enough glory left for the National Foundation. I am not exaggerating when I say that their later work

was one of the important keys for our understanding of existing immunological types of polio, and that their laboratory played a singular role in the ultimate development of an inactivated polio vaccine. I will discuss this story in some detail later.

QO: Dr. Rivers, given Dr. Maxcy’s idea for a research center and the investigative team he chose to carry on these researches, was there much difficulty in getting the grant through the Foundation? Rivers: Lord, yes. I don’t know how many conferences were held between Dr. Maxcy, Dr. Gudakunst of the Foundation staff, and myself. I will say this: it didn’t take long for us to agree that it was necessary for people of the stature of Dr. Howe and Dr. Bodian to have

job security and assurance that their research work would be supported and have continuity. To help things along, the Johns Hopkins Medical School assigned Dr. Maxcy lab space in the new Hunterian

Laboratory building, facilitated the transfer of Dr. Howe from the Medical School to the School of Public Health and Hygiene, and appointed Dr. Bodian as an associate in neurology. Yet in spite of every** As an example of the fruitfulness of research of this team, see Johns Hopkins Hosp.

Bull., vol. 69, No. 2 (1941), which is given over completely to the work of Bodian and Howe. The papers in this issue were forerunners of the volume, Neural Mechanisms in Poliomyelitis, Commonwealth Fund, New York, 1942.

National Foundation: Early Research Programs—Part | 247 one’s agreeing and wanting the grant, it took several months before the final agreement between the Foundation and Johns Hopkins was actually worked out. The basic problem that the Foundation faced was devising a formula for making a long term research grant that would be satisfactory to all parties. At that time there were few guides that could be used for making such a grant, and Mr. O’Connor was very conscious of the fact that such an agreement would probably serve as a model for other long term grants which the Foundation might make in the future. He took his time, conferred with people,

and often argued with them. He is a damn good lawyer, and it is something that one might have expected him to do. I think that it is fair to say that the agreement which finally emerged was the product of many minds, both inside and outside the Foundation. I will say this: although it was carefully drawn and meticulous in defining the rights and obligations of the Foundation, the University and the researchers, it was nevertheless a surprisingly flexible agreement.

QO: Dr. Rivers, do you remember the substance of the agreement? Rivers: Yes. In return for a grant from the Foundation of $300,000 for a period of five years, Johns Hopkins University agreed to establish

a research center in the School of Public Health and Hygiene which would devote itself to the study of polio and other virus diseases. Administrative control of the new center was placed very firmly in the hands of the director of the center, and although it was a very legal document I want to tell you that there were no ifs, ands, or buts, that all the research undertaken by the center was to be determined solely

by the director of the center and his associates. In other words, neither the Medical School nor the Foundation could tell them what to do. It was and is an excellent principle. ‘To maintain liaison between the new research center and the Foundation, a special committee composed of Mr. O’Connor, Dr. Morris Fishbein, Dr. George Ramsey, and myself was created. As I remember, our only real function was to look over the yearly budgetary requirements made by the new research center and to give advice if called upon. Actually the controls set up to police the long-term grant were no different from those established for the smaller yearly grants. In other words, the

248 Chapter 7 grantee had to set out clearly what the purpose of his research was, make progress reports of his work, and render a semiannual accounting of expenditures. ‘The one big difference was that the new research

center could not submit a budget of more than $75,000 for any one year.

Looking back at this first long-term grant, I would say that it had one basic flaw—namely, giving a set sum of money to be spent in a five-year period. It didn’t take the Foundation too long to recognize that it was difficult for a researcher to project his needs very accurately over a period of five years. Hell, in any given year things might open up and he might need three or four times the amount of money actu-

ally allotted to him; and while the original sum granted might seem quite large by absolute standards, it could easily be a straightjacket for : an investigator with a hot lead. Mr. O’Connor is a hard-headed lawyer, and he generally doesn’t let contracts get broken very easily, but he does know which way is up, and when this flaw became apparent the Foundation developed a new way of making long-term grants. Dr. Harry Weaver, who became director of research at the Foundation after World War II, was chiefly responsible for working out this new technique—it is one, I might add, that the Foundation still uses. Under the new system the long-term grant is essentially a guarantee of the salaries of key personnel in a given laboratory for a period of from three to five years. Each year, quite apart from this grant, such a laboratory can make application to the Foundation for an expediting grant. ‘he expediting grant is made on a yearly basis and takes care of such items as lab supplies and equipment, laboratory technicians, animals, and so on. Its size actually depends on what is going on in the lab at the time. If a lab needs $100,000 it can ask for $100,000, if it needs but $30,000 it can ask for $30,000. ‘The virtue of the expediting grant from the Foundation’s point of view is that it gives the committee making the grant a chance to take a look at what is actually going on in the lab, and to make their evaluation on hard current needs,

rather than on nebulous projected ones. ‘ Now, if an expediting grant is cut off—as sometimes happens— each of the men on long-term grant has a chance to call on a fund of $2,000 which is kept aside for him, so he can finish a given piece of work. Today the government makes it easier for everybody by giving

National Foundation: Early Research Programs—Part 1 249 laboratories $100,000 a year for ten years and the lab can do what it wants. Hell, that’s nice but I don’t think that it’s the right way to give away money.

Q: Several months before the School of Public Health and Hygiene at Johns Hopkins requested a grant from the Foundation to set up a research center to study polio and other virus diseases, a similar re- quest had been made by the School of Public Health at the University of Michigan. Can you tell me how that grant request came to be made?

Rivers: I don’t know the genesis of this grant although I suspect it originated in talks between Paul de Kruif and Henry Vaughan who at that time was the commissioner of health of the City of Detroit. Sometime in 1940 the University of Michigan received a considerable

grant of money from the Kellogg Foundation and the Rockefeller Foundation to establish a school of public health at the University of Michigan Medical School. The Medical School had long had an excellent reputation and there had been people at Michigan who had made considerable contribution to the field of public health. For instance, Dr. Victor Vaughan the father of Henry Vaughan who served as dean of the University of Michigan Medical School until 1921, was a distinguished figure in the American public health movevment almost from its inception to his death; Dr. Frederick Novy of the Department of Bacteriology had trained I don’t know how many generations of bacteriologists, and Dr. Nathan Sinai had even at that time made a considerable mark on problems of medical care. There were others, but these are three who immediately come to mind. Paul de Kruif, being a loyal graduate of the University of Michigan and knowing Dr. Henry Vaughan very well, fell in with an idea to establish a virus laboratory at the new school of public health. As I say, I don’t know who exactly originated the idea; all I know is that in the spring of 1940 the Scientific Research Committee received an ap-

plication from Dean Furstenburg of the University of Michigan Medical School for a grant, in his words “. . . to establish and maintain a permanent central laboratory of virology where specimens from all parts of the United States may be sent for study and comparison;

250 Chapter 7 - to conduct fundamental investigations primarily in the field of infan-

tile paralysis; to develop methods and provide facilities for the

gists.” 7° .

epidemiologic studies of infantile paralysis in the field; to train virolo-

Q: Dr. Rivers, before you go on, since this application was made prior to the one made by Dr. Maxcy, might I ask whether this was the

first time the notion of such an independent laboratory had come up? 17

Rivers: No, it had been discussed before. Actually, it was something that was in the air. At this very time, in New York, I was helping to establish the Public Health Research Institute, an organization that I

am happy to say has since taken an important position in virus research in the country. (I’ll have more to say about this laboratory later.) ‘There were members on the committee—and [Il admit that initially I was one of them—who thought that it might be a good idea

for the National Foundation to establish its own independent research laboratories, rather than to have one associated with a school of public health at Michigan. I thought it would be handier to have it in New York and, if I remember correctly, even made the suggestion that such a laboratory seek a connection with the New York University. Now that idea persisted and came up a number of times during the early years of the Foundation. Just after World War II the notion of an independent virus institute was argued very cogently by Dr.

Reuben Gustavson who was then chancellor of the University of Nebraska. Dr. Gustavson felt that investigations of infantile paralysis were handicapped by the fact that men who were interested in certain aspects of the disease were not trained to undertake more fundamental studies involving basic physics, biochemistry, electron microscopy,

and so forth. It was his impression that more could be gained by creating a “‘virus institute” where all phases of the problem could be attacked simultaneously—especially if the institute were associated 76 A.C, Furstenberg to Basil O’Connor, May 1, 1940 (CRBS #22, University of Michigan, 1940, National Foundation Archives). ™ See here, especially, Minutes of the Virus Research Committee of The National Foundation for Infantile Paralysis, May 13, 1940, where the question of creating an independent virus laboratory is discussed.

National Foundation: Early Research Programs—Part | 251 with a university that was strong in the basic sciences. As I remember, he suggested the University of Chicago as a likely place.

Well, we argued the question backward and forward, and Dr. Henry Viets, who at that time acted as personal advisor to Mr. O’Connor, finally put the idea to rest. He very forcefully pointed out

that the National Foundation was at that time supporting most of the virus research in the United States, and that if a virus institute were founded the Foundation would have to use grantees that it was already supporting to staff it. He felt that it was a better idea to support such workers in their own labs, in the hope that, by spreading its money among various top-notch institutions, the Foundation would avoid the stultification that sometimes comes in research because of ingrowth in a particular institution. I have had more than one fight with Henry Viets in my time, but on this issue I feel that he was right and that we made the right decision not to establish an independent virus institute.

QO: Dr. Rivers, to get back to the University of Michigan, were there any problems associated with giving the grant?

Rivers: I think that the first problems that we faced were the problems of who was going to run the laboratory and what rank he was going to hold in the school. Well, the latter question wasn’t too difhcult, because we initially agreed that the director of the lab should hold the rank of either associate professor or professor. ‘he question of getting a fellow to direct the laboratory was much more difficult, and

the University of Michigan agreed to let the Foundation beat the bushes for a qualified virologist, subject in the final analysis to approval by university authorities. The Foundation appointed Paul de Kruif, Charley Armstrong, and myself to look for the guy. I want to tell you, it wasn’t an easy job. The first fellow we went after was Herald Cox. Dr. Cox had earned

a Doctor of Science degree at the School of Public Health at Johns Hopkins—I want to stress that it was an earned degree; not an honOrary one; there is a helluva difference—and came to work early in his career at the Rockefeller Institute. He worked in Dr. Olitsky’s lab and

got a wonderful training in doing experimental work with various

252 Chapter 7 viruses including polio. If I am not mistaken, Dr. Olitsky and Dr. Cox were among the first to try out chemical blockade as a prophylactic measure for polio in this country.

About 1936 Dr. Cox left the Institute and took a post as bacteriologist with the U.S. Public Health Service. While serving at the laboratories in Hamilton, Montana, he recovered a rickettsia from a tick that caused QO fever. Prior to the time that Cox isolated his agent, it was thought that O fever was restricted to Australia; however, Cox

demonstrated that it had a wider geographic distribution than had hitherto been thought. For his part in the discovery, that rickettsia today is called Coxiella burnetti. Originally it was simply called Rickettsia burnetti after Frank Burnet who helped classify it as a rickettsia.

Cox, as I say, was a very attractive candidate and I wasn’t the only one who thought so; Charley Armstrong thought so and so did the Public Health Service. I don’t know for sure, but I think they pressured him to stay. In the end, Cox turned us down because he wanted to complete the studies on rickettsia which he had begun the year before. We just happened to have come at the wrong time. QO: Whom else did you go after?

Rivers: ‘The fellow I wanted very badly was one of my old boys, Dr. Jerome Syverton. In 1935 Jerry left the Rockefeller Institute to join George Berry at the University of Rochester Medical School, as an associate professor of bacteriology. I knew what Jerry could do from

his work with me’® and with Peter Olitsky, and I was satished with his development. Although he was then only 33, I supported him very strongly. In the end the boys at Michigan turned him down, largely, I suspect, because Jerry held out for a full professorship and they felt a young fellow that age shouldn’t be a full professor. Jerry’s subsequent development as a virologist, I think, shows that he warranted the confidence I had in him. 18 Dr, Syverton never worked in Dr. Rivers’ laboratory. The slip is, however, indicative

of the high regard Rivers had for Syverton. During his tenure at the Rockefeller In-

stitute, Syverton worked under Peter Olitsky. ,

National Foundation: Early Research Programs—Part |] 253 O: Dr. Rivers, the first candidates that you mentioned have one thing in common: both are alumni of the Rockefeller Institute. In your search for a director, did you incline toward people who had been trained at the Institute?

Rivers: Not at all, not at all. Oh, I know what you are thinking, but bear in mind that in 1940 there weren’t many trained virologists in the United States who were capable of taking over the directorship of a new virus laboratory. Senior investigators already had jobs, and it just so happens that many of the younger people with a lot on the ball were trained at the Rockefeller Institute. ‘This doesn’t mean that we didn’t consider people from other institutions—we did. As a matter of fact, very early in our search for a man, Henry Vaughan on his own wrote to John Gordon at the Harvard Medical School and asked him for likely candidates. ‘That was a good move. Harvard had a first-

rate bacteriology department and had long been interested in virus disease. In the spring of 1939 the Harvard Medical School had a bangup meeting on virus and rickettsial diseases—it was so good that later the proceedings were published as a book and for a long time after-

ward served as a text..? Well, Dr. Gordon got in touch with Hans Zinsser and Hans recommended two fellows who were then working

in his setup—LeRoy Fothergill and John Enders. As I remember, Hans wrote that if we wanted someone who had clinical experience we should go after Fothergill, but that John Enders was more ingenious in the lab.

Dr. Vaughan wanted a lab man and so he invited Enders out to Ann Arbor. Enders was then 43 years old, and I want to tell you that he made quite an impression. Vaughan wanted him, but in the end

John wouldn’t come. I believe that the main reason he turned the post down was that he felt that the major policy of the laboratory would be decided by the School of Public Health, and that the laboratory would essentially be a practical lab and serve under epidemiology, and that he wouldn’t have a chance to develop his theoretical work. I also believe that there was an unspoken reason. © Harvard School of Public Health Symposium, Virus and Rickettsial Diseases. Har-

vard University Press, Cambridge, Mass., 1940.

254 ) Chapter 7 John is a hidebound, rockbound, every-other-kind-of-bound New Eng-

lander, and I think nothing less than a charge of dynamite is ever going to loosen him from that part of the country. He just likes where he was born and brought up.

QO: Dr. Rivers, some correspondence I have seen suggests that you weren't too enthusiastic about Dr. Enders at that time.”°

Rivers: Yes, I would have to say that that is true. To be sure, it would be very nice to say that I recognized from the beginning that John Enders was a genius in the laboratory and would in time win a Nobel prize. Hans Zinsser had such high regard for John, almost from the time he came to work in his lab, but I didn’t, and I will tell you

why. John had his own means and could literally do just what he wanted to do—and if he wanted to be casual he could be. I just didn’t know how much self-discipline he had. In his early days as an investigator, I don’t think that John was as industrious as he is today. If he was, God knows I didn’t know it, and I know he is industrious now.

QO: Dr. Rivers, was the committee disappointed when Enders turned the job down?

Rivers: Yes, we were. At that point Karl Meyer wrote to us and suggested that we consider John Kessel for the post. Dr. Kessel was in many ways a good suggestion; he was a professor of bacteriology at the School of Medicine of the University of Southern California, and had done considerable research on problems of polio. As a matter of fact,

the National Foundation had early supported his research, and as chairman of the Scientific Research Committee I personally approved many of the grants made to him. I must say, however, that 1 opposed

his selection as director, because I had the feeling that Dr. Kessel never quite finished a piece of work. Perhaps I am being unfair because you know, on more than one occasion Dr. Kessel came near to making a number of basic observations about the nature of poliovirus. 20 See, especially, T. M. Rivers to Basil O’Connor, June 13, 1940; Donald Gudakunst

to Henry F. Vaughan, July 22, 1940 (CRBS #22, University of Michigan, 1940, National Foundation Archives).

National Foundation: Early Research Programs—Part |] 255 For instance, he was one of the first—along with investigators in Australia, Howard Howe and David Bodian in Baltimore, and Trask and Paul at Yale—to suspect that there was more than one immunological type of poliovirus. Although he pursued the question diligently he always seemed to come up against a blank wall. You know, too often we tend to forget the obstacles that many of the early investigators of poliomyelitis faced. First, practically everybody believed that there was only one immunological type of polio. Challenging an accepted idea is hard enough, but this particular idea

also contributed to careless lab practice. Up until about 1940, the only animal you could use in polio experimentation was the monkey. It was an expensive animal, and many investigators, in order to cut costs, would sell their monkeys to dealers if they survived given experiments and appeared hale and hearty. ‘The dealers, in turn, would resell the monkeys to other laboratories. Under such conditions, an investigator could buy a monkey from a dealer and have no reason to suspect that the animal had ever even seen a poliovirus when, in fact, it may have had all three types of poliovirus. And how was one to know at that time which type or combination of types it had had? No one knew about types. You can imagine how cockeyed some of the experimental results were, and they were cockeyed! I think that some of Dr. Kessel’s early experimental misfortunes came from using monkeys that had previously been used in polio experiments. ‘T’oday it’s

easy enough to understand what happened; at that time I didn’t know, and I’1l admit I had a down on Dr. Kessel.

QO: Dr. Rivers, I wonder if part of that down was also due to the

rivalry of the Hooper Foundation and the Rockefeller Institute. , Rivers: Oh, I’ll admit that there was rivalry between boys on the west coast and boys on the east coast. Sure, but I really don’t think that it played as significant a role as your question seems to imply. | think we gave a fair shake to both coasts in our search for candidates. There just weren’t that many qualified virologists around. Hell, at one point we even made a concerted effort to get Ermest Goodpasture from Vanderbilt, but he turned us down flat. I guess we would still be looking if I hadn’t thought of Tommy Francis.

256 Chapter 7 QO: Dr. Rivers, what brought Dr. Francis to your attention? What were his qualifications for this particular job?

Rivers: I knew Francis very well and I liked him and the work that he did. Tommy is an M.D., and received his medical training at the Yale Medical School. In 1928, after an interneship and residency at the New Haven Hospital, he came to the Rockefeller Hospital. He was then interested in respiratory disease, and that interest brought him to Dr. Avery’s laboratory, which was almost exclusively concerned with problems relating to the pneumococcus. Dr. Francis, like any young doc in the Hospital, had many clinical duties but in a very brief period he demonstrated to anyone who was looking that he was

no slouch in the lab. Together with Bill Tillett, who had earlier worked with me, Dr. Francis helped delineate the role played by typespecific polysaccharides in pneumonia immunity. In 1933 when Patrick Laidlaw, Wilson Smith, and Christopher Andrewes found the virus that produces human influenza, I said to Tommy. “Look, Francis, there are a hell of a lot of guys in this country who are working on pneumococcus, but nobody, as far as I know, knows anything about human influenza. Why don’t you jump on the virus bandwagon fast and get to work on human influenza?” Well, I worked on him for a while and,

when I thought I had convinced him, I went to see Dr. Cole and urged that Francis ought to be allowed to try his hand at investigating human influenza. Dr. Cole thought the idea a good one and provided Francis with a lab in Founders Hall. In a very short time—a year at

most—Francis confirmed the results of Laidlaw, Smith, and Andrewes, by successfully infecting ferrets with a strain of virus re. covered from influenza patients during an epidemic in Puerto Rico. (This is the famous PR-8 strain.) I need hardly add that that confirmation was of great help in establishing the viral nature of human influenza.”* * Dr. Francis makes the following observation on Rivers’ comments: I asked Dr. Rivers to come see Dr. Cole with me because I wanted to look for a virus which I suspected was a precursor of pneumococcal lobar pneumonia, and that was the work I began in 1933. I used ferrets, and the influenza material which led to isolation of PR-8 virus came about through Dr. Wilbur Sawyer of the Rockefeller Foundation,

to whom it had been reported that there was an epidemic in Puerto Rico (private communication ).

National Foundation: Early Research Programs—Part 1 257 Soon after he completed this work, Francis did an even neater trick—he successfully passed human influenza to mice and, by so doing, made available an animal obtainable in large numbers for experimental purposes. Well, that about opened the door. ‘Through the use of the mouse, it became possible to type strains of influenza virus recovered from very widely separated parts of the world. For instance, Francis was the first to show that Puerto Rico, Philadelphia, and English strains of human influenza virus were serologically alike. ‘Together

with Dick Shope, he was then able to demonstrate that, although swine influenza virus was serologically distinct from human influenza

virus, if you repeatedly inoculated a mouse with human influenza virus, the serum of that mouse might develop the capacity to neutralize swine influenza virus as well. I cite all this early serological work on human influenza virus because, in 1940, it culminated in Francis’s

isolating a human influenza virus which was totally unrelated immunologically to the earlier type A viruses. Dr. Francis designated this new type as type B, and he soon proved that it too was capable of causing widespread outbreaks of influenza in man. This particular

work was exceptionally important, because it made investigators aware of the presence of two immunologically unrelated types of human influenza virus—a factor that was a key in the consideration of any immunization program to control epidemic influenza. I think you can see from this why I was excited about ‘Tommy Francis.”

O: Dr. Rivers, at the time you suggested Dr. Francis for the Michigan post, was he still at the Rockefeller Hospital?

Rivers: Lord, no! In 1936 the International Health Division of the Rockefeller Foundation indicated that they wanted to take over on a ® For details of some of the early important work engaged in by Dr. Francis and his associates on problems of influenza, see T. Francis, Jr., “Transmission of influenza

by a filterable virus,’ Science, vol. 80:457 (1934); T. Francis, Jr, and T.P. Magill, “Antigenic differences in strains of human influenza virus,’ Proc. Soc. Exptl. Biol. Med., vol. 35:463 (1936); “Antigenic differences in strains of epidemic influenza virus.

1. Cross neutralization tests in mice,” Brit. J. Exptl. Pathol., vol. 19:273 (1938); T. Francis., Jr., and R.E. Shope, “Neutralization tests with sera of convalescent or immunized animals and the viruses of swine and human influenza,” J. Exptl. Med., vol. 63:645 (1936); T. Francis, Jr., “A new type of virus from epidemic influenza,” Science, vol. 92:405 (1940).

258 _ Chapter 7 large scale the influenza studies begun by Dr. Francis at the Institute and asked Dr. Cole if he would release Dr. Francis to their setup at the Institute. Dr. Cole agreed, and ‘’ommy moved over to the labora-

tories of the Rockefeller Foundation. ‘Iwo or three years later, the New York University Medical School invited Dr. Francis to join their staff as professor of bacteriology. When I asked ‘Tommy if he would take the job at Michigan, he was a professor at New York University Medical School. QO: How did Dr. Francis react to the offer?

Rivers: Almost the first thing that happened was that ‘Tommy came to see me at the hospital. I can still see him pacing back and forth in my ofhice. He had qualms—partly it was his nature, because as far as personal things go Tommy is a fella who just hates to make up his

mind; the other was the qualm of leaving a job that was running smoothly and taking on a new kind of a job, as professor of epidemiology. Like John Enders, Francis was worried about having the

lab as an arm of the School of Public Health and wondered how much time he would have for independent research. He indicated to

me in no uncertain terms that he didn’t want to be tied down to polio. Well, I was in no position to tell him how much Dr. Vaughan would try to boss him because I didn’t know. But I could tell him that the Foundation never tied anyone down exclusively to polio research.

O: Dr. Rivers, I wish you would explain that last point in greater detail.

Rivers: When the National Foundation first started its work, it was difficult to find people who knew how to do polio research or were even interested in doing such research. I think that it is fair to say that, in large part, such research had been usurped by Dr. Flexner and the Rockefeller Institute. To be sure, there were others but they were

just a handful and often their work was hampered by the fact that they couldn’t afford the monkeys so necessary to experimental work. Monkeys were damned expensive and the cost discouraged more than one investigator. Even in the late thirties we actually knew very little

National Foundation: Early Research Programs—Part | 259 about the nature of poliovirus. To be sure, a number of interesting leads were opening up, but they were tentative; often we didn’t know what question to ask. Many virologists when faced with an insoluble question with one virus frequently would turn to another virus about which they might know a little bit more, to see if they could get any insights into the problem they faced. Dr. Olitsky’s lab at the Rockefeller Institute, for example, not only worked with poliovirus but extended their investigations to other neurotropic viruses for precisely this reason, and I might add that they were not the only ones. As chairman of the Scientific Research Committee I had a certain amount of influence with Mr. O’Connor—TI think that other people did too, Karl Meyer, for example—and from the beginning I tried to tell him that sometimes it was necessary to go clear around the barn in order to get an answer in virus diseases. I made it plain that, if we wanted answers to problems in polio and they were not forthcoming, it might be to our advantage to study related viruses where we had

better information and techniques. You know, on more than one occasion, ‘Theobald Smith said that the good research man was the man who knew how to ask the right questions of nature. Albert Einstein expressed the same thought by saying that a great hypothesis was frequently of more importance than its proof. He himself proposed the theory of relativity but never proved it. Actually, some ten years after he proposed his hypothesis, a group of British scientists proved it. Now, I don’t know the name of those scientists, and I am willing to bet that you don’t either. The point is that it is no mistake, because we tightly honor the fellow who proposed the theory rather than the fellows who did the proving. It is not that the latter work is

not scientifically important; it is, it is just less important than the hypothesis. Asking the right question is the key to understanding in science.

During the late thirties, we had to learn how to ask the right questions of poliovirus. In part, we learned from an examination or investigation of other neurotropic viruses, and I believe that it is to Mr. O’Connor’s credit that he understood the necessity for the Foundation to support such related research. If you look at some of the early

grants made by the Foundation, you will find that they were not made for polio alone but for polio and related viruses. ‘The prime

260 Chapter 7 example that comes to mind is the grants made to Dr. Karl Meyer’s lab at the Hooper Foundation. Originally those grants were made to study the epidemiology of poliomyelitis in the western states. However, when it became apparent that the diagnosis of polio cases was made dificult by the coexistence of epidemic encephalitis, the grant was broadened to include epidemiological studies of other neurotropic viruses rather than polio alone. In research you have to be prepared to go anywhere, and I want to tell you that Dr. Meyer and his boys and girls—the team included Bill

Hammon, Beatrice Howitt, and Bill Reeves—did a bang-up job in working out the epidemiology of western equine and St. Louis encephalitis. It wound up with all of us learning through their work that western equine encephalitis was transmitted from bird to bird by mites, and from birds to horses and men by mosquitoes. (‘That’s true of eastern equine encephalitis, as well as of St. Louis encephalitis.) It was beautiful, beautiful work; yet the chances are that, if we had had a lot of people asking us for money for polio research, we would probably have given it to them in preference to giving it to Dr. Meyer. In the end, the work of Dr. Meyer’s team not only made it easier to make a differential diagnosis between epidemic poliomyelitis and epidemic encephalitis, it also trained a good many people in the fundamentals of virology. I am proud that the Foundation supported this early work in encephalitis—it was some of the prettiest work done under Foundation support.”* 3 See also W. McD. Hammon, B.N. Carle, and FE. M. Izium, “Infection of horses with St. Louis encephalitis virus, experimental and natural,” Proc. Soc. Exptl. Biol. Med., vol. 49:335 (1942); W.McD. Hammon, and B.F. Howitt, “Epidemiological aspects of encephalitis in the Yakima Valley, Washington; Mixed St. Louis and western types,” Amer. J. Hyg., vol. 35:163 (1942); W.McD. Hammon, W.C. Reeves, B. Brookman, and E.M. Izium, “Mosquitoes and encephalitis in the Yakima Valley, Washington. I. Arthropods tested and recovery of western equine and St. Louis viruses

from Culex tarsalis coquillet.” J. Infect. Diseases, vol. 70:263 (1942); W.McD. Hammon, W. C. Reeves, and E. M. Izium, “Mosquitoes and encephalitis in the Yakima Valley, Washington. II. Methods for collecting arthropods and for isolating western equine and St. Louis viruses; IV. Summary of case against Culex tarsalis coquillet as a vector of the St. Louis and western equine viruses,” J. Infect. Diseases, vol. 70:267, 278 (1942); B. F. Howitt, and W. Van Heinck, “Relationship of the St. Louis and the western equine encephalitic viruses to fowl and mammals in California,” J. Infect. Diseases, vol. 71:1179 (1942). These papers are but a sample of the work done by Meyer’s laboratory on the problem of encephalitic viruses, under grant of The National Foundation for Infantile Paralysis.

National Foundation: Early Research Programs—Part 1 261 Now, that kind of far-ranging support for Dr. Meyer’s lab was not an isolated case. For instance, when Dr. Margaret Smith began her work under Foundation grant, she studied the development of neutralizing antibodies in mice to Lansing strain poliovirus and ended by studying the transmission of St. Louis encephalitis virus by chicken mites.** It didn’t matter one bit to the Scientific Research Commit-

tee; the important thing was that it furthered our understanding of neurotropic viruses. Actually, Dr. Francis didn’t really have to worry

that the Foundation would restrict him to epidemiological studies and poliovirus. To be sure he has done such studies, but the Foundation has also supported him in investigations designed to explore the relationship between chemotherapy and virus disease. So 1 wasn’t wrong in the advice I gave ‘Tommy. Everybody benefited when he moved to Michigan—the University, the Foundation, and Tommy.

O: Did Dr. Francis’s laboratory have any particular problems in getting under way?

Rivers: None that I remember. Although ‘Tommy Francis started his laboratory from scratch in 1940, within a year it was doing excellent work in the epidemiology of polio—tracing the dissemination of the virus in particular communities and examining the incidence of family outbreaks in the midwest. In addition to this work, he set up a first rate program for training young virologists. ‘he work went so

well that in the spring of 1943 the Foundation awarded Francis a grant of $120,000 for a period of three years. I would like to add that the model for that grant was the one that had been worked out earlier for Dr. Maxcy’s group at the School of Public Health and Hygiene at Johns Hopkins. A short time later, it was used again for a grant made to the Yale polio laboratory. As for problems, the only problems Dr. Francis had during these early years was with his monkeys, many of whom died of TB. The lack of healthy monkeys to work with inter-

fered with his laboratory programs—not enough to stop him, but enough to gray him a little or develop an ulcer. **M.G. Smith, R.J. Blattner, and F.M. Heys, “Further isolation of St. Louis en. cephalitis virus: Congenital transfer in chicken mites,” Proc. Soc. Exptl. Biol. Med., vol. 59:136 (1945).

262 Chapter 7 Q: Dr. Rivers, I am glad you mentioned the Yale polio laboratory because many of the important epidemiological observations of polio

in our own time have come from this unit. I wonder if you would mind speaking with me about them.

Rivers: I don’t mind. I am very fond of Dr. John Paul and the boys and girls in his laboratory.

QO: Dr. Rivers, I think that you will agree with me that one of the eatly key figures in the Yale polio laboratory was the late Dr. James Trask. Could you give me your impressions of Dr. Trask?

Rivers: Dr. Trask was slim, walked straight, and was addicted to wearing derby hats which made him stand out. He would have stood out in other ways. He was an odd looking man, and when you looked at him you couldn't help feeling that he didn’t have any sense at all, that he was a dumbbell. Now the truth is that Dr. Trask was anything but a dumbbell. He was as sharp minded an investigator as you would ever want to find, and he was possessed of a good deal of courage. Early in his career he had worked at the Rockefeller Institute with Francis Blake, and together they had done the classic piece of work on measles that I mentioned earlier. When Dr. Blake left the Institute to go to Yale as a professor of medicine, Dr. Trask went with him as an assistant professor of medicine. He remained in Dr. Blake’s department for several years, and later, sometime around 1926 or 1927

shifted to the Department of Pediatrics under Dr. Grover Powers, where he took charge of the infectious disease service. I don’t know the reason for the shift, but Dr. ‘Trask remained in the Pediatric Department until his early tragic death in 1942 in an army camp somewhere in the midwest. Just let me add here that, for his contributions

to our understanding of polio, a victory vessel was named in Dr.

Trask’s honor during World War II. ,

You know, you really can’t speak about Dr. Trask without speaking

of Dr. John Paul, because many of the early polio investigations at ' Yale were done under the joint auspices of ‘Trask and Paul. Paul was entirely different from Trask. He was and is conventional—he dresses like everybody else and, as far as I know, has never worn a derby hat

National Foundation: Early Research Programs—Part 1 263 in his life. Dr. Paul is a graduate of the Hopkins and very early had a deep and abiding interest in pathology. I would say that much of his early career in medicine was devoted to pathology. After graduation from the Hopkins Paul went to the University of Pennsylvania Medical School where in time he became director of the Ayer pathological laboratories. In those early years he was more concerned with rheumatic fever than he was with poliovirus. I don’t think that I am far from the mark when I say that he didn’t become interested in viruses until he came to Yale and teamed up with Trask in forming the Yale polio lab sometime around 1931. Dr. Paul worked in the Department of Preventive Medicine.

QO: Dr. Rivers, can you give me some account of the kind of work that Dr. ‘Trask and Dr. Paul were engaged in?

Rivers: JI don’t think that I can do it justice by a summary from memory, but since you ask I will make the attempt. Please keep in mind that what I am about to say is a summary and that I have forgotten many things, although at one time I followed the work of Dr. Paul and Dr. Trask very closely. Let me begin by saying that during the first two decades of this century much of the polio research that went on in the United States was of a laboratory variety, devoted to producing experimental polio in monkeys. I think that it is fair to say that by 1930, although we knew a hell of a lot about polio in monkeys, we didn’t know very much about the disease in human beings. This, however, is not to say that there wasn’t any good epidemiological work that had been done on human aspects of the disease—there was. As a matter of fact, Dr. Charles Caverly in Vermont and Dr. Wade Frost of the U.S. Public Health Service had both done classical epidemiological work on polio.2> What I am trying to say is that the Rivers’ reference here is to Charles S. Caverly, President of the Vermont State Board of Health who in 1894 wrote the first report on epidemic poliomyelitis in the United States. All of Caverly’s papers on poliomyelitis have been reprinted in Infantile Paralysis in Vermont 1894-1922: A Memorial to Dr. Charles S. Caverly, Burlington, Vermont, 1924. Wade Frost was one of the pioneers in the U.S. Public Health Service who early devoted himself to the study of the epidemiology. See W. H. Frost, “Epidemiologic studies of acute anterior poliomoyelitis, I. Poliomyelitis in Iowa, 1910; II. Polio-

myelitis in Cincinnati, Ohio, 1911; III. Poliomyelitis in Buffalo and Batavia, N.Y., 1912,” Hyg. Lab. Bull. No. 90, 1913.

264 Chapter 7 majority of people who did research in poliomyelitis during this early period had gotten away from human beings. It is to Dr. Trask’s and

Dr. Paul’s credit that they went back to the human patient, and, beginning with the Connecticut epidemics of the early 1930’s, began investigations designed to learn about the nature of polio virus and the various clinical circumstances under which it could be found. [ would like to say here, and I don’t think that Dr. Paul would dispute this point with me—you might check with him later—that both he and Dr. Trask were much influenced in their point of view by the

work of the great Swedish epidemiologist Dr. Ivar Wickman. Dr. Wickman’s work was well known in the United States; and although it was originally done about 1905 or 1906 a translation in English had

appeared in the United States before World War I. Dr. Wickman, for example, early held that polio was conveyed from person to person by those afflicted by an abortive type of polio or by healthy persons

who carried the virus without ill effect. He supported these contentions by working out the foci of the spread of the disease in the school epidemic of 1905 in Sweden.”* Dr. Paul and Dr. Trask did not forget this work, and during the Connecticut epidemics they paid very close attention not only to the paralytic cases that occurred in given fami-

lies, but also to the minor illnesses in those families that had been passed off by doctors as colds, tonsillitis, grippe, or what have you. In a very brief period, by means of isolation of virus and antibody tests,

Dr. Paul and Dr. Trask identified these so-called minor illnesses as examples of subclinical polio infections. Quite apart from the importance of these studies in charting the incidence and distribution of polio in various Connecticut communities, I believe that it was these immunological studies which led Dr. ‘Trask and Dr. Paul to suspect that there was more than one immunological strain of poliovirus. It’s easy enough to say now, but it was not easy to say this in 1933 or 1934 because orthodox opinion, led by Dr. Simon Flexner at the Rockefel-

ler Institute held precisely the opposite point of view. I might add that it wasn’t easy to fight with Dr. Flexner, because few could challenge his authority in the field of polio. Hell, he was the authority. Oddly enough, I believe that both Trask and Paul were fortified in *°T, Wickman, Acute Poliomyelitis. Nervous and Mental Disease Monograph Series, No. 16. New York, 1913.

National Foundation: Early Research Programs—Part 1 265 their belief of the multiplicity of polio strains because of a piece of research that they did with Leslie ‘T. Webster under the auspices of the Rockefeller Institute on the “so-called” polio epidemic of 1934 in Los Angeles, California. I say “so-called” because, while it is true that a strain of polio was eventually isolated from the cases studied in that

epidemic, the likelihood today is that that particular epidemic was caused by either a Coxsackie or an ECHO virus. (At that time of course we had not yet developed the technique of identifying Coxsackies through passages in infant mice, and we were at least 15 years away from using tissue cultures in identifying ECHOs, so there is no way of really knowing today what kind of an epidemic it was.) There was relatively little paralysis during this particular epidemic, and I re-

member that some docs even thought it was a diphtheria epidemic. While Dr. ‘Trask and Dr. Paul were out in California, they paid a great deal of attention once more to abortive cases of polio in family groups and sharpened their immunologic techniques of isolating virus and doing antibody tests.?”

QO: Dr. Rivers, besides this work on the epidemiology of abortive polio in human beings, and the work that led to an understanding that there was probably more than one immunologic type of polio virus, didn’t Dr. Paul and Dr. ‘Trask do one other piece of work that was important for the understanding of how polio passed from one individual to another?

Rivers: If you would let me catch my breath, I would tell you without prompting. In 1938, while examining the feces of a baby who they suspected was an abortive case of polio, Dr. Paul and Dr. ‘Trask isolated a strain of poliovirus which they named the SK strain, in honor of the baby from whom they recovered the virus. It was a most 7).R. Paul and J.D. Trask, “Detection of poliomyelitis virus in so-called abortive types of the disease,” J. Exptl. Med., vol. 56:319 (1933); J. R. Paul, R. Salinger, and J. D. Trask, “Studies on the epidemiology of poliomyelitis, methods and criteria for the detection of abortive poliomyelitis,” Amer. J. Hyg., vol. 17:587 (1933); J. R. Paul, and J. D. Trask, “Comparative study of recently isolated human strains and passage strain of poliomyelitis virus,” J. Exptl. Med., vol. 58:513 (1933); “Neutralization test in poliomyelitis; comparative results with four strains of virus,” J. Exptl. Med., vol. 61:447 (1935); J.R. Paul, J.D. Trask, and L.T. Webster, “Isolation of poliomyelitis virus from nasopharynx,” J. Exptl. Med., vol. 62:245 (1935).

266 Chapter 7 interesting finding, because it gave support to another idea that orthodox polio investigators had also opposed for many years, namely, that polio was more likely an intestinal rather than a respiratory disease. The corollary to that notion was that virus that was passed in stools was instrumental in the spread of polio epidemics. I would say that this work, in conjunction with the later work of Dr. Albert Sabin on olfactory lobes in human polio, and the work of Dr. David Bodian and Dr. Howard Howe on the neuropathology of polio, did much to finally settle the debate among virologists on the problem of portal of entry of poliovirus in human infection.”®

Q: Dr. Rivers, would you say that it was the recovery of poliovirus from feces of abortive cases of polio that turned the attention of inves-

tigators to the fly as a possible transmitting agent in the spread of polio?

Rivers: Before I discuss your question, let me say that the initial im-

pact of the discovery of poliovirus in the feces of abortive and paralytic cases of polio by Dr. Trask and Dr. Paul made them focus their attention on sewage as the likely agency in the spread of polio. I would like to add that they got quite an argument when they published such views. I personally didn’t think much of that particular idea, because polio epidemics hit good sanitary environments and clean healthy kids with more force than it did slums, where the kids might have been scrawny and dirty, and certainly not as well fed. One of the important corollaries of the sewage idea was that polio epidemics might be water-borne, and Dr. Paul and Dr. Trask pursued that notion very carefully. In this way they went back to an idea of old papa Kling, the Swedish epidemiologist, who pointed out that some of the early polio epidemics in Sweden followed streams.”? Well, again they could find no hard proof that water was actually related to the spread of polio epidemics. I opposed them on these ideas, but I don’t know that I wouldn’t have done the same had I been in their

shoes. You question things in science and you take nothing for *°7.D. Trask, A.J. Vignec, and J.R. Paul, “Isolation of poliomyelitis virus from human stools,” Proc. Soc. Exptl. Biol. Med., vol. 38:147 (1938). °C. Kling, “Recherches sur l’épidémiologie de la polimyélite,” Svenska lakartidn. sdllsk. handl., vol. 55:23 (1929). \

National Foundation: Early Research Programs—Part | 267 granted until it’s either proved or disproved—I should add in all honesty that this is easier to say than to do. In answer to your question, I would say that, long before Dr. ‘Trask and Dr. Paul did their work, many investigators thought of the fly as a likely agent in the spread of polio. In 1913, for example, Dr. Wilbur Sawyer tried to transmit polio by means of the stable fly. I don’t think

that he was the only one, because Dr. Milton Rosenau of Harvard School of Public Health and Dr. John Anderson of the U.S. Public Health Service tried the same trick.*® I might add that several years later Dr. Simon Flexner at the Rockefeller Institute did his damnedest to destroy that notion and had some success. Nevertheless, some people through the years held on to that idea. When Dr. ‘Trask and Dr. Paul published their findings on poliovirus in feces, a number of investigators began to reexamine the role of the fly in epidemic polio. If I am not mistaken, one of the first to do so was Dr. Albert Sabin. By this time, Dr. Sabin had already left the Rockefeller Institute and taken up a new position at the Children’s Hospital in Cincinnati. ‘T’ogether with Dr. Robert Ward, who worked with him at the time, Dr. Sabin collected flies from the vicinity of various polio epidemic areas and isolated poliovirus from such flies. At about the same time, members of Dr. Paul’s team, particularly Dr. Joseph Melnick, also trapped flies in epidemic areas and were also successful in demonstrating that such flies either harbored or carried poliovirus.**

While there was evidence that pointed to the fly as a possible carrier, proving it as an actual transmitter was much more difficult. After World War II, the Yale team headed by Dr. Melnick sprayed an area somewhere in the midwest with DDT during a polio epidemic, and, while there was decrease in the amount of flies, such decrease had no apparent effect on the course of the epidemic itself. If my memory *°W.A. Sawyer and W.B. Herms, “Attempts to transmit poliomyelitis‘ by means of the stable fly,” J. Amer. Med. Assoc., vol. 61:461 (1913); J. F. Anderson and W. H. Frost, ““Transmission of poliomyelitis by means of the stable fly,” Public Health Rept.,

vol. 27:1733 (1912); M.J. Rosenau, “Poliomyelitis transmitted by the biting fly, Stomoxys calcitrans,” Public Health Rept., vol. 27:1592 (1912). * A.B. Sabin and R. Ward, “Flies as carriers of poliomyelitis virus in urban epidemics,” Science, vol. 94:590 (1941); “Insects and epidemiology of poliomyelitis,” Science, vol. 95:400 (1942); M. Power and J.L. Melnick, “A three year survey of _ the fly population in New Haven during epidemic and non-epidemic years for poliomyelitis,” Yale J. Biol. Med., vol. 18:56 (1945).

268 Chapter 7 doesn’t fail me, at about the same time the government carried out a

like experiment in the southwestern part of the country, during a double epidemic of typhoid and polio. In this particular case, although the typhoid epidemic diminished considerably, the polio epidemic continued unabated. After these experiments, the notion that flies played an important part in the transmission of polio just petered out.**

QO: Dr. Rivers, can you give me any indication of the attitude of the

Virus Research Committee toward the work of Dr. Trask and Dr. Paul?

Rivers: ‘That’s an easy question to answer. Both Dr. Trask and Dr. Paul were supported in their work by the President’s Birthday Ball Commission, and when the National Foundation was created in 1938 that support continued. Actually, the first research grant ever made

by the Foundation was to Trask and Paul. The Virus Research Committee thought very highly of their work (which I have just outlined) and felt it worth pursuing. I don’t remember any time when Dr. ‘Trask and Dr. Paul made application for support that the grant didn’t go through. ‘They were not ivory tower laboratory workers, and when the occasion demanded it they didn’t mind doing shoe leather work in the field. As a matter of fact, when polio epidemics broke out during the late thirties and early forties, it was very unlikely that you could find them in their laboratory. Invariably they would hop trains to the scene of the trouble. It didn’t matter where it was—Canada, Indiana, West Virginia, Alabama, or New York—an epidemic was the signal to collect stools and examine sewage in the epidemic area. Later they would return to the laboratory and try to devise more refined methods for detecting poliovirus taken from such sources. O: Dr. Rivers, was their work exclusively epidemiological in character? 27 L. Melnick, R. Ward, D.R. Lindsay, F. E. Lyman, “Fly abatement studies in urban poliomyelitis epidemics during 1945,” Public Health Rept., vol. 62:910 (1947); for further detail of government activity on the problem of the fly and its relation to dysentery and neurotropic virus disease, see J. Watt, “Insect control methods,” and G. E. Quinby, “Insect control methods,” in Proceedings of a Round Table Conference on the Importance of Insects in the Transmission of Poliomyelitis. Washington, D.C.,

January 9-10, 1948, pp. 67-117 (National Foundation Archives).

National Foundation: Early Research Programs—Part | 269 Rivers: No. No. They did other things as well. For instance, before World War II, most of the monkeys used in polio research came from the Far East and the Philippine Islands. When our supply of monkeys began to dwindle around 1940, Dr. Trask and Dr. Paul decided to investigate whether monkey species from other parts of the world were susceptible to polio. For a year or two they experimented with the green African monkey, and it was they who made the discovery that it was highly susceptible to polio. One of the things I remem-

ber best about these particular experiments was that Dr. Trask and Dr. Paul were able to bring this species down with an intercutaneous moculation of poliovirus, and later recovered the virus from the stool.

It was a nice technique and I believe they later demonstrated that they could bring other species down by the same method. The search for another monkey species that would be susceptible to polio was quite an important task, and perhaps I ought to say a word

or two here about the general problem of the laboratory animal in polio research. In 1939, when Charley Armstrong demonstrated that Lansing (type 2) poliovirus would go in cotton rats, the Foundation began to encourage a number of its grantees to search for other animals that might supplant the monkey in polio research. Such a search

went on for a very long time and animals all over the world were tested. I could swear that at one time or another almost every animal that we could get our hands on had polio stuck into it—even gerbils. In case you don’t know what a gerbil is, it’s a rodent that looks like a rat and inhabits the Sahara Desert. That search was unsuccessful and the monkey remained a problem for the Foundation. During the war years it waS.a particular problem. Let me explain.

Prior to World War II, the Foundation purchased its monkeys from a New York animal dealer named Henry Trefflich. In 1940 you could still get a good healthy monkey in New York for between $10 and $15; however, as the usual sources of supply in the Far East were cut off by the war, the prices for monkeys began to rise. Early in 1942,

the National Foundation decided to buy and ship monkeys from India under its own auspices. I can tell you that that decision made Mr. Trefflich very unhappy, but I can’t say that it ended the problem.

Although between 1942 and 1943 the Foundation was able to buy and ship approximately 11,000 monkeys from India, no more than

270 Chapter 7 3000 survived passage and disease to reach research laboratories. After the war, the monkey still continued to be a problem, and in 1952 the

Foundation was finally compelled to establish a monkey farm in Okatie, South Carolina, to help supply the needs of its grantees.

QO: Dr. Rivers, in one of the early grant applications made by Dr. Trask and Dr. Paul, I noticed a request for special equipment, in this particular case, an ultracentrifuge. Other applicants, of course, made like requests. What was the attitude of the Foundation toward re-

quests for equipment? Rivers: When I began virus research, virologists used very little special equipment in the laboratory. However, by 1940 the ultracentrifuge, the electron microscope, ‘Tiselius apparatus had become a

part of the armamentarium of the virologist. Such equipment was used and needed. As I remember, Dr. ‘Trask and Dr. Paul wanted an ultracentrifuge to help them isolate poliovirus from the bacteria and

other toxins found in the highly contaminated fecal material that they were using as a source for their virus. It was a perfectly legitimate request and the Foundation granted it. In general, however, the Foundation didn’t like to make grants for

equipment, any more than they liked to build laboratories or buildings. From time to time, during the early years, the Foundation devi-

ated from that rule, but only under pressing or unusual circumstances. As far as policy goes, the Foundation has always felt that a university or medical school should assume the burden for furnishing

equipment or constructing a building or laboratory; on the other hand, it has always been willing to furnish money for animals, expendable supplies, and technical help. I would like to point out that in virus research the latter is not an inconsiderable item.

In the beginning, when the Foundation allocated funds for the purchase of special equipment, such equipment remained the property of the Foundation and in theory could later be shifted to other grantee laboratories who had need of it. During the late 1940's, a modification of that rule was instituted, and, if the Foundation did not reclaim equipment that had been purchased with its funds within a year after the completion of a given grant, the equipment became _ the property of the grantee institution.

National Foundation: Early Research Programs—Part | 271 QO: Dr. Rivers, in the fall of 1942, Dr. Paul put in a request for a grant of $150,000 for a period of five years. What was the reaction of

the Virus Research Committee to this request for a long-term grant? **

Rivers: I don’t remember that it caused any commotion. You must , remember that by 1942 a precedent for making long-term grants had already been established by the Foundation. Furthermore the Yale polio unit was not an unknown quantity to the committee. Actually

the Foundation had supported Dr. Trask and Dr. Paul on a yearly basis since 1938, and as I have already indicated they did excellent work on the epidemiology of polio. To be sure, Dr. Trask had died early in 1942, but in John Paul the committee knew it had a tried and

tested investigator who had imagination and drive, and that the laboratory had some damn good youngsters in Dr. Joseph Melnick, and Dr. Herbert. Wenner. At the time, Dr. Paul actually had great need for such a long-term grant. In the beginning of its existence, the Yale polio unit had obtained a good deal of support from the Department of Pediatrics of the Yale Medical School. ‘This department furnished laboratory space and funds from its departmental budget; however, when Dr. ‘Trask died there was no one in the department to pick up the burden of polio research and the connection between the polio unit and the department was cut. Dr. Paul who was in the Department of Preventive Medicine was then faced with the burden of reorganizing and shifting the polio unit to his own department. It was not an easy job and was complicated by the war. In 1942 the headquarters of the Army Neurotropic Virus Disease Commission

was established at Yale, and Dr. Paul, as leader of the investigative | unit of that commission, had new burdens put on his laboratory facilities. He not only had to have continuity to keep and attract first-rate personnel, he also had to expand his lab facilities. ‘The Virus Committee didn’t have to have a picture drawn for it—it knew the neces-

sity and importance of supporting the continuation of Dr. Paul’s epidemiological work, and it granted his request. See J. R. Paul, Application for grant to the National Foundation for Infantile Paralysis, October 22, 1942 (CRBS #1, Yale University, 1941, National Foundation Archives).

272 Chapter 7 Q: Dr. Rivers, if you examine the long-term grants made by the Foundation you find that all the grants have one thing in common, namely, they are all in one way or another concerned with problems relating to the epidemiology of polio. Was the Virus Research Committee ever concerned with making grants that overlapped?

Rivers: I can’t honestly say that that problem ever bothered the committee. To be sure Maxcy, Francis, and Paul all indicated that they would be working on problems of epidemiology of polio, but the Lord knows there were enough problems in the epidemiology of polio

at that time to keep twenty laboratories at work without jamming each other up: I don’t think that it ever occurred to the Virus Committee that Dr. Francis and Dr. Paul, for example, would ever tread on each others toes because they were working on like problems. So far as I know, they never have. When we made a decision to give a grant to a laboratory, we not only looked at the work that they said they were going to do; we also paid a great deal of attention to the fellows who were going to do the work. Hell, it made no difference to us that Francis and Paul both said that they were going to work on the

epidemiology of polio; we knew enough about them to know that they defined problems and worked in the laboratory in ways that were uniquely their own. Even if they didn’t, I don’t think that we would

have hesitated to give them grants. We have never given a damn if three, six, or nine laboratories worked on the same problem. In science, if a discovery is made it has to be corroborated; nothing

is accepted on faith, and the fact that laboratories work on the same problem makes the task of checking results easier. Also, if one labora-

| tory gets a good lead, you have a better chance of exploring possibilities if you have a number of other laboratories working on the same or like problems. Overlapping is not a problem in science; I think it is a necessity,

Q: I think that, to this point, we have touched on most of the prob-

lems relating to pathology and epidemiology cited in the eleven points of the Virus Research Committee. There are, however, two problems of the eleven that I wish you would make comment on. ‘The first relates to chemical blockade. By the summer of 1938, wasn’t it

National Foundation: Early Research Programs—Part 1 273 fairly conclusive that chemical blockade was not a practical method of dealing with the polio problem?

Rivers: 1 wouldn't say that it was conclusive. I believe that the com-

mittee was only agreed or convinced that the techniques that had been used to administer the prophylactic—whether zinc sulfate or picric acid—were defective. I believe we were all anxious to discover if

a more effective method could be devised to administer the prophylactic. It was one of those experiments that had not been properly wound up and completed. Actually, the committee lost interest in this subject very rapidly and, as I remember, never voted any money to prosecute further work in this field.

QO: ‘The second problem relates to the ninth point in the elevenpoint program, that of chemotherapy. Isn’t it almost an article of faith among virologists that few if any viral infections, with the possible exception of psittacosis, respond to chemotherapy?

Rivers: There were good reasons for the Virus Research Committee to turn to chemotherapy. In 1938 viologists were still impressed by the mess caused by the Brodie-Park and Kolmer polio vaccines and were determined to prevent such a debacle from occurring again. You will notice that the last research category the Virus Research Committee thought should be supported was the development of a vaccine. We just weren't ready for vaccines at that time, and I think that we were wise in staying away from them.

Chemotherapy, on the other hand, offered a possible approach to the solution of the polio problem. By 1938 chemotherapy had marked success with certain bacterial diseases, and it was perfectly natural to wonder whether chemotherapeutic agents would work on viruses in general and polio in particular. Paul de Kruif was very active in pushing this point of view in the committee and at one time suggested that the Foundation establish relationship with American Cyanamid

Corporation to test the effect of certain drugs on polio. Nothing much came out of this particular suggestion, but it was a notion that very definitely was in the air at that time. Certain workers who were struck by the success of the use of sulfapyridine in treating pneumonia

274 Chapter 7 wanted to rush off and try it on polio. That happens very often in research. If something successful is accomplished in one field, a hundred hands want to apply it in another field and they go looking for money.

The Foundation at that time did give money to one or two laboratories to work on chemotherapy of polio, but nothing much came of that research. Now that doesn’t mean that the idea of chemotherapy

was a bad one. It just means that at that particular time we didn’t have the biochemical techniques to develop it in a satisfactory way. If you want my opinion, I believe that the ultimate answer to virus disease lies in chemotherapy. But it is also plain that it will be necessary

for us to know how the host cell manufactures virus before we can develop a chemotherapeutic agent which will halt that process without harming the host cell. Quite a trick, believe me, but, as sure as I am sitting here, someone will crack it. As a matter of fact, the Foundation is supporting such studies now in Igor ‘Tamm’s laboratories at

the Rockefeller Institute and Tommy Francis’s laboratories at the University of Michigan. ‘They don’t talk much about chemotherapy —but that’s in back of their heads, believe me.

CHAPTER 6

The National Foundation for Infantile Paralysis: Farly Research Programs—

Part 2 The Foundation is a holding company for the People. It has several justifications—as critic, as originator, as catalyzer. Dr. Alfred E. Cohn, Minerva’s Progress

QO: Dr. Rivers, late in 1939 the post of medical director was created in the National Foundation. Could you tell me what events led to the creation of this post?

Rivers: Up to the time a medical director was appointed in the Foundation, most of the applications for grants were received by a secretary in Mr. O'Connor's law office. This girl, although very competent, had no medical experience, and consequently had no idea whether these applications were worth looking at, much less supporting, and as a result dumped all the applications, the good as well as the bad, into the laps of the various committees. For instance, during the

very early days of the Foundation, the Virus Research Committee had to spend a hell of a lot of time just sorting grant applications before they could settle down to discuss those worth discussing. It was a

time-consuming job and I can tell you that I and other committee members didn’t like it too well. ‘There were other problems. When the various chapters of the Foundation began to give direct medical 275

276 Chapter 8 assistance to polio patients, they quickly found that in many cases they needed expert medical advice, and that the lay people at headquarters were just in no position to give them the advice that they needed. When such questions came up, Mr. O’Connor would turn them over to Paul de Kruif, or if they were particularly pressing he might call me at the Rockefeller Hospital. It was an awkward way of

doing business and I think that it was quickly recognized that the. Foundation would eventually need the services of a medical person to handle such problems at headquarters. My knowledge: of the appointment of the first medical director of

the Foundation stems from a visit that Paul de Kruif made to my ofhce in the Rockefeller Hospital late in the fall of 1939—I don’t re-

member the exact date. The point of Paul’s visit was that the National Foundation had great need of a medical director, and that in his view Dr. Donald Gudakunst was the best man available for the job. He was sounding me out. That was all night. Hell, I knew about

Dr. Gudakunst long before Paul spoke to me about him. Dr. Gudakunst had received his medical degree at the University of Michigan, and prior to 1939 had had a first-rate career as a public health officer. During the early thirties he had been commissioner of health of the city of Detroit and in 1937 became the commissioner of

health for the entire state of Michigan. In addition to his public ofhce, he was also a professor of preventive medicine and public health at Wayne University. There was never any doubt about Gudakunst’s ability; however, in 1938 he had a knockdown dragout fight with the governor of Michigan and left his job and joined the U.S. Public Health Service.

I don’t know what Gudakunst did for the Public Health Service but it was clear from de Kruif’s talk that he was unhappy in his post and was looking for a job more suitable to his abilities. Paul could al-

ways add and so could I: it was plain that the Foundation needed a medical director who could sort out grant applications, visit laboratories, and evaluate physicians and their work for the medical committees of the Foundation, and it was just as plain that Gudakunst needed a job. Paul pushed his appointment and in the é€nd he got the job. It just so happened that Dr. Gudakunst made a first-rate medical director.

National Foundation: Early Research Programs—Part 2 277 Q: Did Dr. Gudakunst have any training as a virologist?

Rivers: No. Dr. Gudakunst was primarily a public health man, but

he knew a little bit about laboratory work. He was smart and he learned very rapidly. Actually the man did the work of at least two people and, if you want my private opinion, I think that he killed himself working for the Foundation. He worked night and day, and drove himself and others. He never rested and in the end he died of a heart attack. He was one of the hardest workers I ever saw and Paul de Kruif made no mistake recommending him.

QO: Dr. Rivers, how large a department did Dr. Gudakunst administer initially?

Rivers: In the beginning the medical department wasn’t very large. However, as the Foundation’s interest in medical research, professional education, and medical care grew, new people were added to the department. Gudakunst was an excellent public health man and knew a great deal about problems like epidemiology; however, research and education were just a little bit outside his ken. To help him, a department of research was added to the medical department sometime late in 1942. The first director of this new department was a former big league ball player named John Lavan. Unfortunately, Dr. } Lavan didn’t work out, and after the war Dr. Harry Weaver was given

_ the job. (Ill talk about Dr. Weaver later. ) : Early in 1944 another division was added to the medical department to care for the Foundation’s expanded program in physical therapy and nursing education. I forget what its original name was, but in time it became known as the Division of Professional Educa-

tion. From the beginning it was administered by Dr. Catherine Worthingham, who formerly was a professor of physical education at Stanford University and a past president of the American Physical Therapy Association. I didn’t know her very well until I came to the Foundation full time in 1955, but let me tell you she is quite a gal. In the past eighteen years since she has been with the Foundation, she

has been responsible for developing one of the finest programs in medical education anywhere. I don’t mind admitting that I am very

278 , Chapter 8 fond of her—but don’t you think for one minute that this means I go around patting her on the back. I have fought with her on many occasions, and I want to tell you, she gives as good as she takes.

QO: Would it be fair to say that, when Dr. Gudakunst became medical director, the Virus Research Committee leaned on his initial judgment about applications for grants?

Rivers: If you mean did we trust him to weed out the obviously sorry applications, the answer is yes, and for that matter we still depend on the members of our medical department—Dr. Clark, Dr. Boyd, Dr. Apgar, and Dr. Worthingham—to do that job. I should mention here that Dr. Gudakunst had another important job, as far as grant applications were concerned, and that was to advise prospective applicants on the merits of their applications. For instance, if a

fellow submitted an application which Gudakunst knew had no chance of passing the Virus Research Committee, it was his job to advise the applicant that he was not likely to receive a grant and that it might be better to go elsewhere. Now in no case could Gudakunst tell them definitely that they would get no money. He could only tell them that it was unwise to make an application for a grant. If the applicant persisted, Gudakunst was honor bound to put the application through to the committee. ‘The final decision to make a grant or reject an application was always in the hands of the Research Committee, and as far as | know Gudakunst never fudged on these obligations toward a grantee.

QO: Dr. Rivers, was there ever any conflict between Dr. Gudakunst and the Virus Research Committee? I raise this question because early

in 1944, several months after long-term grants were made to Dr. Francis and Dr. Paul, Dr. Gudakunst prepared a memorandum that questioned whether the Foundation program in epidemiology was progressing as well as it might." 1 Proposals for a Meeting of Epidemiologists. Memorandum, Donald Gudakunst to Basil O’Connor, January 7, 1944. See also correspondence, Henry Vaughan to Donald Gudakunst, August 2, 1944; H. J. Shaughnessy to Donald Gudakunst, February 8, 1944; Joseph Melnick to Donald Gudakunst, February 7, 1944; Thomas Francis to Donald Gudakunst, February 21, 1944 (folder, Epidemiologists, General, 1944, National Foundation Archives).

National Foundation: Early Research Programs—Part 2 279 Rivers: During the winter of 1944, Dr. Gudakunst wrote such a memorandum and circulated it both inside and outside the Foundation. Later he called a meeting of all of the Foundation’s grantees who were interested in epidemiology to discuss the question of the Foundation’s epidemiological program. I never attended that meeting

although I subsequently saw some of the correspondence that was written as a result of the meeting. In a word, nothing much came of it. What Dr. Gudakunst did was understandable; you must remember that he was essentially a public health officer, and he undoubtedly felt

that too little attention was being paid to the strict meaning of the word epidemiology by Foundation grantees. -I myself never felt that people like Dr. Francis or Dr. Paul were spending their money incorrectly. Actually it didn’t make much difference to me if in their grant application they said they wanted to study an “epidemiological problem” and wound up studying a straight problem in virology. ‘This didn’t happen; I am just giving it as an example. That’s the way research is done. You start out to do something and if you run into a snag you do something else. If you didn’t, you would never get anywhere, and all you would have to show for your effort is a bruised head from butting your head against a stone wall. ‘That’s not very smart. In research you make a start, and if that doesn’t pan out you try the wall in a different place until you get a foothold. Other people widen that foothold, and sooner or later the wall disappears, and you discover that you can proceed down the path you wanted to take two | or three years previously.

O: Dr. Rivers, how much pressure was put on grantees for quick results?

Rivers: So far as the Virus Research Committee was concerned, I can say unequivocally no pressure at all. However, I really don’t know whether Dr. Gudakunst believed that he should get results quickly as

you do when you administer a public health program in a state or a

city. In such cases you at least get something done. Whether it amounts to anything or not doesn’t matter; at least you get something

that you can write a report on. Most of the men on the Virus Research Committee knew something about research, and the commit-

280 Chapter 8 tee, as I say, never put any pressure on the boys. Now, on one or two occasions, we did cancel some grants. But we didn’t cancel because we thought that they were doing something wrong; we canceled because they weren’t doing anything at all, and in such cases I feel that we had every right to cancel. It is true, however, that Dr. Gudakunst felt differently about research and how to handle research problems than I did. For instance, for a long time it was difficult to persuade him about the necessity for giving money to research projects that had no immediate relevance to polio. However, just before he died in 1946 he saw the validity of that approach and even urged the Virus

Research Committee to:support a grant to William Robbins at the New York Botanical Gardens to do research on phage and a grant to Linus Pauling of the California Institute of ‘Technology to study the structure and nature of proteins and nucleic acid. Unfortunately, Dr. Gudakunst was never able to carry through on those grants because he died. However, his successor Dr. Harry Weaver did.

I want to tell you that Dr. Pauling was not even remotely interested in polio, but in the end his work helped us immeasurably in gaining a better general understanding of the biochemical nature of viruses, polio included. It is a matter of some pride to the Virus Research Committee that Dr. Pauling won a Nobel prize for his work in

chemistry while under grant of the Foundation. I should add here that, while the work of Dr. Robbins’ laboratory on phage was less fruitful than we had initially hoped for, it fortified us in our belief that such studies would in future prove of enormous value in develop-

ing virology as a discipline. Some years later, several Foundation grantees, among them Earl Evans of Chicago and Max Delbriick of the California Institute of Technology, amply confirmed our beliefs of the usefulness of working on phage, and during the last decade such work has truly helped revolutionize our understanding of viruses.

QO: Did Mr. O’Connor ever try to put pressure on the committees?

Rivers: Hell, no. Mr. O’Connor is smart and he had better sense than to try that. He knew that if he tried to put pressure on the committees they would have told him to go to hell and packed up and gone home. They were just as busy in their own work as he was in his.

National Foundation: Early Research Programs—Part 2 28] He valued their independence and their judgment, and if you ask me he depended on it. QO: Dr. Rivers, from time to time you have spoken of the importance

of Paul de Kruif in counseling on early Foundation policy, but it is clear from material in the Foundation files that Mr. O’Connor frequently called upon you and Dr. Karl Meyer for advice. 3

Rivers: Well, I worked at the Rockefeller Hospital, and if Mr. O’Connor needed anything in a hurry all he had to do was pick up . the telephone. He could get me at any time. I think that that accounts some for my being used so often. Karl Meyer stood well in virology and I think that Mr. O’Connor was impressed by Karl. Karl is no dumbbell and, like myself, doesn’t like to pussyfoot. If you asked him a question, he would say yes or no, he wouldn’t say maybe. Now that kind of an answer was very helpful to Mr. O’Connor. Remember

that he knew very little about medical research and nothing about virology, and if he was to function efficiently as an administrator he had to have people who could say yes or no to him. It’s pretty difficult to operate on maybes. I could say yes or no, and Karl could too. Karl still can and I still can. I think that this is the reason that Mr. O’Connor called on us. I am not saying that we were always right. Hell, no. But right or wrong, Mr. O’Connor would be able to get his yes or no.

O: Dr. Rivers, I will return later to problems of epidemiology in another context. Now I would like to ask you about another early administrative officer in the Foundation named Peter Cusack.

Rivers: I knew Peter Cusack slightly. Originally he was associated with Keith Morgan in the administration of the President’s Birthday Ball Commission. Later he joined the Foundation as executive secretary, and in that position played a key role in the day-to-day adminis-

tration of the Foundation. I didn’t see much of him, because his function within the Foundation had little to do with science, although it is true that he signed the minutes of the Virus Research Committee. The main thing that I remember about Peter was that he thought

282 Chapter 8 the world and all of Sister Kenny, and I couldn’t stand her. Originally she came to this country from Australia, and half of the provinces of Australia liked Sister Kenny and the other half would have nothing to do with her. ‘The virologists that I knew in England told me all about her, and so I was well acquainted with her work before she ever came to America. When she landed in this country, she had introductions to two people; she had a letter of introduction to Mr. O’Connor and one to me. I was sitting in my office at the Rockefeller Institute one day when Mr. O’Connor called me. He said, “Tom, there’s a person

here who would like to come up and see you.” I said, “Who is the person, Mr. O’Connor?” He said, “Well, it’s Sister Kenny.” I said to Mr. O’Connor, “Would you answer this question, yes or no? First, is

she sitting there?” He said, “Yes.” I said, “Please answer the next question, yes or no. Have you bought her?” He said, “Yes.” I said, “If you have bought her, and if you and I want to remain friends, it’s best that I not see her. You can make whatever explanations you wish of

my refusing to see her. Because of the friendship between you and me, I’m not getting mixed up with that lady. Sometime I'll tell you why.” And that was that.

) Well, Mr. O’Connor bought her and so did Morris Fishbein of the AMA. They gave her money and she set up shop under University of Minnesota Medical School auspices. Some years later, she wrote a

book on infantile paralysis and the Kenny treatment, and in the preface of that book claimed that the National Foundation and the AMA had asked her to come to this country to demonstrate her treatment for polio. ‘That claim was just a plain lie, because the fact is, the

National Foundation and the AMA did not ask her to come here.” Within a very brief period of time, the Foundation became critical of the way Sister Kenny set up her courses of instruction at the University of Minnesota and her increasing demands to put everything aside

in the Foundation polio research program except the Kenny treatment.

~ In 1943 things came to a head during the course of a polio epidemic in Argentina. At that time, the Argentine Republic requested President Roosevelt to send Sister Kenny and her team to Argentina 2 Dr. Rivers is mistaken here: Sister Kenny made no such claims. Cf. E. Kenny, Treatment of Infantile Paralysis in the Acute Stage. Bruce Publishing, Minneapolis, 1941, pp. 1-2.

National Foundation: Early Research Programs—Part 2 283 to aid doctors in that country fight the epidemic. Mr. O’Connor called me and asked if Kenny should be sent. I said, “Yes, I think it would be a nice gesture, but I think you ought to send a good doc

along with those physical therapists. I wouldn’t send them down there alone.” He agreed and got Dr. Rutherford I. John, an orthopedist from Philadelphia, to accompany Sister Kenny’s team of physical therapists. Sister Kenny’s niece was on that team—she was a good physical therapist and a doggone good-looking girl. Well, that trip was a disaster. What happened was that all the rich people in Argentina gobbled up these therapists to care for their own

children, and the purpose of the trip—to instruct the doctors in Argentina in the Kenny method—went by the board. Dr. John got sore as a boil and came home and reported to Mr. O’Connor what had happened, and Mr. O’Connor got sore. He and Sister Kenny had a blow-up, and from that time forward they hated each other. Before the blow-up came, the Foundation gave a luncheon in honor of Sister

Kenny and Cusack called me and asked if I would attend. I said, “Yes, Pl come to your luncheon but under one condition, and that is that there will be no reporters present and that nobody will put my

name in the newspaper as having had lunch with Sister Kenny.” Cusack said, “I can guarantee that,” and so I went. When I arrived, Mr. O’Connor took me over and introduced me to |

Sister Kenny, and I stuck my hand out. She reared back, put her hands behind her back, and looked at me. She was a big woman, bigger than I was, and she said, ““You were the man who wouldn't sce me when I first came to this country.” I looked at her. “Madame,” I said, “I am that man.” I then turned around and walked off.

After the blow-up with Mr. O’Connor, the Foundation stopped inviting her to its scientific functions. During the First International Poliomyelitis Conference in New York, she asked to take part in the conferences but was refused. She thereupon got herself appointed as a newspaper woman and attended the conferences in that capacity, but of course couldn’t speak. When the Second International Poliomyelitis Conference was held in Copenhagen, she again wrote and asked to be put on the program and was again refused. She came anyway. By this time her health had broken, she had a myocarditis and the beginning of a fairly marked paralysis agitans—you know, the

284 Chapter 8 shakes. Prior to the opening of the conference, Mr. O’Connor gave a reception and she attended. I was in the receiving line when in came Sister Kenny—she could hardly walk—when she came to me in the receiving line she stuck out her hand, and I shook it. I am sure she didn’t recognize me. Hell, it made no difference to me what she was —the poor old soul was damned near dead—and she was still a person. Shortly after the conference she died. I think that all of this is rather a sad story, because you know Sister Kenny did do some good. Before she came to America, doctors put patients who had infantile paralysis in splints. ‘Treatment at that time called for the immobilization of the paralyzed limb. I think that it is fair to say that many doctors and therapists on their own were at that time ready to change that practice, but I believe that Sister Kenny got

us away from this much faster than we would have in the natural course of events. Kenny favored moving the paralyzed limbs and edu-

cating the patient to make that movement. Her big problem was explaining how she got the results she got. She had no notion of the nature of poliomyelitis as a virus disease and certainly knew nothing about its pathology. For example, she thought it was a disease of the muscle. The kindest thing I can say about her ideas of physiology and anatomy is that they best be forgotten. ‘There is no denying, however, that she got effects, and I think that on the whole she did some good. QO: Dr. Rivers, I would like now to examine your relationships with some of the other medical advisory committees in the Foundation.

Rivers: I don’t know how helpful I can be to you here. At best, I will only be able to tell you about the purposes of these committees, some of the people I knew who served on them, and maybe a hassle or two, but not much more.

QO: ‘That will be quite all right. Could you, for example, tell me about your relations with the General Advisory Committee? °

Rivers: ‘This committee was one of the oldest committees within the Foundation and if I am not mistaken existed from the early for* The General Advisory Committee was organized May 15, 1941, and was dissolved on October 8, 1958.

National Foundation: Early Research Programs—Part 2 285 ties until the reorganization of the committee system in the Foundation in the late fifties. Briefly, the General Advisory Committee was responsible for finally approving or disapproving the grants made by the other medical committees. As such, it served as a court of last resort. However, I don’t actually remember whether it ever disapproved anything that had previously been approved. Its membership was

composed of the chairmen of the various medical advisory committees—the Virus Research Committee, the Committee on Prevention and After Care, and so forth—and distinguished physicians from outside the Foundation, people like Dr. Irvin Abell, who was at one time chairman of the Board of Regents of the American College of

Surgeons, and Dr. James Paullin, who had been president of the American Medical Association.

Generally the outsiders on this committee were chosen for their standing within the medical profession and not necessarily because they knew a great deal about polio. They might know something about polio, but it wasn’t a prerequisite for being on this particular committee. Take Jimmy Paullin. Jimmy was an Atlanta boy and I had known him since 1909. He was a damn good doc who knew a

great deal about pneumonia but not a hell of a lot about polio. Jimmy, however, was the kind of a person who could make a sound medical judgment when presented with the facts, and was very help- ful on more than one occassion to the committee. If anybody on the General Advisory Committee wanted to talk on what the Virus Committee had approved or disapproved, they had to argue with me. ‘That was also true of the chairmen of other committees. Now if some one on the General Advisory Committee raised a question about a grant that had been approved by the Virus Committee, it didn’t always follow that I would defend the action of my committee. I might defend it if I believed in it, but if I didn’t I would tell them what I thought. You know on more than one occasion I was outvoted by the Virus Committee. The General Advisory Committee no longer exists—it has been done away with. Jimmy Paullin is dead, Irvin Abell is dead, Frank Ober is dead, the old boys are all gone. | don’t know that that committee was ever needed, but while it did exist it was an ornament to the Foundation.

286 Chapter 8 O: Dr. Rivers, did your work for the Virus Research Committee ever bring you into contact with the members of the Committee on Prevention and Treatment of After-Effects? *

, Rivers: By and large I didn’t mix in their affairs unless they impinged on the work of the Virus Research Committee, and that |] assure you was not very often. This committee, as its name implies, was largely concerned with clinical investigation and evaluation of various methods of treatment of aftereffects of polio. ‘They dealt with such problems of physical medicine as muscle testing, muscle physiology, and orthopedic repair, as well as with the problems of respirators and splints. A great many orthopedists served on that committee,

among them such distinguished practitioners as Dr. Frank Ober of Boston, Dr. George Eli Bennett of Johns Hopkins and Dr. Phil Lewin of Chicago. During the early days of the Foundation, it also had the services of two of America’s most distinguished physiologists, Old “Ajax” Carlson of Chicago, and Walter B. Cannon of Harvard. I am

not telling any secrets when I say that these two fellows didn’t like each other very much—but you would never have known it from their

work with the Foundation. When they worked on Foundation matters, they worked closely and in harmony.

The fellow on the Committee on Prevention and Treatment of After-Effects that I knew best was Dr. Phil Lewin, who during the early years was the chairman of the committee. Phil Lewin is now dead. He was slightly older than I. He was a great friend of Paul de Kruif’s, and I don’t think that it is an exaggeration to say that in his time he was one of the leading orthopedic surgeons in Chicago. He

| was a rather unique individual. I would say that he was one of the best-hearted men I ever knew, one of the nicest persons I ever knew, but in some respects one of the biggest numbskulls I ever knew. Phil

was a damn good orthopedic surgeon, but that didn’t prevent him from suggesting—I believe it was sometime in 1941—that the Foundation publish 10 volumes covering every aspect of polio. What we

knew about polio at that time could have been put in a small box. * The Committee on Prevention and Treatment of After-Effects was organized on October 6, 1938. It subsequently underwent a reorganization, becoming the Committee on Research for the Prevention and Treatment of After-Effects, on January 11, 1940.

National Foundation: Early Research Programs—Part 2 287 Hell, you don’t publish books when you don’t know anything, not in my book you don’t. I had a hell of a time talking him down—if we

had published at that time we surely would have regretted it. As I said before, in the beginning Phil was the chairman of the com-

mittee. Mr. O’Connor liked him personally very much, but at one time it was decided at the Foundation to drop certain people from various committees, and I was delegated to write the letter of notifcation. Phil Lewin was one of those to be dropped. I thought I wrote

a good letter, but I want to tell you that in reply Phil sent Mr. O’Connor one of the hottest telegrams I have ever read. He just didn’t want to be dropped. He wondered out loud why in the hell he was being dropped, and he didn’t mind telling the Foundation that he was the best person they had ever had, and so on. The funny thing

about all this is that neither Phil Lewin nor, for that matter, any other member of the committees of the Foundation ever received a red cent for the work they did, outside of the expenses they incurred attending meetings. Well, when Mr. O’Connor received that telegram, he came over to see me and said, “Tom, for God’s sake, please get in touch with Phil and tell him we have made a mistake.” I said, “Yes, Mr. O’Connor,” and promptly sat down to write Phil. It was perfectly all nght. Phil came to all the meetings after that and acted as if nothing had ever happened. He served on the committee until the day he died.

Phil did one of the nicest things I think I ever saw done. He was | married to a wonderful woman who, I believe, was an actor’s agent. They were well off financially, but they had no children and later in life they adopted a child who was terribly crippled by polio. I don’t know how many times Phil operated on that little boy—I think it was *'The debate between Dr. Rivers and Dr. Lewin on the question of publication was one of long standing and apparently erupted in 1939 when Dr. Lewin made the suggestion that the National Foundation prepare a pamphlet on its research programs. Dr. Rivers opposed that proposal, because the suggestion was made that he be the author. When Basil O’Connor informed Dr. Lewin at that time of Dr. Rivers’ objections to publication, Dr. Lewin replied, “. . . My immediate reaction to Tom Rivers’ answer to you was—first, that it was discourteous, insolent, and dumb; second, it was typical of the full-time worker who recently had his picture in Time.”—Philip Lewin to Basil O’Connor, October 7, 1939 (folder, Philip Lewin, Public Relations Files, National Foundation Archives); Thomas Rivers to Basil O’Connor, September 25, 1939 (folder, Thomas Rivers, Public Relations Files, National Foundation Archives). Later, Rivers and Lewin became friends.

288 Chapter 8 seven or eight times. Today that boy can walk, use his arms fairly well, and even ride a horse. Just before he died, Phil and his wife came to one of the annual meetings of the Foundation in Florida. I saw that little boy swimming in a pool with Phil watching over him like a mother hen. He was wild about that little boy, and the little boy was wild about him even though Phil had put him through all those operations. That’s the kind of a guy Phil Lewin was. A wonder-

ful person, a damn good orthopedic surgeon—but when it came to science he just wasn’t there.

QO: Dr. Rivers, you indicated earlier that the Virus Research Committee supported epidemiological studies of polio. I wonder if the consideration of such grant applications ever brought you into conflict with the Committee on Epidemics and Public Health? ® Rivers: Broadly speaking, epidemiology is the study of a disease as it attacks a human population; and while it does have laboratory work connected with it, it is actually a special kind of study which, by its nature, can’t be contained within the four walls of a laboratory and has to be done in field. It is true that the Virus Research Committee and the Committee on Epidemics and Public Health were both interested in problems of epidemiology. However, I will say that we didn’t tread on each others toes, because I suppose we were different kinds of folks and had different interests and training. With the exception

of John Paul, most of the original members of the Committee on Epidemics and Public Health were people who were trained in public health. For example, Dr. Kenneth Maxcy, whom I spoke of earlier, was a professor of epidemiology at the School of Public Health and Hygiene at Johns Hopkins. Another member, Dr. George Ramsay, was commissioner of health of Westchester County, New York. Dr. Herman Bundesen was commissioner of health for the city of Chi-

cago, and Dr. Thomas Parran was Surgeon General of the United States. Earlier in his career, however, Dr. Parran had served as commissioner of health of the State of New York. *'The Committee on Epidemics and Public Health was organized on June 6, 1939, and reorganized on September 30, 1947, as the Committee on Virus Research and Epidemiology.

National Foundation: Early Research Programs—Part 2 289 Dr. Parran was and is quite a boy and I think that I ought to say a few words about him. I don’t think that history will remember him for his contributions to polio, but it will remember him for his general accomplishments in public health administration, and as the man who had the guts to bring the word syphilis into the sitting rooms and parlors of the homes of people in the United States. You might say, what kind of a wonderful trick is that? Wasn’t the disease in the bedrooms of those same homes? It was, but I want to tell you that at one

time you didn’t use the word syphilis in public, much less in the home. It was a forbidden word, and even doctors in talking about the disease used the word luetic or lues. Parran brought the word into the home and, calling a spade a spade, was able to use it as the opening gun in a national venereal disease campaign. Syphilis is a treacherous disease, and knowing it by name has helped bring it under control. When antibiotics came in, there was hope that we might be able to wipe out the disease entirely, but we haven't, and it is distressing to read about the rise of the disease, particularly among teenagers. However, Dr. Parran’s work has had one lasting effect. ‘I’oday people know

about the disease, and when they get it they seek treatment. ‘Io be sure, we still have a hell of a lot of primaries and secondaries. However, because of early treatment, we no longer see the tertiary paretics and tabes that I saw when I was a young doctor. That’s on the credit side of the ledger and we owe that to Tom Parran. I don’t want you to get the idea that everybody on this committee

was of Dr. Parran’s caliber. I can tell you now that Dr. Herman Bundesen wasn’t. Dr. Bundesen was the commissioner of health for the city of Chicago and one of Paul de Kruif’s friends. Like so many of Paul’s friends, he too was invited to join the Foundation in an advisory capacity. | suppose that initially Mr. O’Connor was impressed with the importance of Dr. Bundesen’s position and assumed that, as

commissioner of health of the city of Chicago, he ought to know something. It was a fair assumption, but, as far as competence in epidemiological research was concerned, Dr. Bundesen just didn’t have

it.. The only knack he did have was the knack of getting along with people. He was a doggone good politician, and he got along well with the politicians of Chicago, particularly Mayor Kelly. Come to think of it, being a politician was not an unimportant talent, and I'll have

290 Chapter 8 to admit that Dr. Bundesen probably accomplished as much for public health in Chicago with those politicians as anybody could have. Early in 1941 Dr. Bundesen presented a plan to the Foundation for a national epidemiological research program.” In brief, his plan was for the Foundation to hire its own epidemiologist to do epidemiological research in the field during the course of epidemic periods. It was the most detailed and all-inclusive program I have ever seen and just about covered everything. It called for an expert epidemiologist, an expert diagnostician in polio, an expert virologist, an expert this, and an expert that. ‘The only thing that Dr. Bundesen seemed to forget was, where in the hell he was going to get all of these experts without

emptying medical schools and the state and federal public health services of their people. Believe me, when I tell you that it was impractical not only from the point of view of acquiring personnel. ‘The purpose of doing epidemiological research just seemed to elude Dr. Bundesen, and he could never really differentiate between trying to control an epidemic and doing epidemiological research. Some of the all-inclusiveness of the program was downright silly and a dead giveaway that Dr. Bundesen just didn’t know what the hell he was talking about. For instance, he made a great fuss about wanting to study the possible relationship of milk pasteurization and postpasteurization protection to the spread of polio. By 1941 it was clear to anyone who had spent any time at all on the problem of polio that milk played an insignificant role in the spread of polio. ‘There were only two very small authenticated epidemics on record that could at all be traced back to contaminated milk. One of these had occurred in New York State and was investigated very thoroughly by Lloyd Aycock of Harvard, who traced the origin of this particular epidemic to a milker

who was infected with polio. But it was a unique case, and most virologists and epidemiologists realized that studying milk would not be a fruitful way of spending research time and money.

Eventually Dr. Bundesen sent this plan to virologists and epi*Herman Bundesen, Suggested Programme for the Study of the Epidemiology of Poliomyelitis, presented to the Committee on Epidemics and Public Health of The National Foundation for Infantile Paralysis (no date, probably late 1940). (Folder, Medical Meetings, 1940, National Foundation Archives.) °'W.L. Aycock, “The epidemiology of poliomyelitis with reference to its mode of spread,” J. Amer. Med. Assoc., vol. 87:75 (1926).

National Foundation: Early Research Programs—Part 2 291 demiologists all over the country for comment, among them people like Dr. John Paul of Yale, Dr. John A. Ferrell of the International Health Board of the Rockefeller Foundation, and Dr. Charles Armstrong of the U.S. Public Health Service. The replies were all very polite and spoke very well of the importance of doing epidemiological research as a principle and then ripped hell out of the plan. I don’t remember that anyone had a good thing to say about Dr. Bundesen’s ‘specific research proposals. You can believe me when IJ say that I

| wasn’t the only one who made critical comment. I don’t know whether Dr. Bundesen ever really expected to get such frank analysis of his proposals, but I assure you that he got them.° However, that didn’t end the matter. Dr. Gudakunst and others in the Foundation were convinced that the Foundation should have its own epidemiologist, and tried to cut Dr. Bundesen’s proposals down - to size. In the end, the Foundation held a special meeting in Chicago to discuss the feasibility of the modified proposals. I was invited but I didn’t go. However, other virologists and epidemiologists that I know did attend. I am sorry now that I didn’t go, because I understand that there was a knockout teardown battle. ‘The upshot was that Bundesen’s proposals were finally buried, and the Foundation decided to pursue epidemiological research by making grants to people like Kenneth Maxcy, John Paul, and Tom Francis, which I might add was a hell-ofa-lot smarter way of attacking the problem.

The Bundesen affair caused a commotion in the Committee on Epidemics and Public Health and some committee members began : to wonder about the usefulness of the committee and resigned. After World War II, when it became clear that a special committee was not needed to deal with problems of epidemic aid, and that the problems relating to research in epidemiology were best handled by the Virus Research Committee, the two committees were merged. ‘Today ® Typical of the many sharply critical letters Dr. Bundesen received are L. L. Lumsden to Herman Bundesen, February 19, 1941; C.C. Dauer to Herman Bundesen, February 20, 1941; Abel Wolman to Herman Bundesen, February 24, 1941; Roy Feemster to Herman Bundesen, February 25, 1941. ‘Thomas Rivers to Herman Bundesen, February 26, 1941; George M. McCoy to Herman Bundesen, February 27, 1941; Charles W. Armstrong to Basil O’Connor, February 27, 1941; W. Lloyd Aycock to Basil O'Connor, March 3, 1941; Edward S. Godfrey to Herman Bundesen, March 3, 1941; W.G. Smillie to Herman Bundesen, March 3, 1941 (folder, Herman Bundesen, Public Relations Files, National Foundation Archives).

, 292 Chapter 8 the Virus Research Committee is still officially known as the Committee on Virus Research and Epidemiology. Actually, epidemiology was never the principal concern of the Committee on Epidemics and Public Health. I would say that basically they were concerned with

such problems as what the Foundation could best do to render assistance to stricken areas in times of epidemics, and what form such assistance should take.

QO: Dr. Rivers, what kind of public health advice could the Committee on Epidemics and Public Health give to a community faced with an epidemic, let us say, in 1943?

Rivers: It is interesting that you should ask that question, because I remember that, at the very first meeting ever held of the Virus Research Committee, we were asked whether we knew enough about -

the epidemiology of polio to recommend shutting down public schools in times of epidemics. ‘he members of the committee were polled, and half of those present advised closing the schools, while the other half advised keeping them open. The only time that the committee achieved some semblance of unanimity was when we were

asked whether kids should be kept out of swimming pools and crowds. We all agreed that children should be kept out of pools and crowds, but, for heaven’s sake, don’t ask me on what basis we reached such a conclusion. It’s my feeling that we gave that advice as a reflex action, because we certainly had no hard scientific evidence on which to base such advice. Even knowing as much as we do about polio to-

day, and it’s a hell of a lot more than we knew in 1943, I still wouldn’t know what to tell a public health officer to do during an epidemic. All I could possibly do which would be rational or effective would be to advise him to vaccinate the population in his area. But I

wouldn't know enough to tell him to keep people out of swimming pools or ball parks.

I think that the lack of good hard advice was precisely the thing which led Dr. Gudakunst to circulate the memorandum you mentioned before on epidemiology. In 1942 the incidence of polio in the United States happened to be at a very low level, but in subsequent years it began to rise once more. When that happened, Dr. Guda-

National Foundation: Early Research Programs—Part 2 293 kunst, as an old public health man, began to reach for something concrete he could tell the public. Lo and behold, when he went to people like Dr. Francis and Dr. Paul, who were working on problems of the epidemiology of polio, they could not give him the hard and

fast advice and rules that he wanted. The funny thing about all of this is that their epidemiological work at the same time was giving us greater insights than we had ever had before into the nature of polio. Sure, they were groping on the role of the fly in polio epidemics, sew-

age, and water-borne epidemics, but, hell, that’s what scientific research is—it’s a search. As far as public health advice on what to do during a polio epidemic went in 1943, the committee couldn’t give any better advice than the course which was followed by Dr. Haven Emerson during the great polio epidemic of 1916. Today we don’t actually know how many cases of polio occurred in

the United States during that epidemic. At that time it was not compulsory to report polio cases, and many states didn’t keep figures on the incidence of the disease. ‘he cases that we do have a record of are, of course, far below the actual number which occurred. In New York City alone, over 9000 cases were reported during the summer and fall of 1916.*° The epidemic actually began in mid-June but was still raging in September, when the mayor and other city officials called on Dr. Emerson, who was then commissioner of health, to de-

cide whether to open the public schools for the fall term. Many physicians in the city urged that the schools be kept shut, but Dr. Emerson laid his head on the chopping block and fought to open them. In the end he won out, the schools were opened, and to everyone’s happy surprise the incidence of polio in the city began to decline.

Today, looking back, we can say that it was coming to that time of year when the incidence of polio would drop anyway. But what was

probably more important was the fact that when children went to school they came under school discipline—they didn’t run around “There are two excellent contemporary analyses of the polio epidemic of 1916: New York City Department of Health, A Monograph on the Epidemic of Poliomyelitis in New York in 1916. New York, 1917; and C.H. Lavinder, A. W. Freeman, and W. H. Frost, Epidemiological Studies of Poliomyelitis in New York City and Northeastern United States during the Year 1916. Public Health Bulletin 91. Washington, D.C., 1918.

294 Chapter 8 putting their hands in each others mouths, and they were more careful in their personal hygiene going to and from the bathroom. That’s hindsight. Actually, Dr. Emerson was very courageous to give that advice. He certainly had no way of knowing what would happen, be-

cause our experience with polio at that time was extraordinarily limited. Hell, if that epidemic had continued, they probably would have nailed him to the door.

When I came to serve on the New York City Board of Health in 1937 I got to know Dr. Emerson very well. He was a member of the New England Emerson family and, like his forebears, was of an inde-

pendent turn of mind. Physically he was tall and rangy, and in the days that I knew him he wore a kind of rabbity moustache. I don’t know how old he lived to be, but I believe that he was in his eighties when he died. He was vigorous even in old age, and ] remember going out to see him at his home, a year or two before he died, and finding

him chopping wood and doing other household chores. He was a tower of strength to the Board of Health of the City of New York, even after he retired. He attended meetings faithfully and invariably sat to the left of the commissioner of health. I used to sit beside him, and I would always get a charge to hear someone raise a problem as if it were brand new, only to have Dr. Emerson tell him how the board handled it twenty or thirty years before, and what mistakes had been made in setting up policy. Dr. Emerson’s memory was extraordinarily important for the board, because frequently*there was no record of the debates attending earlier decisions, and I want to tell you that the

same problems came up over and over. Dr. Emerson helped keep things in historical perspective for the board and in so doing kept it from becoming stultified.

Q: Dr. Rivers, since you had this favorable opinion of Dr. Emerson, why did you later turn down his application to the Foundation for a grant to do research on problems of the epidemiology of polio? **

Rivers: The fact that I liked Dr. Emerson had nothing to do with the case. [ was very fond of Dr. Emerson, but I didn’t think that he could do research. ‘That doesn’t mean that I didn’t think he was wise % Haven Emerson, Application for a grant to the National Foundation for Infantile Paralysis, April 18, 1939 (folder, Haven Emerson, National Foundation Archives).

National Foundation: Early Research Programs—Part 2 295 or could be helpful. During the 1940’s the American Public Health Association published recommendations on what to do in times of polio epidemics. Dr. Emerson played an important role in keeping these recommendations up to date and advising the people charged with publishing them. I’d give him money for that kind of work any time, because he was a master at it and wiser than anyone I ever knew. Make no mistake, he was one of the pioneers in American pub-

lic health—a great figure—but, damn it, he wasn’t a research man, and I would never give him any money for research.” That doesn’t mean that he couldn’t think. I believe that I could tell you a story right now that would indicate the breadth of Dr. Emerson’s views. In the middle of the 1916 polio epidemic, Dr. Emerson asked the Rockefeller Foundation for a grant to help fight the epidemic. ‘They listened and later made a rather substantial grant to the City of New York. However, on receiving the check, Dr. Emerson wrote the Foun-

dation and said that he hoped that this grant wouldn’t prejudice his application for a future grant to fight alcoholism, because he felt that the latter was a more important public health problem. You would have thought that the polio epidemic would have absorbed all his thought and energy. It didn’t. So far as I know, his dislike for alcohol persisted right up until his death. It was a phobia with him. I personally could never see why he got so wrought up about alcohol. There 1s

nothing sinful about getting drunk anymore than it is sinful to eat green apples and get a bellyache. Hell, when I was younger I used to drink; to be sure I later quit. But I didn’t quit because it was sinful; I quit because it bothered my ulcer, not because it was wrong.

O: Dr. Rivers, an examination of the grants made by the Virus Research Committee reveals that all such grants were made to investigators who were attached to universities and medical schools. Were

any grants ever made to investigators who might have had “good ideas” but no institutional attachment?

Rivers: ‘The Virus Committee rarely made such grants. In fact it was our policy to discourage such applications, if at all possible. On its

face, such a policy might seem harsh and discriminatory to the lay* For a measure of Emerson as a public health thinker, cf. H. Emerson, Selected Papers. W.K. Kellogg Foundation, Battle Creek, Michigan, 1949.

296 Chapter 8 man. Actually there was good reason for it. Virus research requires good laboratory facilities. It goes without saying that the doctor who

was not connected with a university, medical school, or hospital would have had to expend considerable funds to build and equip such a laboratory. If he wanted to work on polio, it would have also been necessary to construct animal houses to keep his experimental monkeys, rabbits, and mice. I know of no private investigator who had the

wherewithal or interest to do this. It is true that on occasion we got applications from young doctors who had interesting research ideas

and at such times we did try toencourage them. I remember that once a young doctor in the Bronx named Benjamin Sandler wanted to study the effect of disturbance in carbohydrate

metabolism as a factor altering susceptibility to poliovirus. For the time it was a nice idea; however, the problem that the committee faced was that Dr. Sandler had had no extensive experience in handling viruses. We kicked it around awhile and finally told him that we would be willing to assist him, if he could get help from a virologist

approved by the committee. I guess he felt that he could do it by himself, because he never did present a virologist for the committee’s

approval, and in the end we rescinded our approval for the project. I don’t know how long this dragged on, but it went on long enough for me to get sore at the guy.* _ I don’t want you to think that, because an applicant was a doctor, it necessarily followed that he had to have good research ideas. Often

the reverse was true. Once we got an application from a doctor in California for a study of the relationships of areas bounded by high tension wires and the incidence of polio. It was his unique notion that the electrical currents given off by high tension wires made cells susceptible to poliovirus. Another time considerable pressure was put on the Virus Research Committee to try rabies vaccine as a prophylactic against polio, Well, that idea didn’t appeal to me very much because

it meant giving rabbit brain and cord to people. It was well known, *° Rivers later became disenchanted with Sandler’s idea and opposed it, although orig-

inally he had supported him. See Thomas Rivers to Gilbert Dalldorf, June 21, 1940; Thomas Rivers to Donald Gudakunst, February 21, 1941 (folder, Benjamin Sandler, Public Relations Files, National Foundation Archives). In 1952 Sandler published a volume called Diet Prevents Polio (privately published), which argued that low blood sugar or a diet of high sugar content enhanced susceptibility to poliomyelitis.

National Foundation: Early Research Programs—Part 2 297 even at that time, that a certain number of people developed a demyelinating encephalitis after receiving antirabic treatment. Furthermore, I had produced such an encephalitis experimentally by injecting monkeys repeatedly with rabbit brain tissue. ‘he applicant would have had to kill me before I supported such a fool notion. Now, the bald fact is that the Foundation received a great many such crackpot applications and letters and for that matter still does. The Virus Research Committee always answers such letters and applications in a friendly way, indicating that the ideas are of interest but that the Foundation cannot support them because they are not likely to yield significant results. It never pays to make such a crackpot mad, and you can’t cure one so far as I know, so we brush them off gently.

QO: Dr. Rivers, you earlier made the point that in 1940 there was a paucity of trained virologists in the United States. As a matter of fact one of the purposes in setting up the virus laboratory at the School of

Public Health at the University of Michigan was to train young virologists. I wonder if you would speak to the point of the pool of virologists that existed in the United States about 1940.

Rivers: I think that it would be fair to say that in 1940 there were a small number of virologists in the United States who were capable of doing competent research in the field of polio or, for that matter, other virus diseases. I am not going to say how many, because I don’t

want to go around upsetting people—just let me emphasize that it was a small number and let it go at that. It was pretty obvious to the Foundation that, if it was to get any work done in poliomyelitis, it would have to train some youngsters to carry on when senior investigators went to their reward. Although Mr. O’Connor agreed that it

was proper for the Foundation to undertake the training of such young investigators, there was no machinery then within the Foundation to get such a program under way. Sometime in 1941 the Rockefeller Foundation gave a grant to the

_ National Research Council to set up a fellowship program in medicine and closely related fields, and I thought that if we approached the Research Council properly it might also possibly be persuaded to

298 Chapter § administer such a program for the National Foundation. Mr. O’Connor approved the idea, and I got in touch with Dr. Milton Winternitz and Dr. Louis Weed of the National Research Council and asked if they would administer such a program if we gave them the money to carry it out. They agreed and in 1941 it got under way. I conceived of the fellowship program in broad terms. For example, I didn’t think that fellowships should be restricted to training people to work on polio alone. I wanted to train broad-gauged virologists and, if necessary, to give them solid backgrounds in the basic sciences,

such as physics and biochemistry. Mr. O’Connor wanted an even broader program and urged that fellowships be granted to train orthopedic surgeons as well. In the beginning, fellowships were offered to orthopedists. Unfortunately, however, only one or two were able to take advantage of the opportunity because the war intervened. In the end, the fellowships were awarded to those who wanted virological training and experience. I must say that it was a very successful program, and many of the boys who were trained under its auspices later went on to distinguished careers in virology. For instance Dr. Joseph Melnick, now a professor of virology at Baylor University Medical School, and Dr. Herbert Wenner, a research professor of pediatrics at the University of Kansas Medical School, got their start in virology under a fellowship grant which allowed them to work with John Paul in the Yale polio unit. I think that almost everybody in America to-

day knows that Dr. Jonas Salk developed the first effective polio vaccine with the aid of grants from the National Foundation, but few know that he was trained in virology by ‘Tommy Francis at the University of Michigan under the Foundation fellowship program. One fellowship holder, Dr. Fred Robbins won a Nobel prize while working with John Enders at Harvard, and today is a professor of pediatrics at Western Reserve Medical School. You know, there is a story about that Nobel prize. It is said that, when Dr. Enders was informed that he had won the Nobel prize for growing poliovirus in nonnervous tissue, he indicated

to the awards committee that he would not accept the prize unless Dr. Thomas Weller and Dr. Fred Robbins, his two young assistants, shared in the honors, and that in the end, because of his stand, the award was given to all three. Some claim that the story is apocryphal,

a ee ee

SESE aE OEE a a a ates Sage ties ora ccs See eee Cais eh iach Si ohana pupa ee ceacagagels Sac ho ove Malu St hia Shea chbae att gata celine ca Alga, narnia ne eee Soreae eae anne nae SCR CRD CRE DR Se NE CE RR aR SR CER NOR SERES HSS UES ESR SU RRS SS SR ree EEG SSS COA CEE UE RR hag Coca tistics mn eee ee SERRC SESS ISSA SRE SOS RRR ES SS US SoS SIC ESS SE ESERIES EEE EELS SIS EES PS SUDO E EE aaa cos coneeanatemeniaaten omega “ue heea nh aenenensntn ets nenmerenmee mentee maaan nee nne mee rename SERENA SERS SEES LE Saste Cae eee RRR" SRL ASS RRR SAE ROE BER SSR SSS cS CSRS ELEN: SUDA NEROCNT SOS SRR ESRDSNG “UREN SCN ae EASE ORE

SESSA Se POR SS Se SERA OR REN RSENS BRODER UBER TALL RS BEARERS SSID RRS S CORRES Si Cane ee SSD SEU RRC REISE RRRARS eSNG OREO SNS, TLRS CC DARI CE SAG St RISO ERI REESE REND (AED RECOM ITRD ONIN“ SARREAS SRE SRE CREME SSS

ESE RR RNR S ASSN AS ARAN ERE DE RSME RAMEN MAN HANNAN SAO SU RNRSRUR TRE RR SERERE RN ©: 2. -, CR ARAB AN RRR SERS RR ARE RE NARI OS SORT tera ORD SARE RR ENRON PORREAIEIIS AIS SUES SS EEE 0 SRR SC SELL OURS ten Sores Peg ne DUS ae boc Na eye SY SRURERE SKREENED. SOUNNG SAS SRR Re SMa SESE ES

SERS REE RDS ORAL CRE REA RRR EPS TOS DER MRR R ER ICCAD THARRRISG NCURSES CORE SS NASR ORE SEER RSS COE CRS DSDNA BRR ESEE CEES EE POSE 0 Te SES SORA NENCIIE RAED - SIRS REARS ISITE RGS SES DENSE ORS NS SESSA SSE RUSLAN SBD SERRE DRESSERS: TERE Ren oR

Ra RDN E ae SERIES A SAAR ESR ENDL LSDENRA NERS ED SOLAS SESE ERERS Nc3 ONES BABE OE RDS EMER R KEE UCESS SOE SR SE DROSS USE SRSLEAN DegSEER Sg ny YATE BEMIS TLESSE es, Ir agers DREN RMIT ER NET EN NOES SABR NINA EXTERN RNOZI RE HEROD PUSS ERNE IRR RENE SAAB TS. MMNIR 0-5 0.2.1.1's-0 SED RI SDR OPISSESE ER ES RRR ER COS OERRRC ER RPISSE RIEDRASS Se) SURE NER ORROSS ER ELSES DSS eS SS RRR REE REESERIES MRSS SORES. NOUNEEA ORIENDE oP SIS IASI) SEE SOGRe Ae is RErcnaphegccnanaerrae Creu pc rg Soca ane aa, a

Gera eee gee ea Ch Cee WASSER BRS ggREE 2SSIES CES SSS ee Se ee ee HE Se SE eS, cere hes eee SESE IE SS Se Ce Betanpsnn aia SN RS OSU Ogee EES ESSERE eS eS RRS SESS SSS SS CeBRE RENE oeUR 2 OSES SS Sa Meena ero c rec cers ey ePID UE te aia tenet ane te caseeeteeesg SORERE RSE RENE MANO Nek ae Pee ER ape A tna eae av mee pam nreaneiate een ee SSAA SDSESSE RSD ReRESe SESS IDSOTSOI TNCs SSS SESE ESS NSCOR IOSTSSOESESES 1S Sa OOSTaDNSSTSSCRISUSSISR. 5 SSE SS SIE SSUES I EGS SOLS SSPE CORDS SE SAR SUSU DSR SLORIRGSSESE” OO TEESE SEEDS SES DD MEOEISG UESID NSS OCS OS a a it

RUDRACRMBEE USS ANA ONEE SE ORE SSO NN NTU OSEE NEB N ED NE SEU URIS SSO OSS RUST M I Cote ISOS RSR ER RD RS SOSREU AUS SASS KSC RR RES SAREE! SEE EE TS STE ED LS En gh SEIS SES TSS SRR ES CEE EO ET ool

STEEDS SSS SSE CEES GURL SU PRUE ORR oe ee his ee eae cana Sra RNa Rs Rak enn Rene CORNET SOSA, OR NRE EIS NOLL NUTS ORR REO SRR RSE SE SNORE EOS RON EEE SESS CEST DU RU Coe EOL Rao RNS

eae OT Tao er RESON COIN ater e cca cprs ci inre cist 0 oh Sh SRR ORE ERG ISSR IS cS SRS CSS SSS Pee SE eR RR a RR RR Rg RG Bee ee sec cea Soa EE SR ESE ESS SESE NSOs SERS IC EER So CS Se SS SUES crs Ue OO BE RO 0 ER ENR CS a ee as Raaecnca came nent RaemeRatRNCCRERN N SS EE SEUSISRECEEE SEE ASOT Eg SERRE Se Seon enn Anema EE ES SEE SS aR Cc eye eeR SE ee SS SSS SRR oC SR cach Se ete eee See Pe RARER SoC SSE SEE RRR RRR ohne nan nh eemnnt yaaa anne mace nmcuntineneeennci ee SSeS Raa NOSE ABNER NSE SEES SMEEE RSENS MRSSRRESSORRCRDEO SN Soon RRO RN SOS ERR G OR NER SRS OO ESOS REN SOI SEES EU RRS RESON E RENO OAS

Panienrhoe chee ees pcm autre csuvens Weng ava duriastioanmetan seers SoS EEIESL SS SOS SeEn Se ORS SS Seance are SS: RES ROR EN RUS RRR CS SS REISER ROCESS SESS ISS oe ESE EERIE IE a CORSA See SEM DRMBE RRs Sec ornare ere e hung gninanernpryneenereerne rece ear aa Ee RU SEEDPEER NC rts iirertrrcin-icn ne nee errno ater aN SR ON ae a aE GR NES SS RR SSS SESS ENED NEES TE SRD DAO

,,—rrsS—i“C SSS SSE SUSIE ae en NN SRR ESRRMRN ELSE ona SOEUR OTT SUSE angesnates Be icici Sarina eee {SS Cae aOR ERERS E SRSA SESE RE he RRR eR SRRS RRR ERR EDSsee RUN SEIN RENE aC SRO NSSCEE A TREN seer eceBESS innit eons necinremommnren SS SEE SEI EEE ECC CRS SSSR SSSRSENS.” at SRN OROSon SRCRENEE RRR ENCOAS SS TRENT MRRESIC See ccna iy gpk saat near reste SEE RSES AEE ao

CEE SO SSertaram SS SaaS PESTS EMSRS STE Soge PE SSRIS Se BSS SES SES RS SS eSete eee RORRERLRRE SREa oS NRA OE SESE SSSSs. eee See Senta penerstoseu aioe Se NARS SNERSS ORieERR eee ater sca ese Seesa ERRORS. eResBRS SEROUS REE eRSSS RR Ge SES SSS ea gene SRR nna SEE ent soreuraiicanmenmnnngentnee uote EeSata Se eReo ERC Se eS BARRE SSE ERR caer Nt Res PS ne SENS SR RS cece ERS a eee SRE ESS Ree Se SEN SER eo RE sR SR Rapenrmnern erence reap SOAS SONGS an RRO it che toan niece tunreecnencanns ned ook: SAS ec 2 SRS a Sareea A SOS CCR aU OCRRO DOR SARRUAN SOx RDRRAS SESS ROU SREB ESS PSOE aU RR RN RA NS DRE ane SN occuEU stentOD neh hnemtanea ena crtmstnnstaeneceeetaes PRR SECS EOSOS TS SNS BecSoo Rr ORR a httSSSR SBR ROR Soccer TEE SPREE AR REBECA e RIBR SCS eRateeaantas emus torrente abet RORMaaRRRRENEREN Rae RNRN CNS. EES SR raesaSSSA SELREN ae Oe pyaar En RSE oe oo SNRR a eR CESNGONERS. SODRERY RRR RRR URS ee URE

PARES SRSAS RERRR ceceERR hetOren kc ntanciunutabagsa nage araerc PERERA SSSRSRR NARS aS SERS a astnnng RORopSERURGR: SOSEIEN. sy OOOO pea SINS EES GSS Rec icSie Oo Re asia omnntnnamensmenenmnrne nnerras menenestceseneens TOES ea SkSSeORRSP RRS ness Ta Rc SIRS a eee Sac erechntemwamaernenoe

REISS SROccc ISAS DORORA LIN ABER EMS CERES assed NRa a2 NC RRRsee ROBERTS PRRSSE OSES SLee Sens noneUREEEET AR RRR So NULEAI E e E RR USER ERODES TINEES. SALORSS SRR ORNS OR EE Baareeatace oiea orencnna naEEN resent ointanramnetiorenctiwanmeancrc vauancnaa SEER EEE ERS ShBienen oaaae ERIE oaRC cacao nener cece | ones| SECIS Bape a SRN SE aS ENC eOSU Ne SR SRRoon ROEM os eis onseenninnrennnrmnneenrnranmnncenee ner nensionenioien SORES Ee ESLeSOS) Se LON tannerSS eee ECR DRO NITE ASS ae LATS cc a MOPS SROtra RRS RESIS SOMERENN: SSO RRR IS

Se eeOR OOS eesRRRSee aE oR GE PR Ghiate Soh.Sh ee aeba CET Sea SoS SERENE Se i greeeeCEE ee CERES NRO, ev es cha ultSOS unnennannenennmenenntunnaeemnaay eanennenneeesrt Seana eae ene CRESS SR SSS ESR RRR atta SSO Cyan 0S ES Se one a aetncaeaeee cumpnnseernies ERC Se oe SRR i URE ACERCEE Recerca niacnanmcnegn tenon tagger PERS SSCs SS 2 ERR oo SISEERESTSE SRS CES RCS ace oc renege sehrnecneceerae ae SEES * OR E RELL einer Saecaten came pieden BERS. SCA SCARS ORR SOS ERS Rone RRS RRS Se SEEERE SUSUR RR.ODN coche etahnagASNT niniaan tiempo. OCONSS tsar egestas aeeemnene rencastay Mimi MRE OR ERPEER SEE RSE RRO ene RO RAC RRRR tenmnanmeniianet S RRR D on hcrnteineeeehe nn bnseetnaee, aah tn neice tka lannecieianeca EDS CERNE SPEREET ES CLS REESE EERO TN ESLatiprninaeeni SEN: -SBERSED. ERNE ANE RSnna ERIN SRN OSESS

SESS Da ROPE BERR ROSUOC NCU NOMENEDR =. SEN TY UN ona ica nnn ace eRe Ee te ieee hts A RS DRDO ESR ROE SS SRDS BASE RSS ONDE ROE SDISS SARRESSTEISO SE ESOL UO BOUL TEE SONS a ca aS ROSES TAS OREER SOS. E RE INEM NU IIRC CEODy SENSES SAA RA SOR PR SPR MEE RS ISCAUORKEDEEN. | RASC CERN RR Se RSE ARAB Soc elder stegene trea nntereenaenitammnent numa atasiannsheseeentenntese Bis. eae CSO SE RES Botan ea nner isan ehte Ne NEN ERA ROOK URS SSL RS aE ee ROSAS ORU SRE SIEEE? - SERSERS. EDIE EONRNT DERI MORRO

Stance MARC ERESRER RN LS SERRE CSRS 1 9 Et ROSE a ea gt a Rc ERE See See LENS SOSA eR ONES RSS GU SER SORE TRERS. CENCIES' MUD RONN RRR R RR ERM EARLE

ORISSA eRe eeences TScarrer ee RS Se avian Deeaoana a RRS SOC ONSS CIES RR RE aS Gc SSE SOEDSIE RE Be CCSSees es SALE Rs Pe meencie tmuauana aS oaneneninnneeeytepeeehand saintNOOR. SRR Set BsSRERAER Pe ae UN SRE EE | SSS SORES eA BLE oe aaES

SEIS EET eo, RN eet SS Uy PR RRMSMRIN css nonachduraimntenctgeen merece Te mete enemas eeeareeneestae tater mere r ett Lampe oases SEL as UU TTT RRR SS Sea OR sR SSMS RS RE ERR one euateetr-corsctaiar camming. anise gang ssariecanrsnegeh geba tee paaeaeaeh neameensocies Mieco cram oneeaeromratrehantmbennmnnnenngetty

SEES SS an Oc aSO RRR sedi erin srsniotennnenenees hirieaaareesreeneememeietoe eons SERRE CO Secon ern osetia SNE SOR: RGN cence CERRIRE: SRAN SERA MRUSEREORY . SOROS NUR ROR NORE IG TESS aan os a OPM REEES Si is) caine ia huntirseanemeuamuiurnie miucnamaennannerenuneneetmernins, SARS SOSERRE SI 2 SRB SSESR SSR eee Saree sorsancmee RECSSROUOG:: :. SOSE R SARR ER RNERES CERNN RARSRES | SOREN REDRRETR RNS UDOT

REESE RRS enc raat net Sh pecuhcuras Arwagnawes paemmnnceneens epee SRY SGI SE SERIES GR ES a 2 AESEEg x SELECULIS EE oR RR Ee

Pape Ra a Len enne eee Ay NR RRNR Ont Seen tocansa RRR eth EERER REN RNC ege celmtibitanteihtdate resp were ones ateann memerch nonetemenenennnnnnnn aeienniet tt 1S. Sas SROCERES TO STRRRE See CEREAL MSORERIOS SS oT RSS ARR RR NSE,SROINGN SSSUCEN' NNO SM ESSE EEN saeroi Sodvon Rare IE eee OE." n NN RENCR UC sect urannetatise austenite eaienceg Se Senet eieierne ihmura hit SELIM 1 RESO Sek RARER COD RCOC RAR ERERARE 0 PST Seer Ne SERENE ENSURE NRERSIS DMRS. 7 Ra NSSOROS SN RONAN

PacerSSS er ena CT RRR: eS Sesoi ‘SEER RO ES Shgeeneieg ssiunenenanteanechta sh ese REECE perenne teen Se CORN RIE SO CE ca |»eres EEE SS Die ManesSIRS tenerean taaatER cioserCuntaucuan dude ci ern Bs SR a eR CANCE URcramer RC RESSere Re

Rea aeRe ER ER Se URS a HERES aE ee en coc occa ee SS Ce nc, eee ee ee ee mca roeesee ere ee | ee eeeaeeee

Sa ESSERE RS IRIS Se RRR CE CRD ce hc san tn etetaneastacs in. Guanceunnuemmontronrunuteidaniracueneamnmanttee SERRE DS RE cUAC Rn cee gescne = SOREN : Sans cen «RSENS RE SEO CEST RUN C SERAERR CREE CORON ORO RRR RR

EIS EERsama Se SSCS 2 CsASTER co ge oR eraSNathena ner terabn ciennecceam aurMRE spaene treetRT SRS Ghar Sao ES ES RRR ae SEsca"gS eee ee eectsBR SOS Eee Reeconee esaON ARNG CTU SRR RRR RSLAOS aaria Sea CS Se TSE OS ROMA CSSSee Po ena ReSOR oy Maat eecrearecewanr BSR RRR ERR Se ESRD NAR 3s,snRR Fak: SoS SOCOM AEIRREET SES OSESOSR ; oeARON DORRR rane sheen aA. SRR CERCA RB ROR eD

Ss an OES REARS "SRR a cn ee BRR SOE aRSSSR So cae ee SEES SS eSRRR aR Ere Re eacocee SEER ee RAR OU SIR ec oes ES Ce STERN SoeREG Gace SE EE eS SSRRE RSS ara serena re mah ne aoe epee Ucn sucess numa tenteget EERE CERES SA SSS GEESE SS EET EC NSS eceaa aay uae cnet eee Ey

Pessokeee coccinea coun cee aetna rere NRO ARR MaRS NMR cere n cena nnuumnnunminenr ce muon inane nevmesnnimnenincue sonnet BEd. SRSANS SERRE ESS CRO ERENS SESS IDR SRD MOROURMMER ARERR SAKE CCC SS SHOES MER BRIAN NOS SAO S EER AERERERERERSS: SESSION. SSE PERN NEM RRR RROD,

Rate RRR aR EMR IS he RRR ORCS RR RRS COS RR ER SSS: oe SSR ae EES NESE SEES SOEUR RREREN IMSSEROSEERS--“SOTISICOR IC TS ~ "GOSS ROS SS SANGRE RDS RRS NRSS ROSS UR ERSSMNORN DUELORS SOUS a RRL E ENS NE NNER ES

PROS ee aU eR EA RRO LCE CORRE CURR SOREN USSR EA ANS RS SERRE CES ives on SS aS Slee Sa hauianceniiacechane hie pene penn poche AiG. SRG eas pac innchacene te

ee SEES SESS ER SO IR MRE oto S crarat eoaseng cine erates au Gee SESE RE SORES a ispagrae secs ae eaeeE E Ar Eekg aegis eespenny ceer eieae nmNunanaeg EnA eR tant ESOuuseerhnpae RSE eae aaga ORNS ERTESS ORROSS RESTOR eos Raph earn nmnnonnannene reneeime saasrcnennpabieeag eangna cathe na oan gensbaeeenerees uaa neta PSEREES SERS Senet) SERREEME Ue eR het ac caste gaan NSD neta eer TO econSECOOCORRIN che seabeb en ecannehed noahcntioaraa oa aaa eeandeneaaueran anemone cea eeeiceena eee ee aT i naenunnrgarenbweni acamecuvacne

Soe ee er eC, SR ERE ene te rgb eu agen trans vanubnaonrnebeunenctene Bes a AR CR oe SOR ERSRRTRSRORRS SECURING? «BORA RNR LSE RE RS RC RR REN Cr SREB DO Re ROAR SEA SR RRS SSS SSSR RS RR RE SESE Se ee RETRO ORE EARS SASS CRRES? «RRR RRR ERR NS SSA RRO R SES SOROS ORDERS ERE SER MER RSTO SE ERREE SERUM SC SNES RCSOEOS

EES REG a aSaR MARA RRsaR Be Sao RNC AES 2 SURE CEES ORR SOERses |. OUR NCSLaa RCRA ARSE AES EA ROSES SENNGER S CR ESCO RE SRR E RaS Bea Re SSR RRR CSTE BSS Rea aoAEG RRO SERS ONL EROREEE SNS CRS aS Rreesrrannati sR NE SRE a CSRs aN RR Rw cS SERRA CR RRC BREORRR RENE SRDS CRD Sea es SoA NNSA RRR SET RE RMARARINESENS? SBREESOIOS NETS. Dea RUS ONESIES RRR AAAI AAD ANAS ASAE ESOT SRO BRER REAR RRNR NERS SRO YORE D ISI SENSO RRR SILT RER ER RE RSE TR ERT

Boseanens SHES araptaenagug anette oar ERR i Rn ger aeeaecetate eemiean enone SCONE RE ENS ESMUEN NS SCONE TANS SNARE: SERCOREEES ACR: SOMRESERNE CURES ORNS NS CES NO RSNA USB SSO BROERE RSRAER CRSSSNOS SOUR DTS SS SERN MRS RSAC NS RO Dae SIRO EORONS NURSE TNL OD RK RERN ES MEE ERM ER SERENE NE AAR EA SHER BENE SETUPS RERERIB SX NERY NO DNR ABRAM SADSBAL NERA ES ES IUX MAN ARON I ARE RESEDA RS EAE TORS ER SERN SNM NEMS ARTE SEED E MSERSCE EERE NSE ES ERS ERSSNN: SACRE SANDERS MNT RASS BEL RAM LESSEE SRR AC RER EER SS BORNE RRND ORME ACEC SIY SA EASA DA SRS SARE REALE REA ESO

SEES Bese aE aR RR SSE eE ELAINE Sea tienen aiine ne an Thie Av en One ene on wenttie sieiatacncat naieaeemnmaity ote esnas hee gmnee ein lamenenanar ele nent ryan nbsa neta teyiciimvntte saeeenemannnneitinetn as eginnerenneceeom oes

SONORAN: nan RRR RRR CREASE REET OAS ARS RPC ES Rk RR RNS CR RS RR IEE ISTE RUE nceMI ontitelpiens og einietan«ions tntehhint Saha PERRO ns ia agen EO Gun Cann Cale rene tr ginalane narnia nie statesSN a ete catneehsoenen shan pink ERED enn ha iOS amen neta REESE PEERS. FEESReeiortna REE SEO EEcetenian oe eee ereUR anes PRESEN SNas SDERS PEO ENERO OUTRO NOSSO REARS RSOSCU BoB SE ARSRRERENT MRMRR RON ERR Ree RO SONU OR Oe ASR RERUNS SRST CSREES DREG ENOSOSGUD SSN ORES MRRP

OESca SE RSS sReteee aeaera SeeeeBe SENHA CACORE SS SS RA SSEREREAD CSD SOROS RERORERSS RRA UME E SERS NAS SMBUS SAIS SSSR DED REATEARED SO OIA SERS E RSCSREES SSS SNS CHIE REN RENO FEA res oc ce ateeR a ooEE cae Re eee cee Spa Cree EASONCc SRN UR ES a MENO SSIES AIUSD NUS RSNIBS RS ERE SAAN RACERS NR EMSRS SSRISTSE SOUSA SOUSA NARS HONE AI NRRBEN SERENE RAN REO USSU SNS RSSNS PAS NOSE AUR OCU ERAS CRRCRSESS RASS RE DRER ERR EN Ciena MNES OED Rana Sirens sat Neen RECN SRS UE STS RRC A CaCO ER Ora AR RNS M EERE RECESS URI LOOa RK CES BREMEN Sea AE DR SRR RIN INN ASAE EES BUNSUAK SUMDSNK CATR AIT NT OE OR RU SSO OER Nee AN REN SEERA RNR EG SSSR RE CAR US OTS SERS SSO NRSC

ORE SAS Re cere rpc ec eee apeneaeamety Ceee ots eacnc sec aetc ns gts oe RR Nao es ageeteeag te eg coee RSNA a Ne RUN Uy tate SNS eR ERE ROCCE REL ARERR RRS CRRA RN CaSET Se eee SOIREE EES SSS OOS Se EC RR oneren Se a gee pe sree

SSNS SOI RS TE NEE RE RR SOS DER SECA TIRES ERS Ree cas ota cregniasuean sas coreg iteeauncinnnennennen beg aeeeeene nian eerarnesdaaueainrecure cure gunnis ccnegeainsemee genie el numenmnnntternerniae teste spaeveneeerercen CR RSE cS SEs ene ie a eta eee SERIES Eco Bee SR RS Oe Baoan Sees er eR es PN ere caters nae nate sta ee

EROS RED RAN REE E NMS SU SS SSN Ah AAA NAP MER EA RELA EASA N EN SESE WSCA NONE SR RAREST KBE RN RL RES « SRLS SRNR NAS earn enranee CARS BRR RE ON NCS SRN EAS SR RA ASAE SE ROR RRR ARE NER E MNS ARR SS SRE ER Aaa S BREST SRA S NAAM ERR AR ELAR: RENEE SOM BRNO NSM SUNS OAR SR REAE SEAR ERS S RETR eA SN OM Ee RAISER ORIN se NRCS NRO ac

1 REESE Ee ari eonninn ava ae teane eg etbieee seem ameter ote deee eee eae REM ET ae oR ee oder a ree runeN irene eT EERSTE RE EE SRE a Slane nate a seesegaamagnscioniton act npetonene uum epee eere ree mie tteesee comer eae ees debe cee ea ee Ne Ie RR IARI SUES eR ete ect caterer RO NS ANC ARDMORE NAH ASA SIAR ENR EM URES EUSA DARSEY ENASIAS A CE RK ERE ERS UTS EM ERS SENS SERIES SESE RARERA BREN CRN ANT POUR TRIAS SAS SERRA SSAA SE SERED ELSA DE SRR DR NS SHERRIE SRC NOAA ENOTES ROSE SESS EASE NEN NY RB IOS SN MENAMSIDEES SSRGCNT SN SM ROED ESSE NESTA DOE AS NOME RD RENEE SASSO ES CHARMER NERS SEES MINER ACSA SS SRSA RA DALE RS LL ERR RRRR MRE an CONT RS ERD ESSER GOON eR EST ESC aR ERTS AREER SERRE BIOS SPER Utaeinata rss Gta eee PESOS SURO Ge Ree REESE EER ERC CRE SEE ORR an heen ee eatirnany cant mies eaemene aah meson vane nummy ang een nanny esa ueeeyecg jceenmraendgee eee

BEES OSES eea EEE RSS SRR BRR oS OR Se

EEE RS 0 OS OCS RR SEC oS

EROS EA SEEE RE AES Ue cechahy ac oa bhge se peepee ne Rereneg gaguins oe uate se ge cy neha rempenneer amuse samen moe see smug SEES ROU Sr medi fags ueeteine urthon gat neice irae omen een eere meenronne eenn baer encima ie amnenniinne rtneacauniuntin ins nian nennutnnnenaney nn Srergncatresmes

RORSUUOSDULER SSDS ER ETE CRT OTRO BROT COO S ELE ODC SOCIOL SE DD EER SOOO CRON CENCE ENON EN ee Se COIS RSOOUOE SRE SMCS Ses RE CE EERE RS eco SS ee ea PSs SORENESS RNIESA SOR AERE REED SENNA RE BEREAN BER OOEERS RSC ROMER ST SEDAN RED DMY “SAES CRRA SRRARER SES BAS SUNAS ADESSO ERED SES DEEN SNEED eT S SD ROR SERERE REED MIRE RE SSRN SSS

SSeS RRS SS SORE RETO oie Se Ce SER aa Shane eeacea dann dhanvesee cress canescens auaoeernanant ukenanemnherrennninawachercreraeeyenomey PREECE SRC Ee ee ec Ce Unchnn cove goa RRO aabamrceecne sammentane anc yunnnmoctnuasgauetsnbbnnenatay car cumseuacasaaanc sac cuatemmee

SE BSE Siar areca een clea Rn cones Oona CUouny cenfare chain daaivancnchcaannaa nie mentee renner shi eee cee SUC eee

Paasche RENE ORREY ON Ra aE OCA ADSENSE SSE SEDAN SSE OUNNE BEEN SUOS EISEN EARNS. SUS ACERERSADRIK SS SRDS SERBE BENE RE SE SI SAGE ED REEEN OE SU EYES UREN RUNES ENS RONE NSS NSREED ES DDE SOBRE

SERENE. URES SRE nn erraonee hein aig nk) RRReMe en mpe coeuttt RES eo DER ER Anche aantaenanunencpeaaecionn nasal steers ERIE U ER EU Se CO RN RS RSS HOSS EG Se Se SRoC ReaT ors eeER chCOE creer HAR aetna ca gate tnttla at bettie abe aati aaa a athena tattered eat thee neat ai terme anetteSAAS eh eceadennede FeaSS ae aS ER Re ORE SCcg SRcee

SERS Oe a ce ce rime ee eS kh mint hetero gee Ee eee UMD Las apecisios gs ee ERS Ee SIR ORR CG Oo ES a ce nes tanec ve Egat secre Scere aCe iene unneeenrn nis aacnebenmnnnsnnanhurymmpan serie ninguna ssennnrpnneenaesnneeer nm sasesenuecursaneeescananeeeysenverswsannprenanteseeoonnneeerecs SEES SESE TESS et ee Me chee re ciamecrs oie Coo yee ge ran CoN AR SE SELES EA ee ee rc cece RR es

BOE ee LE ee eSerega Ee egeeee SESE ESE eS RE ee eeSe ae

EERE SEE EERE EE ee ee cee Cn enn thie cima ante) phat rise nant upetnessnnegaahbtnbnesnanennhahnennt in tnaimtggane fietets nani oneltdaidsltnmepnupes thyme phgcnsarnnin nin, RSAC aE SRN Ne ASEAN SREB ERED ER ERNE NSIT ENR RSD LORDS NA ES DED RAE DENA EASEN LE DEAE URERD RE RAORININ CORS.- NUS SN ADO RM SNES A ARIR SED R ASN E EN SARNIA DARE EERIE ROE REMERON CS”. SE SPOON

Ea Sea eee ee eS Cee

cr

rc

rrrrrrrrrr—rr—Cc

a

Ba aR TE RR

eT

SERRE or cease tgaaiencnninret hy gunkicss ciuitnmunnnincescu henner schtgvemaasuescnegeemmmnnscwoctagyevnunieswesengrgenteaeae Sa Sent

Ea eR CORY cs age ia RE erynecup aR) Peenartewis MRS RRyeeRS SEES Sa SSEE RMS ER RS ADE CL RRRN catch hhc athhnnnnncusagey eyed iat SS ngthrnngwesent oor ERS ER A OER RC craic este eeth ee IEEE tS RR EE EE SL ERR Forah eaunesRO suntan anak SERRE IRR. aweret cc oggaththnn se SE eS eS MS SS Ree ee Ranaenaon RE eRtn nea ae ROC chinhneu eekocca Meni OR a cs eeeacnanneents a a eS eRe een

ee ——SCE Eanes ae ae Soa ORR PRE RRR EE RRS RRR

ZEEE As RRR ct ditt ton rtyhiteatden nee ymnueronmsucrryennaeynescoue yy RASA RR RRR RAN NA NAAN MEARE E RARER SSRN MARA D ARAN SRNR SRN UN STREP URES ESS EESennmnn PAYEE Rincline RN RS EMENE NARHA Esar RS entre ERE REM EAASE SESE DE DE SESAME SST SN SERN eens SENTRY SEREEREEE REISS ECC ORE ree ORR co rnin piiatursennnsommnmcranteniecnieesnnentinnoccesnrneene [ehh RE tehSEAL eee eek enn SASS onto SSO reese en enkmnnaimenncenn cena reveal NOISE senenteneteg cenncnkinntnnnrnnerntcereeesneeneeme RRS ecco EE RSIEE ERCOC EROS na BRS nr hsRSE ict SRR ERR nsConn ccna ich peateast tettenissan payeyeeennrnnm pr manhnt enti nnenan aNnhditetet SRNR cimatay RRR PRS SS MNES ENSURE SSR REE RANE MEARE READEERE EERE SERRA RE RSD RSS EOD DOME RNS RNIN ES NNS SSNS EE REM EMBER ERANSeSRSA RRR SEALS EUR SRR OR SEASON [SHEEeISESE SSORS ROC SES OSA RRR KROSS Reta ret ROR COTE CRBS os tare hentena tioningyeh naan i eenephphnenteisniengenartgney bet tinsnsaties SEEESEEEE SRoE UT EDU RE nhSOSA ehbenontianniiiiiinrannshntiesncenresegiieiinn LOLI TESRS SERRE EEL ERR EEE REE nec eecEec re icheasneaeanentinsaniieeseeennsre cea

TEASE ee er aa RRR ERS CS See COR SR RR AEDS SS Se Sh eercecne heen cgegegns eee ig 0 ee ee ete aa ete etcmnsnereh cacegunans meune te cinta EERE EERE nn Rane CREASE Ns SS rhpepooaees SRR CA) RAR RRR ARERR RIE RR RRS RICE ESSER ENDO IE I RRS IERS COEEEEESISSS IS a acne enone sce eRe Ln tee caumeinesseeseneseenreetntrl SURDIEIIEEECIIREES sige ccna cecneenannencoecnerenenes gets smnnnemnnnsnrnennsears Biman RRR Pie Ru MRE SEER EDURMRRE fh sie ier cep ken ret emis cP eee ee RASTER COO ERRRSC Ce CCCSESONN: COG ES Ea ROSE CSR SS RS SESE EETEECEEE EE EE EEE EEE ESSERE Danity urnalangaannenrnrany deere hen ebb eben eneh bab nnesnenrsns? TYE RM este) 0cn ICE EREES oR SRR ESE eau paiee ee bee ee eee Gk eee REET

BOOMS Sse na a RAI RRS rE ERR nc (gate seed cle etn ur enn CaN Gu ee Ree REESE RRMA SS CRSA SRS Fst SNES SO OTS SO SSCS CSC IOC SOE RC EE SR SR RR ESS ESO CR SACS A RRR RUE SAAR SCS RSS CE ECR PEE pSceaticaa pee Sees aEEL ESS eha RES SEEDER EERE ESC ORE CSE Sogn deer cere bere cipy Pe reece ec een EEE eC ROOD CS ZEEE EEG a RSE SESE eaaa CA Es RES RRR SAARESE RRS SRA SRE SOOOOUIR ESSERE SA ape A OCR ROEoe REE KRAUL RRR ARDROSSAN SOOO COR SESEERESEEEEEEE SESE OEE EE BIE CO SRRRR SERGE EE pe OARS DISSES CTSERBS EY SRC EB ECE LL co ent nee r ep ae Seer eeeSS EnRRR Dn noINORE SEES EE POUEEEEEEESELEEESS PERE SNARES RAREST ROR ER ERRORS 9 oc ee erent. cotinauty ce vreinmey 0.5 oS UCR RE SOE Sa SE SE SSS RSH REMERON SAE SESS SESS SSS RSS SOS SRCNS ANSE MRSA NOM RUNS RRR ENS RENEE ES BESS SEER ERS XARA E ARRAN MASSE ASA SOS. SASSOON SRS SSRIS SRLS USE REE REE EOCRRS Lee RKRRRAR NTR SANSOME NERfrRRRRRRAREEE 822 Levene reeTRE eMeneut het eee ete mae BREE ee CCR ERK K KR SESS KRM PS SANS SEDI ENN NNO NHK ERR MRM NSM AEK Seehe RRR eh Ne ESSN SELENE KM RENN SS SSR ER MRR CCNA OOM RiRAc eT RRSSAA SOREN RT RARER erhreorneeer neg. co 2 re ECE on ESS ee een a aR S a SRE eS cc ELKRSM a Re RA eeeTIO e eee E AAR EEEONE EEECCR CEL Cen Ri Late cen ae nnNR bnisnaannr nmrDUS eneMONS kh hhh GhRRM hihee USO IEEN Hc ign ccrs chiKERR one RRR ektenRARER becher cnfenerny innSRY mania nbetpmnsnngensorscarenmestnnen centRN Senne

aaa Seana SERIES SERRE REESE RR RNR cn EERE SO SER SER SC eee eo perro SER SAREERR RR REESE ASIN EIU EERE REESE CEREAL ERE RRR ERE RAS SOS See Sana a RE RERESEE SERESE RE SAE REE REERE EAS IND ORRAN ERASER SSS S AAA SEE SMES RAR SRR OURS SED DIN SONS NST Baer aa cn RRR es Lene ere e Ro $334 SE EES Seer SUR RN ae Seat NR Eee DOORS sea LE SSESESCEEESE EES oun aagucina yume veeeurerayvecigyecieeeh ae vennd uesnaa gente Seen M EER EEEI A ACCP SEEAESERERE EE oh chesninnnauctunnny sreepireebarrst eee yy pehiaa eee ae beng ERR ER EERE PEPER ELA

EERE ECE EC ROR MMC 5 POROROREESE n ciihatgescncciittaenste ccuknaanaer sess cdvarenkeseriec ceva ent Eee SARRAAII SA AASAAA AAA SRADASSS SOARES OTEESSEOTINESSS RR ES SMOOOT NESS CORS SOULE ERM Ramee eebicuananncaa me era ea ane TT SR a ane

SEES eee EERIE EE SEE EEE EECA CeCe: OMe 2 EET SSS SE EEE rE cece cece Rean ee RCo CEO rea eee ec ea eee Cee eee

BSCE Ca EEE RRRO RRR hcEEyes ta CARRERE CS OSS RRR i ERRES SSE ene EERE URE ER ooELEEn keeereesy dennaSEE adeeb get beeen seaeeracennnannecesunthcoulanngsesen cunts FREESE EES ORR ERR RRA RAE OREN OR CNRS ROR RRR RSSSs ROPER S Sa EcEae SS PXRERSRESA SSSA See SEES ReeOE ERS Cee SASS See SSN SN ESS Yo OEScoo SESEcoo REE ean RE NEES EX ERASEyee SESMRAD LSE RE Reaed ASA SSNS BOSS N RS SSIES SON IT NSS SEMEN EMSA SET SRE RE LS aEReR SocVitiCLE EEL SSRARER ROSESTa CURR SI Rao Soyhuhncoo Se uaa eetgrrprriengantenteenate OonT Se Sonoita tag ateennenteeciecey tiene aacingcnea nea FRESE RR a ARRAS PERSON ery ereRRR heen eR EES RUELC UT RRR AN cate ner ntinseccnnunnbtrnnnten cys cracker nn ine coptie enee ntereoerereieupeneresgnenin nner igeny CER EEEEEES CAS CACES SEE CCRCoCo REE EE inn erence ning concen eeniakietiiig reer eee cnn Reber benmnunnnes nr eter bres hth coche Sachi resereetee Saar eneenekenneieaaiecenccnecehit

SSS eeRRRerERAt CUS GE EEE Pee a NN eae cones MM pentane ehyRC eAy STRUT TERRE eS, SEER CROCEEEE a PS ea eRACER SER ES RE RRRR a EERESERRE TO Co ERC SS a SER oS" SCEPE ER UU RRR OU IDE a thine iiamona ns acre terera rears hata ecco SRURRERRRL: ECOG CORRE oR BES er a PRS SSeS tens Sen ener hn necnconcenbebeenenbenmensnenkeeenenctincgecbeprneenmentsnrberernenes RECESS RSRODSOORS ES EES ER RETO REBAS SSO NSE EEE EE TS SESE SEE SSSR So ORE RE URLS SRR SR PE BREESE ERS En Sa RR

SERS SR ES eee BUEN ESC EE ES eee cee ai ERE Seppe niibnrnniy hin eneemnercr hire pehenincneneelcntheph he nein eh penne ren samira rerehe SAS AA ASAE SORES SS SSSR SESS ORR EN SERIA SEA E USES BAN ESRSTTSSIONNS NENRSSSXESSS NARS E ESSN IT REE REE SORE RAS ES SES SSS oo Y SSSI RNASE ESS SAREE RARE SCORN

ESiSaeebiehnerssccvccommesreeseakecec a Pas eae eR ERIS SA SAARAS SEIU ROS CE SREAUABAN YAY SOS SAREE SERA ELS SSN SSE EE RRR SDE EEE BSE ISS STE Ss SO SSSISS EK RSS SSCS SSL SSCS ER SE SEES EE ETT eP ecco cE PEE Dna AOE HEE er On ROE ee ee OOS See ESS SESS SSeS ESS ESSE ERENT EDR E EERE SESE SESE RES

Eeeeaaa Serta Gee, AUS eeu 6800 2S SSE ERR Tc ES Seeaes eee Sea aaa eee eee SERGE. (RRR RE SSE See eRe es VERSIE Bitror SROs r eRe Sh REE a recreate ccrrru rine erauinnetttcerrp enter a SEERA BESS OCOD ODT RES RE REL ESS SRS ERR ER RRR eS Fee ES Rptiee eRERNS RERARENASENTRA SITES ACNE RDI ER EASA TAMER NEMEC SS TERRANCE SES RR ARSON SR ERE ER LARAMIE SE RE ARAMA RCR SSN SEERA RACES EE RRB FPPRERER NISSEN SES RISB ERE MMOH CHEER RMRAX SK SAAT RO ESOERK RITES MRSS SERRA CRESRABIERR SNS AROSE CN REESE ERE SOSECUEO ES SSD CERES SSS RS RRR

SEEEREESEREEESEEE SRE ae res EEE SERRE cone ROR OMER UTS SO RPT EERIE TT EUROS occ cect eneeheiea irish pitti ninstennn pyri neeimtinnsnan pppngeilanmennannnnaappmnttnnonetyeen ibe ts SSeS SSS ONGC SEN SESS DESTRESS RISES SET SEIDEN INCH Het ES I REN SSE UE SRA LEER REC RON SSR SL SSS SSS NSN 1... RUSE DSRS SSE SE OCDE SO

nO Ne OGRE ES ORE EES SSUES ERR SRR RR ROSIE RENNES SIS SRR ORR ES NSCS TEESE eseeesteree LES ECOG RR ERROR SR PAE LEEeeecch rr rrniesneencentoniienuentinnrsnerentreprenrrcrrrer verte SS Se Soe ee ee cn eer uc PSone bb hhnedeeenaugeregaeenin co caune beynnebndteanuetenneeebentoncsmmpureekteeeccunaeeteens RRORR SERRA SSE SEE UIE ree etn RE NESS CLL CK SON ROO ETT Rae RSE ROE RRO RR RRR SGU Sree SS ERS EET CEES ERSTE SRR TEER ECO EEE CRU Een Sc a oo SRE Oe OC ERRNO KC CRRA R ey rents ci rnerbi nce tinertnnensnnaltinnsbremnanine coniherhrnmnssonsnigenconerssness a Fe eee eee EEE eee EE Een rien Dre ene ee hiner nina neuter ureter eigen Cae Un rn ea tain e ne RE EEE EEE De ELER REE hr pemereer seme be ni cree nner enn mening matin in eee Se RE EERE T EERE EEE

Erinn Ra RRR SNS SRE Pe ees ee eS SH SESS SC ean Se RR Se RRR OE eR a BOS SOROS ngM on OS oC EN ORCC SORE a RS RES SLSR ES SES RRR ESE SEE eS ee ERR RER eR es ea aE ks RR OC BEES SSSEER EE EEE EEE CRS SARE NA RASS, 0 2 ene: PEE STRESS NS ORES OL rn nineh tir it nrinma gp pabhtarnenasinppgiayt bien teen pgnnt ttn tieeensten ppp nrstetnwneneceiangege eee HESS TSE an ca ea cteraitrcadi naguenigietip mmgemmionsbars corre gE Seen tee RE SS Seren he Rn Sethi Fab bahebbenhehbee neeeene nes kenenenneninenereeenenenerretn

SEERSEER SEE SRE eee EEE cer aSBS eanCreer aea eer SARTRE reycsssc ati tyeernrescicacretymmniicesianucriemereees ekcapenrnntnwuo-cuermnnptensenocieyymnnreees SuSE te eens eeregaa tnnntnerecncboncenrereerbenrebertrn nesnennsne eS che niunpnieienns nee rieiiapenseen seen tite ts a a RRRcnREN tusnreyrenteccorepniietrnmscansscnetereneene ces pinnbrdionenaetrbneghbennnnia anne neeinennaen EEEEEEE ESSE OSUSSTEES eRe SES PEE CEES CEE re nein gin nean eek See PRE EE EEE EERE RE eee ORR ERR caSan nre bee narniateieiteecr ciinnmnnnich eentnnathe revebbkneiniehebesinemeennmanmenen ey eee SRE

Pea RRR CLL ERR Cech a a eS ER RR EES Ecce ee MBN ge SRRuRR ise caer mnie aan ree Eee

Poca eR CORSO RRO rtd OES ca oS aS SS SSS ROSTERS MaRS CRORES ESS Ba SNR REESE Sea ES SRE SM ERENT SESS NSNNSUNR ENE ESERRS ENIX SS ERD REAR RARER CRG SE Soc eC ceeeccaa gg rec SELLER TPES ESE SSS TEEEEEEEEE ceeRET cee aD SSRN ere: SUED... ARERR ene encenee errnnneniconentrnrbinuncnn ene nnatnernenn econ rrennnnetenenmirrnuncnces EOSIN cece eeeceec eee seein eersteee Ren SS SREY ricer cee RANAE reriirreernernncnnennemnennenentennenienereensernrennrnnes SEES Cee ee RR ORES RRS: EMER eT So CE Rere SOE Geney CRurnienrnen eT Cee Seneheteceeecgense rece nener IEEMICER IRIE REE EEehSIE torcece eisisnsn canis OeEN OrSeah 35 IONIC AAeae SRR CRN ARE REARDAN e eT Se RENE N TN TERI RNIN N Ne Darr Seen eS CR ICE, pes nS OLR RRS ERRORS G0 ESR Bee stent cic eenun rr ninth senee enn nhun nines ees hienneh niece nin nrnrneesiansnirbnentccenoeanrnanersrs IIShihiiaiinamsncenneeuciaanmmaneenncersncennatreserrreeh retires beerieee SONS eRe CS ee eeeeT oe Re MRR a RSE NSO RE ORR aa RRR

CORTESE ICESTTD ReeKARR nti ict conc ECC eeERE eeuRRupREytORRNS pe bien COOK ANA HCE RRR RRS ERS SSS RSS Ae caeEEE RNASE RAE RECS EEE R ME ASEECRS UENCE EEE EEEEUEEECESELE te CUE ninierninninnng ne RTE tehhbnibebebietsenne eee ERIN MRR ROSNER RRR RERRRMOS C e nuupenrbynnincnnmapenenyhenneeensant reins Sere Bit achenchiretn ens ciknnnibtnnnssnnccil san trbeinoscncnknnnenrnie Gccebrrrnererntcrnrnrprsncrrsnannncer caren: SEE EIEEE ECan cig Sh eee ee EEE ER Ree EEE Seth COLE ae CUR ERENT EEE CEE C OUD ER BREE ETS oe CR LEER EEC LL REE EERE ELE EER ene ne ee ece nine rnrernenrnreeneny

PoaSee RieCER ARRAN SAaaROUEN Yaa a RRR ee TREES Donaar SECA ERESSS cae CU SoC eS RRA SS cea A ea CrS|RR Ro ee NOE Re IEEE RE EEEASSESSES ESS cu cuae casa e eae aa Ct UNCERec Rea Tescuenmeagers/ RRR Ree eR aerate ea RULE ee enReuaAT TTLBR SRSAS ESS USED IRERESEEEECCEE Ee Ec CEE ens ee a [OB URRRES SRE ocr ee rene nceccrecnnnnnn rnin ne enten canine coerttn treme anncaga vnwenrnsinnnpsrennenerrsrntn SSEEEEREEEEECECECECECESISEC EL er eect reer ernreenenenennnnnnens acct gill ae RNS SSS SRR EEE CU EE HUN OR ec coconcnstegeyneacaiaiecntecceersoucnnmnanseaenenee TERESA oo ER CS CC a rrr Oe » SRO ea aeRO REALS, es SONS aaa Sr aS SEERE EEE EL REM Ene ei een Gh SE SDE Dlsisiecscossselepeesertay seerinepersneeaneete renee eerie ROCESS RIOR NCA acele e444 08 Ee, CIS SRR *. SOE : SU NANOOOOL EERE EER EERE BERR RLARE SEER NEE EEE ES SREY

RoE DURST ESSN -7- ” ORME SU nS nS ESSERE SRS oso R20 RRS SR OE SSE ORES "oa. SORES SSeS ORE SSSR CERES SUR ee Peer e ren rrennrrsnag SEUSS coos sneer eer CCE Ee Ce IR - | SS SS RUSESOESCR A RES R AASSTEEICR OSES KN SERENE RESO DRDO AUR REE RSRRMEES, SOREN 3.2 SS RRR as eeneseeaPaCR a RS cea eR RECREATE OES “as See RLS SEER SCE TEEEEEEEEEIEE EERE ISIS aan SSE EES CON SRS a a I ERNOOMGS Scecieccrirrerctrccrrerrs Ty

ERRERRARRRRBASNS TT RCRA REARING. CREEK RRA SAAR S ERNE RET RRRMRRIEOES CRRRS sR. Oo Rca eae one eR REAR AROSE SDs. SARE SONCEN SK ORR RRR ERE Rie SESNRRER RRR SSR RSIS SASSER ERRNO |. Sis RSRREREE CAEL US.CC CCE aR RROD rear nee eR RELD YUL TES e bet 0 SSSR ag BaaRA ARR e a REE tea SRR ERR TTR OOMROROO ERR EEEER © TE eR . 5:2: Sa eR OS Re RRS SSR CoN ae Re PRESS SE Ue Ea AUR ae osc RE eg EE he Sa eR EianeaskcavOne aI SRDS BARES SHIN: SSR RARITIES ER ERRRRRORERRE 0c cE, cs accent Tn a SSS aaea aS ESSE Ra SRORaRRTTS CCS” Cane” REIN ERR aca IRE RRS URNS SNR EM TENE RNR ESR REAR ROUEN RERRRSERR RE 2 CAS “TEESE URNS ES RYERSS a PRE DLS SE ed OSE a : _ | ROSSER

RSareetena ners ata iS TSE TRE SITES SSD SRST SSE SSRIS CESSES cS Deng Tc, ooo gRNanens 410 fA SR RO EERSTE SRR SRR SRA NR RRNA ARERR EERE RERGRRARRARERERRRRT 7 CN CRO Meer nccunnnemnnrenmnraneterrererrt rere nes aen tt ee . . * . : RMS ocecetececicicectieaeeaee

SEES ERR Sos SeeeS ORR I SCEarena Sonccee eSReno Sai iereen Snag goa scent ESSE RSRCO OO a eae teRES a SSSR SAS STE OSU re: 2 SR DEUS RESSee ERECeE ESS cee ee CeO ORES oonSSE on Cea cnn cnn OIEC-SRC con cen ike nnencteta sitiescenbeneehitnyyenyces (EEE SEER EEE SST CRN Re RRC ORATOR 7 5-1 CO CROC RIURS RRS CRREROU ROCA. CS aen SRRhet SEES SSS A SSE ESS Soon 00Rennes RRR. 2 SSSR SSR Pos cocrienrtrreki pence eeaIRSaaa ASU SUNS ERSOR REESE SS |Sosxores RRS Been sa CR Ounce eReESS SERRE RR Cee EEE orcas cesses gee eye beac ce SeepESS pees orig EEELEEEEELEEL Os SSO ESS COCCI ARCS ESE SS ROS Bs OeTSR eres ere eR. oS . CORSE RRR ‘RRS

oes CC SRO OS GG=aaaa aea EES Seco EEE SAAS : NES Pear 8 EAS eS RR Rae aacra RN SSN TSS ORE RI a R RRC RTERE RS 1aOCU S oS 7sees 7Baoana cairn ann RRR Sone cs” a coor cane eon eae eRe SS 7) a acca aa ee ee ee TO AEOTaog SEIS ES SO USS ge 74S DUIS Asa CERO REAR SER SANS RSE Ce ee CREE SRR SRE 00000.” a cs ee ck eee eee ce. ccna : eaa+cacca arS RAUL ER SARNMRR RNctsISAO OLERERERS BR MER RE REET REE OER SOOCUC OCS 61.01 Sh aS fenSESD Oe Tae stots : [oe SESS CREE ce CAPER RER escent ice ARO hin tego s cies erin ni gaanRRRAR aR eS eer ticoc tne ieencrcenen sciLe Pisani eh ncn aR SC CEE EERE SEES ADA Iecitases Noone epee aN an STONE NERIAI ERRORS REETERE...” Ia CSSA OGRA See Bc TULES TS aDOSE RR RRR RSA HET aT TRIC® SOULS 0: TEA SERED EDeae EMI Woe RRO Foseennth Or taanUaT ODD SS ERS OOLRRER: SOO OOERRES ROUNDS 900. eo eae aaa aaa SS RR REO RORERER 00 Lac "oR eas Oa Sacer nN RRNA ERR RNR RRR CORNED MONIT SIE SRRERER SN rrr errr sence USERS ESERESSRECREES LR aS co SP eges t OS eobood SDE Shanti ec CURSES Ik DORR RERRTTES TS | RRRERERERT OCR RRR (5305-05-00 2 aS Re eae Oo OR WCRI 2 500 et alr a Rc! SRR S RCS RS GS San a OR Sa ERR oS 1 ORR ER OOOO kee cee TSEEEIEE SEES ST ata tN C3 Roo

BODHI UL CORSO CR UCC SRR RT CRS CRUSOE GE S| OUR SRR aaa SOULS ca SCL S. a O RU Pat teh Pel RERUN BIR RARE REA NER AR OULD RUBE SERRE SEEDS DKAE RRR SRSA CEC CEC ENCE ELEN EEE ENE LIS ARRIOLA pyoccenr RRRARSRRS REED OR RARRRR SEC RRR: See CORRS S| ea OOCRRRRRE NOOSE REDE SC) a oS eae SSRs eunG SRRRS AT SRAESUNS Saas NER ARGS Aes RRS RR SRIRAM MRM ere rreierrieietiit teh tech OOM ugee sc eee ye nt a Deke Seg SASS SSS BEBE BRS Eat Rea OR SSeS. SEUSS ERRORS |. | LUND Aaa OR Se eee ST TS oa”: aa PSI os coupe tartetiany trungtanig aruageh jaar eaten SERGE RAS Shh | eiiceen ttc SEES MRR SECC CO an a

eR EERE CESS SRR eM EER EEE ERE RSSdoee cos rest cerasey tas usieisis ei vets es eC Td (00S rc TG. CR RRA e tS 2 OR DRESS SERRA ee OE SR OOS... Oa cen SeanO nk CaS CORRE 2022 ROO J a a oc ae RREECRCCTS EO COVER EEE EERE per LE CL CULE EEC CECRUCOLE Ente C232 AS a eR SSS RROD SR 60-55 02 -QOOOUOERRMRSSMMMRRR «6S EELS 8 TERRI DEAN aS Te Toekkkhhnkenees RRNOO Raa eee CCR ees Eee Rane RR TERE RROD Cierra Soke DSeOG: |!" OAD Re. cciocneeh Selene SAA ana RS ROA es Sis Wa SAN NEN CN TERY ORE ND STEERER SESE SEI EIRD SERSERE OU XESERSSRAREAREADUREORRERARAARR .....” SOORERRRRRNTE SS STOKER Fhe ie kes v 1

RS SaaROnrR RRS EEE Sn NaN OTE RERSnen OER RET EES- OUUREREEERERRSSOSENY |. - Cahn ONT Ean Se CaO RES See) Ro cr fbebeketenentieneersercernreeenereeseronrsceereeenrnrnnnne parece gente RUSSERT TST TREMOR © 9-2: 1) RRR Sheth oh ty

ee

ee

rrr

Ce

Perea ENCE tS ROI EST: | RRR” ORNS RR ec CERES Ea saga adits babs eee ous ee ST eee SLI GPT ES TT 22 ARS OOM wee Hee ahSoe Bee dido aoePa se ee,nes en Ge se eae rena i Or ee SP ges hs i aes Rs ng eat ki assis igh ieee Bone peo a POORER CO

|OEE ms > Heaa — ait : a Me gs Senos 39 a, ues oawie x Rie,prebies ts ines St creas Se Me apa eeate Berens ih ts ae oe gees Tae BgeaH renananes aneagsi Bea genes

oe siKaas oersasaNee Pals Hs feceee gee eg. ae a eihe octaBas Pigs TAR Sea ai eee ee reTee riene LASS SBE: soe: oRaaecget ‘tk: 4‘éhoes ie rs . met pte ce ee aeieaaeaehts ae; re AR caertd l. 'brace

: oe oe a s a ‘

soe. See: .2ie + "Boe te eee gee, ore aes sieaeeaeteasian Sah adigeee ee‘eg, Spee; we ee eee ee oe nici :::A é :7ae soepags: ae atSogis OePi&: ARpees, oe oger eeeateeeSsSeen ones BS cartee

Re Gi‘iOS Py REE 4oie, os Som Seek EeeSagears Oo iy Ph tn. EC Seas a Sraé"2 ae 2RT ;=3 8Pi ae as! es:LAr Cera Semeta aiehenee Beye aegate nee fet «Le :oeshe a tyacs SS oom ee She Bee Ae ae oe ae sR fee, aeee ee oe We apecent ati eaehee ee ache ee eae Ser Seioe igs Re Se 3:ee Be Ps ee 13ae sates res yg Cee pity ete cee eg ie aeSos oe px aaiiiit ae ee ‘ i eee, oes rahe © z ime eg tal ey te Te pied bast ae: ‘ ee oe Ta i er: ee Appecth Wal ee i oem tpt aeE‘eA Bei! Sg eg, paoe Se qi eee re Be Le BiakED OS Sete gears aoa ee” create ieo on E oS ee ee seoye Ettfeie a sree aeFig oN ee ois 3 i Ree ae ee: a ae Reais es ie Joa bs Pk tee rage oc ae Alaa, tes % -_ a: a oe “ta chien ae a sma Wiles peer Ce a peo ee cee ana ee, gs a a ia Se i pee BE rao mo pe Se aia ge sts BAP ke ee. rae pee ae a0 cn a=‘ ‘ TA igs et 5 ane me Gs. e4 hoa FEN pr as < oe ; me 8 ee Mt get Bertone heer Pe a ot Mad ee pe oe

Bie Rie OEBseked ‘boxe gs, i Aa 8. a oiateeeSap: cyan! eM sgh She es Bea ke aoeeee ceed saeg Oe me be PoetBeceis Te comPecstee: He 5 ne ee ve i ge Bresoe ee Sa ae ig ae ahr ‘2 es ae aedat rt) OER % igh 38%, esreps fe,ieoPaon eeihe iidacai Bae ee Hiei igi = aie 5efeee ageSeo ii ores RFS a F aenias aepei i es a IS! ile aL aptesNese ing os

ree ad eB ae tt tir Ce ie ee ee iPi is eae wa aePe sg hss ie a ses res,ee “oad a ee ee = :Pigs a SiBh,coEAasae inbee aevat pes Bate: sidth SeEeee i, aired ety Me ee™orciteee Cg yee:jeSeg ee st iter! eee sa rah2.9eetraced SOON esaesees exci3 Re his Ae ceaoe#5PRESS Py at ad ae hesini i IG telPe reshid tale etek ae eae ce aS.wee ee Had epeeme Brey ie Rae PS at ae ere ee: e; Beiter gees Dotige eeeoy ae ror i oea

ex ra‘aoe PRE CRL Sr Raeao: og oe i ieae Mase Bh 3mee de®See Friis ae ae a 3 taior ee es aes ae Seige SoCode peer nae igs ee es hae ‘Soe a ae -ve ae:Paktt 8 BP oezeHee eeagaEE Fee ath‘ea ae Paws OS NeBe oe, -anit: : ne ey ro sitreegies Seo Fan es, 9s eSfads ae eeotoak Nes 60 aeBiche eee es eae ee I,mie. BiaanSi i ‘ag Pe aRS: .;“fe . x5 pa Recs da :AG ys Boy Ags ne TOES essere ere: ioeiRe ae nee eng socake eget SSa) Nei Co ROS ee 5 Be res gh aeee aie :Bae 7 gtie : : : ae ESai es EK a ve Hoh pee: aeBEE en ae Ke faa fgSiOEE Bearish ye Bee: de heaiSRR ais fe ane sep ge wy fees Rg oe we ‘gen ee Sh be an ‘5 yes ; oe . : : oe oe -: . . gH 8, cig ot oxi . Saperee a ne: ere oe Sar ey Ks a os te sae “ 2h lath earns Let Rape 24, xr agers t yoo Be ae wf 220g care : a — eH rae om ox: :s(t a: " wh 2“ixbi ccd “oh Sak, rae Ve gtcote ag bs eS ge ithe Seg nee ie. ibe oe OB Brigit at. Ree ee septhe. ie oct ae CER ae|Pa HAE Pee Rs Se alae wea! age Soe foe ERE ° lta Pie : ar ate ee, ES te BR BU gt ES iaeaiPay moe gate ©be ip me he 5G. bgt BSE ty SiS ye ae % Me wt Re: we tf Pie os age #9 ae me Saye as e an ‘ “ = 2 " : S . fiae ee a SESE Bor Pe tre : ee _. RE Sa eater TE occas

4 :aee ee aE Eee —7a — 8 a| oo Soue a. SEE ke es CO Unites aoeee eeeSeeeESA i #3...a Ee

Testi: Saab COBEEESES te So ERMEAES StsBR SEER REE BS Rg ES ‘Sena SESE EE sprees So Sake ORR es pL a oon TELE, RS RARER os hg “SEER Prennaeren {RRSTABS Re ea SRkE ae en ReaReae seas Bhaaa Ss Er SONS -«- ERD - a ce

: 2:EERE Pernee “SESS Pag2eis CINTA EES!Nanas SUES Sai ee BEES “SSE : rs eae ess CC —-—ee ge Zz . a 2 EE . 2cea . oS ae ea aySSerahnrans Bese eons RRR aera

Pcernontie seesSather poh! Bene Bernie aren Do CEEEEESSESS Pettheng LDScomes eth USES ESES Sate eeaeSIDS eS Soon ees I EREER, Seeasene SSIES Fess hoona SHEE as i ee a oe a Paaronaeaa PPERERREEE faeeb et py nese Cnn: Linsey wegen EROERRE SOIT a ee SCORE payee '4SEE oo SSE EE eee Saree RaeSpier SSEEEEEEEE penne Siihegsasye se pe eeeee, HECserkhhecni: BE See Gawiursueaeneaas IE satin: Cenehennectt: ws stele Senet! Paened Tonite SRS et Te Pra ncnnce CULEEPP Ere SMES er seeey SISUIEIR Ye SIs ihkcanenereenes ta ad caster LOPE POR RR ERI SOEANS A? ss aetenate SEER EIS SEEEREEEEESE 5 oe oe ee : oe _ _

EORIELLEPSEI See REE SEREEEEEEEESE oo SELLS SSE SURES Ls SEReebehes Sito POSUERE “uit SRSESSA rece SEES pbenunnen titsSana Sereanenee Beas >Iq SOREL oss See Rees ERE pening mseecrenen Peekine So OUSEEEEEEEES Sey SER ae LS EET TS USSR SERENE SEES ree EEEEEEE! Seen SOCRRA LES SEES :ann SEE SSeS amuanens easeee pene Sen 22ra.,.ee— 2g CREE AOEEEEEESIS ay See Bete OF Penner, Fier ceieniens nen SHUSEES ISIS fhe SS LRE Patrecere Shh Saaee SSSOE SSeeeers. BES . Ra Sronewans ERROEEEREAES seg SEE Seeecnehaeee: SEEEGES NERS sean er neeces URE RNaBoeaaetee ee - ._

Seana n eRe wpingeneeee a dicate ie_SEE PRRRRRRE MERE asin nm perenne CELLED seteranetnnenecenete RRR Seohieinrenn cree s Ragetetsr “Shoo ss WE SEDEC Leenreht Ba od REEEES oss 3 ER aA SES DEES, Say SHORE Saas TEER! EERE ES Tis Sane eee RR RRR trek PEEEEEE: page {OLLERREIISE RRRSIRARE Sent ooeee aeRin SESS CC OEey GET ea Uer ae ue aats es ES ee es fe SESSDSR Tt DEREEEEEES EE SST SRS NSEa eae Rkeeret otk Su SSSEeEEEY PEEShinn PEEEEEEEES oT MeL SEEIEEE ONES oa SAE ER URS CE Baeeg. Sa EEESEES fel ag [ees SEER ee teani2eit Ropar orsksiei ESS PEEEEEEEEESS wenn (aeTSE REESE See | h. Leet: OOSU AEEEEY Lnehenene SEHEN MEPEEDEDSEE ES ocean ee CE BETS istcaine SEEOEEE |EEE Spey. i) CEEEELEEEEEEES SE ene) eeeee iatRieti SE ee a Sareea Bist SLC aan oeS asey eeeTELE eS 7 _ cit RR aeeoo | : oye CEES SES hos SEPELIEESS SEERSEE LEEEEES SUES ae Sone etc aeeeeniciis bSPE CEEEESSSS eieer Tae fee SReeiraERnER SSE ie aR ES apc eerie PEE TIL tS POSES fit Pai tc ikne: SPEEEEE Soke CEEEEESEEEEES PERE TYELEESRoe: ES SEE Te 2 Sons 2 enates ON Bea cies SSUES —DhLUlUlU EDL SEE Se ge Ss nibhee COEEE CEPR POSURREREESS (SUEERESEESEIE UEEEEEETESS CODES EEE Sete DERE CEES SERRE BeRUE saeSohenany Ls : mo AER REN Serene CMa itee CREE) BeEe a eeSERS, se -a fee PeCE EEE EES Se: ay ne opelTE INSEE neA CARRE Cr Ee SEE a SSS Sen Snppeceseeess ead COOUpE EES ERieee oaELER Gan ee oe hennenantene See EER REESE Rexenaee SR aes aSENS gate eeSy :“a Le. oo. 2:ee we EEEMEIEES DEE Seniesa Sohey SePe RRR SERRE SEES TrSSE BEEEEED esaET Soi ecesyae SEP Geri enPERRET Barnet SSeS SEER Sean ee Sache ieaRenee Le Seber) EERE Se Mars PeEEESEE TORRE oeerssioomnas SEER SER UST Sy Dikhit SEEEEEE ae SVR nse fan en esDS fehea 7 eo EaSoseneeenncuna a “ESS SSN SEE ETEES SE A -SARLIIVE TESS Se JREE EEEEEEE EES SoSEN EEE Eek “CUESEEEERSEES SEER SEE coer _Re - a ey , a _Boer Rech BA SSR PELEEE SE EERE agSEEEEE Syn DAS TELS SPeRERE See SEER EEREE ES TEESE! SERRE ee oo.a Rr ne eSIEE SS,SERES 2 tsale! SSE Seeyobs er SS Tee Seenirenaats Seeaeeeetntd PUREE | SSE |. :seers aD ee

— :PEPE 2Su a ESS oe ao ee ae OSS ROR 5:SaSeen aan secret cents, i SeeR RGRKGIG AS ec beeae 7Sereaeencreg | oe eeEHS eee _sieree ae sverige cee Reece i Eten. BE SSL oe eecpaoe ESE “EERE ee |oS ; onthe yEES | Fe SEE PAS SEE EEE aLeathe Se: EME te eesOME SPAS Seeing oeSAYRE es Boer SOS SEINE LESS, peers! ts OES SSOe Se ae: s ee Ee eee ppg SE OS SE an Phy oS SPSS, setae ear on east we ike SELES cee Sachs pansies |

SES = nee ee Re opener SeloES aSeeeyUMS SOE, pe - >MES cores Sy Shes idSee SAS aSATELA oy | aannorapnats iedth SMas LR UnC SEee ES PRLS Re we eee as es SESSLER SHEN Ss eae Se SES oyepee EES, OERare a EC oe ISS UN PE LPHESS anaoe A:: oe

SEES SO RES eS EAA 2 gees Rane aaa ienas geet go Es SOS SUSE a pe : oe .Co Sy SEES SEE ane otk aaa beet Rtrrenrtries Ee enema TRIS ane :AEE ae PORES Ban : gy WL e -. Fetes Recent MR ccs SSR CES SSNs pana ea 7Ee SEs REARS RRR weoefA fy SEP Reis cree mea . lrr—CSCS SESE Se pms SEES SET ESSE Sree ena eas fet ayeee ERS mee ELS ES Seah oesyee Sra :Land veeetnats eae re EPSRC Sete eee ie ce ees Beir OaSke aDANE ishr PEPER aS ;SE oSSSE .oeieaSa AOE ee CES SSS SS me EET SS Seaver eSe Reine ere oe eee eS ee eg ee. aT gga ee HES Rpg Setar pene Po es Sasercegn SRR Rik Set ites te ares ; Sh Sane CE SENSES Ree Ret nares SS alk na Rn Run ORICON SESS ESE eeheey INTIS ONE : -; | anos aree neers A Noe ak Oe Sey shakes! Si |LOSER ae -DCENEP . Sees ,Bol * ze =ana Seer eT Soe SE (Se REAR SEEN REECE Shy Shh Pe exer en ats eS EE ne 2at ERRORS APE ne SEED SEPA .,|. ees :SHE eoeasNa EE EC BEERS Stes re iSoe BSS B eae Sr SNe ASE Ug Sepa Han iea lee ee SCE aSesh En EAE __— =... Eee SRR eRgf Po Rea Ee TSE ESSE ee seombreseyee ieAEEE OMS UY

|. =CO a Cerca. ESRyetee? |. vel a ice meres SE A a_REE ge apee _... -— . oe oe ae oe i. a eee =:

=. Eee eesaaPeg EEE EE gn ee [eRe ooSpecs Rote ree sat SSSLEE ree eee Eo SHEE Egae i RS a SoU Bagg SEa : amatte _ : BEeeesSE :ooee Ne nine ieseteee SSE Pere: eePas res Sree SS - oS SESE SO et sus neyo ees: aw oy Sak res ASS htSERENE LES eee:aeBEEPS Baier ee SEES yeep ksiy BEDE ESS SESE CESSES eeSans Peiieecreeteenens THEERE EERE oc EE ig ee “SPIO Peas 3. aaa See) Ses aoS ahi! aaoe REE Pen Fa GE a. seen SpE ce aie ee See es |aS|.aa: .Loe any PN ase a we TeeRa ght Br eePESO Tae Ree. 3SE eecespete Gar caentes NOR IEEEED SEELEM Coneenrirey abe rree zLe fe — : -Shy oo PEP We, Es Rencken ea aes SUS poe BA eserrereeaean Sterkay ive Renee ae eee Senate Bee een Me Bs os i. ae os a PROBS SEER aS ee yee Sere Ronee es BAER EES pee EME EAN Se ee es Saline: . eae E oa V Syye ea aT re aes Prabha Soe ewe Rian canes eens CEA QOCOE SCN ey ARR SRR rare arenes Sevres SRR OR ERE SOR EPIES “SLi Loar. SRW R SoM ENSUE eA ay een Le " a it A. : ‘ ee CORE eee Saati pee Ee fe Saas a —.. Agee eR ee ean epee tig! Se aaa PU ee ea BN. : USEFI e oe Se te ae ea LE BEES BE a Ce ee ees eter pee eres Cia aa Deere nernres boo eae Bee Oe ae pone aa aa. SELES es SEEsee Se CRABS Se SOE aon ae cee eeeex SRN aes ee SUSE eee aaeceeiedd SSRsSeen ioeerseercc coo Meigs 7nna Rane enegs Pee aee ST resis PORE Bo SEES Perma cf te CMS eo hae ooeetLepage Ce ec oo SSS aoeoe pe enya ence aee eee ee Re ech er mae SEES AT Ripobtereres TBR + oe Sey eere Spi ae SC CREE Be ee ehkenvomtera! Rana JESS ose en Rance 5 5s SSAA OOGROD GTC rhnreesth Twice canes Hee ee B a | : a

eas SS os ot EA RSEea:Ee we co eeUSES ER AGS ieee BEpo OUN pceEN h Brett ASHE cosEEtone eg ag aesRey tooeeene ss Mees ~ : EESSS A teBO poleeast Tae De eee SS ER SERRE Hayek PEPSeRpkiegs EEA SUCRE RCE FE cia eee He PereSoh SEE rece Hence te NE ES beGe es aes feeGees Panes EE RRS eepoSoeee SU Geet Geseoccnhehd Pea cert sHuuhaaics eet SEES peeSEES eecic. LEEEEt ea Ee esguess Paes aes tye Me Sei) REAR eee oe eeeeehay EEE So cohen SPapnEE Res rane Fg teenth ties ME asTesaePU pee PRES OF Fe: oe ae Rts oeSes: acetone Re SES ee OPE eee eee Eya ae USHERS | Paar EheeSeedy eas Ce 8ehSELLE Te ccBe ee Soe Peer riers UR PERE eden ccc bok ee ROS Ree RRR SNS SeRRR) as RET eS Sagar ts CE aes OeCtCSRS OSHS eeePeispereecet OScRkER ee } eeieeers PELE AIITNTERE RE EEO os iroeegerolt ripeehNe | OR earees cere TER ES Re scaeos Somes ASe Bite . , co. ae SEED ptasne cakes Rare Ropes RRO RATR RRR etsERR SER eR Pr PEBRSEEE aORtthe boos anaeReRATESE fries: ERR ee DEAE pare Darren Rens He riceBe ea:Pansat penne a a Se She peony

Te SERS esPes aceasta aes ee ce japenns Hae | aeRees Pl aires RRS lg lmOyen Gea eeeeUNE SERS eeBees ahaa. Aikieee eee | Sh PERENED a. Poe —.mr,rlUmDC~sS ORs eee He Peee aie ccgiti cereRape 4 eono. . es i... oeGe pr reas Pe Stet PSS OE ce foe eyhaan Eto ane Peeeeee ns prcanees Re ee Bearers Cee ES ee oe OranLeteengee ESSERE ee ees pears pyeT: aeSEE URE raetes eenOTE Peer rn Sa iene area ne MEER ee O TE eeRSet way PeSt esithe ep SEARLES SO EERE EG TEepee retae eeces os teeheeeer esraeentani ee2 TInt eae PERCU 2 UESE Barevies BSE UE, ee es Co eae pair ace peeing Ses ao pee cree Kerneee Tey ibeiciree ent Sica Tate Raa een ence oe en Ae ee Sh Ue Sn eee eket See SSE STS RARER ER RRS RAO RARE See K RRA NCES rie EET ROR ER Cee Ferree es Nhe DRGRRRES SE ii AIRSET RRS ee gee Se SSPE SOT BESS SNR NRe NNER aie eee ee wet wae wo.

a. a. aPST RCSant ROT eaBikes eS ceeSees eee OO Sa SRR Renda rrmaRece areas HapBore ENSaer eesten SaonTe ener Ben eer:RRY ca reid re oaEo peraeLo Ge 5ees : ae Eee CUA rE nea e eeeuae EESeMSrarhyer Ee VERE nosans Hee er ERE CORSEcpEES EED PP PRORIR REE OTOt EEEC caren

Ras Parca See ane SEES eer RS SRRnnteh SRESAN eerwes Saar ASE GeNcalceep rte SeeEre Reeser ester R ire ROE CORRES SRST ae raii cost MTR i Rees2ay o>Re Lappeees ie2-5ae ty See biaoyTEA Se SSS Ray Reve Sov eecier Res esa Bee Renu aeCON ere ee base iy BEES Gabe shhbtseeg cine SNE PEEEES 22 pair re ae er scie Pere aekia See) Keone ears LHe cere:an :. ER NEES ge =go a:escas SUR eaCn KANRR LAS eremann sses axSU ean Sa EMS CCR Ceecynee CER Eis ate OPER ES SECRET LAS ENE Paes Goaehontes aes COREA TOSS TIRES ART aaa Leak Chan eR SESH TERE Seat RARER PoySGA Teen ORV eu ea apPERCE Oe Renamer SOIREE Sa iPONECEN SRRRRERE EERO Baae eas ses Hides ea Sere Seo Wi oe P ;- ESRI Ce xSERRA eR SRE Seer sree SRR oo. Aras fe frateemenctes PORES Ne piTOR prer reat gown! ttEs oa RR aera ee SR geen ipa TIS G8 aes a seeaaaeO Petey Ceres TED SMe Sy ry“4 EA Se SOE Sa CONES SELES. Frersgr erie AXEL EER tE eines NISRA LS erERt OS chat RGR Te ghee rrr CORSE BEES MEINE oat SEMPRE iisraseresaty oaks PRAASERE SNARE? CRORES eerie Soy pe LC EE EES foe een lS ADR Soi fear oe .

Pe SOAs soe oteiene cert ee ARS ran oss uhtee Ceeoe eee SHEAR PASStes SSCSoares ere ae SONU RUM runnin x Eee Se senso Hiereaieitatieieerse Sees rirePOE Pian eee SSBKe TUES JSST 2 M, CeRe SOD st AUS ereexOAC ona SU eRe yREE as Cer! SERLE EERE epee ateseroRear circaSod caeciecenennnty SeEnekee eae Seely ESSEneSey nles see]

eer eee Seay Ee Saahee TAS DO cuae ae LSI Pen neo Tra EASES Age Se eeRenn Eepa RRR aS ilpsiiyee Ses EE sea Bag eist ees onesDoe See Se Een Pe aa ars 3% PERSIE ee etpoe SES SOROS aires citShen Saeres Seed aaa RRR LSE iercnagetter SEEnES eeeeebiie cetORES eee esCe “LEST eRen] a. ‘ The circumstances as I remember were these. For some years previously, John Paul and Joe Melnick had done a great deal of research relating to the fly and to sewage as mechanisms in the transmission of polio. There

were, I might add, in 1947 a number of alternative theories on the mechanisms of the transmission of polio, and Dr. Paul and his associates felt that a conference might help epidemiologists and virologists clarify their ideas. Mr. O’Connor, on the other hand, was at that time faced with a rising incidence of polio and was getting restive that the

Foundation had no hard information which it could give to public health officials to help control the spread of the disease. He thought that a conference devoted to epidemiology might furnish him with

the information he needed. I will say this, the conference which was } finally arranged was an unusual one, and quite unlike other conferences which had previously been held by the Foundation. First, while previous conferences were almost always restricted to

virologists or epidemiologists, this conference invited sanitary engineers and entomologists as well. Secondly, whereas previous confer* Round-T'able Conference on the Epidemiology of Poliomyelitis, New Haven, February 14-15, 1947.

426 Chapter 11 ences were exclusively concerned with a discussion of scientific papers,

the participants in this conference were asked to make recommendations which would amend the regulations previously adopted by the

American Public Health Association in 1945 for the control of poliomyelitis. It therefore might be said, that this meeting had an eminently practical purpose.

Q: Dr. Rivers, you mention a practical purpose. What, for example, could a virologist tell a public health officer in 1947 about the incubation period of poliovirus?

Rivers: Incubation was a difficult question to answer precisely in 1947, because not much was known at that time about the mode of spread of the disease. Nor was this the only problem. For instance, because polio assumed a wide variety of clinical forms, it was exceedingly dificult to make an estimate of the incubation period on clinical evidence. ‘Take the problem of the first day of the disease. Everybody at the conference knew that some people could be infected with polio-

virus and never show any clinical signs at all. They also knew that other people could be infected with poliovirus and only show signs of - a minor illness, such as a sore throat, a slight fever, or general malaise.

A doctor might tell such a patient that he had the grippe or a slight cold. Then there was the bona fide paralytic case. In the latter situation, it was fairly easy to tell when the paralysis started, but it didn’t necessarily follow that it was easy to say when the disease began.

I remember that, when virologists and others at the conference tried to define the first day of the disease, a wide variety of answers were given and each one was different from the other. I have always taken the beginning of a disease to be the time when the person involved ceased to feel normal. Dictionaries usually give long, involved

) definitions of disease; however, I have always taken it to mean ill at ease. I'll tell you one thing, it’s pretty hard even for the patient with paralytic polio to pinpoint the hour or minute when he stopped feeling all right. It would be easy enough if polio began with a sudden nose bleed, or if the patient’s head fell off; but polio was never that nice and easy. It should come, therefore, as no surprise that nobody at the conference had exact answers to give on the incubation of polio-

Some Aspects of Poliomyelitis Research—1946-—1948 427 virus. [he answers varied. I think that the consensus later put incuba-

tion between 5 and 35 days, although, if memory doesn’t fail me, Tommy Francis once turned up an instance of a three-day incubation period in a newborn baby.

Q: Dr. Rivers, what was known in 1947 about the mode of transmussion of poliomyelitis to humans?

Rivers: In 1947 the answer on the mode of transmission of polio to human beings was still, so to speak, in the inkpot. Following the iso-

lation of poliovirus in human stools in 1938,7° John Paul and a number of other investigators quite naturally turned their attention to sewage. In the beginning the detection of poliovirus in such an environment was difficult, because the laboratory techniques available for this kind of investigation were crude. Nevertheless, in spite of the difficulties, within a very brief period, Dr. Paul and Dr. Trask succeeded in establishing the presence of poliovirus in sewage as well.?” By the early forties, Sven Gard in Sweden and Joe Melnick at Yale had further refined laboratory techniques to such a point that detection of poliovirus from sewage almost became a routine matter.

To my mind, these technical innovations, combined with the singular absorption of Dr. Paul and his associates in examining the sewage in urban areas during epidemic and nonepidemic periods, gave

great impetus to consideration of the problem whether the presence of poliovirus in sewage played a role in the transmission of polio. I

might add that, in 1947, that line of inquiry held much promise. There was no doubt that Dr. Paul and Dr. Melnick had found poliovirus in the sewage they examined. ‘There was likewise no doubt that in several instances they were able to bring down monkeys with virus gathered from such sources. In the end, however, they weren’t able to establish that sewage was the key in the direct transmission of polio. I would like to say here that Paul and Melnick were extraordinarily careful in their published papers not even to imply such a role for *J.D. Trask, A.J. Vignec, and J.R. Paul, “Isolation of poliomyelitis virus from human stools,’ Proc. Soc. Exptl. Biol. Med., vol. 38:147 (1938); “Poliomyelitis virus in human stools,” J. Amer. Med. Assoc., vol. 111:6 (1938). 77.R. Paul, J. D. Trask, and C.S. Culotta, “Poliomyelitic virus in sewage,” Science, vol. 90:258 (1939).

428 Chapter 11 sewage. But in spite of their meticulousness, on more than one occasion newspapers made such claims for them. I know that such stories caused Paul and Melnick a great deal of anguish, and they strongly resented the interpretations that newspapers made of their work. It made them so leery of newspapermen and publicists that at one point they even refused to cooperate with the public information division of the National Foundation. I didn’t blame them then, nor do I blame them now for such an attitude. From the point of view of the newspapers, the presence of polio virus in sewage undoubtedly made a good story. Sewage was some-

) thing the public could understand. ‘Traditionally, filth was responsible for a host of ills, and the newspapers could, following Dr. Paul’s and Dr. Melnick’s work in a superficial manner, get exercised that inadequate methods of sewage disposal were responsible not only for the high incidence of polio, but for a host of other public health problems as well. Let me illustrate what [ mean. Although New York is one of the great cities of the world, it still dumps its sewage directly into the waters which surround it. You can look into the East River at certain times of the day and actually see feces and other sewage floating on the surface of the water. As a result of such practices, the waters in and around New York have become so polluted that New Yorkers can no longer use many of their natural beaches for swimming, nor can they eat oysters or other shellfish which are to be found in the vicinity of the harbor. As you can see, sewage was an old, natural enemy, and it seemed logical on its face to believe that, if poliovirus could be detected in sewage, that sewage somehow played a role in the direct transmission of polio to humans. It was logical, all right; the only trouble was that it was a proposition that was not susceptible of proof. Poliovirus detected in sewage was no more responsible for the transmission of polio to humans than the poliovirus which was discovered in flies. For example, by 1947, it was likewise true that Dr. Melnick, Dr. Sabin, Dr. Robert Ward and several other investigators had already demonstrated beyond a shadow

of doubt, that the flies that they had collected from the vicinity of open privies and sewage in epidemic areas were contaminated with poliovirus.?* Dr. Ward, in an experiment in 1944, had even shown °° A.B. Sabin and R. Ward, “Flies as carriers of poliomyelitis virus in urban epidemics,”’ Science, vol. 94:590 (1941).

Some Aspects of Poliomyelitis Research—1946—1948 429 that when he allowed flies which were contaminated with poliovirus to feed on peeled bananas, they contaminated the bananas to the ex: tent that, when these bananas were later fed to several chimpanzees, one of the chimpanzees came down with polio.” It was, you might

say, fairly good evidence that under certain conditions flies could transmit the disease. Most virologists, however, believed that this wasn’t the usual method of transmission. First, no one could demon-

strate that poliovirus multiplied in flies, and, secondly, several fly abatement campaigns which had been carried on in epidemic areas in 1945 and 1946 had shown no appreciable effect on the course and duration of the epidemics in question.

For me, one of the important results of the conference on epidemiology which was held in 1947 was that it confirmed me in the belief that polio was not spread by flies or sewage, but by close personal contact. I have always held Dr. Albert Casey of Birmingham, Alabama, responsible for my adherence to that point of view, and | still remember the paper he gave at that conference with a great deal of satisfaction. ‘Through an examination of polio epidemics in Walker County, Alabama, and in Chicago during several different periods, Dr. Casey established that in over 80 per cent of the cases there had been personal contact between the polio victim and another child believed to have been in an infectious state of polio. He backed these observations with an impressive array of case histories, spinal-fluid protein determinations, and stool, throat, and mouth specimens. However, the thing that impressed me most of all were the pictures he showed of children at play in Alabama. These children were playing some games in a field, and from time to time they would run off to an old outhouse nearby, do their job, and come back and play.

What caught my attention was the fact that these children kept putting their hands in each other’s mouths. I never realized before that children behaved this way. It was an eye opener. I grew up in the

south, and I assure you that when children left an outhouse it ‘was very unusual for them to wash their hands or to use nice pink toilet paper. It was more likely that they used an old newspaper or catalogue, or, if they were real hardy, bent a young tree, straddled it and walked off, to wipe themselves. The point is that children who left 2 R. Ward, J. L. Melnick, and D. M. Horstmann, “Poliomyelitis virus in fly-contaminated food collected at an epidemic,” Science, vol. 101:491 (1945).

430 , Chapter I] the outhouse undoubtedly carried some of their feces with them on their hands. If you think that intimate personal contact was accepted by everyone present at the conference as the mode of transmission of polio, | can tell you now that not everybody accepted that point of view. Dr.

Gaylord W. Anderson, of the University of Minnesota Medical School, for example, very forcefully argued that polio was spread in a respiratory manner. Through the years, I have always had two reasons for arguing with people at meetings. Sometimes I would go after my favorites and try to push them to the limits of their findings as a way of clarifying thought. In the process, I can tell you that I bruised and

hurt many an ego, because the truth is, although my purposes were good, I was never gentle. I am just not built that way. Other times | would go after people who rubbed me the wrong way. Dr. Anderson was one of those who, for some reason or other, has always rubbed me the wrong way. This meeting was no exception and I went after him. I just didn’t know what he meant when he spoke of

“respiratory spread” or “contact spread.” I was confident in my own mind that certain respiratory diseases could be spread by contact, just as others didn’t have to be spread by contact in the sense that one had to touch something. Certain infectious agents can go through the air. Chickenpox, as far as I am concerned, is probably one of the most contagious of any of the so-called contagious diseases; yet the word contagious doesn’t describe it very accurately, because contagious means touching. I have in my own clinical experience seen patients who caught chickenpox without touching anyone or anything that ‘was contaminated. The infection in plain words was carried by air. | would like to add that such experience is by no means unique to me, and that other physicians have made like observations. My experience with hookworm in Guam fortified me in the belief that it was possible to acquire this infection merely by contact with contaminated blankets or bed clothes, even though there was no visible contamination with fecal material. And physicians had long been taught that the only way of picking up the infection was to walk in contaminated soil. I was, you might say, conditioned by my experience to be sympathetic with Dr. Casey’s point of view.

I told my colleagues in 1947, and I'll tell you now, that the incidence of polio in a country runs parallel with the number of bathtubs

Some Aspects of Poliomyelitis Research—1946—1948 431 in the country. I think we get infected and immunized via the bathtub and the face towel. ‘The children who leave an outhouse without washing their hands, as well as the adults and children who leave a nice pink bathroom after bathing, carry some of their feces with them. It may not be a pleasant thing to think about, but if someone has a defecation and later gets into a bathtub and washes himself, all that person does is to dilute the small amount of feces remaining after defecation. Drying oneself after the bath only succeeds in covering the body with a thin layer of feces and contaminating the towel.

The bathroom is probably the most intimate part of the household: everybody visits it and, although there may be separate towels, | don’t believe that children or adults in a family always use their own towels. ‘They grab what is at hand. I believe that this is the reason that polio spreads so readily within a family. Children who play together can get their hands contaminated with virus from feces. Dr. Casey showed quite clearly that they didn’t have to breathe in the virus, but that they could get it in their mouths from their hands. ‘The point is that the virus could be spread in this way and you would still have an epidemiology similar to the so-called respiratory diseases.

Q: Dr. Rivers, your comments lead me to ask what was known of the portal of entry of the virus in 1947.

Rivers: Early in polio research, many virologists, following Dr. Simon Flexner, believed that poliovirus entered the body via the olfactory tract. By 1940 the work of Albert Sabin had effectively ruled out that idea, and by 1947 it was generally accepted, as expressed by

Howard Howe, that the mucosa of the alimentary tract from the mouth to the rectum was potentially the portal of entry of the virus. However, I must emphasize that not all virologists at that time believed this doctrine as vigorously as Dr. Howe did. I think that by 1947 we were also reaching definite conclusions on the related problem of the portal of exit of the virus. By that time it had long been established that the virus did not leave the body via the urine, and most virologists, if you asked them, would have agreed that the general mode of exit of poliovirus in man was through intestinal discharge.

Some, however, adhered to the notion that the mouth might serve

432 Chapter 11 as a portal of elimination. For instance, it had long been established

that poliovirus could be found in the nasopharynx and_ the oropharynx of polio patients, but no one had ever shown that poliovirus was actually expelled from the mouth under natural conditions. It was an intriguing problem. For example, during the polio epidemic of 1912, the city of Buffalo asked the Rockefeller Institute for help in combating the epidemic. There was little that the Institute could do at that time, but Dr. Flexner sent Dr. Francis Fraser, who was then working at the Rockefeller Hospital on polio problems, to help out. One of the things that Dr. Fraser.did was to take washings from the noses and throats of several of the patients he tended and sent them back to the Institute for study. Later, Paul Clark, using these washings, succeeded in bringing several monkeys down with polio.

It is interesting that Dr. Fraser did not take any saliva; if he had, Dr. Clark would never have been able to infect his monkeys, because

poliovirus is never found in saliva.*° In 1941 Albert Sabin and Robert Ward, working on problems relating to the elimination of poliovirus from the human body, demonstrated beyond a shadow of doubt that, although poliovirus could be detected in throats of polio patients, the virus was never to be found in the saliva of these same patients.** If that work showed anything, it showed that things in the oropharynx and the mouth don’t get mixed up as badly as we sometimes imagine.

What I am about to say has nothing to do with polio, but it bears on the general proposition I have just stated. Sometime after I graduated from the Hopkins in 1915, Dr. Arthur Bloomfield, who later became professor of medicine at Stanford showed that, if you put streptococci on one side of the mouth, those streptococci stayed on that side of the mouth and went down that side of the throat and in no case did they invade the other side of the mouth and throat. To sum up, I would say that, at the time of the epidemiology conference in 1947, virologists in this country were approaching what we now believe to be the case, namely, that polio was spread through close per* S. Flexner, P. F. Clark, and F. R. Fraser, “Epidemic poliomyelitis. 14th Note: Passive human carriage of the virus of poliomyelitis,’ J. Amer. Med. Assoc., vol. 60:1

UTA Sabin and R. Ward, “The natural history of experimental pohomyelitis infection. I. Elimination of the virus,” J. Exptl. Med., vol. 74:519 (1941).

Some Aspects of Poliomyelitis Research—1946-1945 433 sonal contact, that the portal of entry for poliovirus was the mouth, and that the origin of the virus was largely fecal.

Q: Dr. Rivers, in the final analysis what help was the conference on epidemiology able to give public health officers on the control of poliomyelitis in 1947?

Rivers: ‘To be perfectly candid, we could tell them precious little about the control of polio, because there were no effective means of contro] at that time. For example, we were always asked by public health officials whether children should be allowed to go swimming during an epidemic. If the conference in 1947 showed anything, it established the fact that we knew very little about the relation of polio-

virus and water. | remember that the fellow who rammed that fact home to us was Abel Wolman of Johns Hopkins University. Dr. Wolman is a sanitary engineer by profession, but that hardly begins to tell you anything about him. Let me just say that there are few people in the world who are as knowledgeable about water as he is. He is a first-rate scientist and, as you might expect, he put some good hard questions to the virologists attending the conference. For exam-

ple, I remember that he asked us whether we knew what the occurrence and viability of poliovirus was in water-carried sewage and in natural bodies of water. He also asked whether we had any chemical

or physical techniques for destroying such viruses in water and sewage. They were, as you can see, reasonable questions, but ones which we could not answer at the time, and for that matter still can’t answer completely. We just didn’t know enough. We could tell a public health officer or physician that it would be wise to isolate polio patients in the acute stage of their illness, or that the pharyngeal and bowel discharges of polio patients should be carefully disposed of, or that quarantine served no useful purpose, but beyond that there was little of a practical nature we could say or recommend. ‘The fact that we knew little, however, did not discourage public health officials from asking us for answers, and during the next few years the pressure for practical measures of control continued. During the early summer of 1949, the National Foundation held still another conference to see if our then increasing knowledge of

434 Chapter I] poliovirus warranted a revision of the previous procedures recommended by the American Public Health Association for coping with polio epidemics. Although it is true that by 1949 virologists had a keener appreciation of the nature of poliovirus and the mode of its transmission, there was still little that the conference could add to the recommendations that had been made two years earlier, save to advise that it was feasible to admit polio patients to the general wards of hospitals, provided hospital personnel carried out typhoid-like procedures of isolation. Actually, this latter recommendation constituted

an important step forward in patient care, because for a long time previous many hospitals were reluctant to accept polio patients unless they could set an entire ward aside for polio use. I can tell you that it was frustrating to many of the members of the Foundation that virologists had at that time little to offer in the way

of practical methods of control, and I might add that no one was more frustrated than Mr. O’Connor. I remember that, during the course of a General Advisory Committee meeting in the fall of 1950, there was a discussion of a request to send expert help to a community which at that time was combating an epidemic. Mr. O’Connor asked those of us present what use it was to send experts to such epidemic areas. It was a reasonable question, and he was shocked when I and others told him that, from a research point of view, it was a waste of time, money, and effort. When I say this, I am not saying that epidemiology could not and did not help us understand polio. As a matter of fact, it is not too much to say that much of our early knowledge of the disease stems from epidemiological work. I am saying that by 1949 sending experts to epidemic areas was not an efficient way of acquiring new knowledge of polio.

Actually outside of John Paul and his coworkers and ‘Tommy Francis and his boys, few virologists ever asked the Foundation to be

sent into the field during epidemics and those two groups, as you know, did extraordinarily important research. On the other hand, many public health officials often asked the Foundation to send in experts during epidemics, because they felt that they might be helpful in acquainting the population with the nature of the disease. I do not believe that those officials thought the experts would actually discover

anything new. In effect, they were looking for someone to hold the

Some Aspects of Poliomyelitis Research—1946-1948 435 public’s hand. While you might say that such hand-holding epidemiology was useful from an educational or psychological point of view, it contributed very little to research.

QO: Dr. Rivers, if one looks at the developments in virus research during the late forties, one can almost sense a substantive change in the patterns and techniques of research. Would it be fair to say that, when the National Foundation invited Dr. Francis O. Schmitt of the Massachusetts Institute of ‘Technology to address its annual meeting in 1948 on the contributions of biophysics to physiological and medical research, the invitation in a sense was symbolic of this change?

Rivers: I know very little about symbols, but I can tell you why F.O. Schmitt was invited to address the Foundation in this particular instance. Dr. Schmitt, as you undoubtedly know, is a biologist with deep interests in physiology and biophysics and one of the pioneers in this country in the application of electron microscopy to biological research. In 1948 one of Dr. Schmitt’s associates, a young Argentinian physician named Eduardo De Robertis, published an extraordinary paper on electron microscopy and nerve structure.** Dr. De Robertis was not a virologist, but he had taken electron micrographs of living nerve fibers infected with poliovirus, which seemingly showed poliovirus particles traveling along the inside of a hollow nerve axon. That made us take notice, because several years before Howard Howe and

David Bodian had conjectured that poliovirus traveled along the nerves. Still earlier, a number of investigators had claimed that tetanus toxoid and rabies virus also traveled along the nerves to the central nervous system. These electron micrographs seemed to confirm those theories, and it’s small wonder that we accepted them with our mouths opened. The Foundation invited Dr. Schmitt to address the 1948 annual meeting, because it was felt that the path he and his coworkers were charting was extraordinarily important for the future development of virus research. I must say that we weren’t wrong in an over-all sense, but shortly afterward Dr. De Robertis’ work washed out and we shut *°E. De Robertis and F’. O. Schmitt, “An electron-microscope study of nerves infected with human poliomyelitis virus,” J. Exptl. Med., vol. 90:283 (1949).

436 Chapter 1] our mouths. F. O. had a very red face for some time afterward, but, hell, I never blamed him, or for that matter De Robertis, for the failure of this work. It had only proved what I had long known to be true, namely, that scientists, even good scientists, get fooled occasionally and find what they hope to find. We all of us wanted to see virus particles traveling along nerves so bad that for a time all of us saw

what Dr. De Robertis thought he saw.

QO: Dr. Rivers, I would like to pursue the question of change in virus

research that [ just put to you. Let me begin by quoting a statement which you made while chairing a session at a round-table conference on host-virus relationships which was held at the University of Wisconsin in October 1948.

For a man of my age, and I am considerably older than many of you here, I have been kibitzing over the shoulders of virus workers for many years and, as a matter of fact, I probably started to kibitz when some of you were in diapers—and there is a possibility that a few of you were only statistical probabilities when I started. . . . It is too bad that some of the younger ones can’t realize the mental attitude and the work that was going on in virology some thirty years ago to compare what was thought and done in those days with what is thought and done now. It is pretty obvious to some of us that miraculous advances have been made. .. . I only wish that I could live another 30 or 40 years and see what will have taken place in that length of time. Undoubtedly some of the younger ones here will have that pleasure. I’m sure that if things keep going in the next 20 or 30 or 40 years as they have gone in the past in the virus field, that many of the things that we think are now so will not be taken so then, because I can very definitely tell you that, if by some miracle some of you had been set down in meetings 30 years ago that I sat in on, they just wouldn’t believe you—that is, it just couldn’t happen. That is, the things that you say happen, couldn’t happen, in those days. Our way of thinking and our techniques just didn’t permit us to grasp that. As I grow older, it becomes a little bit harder for me to adjust myself to the rapid progress that has gone on in the virus field. Nevertheless, even though I balk a little now and then, don’t forget that [’m entirely sympathetic with the guy that gets himself away out in front and takes a chance.*?

Rivers: I think that it is fair to say that that particular conference was one of those meetings where it was apparent that a bridge would * Minutes of Proceedings, Round-Table Conference on Virus-Host-Cell Relationships, Madison, Wisconsin, October 27, 1948, p. 3.

Some Aspects of Poliomyelitis Research—1946-1948 437 have to be constructed between the older and younger workers in virology if they were going to continue to understand and appreciate each other. Let me add that such occasions are not unique and actually constantly occur in the development of science. For instance, it

happened last night when | attended a journal club meeting at the Rockefeller Hospital. A lot of youngsters were present at that meeting, some from as far away as Australia and Sweden, but, no matter what country they came from, they all had one thing in common, namely, they took ideas for granted that I and others fought over like cats and dogs thirty years ago. ‘That habit of mind among the young is, | expect, not in itself remarkable: the young after all do stand on the foundations provided for them by the older generation.

What made it hard for me to take was the fact that no youngster present had any idea that what they were taking for granted and proved was once nebulous and debatable. Now, youngsters are not the only ones who forget; we all of us forget, and some of us forget too damn fast. Forget is a poor word; perhaps I ought to explain what I mean when I say forget. In 1948 Lloyd Aycock of the Harvard Medical School visited the

Hawaiian Islands and while there got the notion that it might be fruitful to make a study of the racial and environmental factors in the epidemiology of polio in Hawaii. Subsequently he applied to the National Foundation for a grant to conduct such a study. When his application came up for consideration, it was turned down. Now I am not fussing over the fact that it was turned down. To be completely candid, I voted against him. What bothered me then and bothers me now is that, while Dr. Aycock’s application was being reviewed, some

members of the General Advisory Committee of the Foundation questioned his competence. ‘I’o be sure, I never considered Aycock a virologist, but as one of the pioneers of polio research in the United

States I did think him knowledgeable on problems relating to the epidemiology of polio.

Why was his competence questioned? In part, I think that some members of the committee had forgotten the contributions that had been made to the understanding of poliomyelitis by epidemiologists. More important, however, was the fact that the style in polio research was changing. ‘The committee didn’t care about yesterday. If pressed,

438 Chapter 1] I might even say that they didn’t give a damn about today. ‘Their at-

tention was focused on tomorrow. Like most scientists, they only cared about the last experiment, not the next to last experiment, and certainly not the first experiment.

The conference on host-virus relationships which you mentioned was a straw in the wind. Actually it is as good a guide as I know to what some of these new styles in research were which were capturing the imagination of working virologists at that time. Work with bacterial viruses or bacteriophage was one. When I edited my volume on Filterable Viruses in 1928, I asked Jacques Bronfenbrenner to prepare a chapter on bacteriophage. Yet, when the volume appeared, that chapter caused some furor, because some virologists—particularly some British workers—trefused to accept phage as a virus. By 1948, however, phage was not only accepted as a virus by most virologists, but, in addition, many virologists were also beginning to use it as a key in the elucidation of virus-host systems. For example, at the conference on host-virus relationships, Dr. Salvador Luria, then a pro-

fessor of bacteriology at the University of Indiana, showed that through a study of phage one could begin to study the reorganization of the metabolic machinery of host cells. ‘Today we know that viruses do not reproduce, that is, they do not multiply in the sense that bacteria multiply; they are replicated by the infected or host cell. We all agree to this now, but in 1948 we still had to be shown. ‘The idea of replication was first coming in and involved a whole new concept of biochemistry and genetics. As a matter of fact, at that tme Dr. Luna continually told us that genetics would be a necessary new tool for virologists and even began to pose virus problems in genetical terms. | am not saying by all this that we immediately embraced all that Dr. Luria told us, but there can be no doubt that he titillated us to think along these lines.

O: Dr. Rivers, was there much concern at that time with new definitions of viruses?

Rivers: That’s a game that virologists continually play at. | remember that at that meeting Dr. Philip Cohen, who was a professor of physiological chemistry at the University of Wisconsin, tried defining

Some Aspects of Poliomyelitis Research—1946-1948 439 a virus as an enzyme system. Well, hell, before I would accept a definition like that I wanted to know which virus he was speaking about. I don’t think that anyone to this day has given a wholly satisfactory definition of a virus. I don’t think that it is possible, because we still

have not learned the trick of defining many different things as one. How can you define a mouse trap along with an automobile and nuclear reactor? And that’s just about what one tries to do when he tries

to define a virus by a single simple definition. Viruses differ tremendously in size and complexity from the pox viruses that are almost 300 millimicrons in diameter to Norton Zinder’s little phage F2 that is only 10 to 15 millimicrons in diameter. ‘There were attempts at new definitions of viruses in 1948, and in part, I think, they grew out of the fact that the field of virology after World War II was invaded by biochemists and physicists who brought their own language to deal with phenomena with which they were getting acquainted.

Q: Dr. Rivers, can you give me an example of one of these new workers?

Rivers: ‘To my mind Seymour Cohen of the Department of Biochemistry at the University of Pennsylvania was typical of the workers

who began to invade the field of virology after World War II. By training and inclination Dr. Cohen was and is a biochemist. At the time of the conference on host-virus relationships in 1948, he was still

a youngster and housed in a lousy little old laboratory in the Children’s Hospital in Philadelphia. But, God, he turned out beautiful work. He was, even then, as sweet a biochemist as you could find— which means, if a guy has got the goods, he doesn’t have to have a large and expensive laboratory. I don’t think that I am telling any tales out of school when I tell you that for years the National Foundation tried to support him in his work, but he just refused to be bothered. I don’t know how many times I indicated to him that if he wanted money from the Foundation he had but to ask. I assure you that the Virus Research Committee would have given him all the money he wanted at the drop of a hat—but he never asked. At the conference, Seymour Cohen gave a paper on the growth re-

quirements of bacteriophage. He was not the first to work on such

440) Chapter 11 problems, by any means, and it is only fair to point out that much of

| the important preliminary work in this area was done by Max Delbriick and Earle Evans and their associates. I cite it merely as an example of the attack that was being made by biochemists at that time on such problems as the relation of virus growth to the interior environment of the host or the infected cell. ‘Ten years before, we couldn’t even pose such problems. By 1948, however, biochemistry in relation to bacteriology and virology had developed to such a point that Rollin Hotchkiss, at the Rockefeller Institute, had even successfully devised techniques for differentiating the DNA found in phage and the DNA found in bacteria. I don’t mind admitting to you that it was pretty hard for a man like myself, who didn’t have specific training in biochemistry and physics, to understand the niceties of what youngsters trained in this manner were getting at when they discussed viruses. You might say that I understood these new concepts by intuition. I wasn’t completely dumb, because I knew a lot of things about viruses that the new sophisticated biochemists and physicists did not know, because they lacked my experience in pathology. I would like to take this occasion again to remind you that many of the older virologists had learned much about the nature of viruses through studying the pathology of the diseases they caused.

If you examine the minutes of the conference, you will discover that there was much discussion on what the reaction of a host cell might be to viral invasion. The comments were, of course, based on all sorts of new biochemical and biophysical data which were being elicited through the research of people like Salvador Luria, Seymour Cohen, Max Delbriick and others. However, if you go back and read the lecture I gave before the Society of American Bacteriologists in Philadelphia in 1926, you will find that I was able to differentiate what might happen to particular kinds of cells in viral infections on the basis of pathological study. For instance, I had already pointed out that, if a cell could not be stimulated to multiplication (as in a nerve cell), or if the virus acted in a rapid and explosive manner (as in foot-and-mouth disease virus, when tested on the plantar surface of a guinea pig), the reaction was destruction of the cell. In rabies and polio, one cannot see any multiplication or hypertrophy of the

Some Aspects of Poliomyelitis Research—1946—1948 44] cell; all one can see is injury and death. God, the lesion is there so fast, you can’t see anything except destruction and death. In other viral diseases—and this is true of some of the phages—the first response of the cell is growth. The cell grows bigger and bigger and then dies. ‘The plates accompanying Dr. Bronfenbrenner’s chapter on bacteriophage in my volume on Filterable Viruses clearly shows this development by charting the effects of phage on B coli. Such experience allowed me to grasp what the younger workers were driving at. Their concepts weren’t new, but their ways of doing things and expressing themselves were different from what I had been brought up on.

QO: Dr. Rivers, I think that you will agree with me when I say that the study of phage in the period following World War IT had an extraordinary impact on the development of virology. Would you go so far as to say that it was a key to the study of interference phenomena?

Rivers: I won’t quarrel with your first statement, and I will admit that it was a key. But I would like to point out that interference phe-

nomena were studied long before phage became an important analytical tool in virology. If I remember correctly, plant pathologists

in the early thirties were the first to demonstrate interference between various plant viruses. In 1935 Dr. Flaviano Magrassi, an Italian ‘virologist who worked very closely with Dr. Robert Doerr, showed

that, if you took a rabbit and inoculated it subcutaneously with dermotropic herpes virus, and at the same time inoculated it in the brain with a neurotropic herpes virus, the encephalitis which invariably followed inoculation with a neurotropic virus would be prevented.** I should point out that I and many other virologists did not accept Dr. Magrassi’s work as showing true interference, because the dermotropic virus did not actually interfere with the virus which was introduced in the brain. **F) Magrassi “Studi sull’ infezione e sull’ immunita del virus erpetico; Nota II: Sul contenuto in virus del cervello in rapporto a diversi ceppi di virus, a diverse vie d’infezione a diversi fasi del processo infettivo”’; ‘Nota III: Rapporti tra infezione e superinfezione di fronte ai processi immunitari: sulla possibilita di profondamente modificare il decorso e gli esiti del processo infettivo gia in atto,” Z. Hyg. Infektionskrankh.,

vol. 117:501; 573 (1935).

449 Chapter 11 The credit for demonstrating interference between related animal viruses is usually given to Dr. Meredith Hoskins of the International Health Board, who showed that, if you inoculated monkeys with a

/ mixture of pantropic and neurotropic strains of yellow fever virus intraperitoneally or subcutaneously, such monkeys would escape infection by the pantropic strain.*® Following Dr. Hoskins’s work, any number of virologists later demonstrated that interference could also be induced by using such unrelated animal viruses as Rift Valley fever virus and yellow fever virus and influenza A virus and western equine encephalitis virus. There were others; I just give these as examples. It is plain, therefore, that work on interference phenomena initially proceeded quite apart from the work being done on phage, although it is

true that, very early, such investigators as Frank Burnet, Salvador Luria, and Max Delbriick also showed interference between some of the bacterial viruses.

I think that it is fair to say that, by 1948, while we knew about interference phenomena and had studied it, we still had little idea of the mechanism through which interference occurred. The work with phage was helpful in that it furnished virologists with important insights into the process of viral multiplication. Any number of virologists began to see that, if they could prevent phage from being absorbed on the host cell, or if they could somehow prevent phage from penetrating the host cell, or if they could interfere with the metabo-

lism of the cell, they could prevent replication of phage. Some virologists began to look for chemical agents that might interfere with

any of these processes, the notion being that if someone somehow could cause a minor change in the cells which were susceptible to the virus, one could for a time make such cells insusceptible to infection.

It was such thinking, for example, which led in the late forties to several notable attempts at chemotherapy for polio. I will tell you about one of them. About 1947 a pharmacologist named Leon Schmidt in Cincinnati

discovered that two compounds, plasmacid and isoplasmacid, long known to malarialogists as antimalarials, had very peculiar neurotropic effects in monkeys. That work caught the attention of Albert °° M. Hoskins, “A protective action of neurotropic against viscerotropic yellow fever virus in Macacus rhesus,” Amer. J. Trop. Med., vol. 15:675 (1935).

Some Aspects of Poliomyelitis Research—1946-1948 443 Sabin, who quickly noted that, the drug, strangely enough, affected

those areas of the central nervous system that were also hit by poliovirus. Since the distribution of polio lesions in monkeys is similar to

the distribution in man, and since it was known that poliovirus would attack normal cells in preference to abnormal cells, Sabin began feeding monkeys plasmacid and isoplasmacid in the hope that

such feedings would make the cells likely to be hit by poliovirus slightly abnormal and therefore insusceptible to polio. Now this was not bad reasoning for the time; however, the initial experiments carried out by Dr. Sabin were not clean-cut. In 1948 he asked the National Foundation for support to pursue this matter further. I remem-

ber that I took a trip with Harry Weaver to Cincinnati and spent a whole day listening to Sabin and examining his protocols and monkeys. The work he had done was most intriguing, and Dr. Weaver and

I recommended that the Foundation let him go ahead. Unfortunately, in the end nothing came of this work. It later turned out that the interference was not as striking as we had hoped it might be; more

important, the drugs were on the boundary line of toxicity, and the ~ research was dropped. There is, however, no denying that the work was interesting. Dr. Sabin was thinking the way I and other virologists were thinking, namely, that anything that would make a cell abnor‘mal would protect that cell against viral infection. I still think that.

O: Dr. Rivers, if you examine the minutes of the conferences held by the National Foundation, you find that Dr. Sabin makes comments on a wide variety of subjects covering epidemiology, pathology,

biochemistry, pharmacology and the like. He. . .

Rivers: He was and is irrepressible, and he just loves to talk. God, he will talk at the drop of a hat. He also just loves to take a poke at the other fellow. But make no mistake, he is qualified to work in any number of fields. He has always been my idea of a splendid man for research, although it is true that from time to time I have roughed him up.

CHAPTER l 2

Active and Passive Immunization against

Pohomyelitis— 1949-1953 To witness with thine eyes what some perhaps Contented with report hear only in heav’n. John Milton, Paradise Lost

Q: Dr. Rivers, one of the most important breakthroughs in polio research occurred in 1949 when Dr. John Enders reported that he and two of his associates, Dr. ‘Thomas Weller and Dr. Fred Robbins, had successfully cultivated Lansing type poliovirus in nonnervous tissue.* When, for example, did the National Foundation begin to support Dr. Enders’ work?

Rivers: ‘That is a difficult thing to say because, as I remember, the first grant which supported Dr. Enders’ work was not directly made to

him. It was made to the Bacteriology Department of the Harvard Medical School and specifically to Howard J. Mueller, who was then serving as Chairman. As I indicated earlier, that department was originally Hans Zinsser’s baby and had long had a considerable reputation in bacteriological and virus research. It had many fine investigators and, during Zinsser’s tenure and later, had strong financial support from a wide variety of sources, including several private foundations, *J.F. Enders, T. H. Weller, and F.C. Robbins, “Cultivation of the Lansing strain of poliomyelitis virus in cultures of various human embryonic tissues,’ Science, vol. 109:85 (1949).

444

Immunization against Poliomyelitis—1949-1953 445 the state, and the national government. Actually it wasn’t until after World War II that Dr. Mueller first approached the National Foundation for a long-term grant to develop their virus studies. If you examine Dr. Mueller’s application, you will find that the Harvard group

was interested in exploring such problems as the relation of viruses to : host-cell metabolism and the cultivation of viruses by tissue-culture techniques. I think it is fair to say that, at that time, they were more interested in investigating mumps and influenza virus than _poliovirus. ‘The Foundation, of course, had no doubt that the investigations they had in mind could also be applied to polio research, and they got their grant. | remember that one of the things that impressed

me about the Harvard application was that almost half of their projected budget was set aside for animals and experimental supplies. In other applications at that time, it was more usual to find the major part of the budget allocated for salaries.

This was an unusual grant for still another reason. After the war, universities were beginning to discover that, when a member of their faculty received a large grant for scientific research, it did not necessarily follow that such a grant was a financial asset to the university. It was more likely to be a liability, since such grants rarely, if ever, made provision to cover the indirect costs incurred by the university

in administering grant funds. The National Foundation was one of the first philanthropic organizations to recognize this problem as a threat to the development of the research programs they were supporting, and when the Harvard application was being considered

Harry Weaver worked out a plan with Harvard President James Conant for the Foundation to give a special supplementary grant to Harvard to cover the indirect costs of administering the grant being

made to Dr. Mueller. This plan not only made it possible for Dr. Mueller to accept a grant from the Foundation; it also provided a new model for making research grants. Today, for example, other foundations as well as the government follow this system in making research grants. I was not intimate with John Enders during his early years at Harvard. At best, I think I may have met him several times, but I nevertheless knew a great deal about him, because Hans Zinsser, whom I did know well, always used to talk about him and tell me what great

446 Chapter 12 ability he had. Very few people in those early years were particularly burnt up about Enders, because he was a quiet person and published

modestly, but those who followed his work on panleucopenia, mumps, and vaccinia knew him, at the very least, to be a careful and

| ingenious investigator. I don’t remember the precise date, but sometime in 1946 Enders decided to leave the Department of Bacteriology at Harvard, and took a post as director of the Department of Infectious Diseases at the Children’s Hospital in Boston. I don’t know the inside story of that move, but I think that Enders had come to that point in his career where he wanted to devote his time to research and writing and to get out from under the teaching load he was carrying. In spite of his move, he continued to work under the terms of the grant originally made to Dr. Mueller and, if I remember correctly, devoted himself to such problems as isolating the etiologic agents of pleurodynia and chickenpox, searching for better methods of propagating viruses, and working on problems relating to vaccination against influenza. | mention this not only to show the kind of questions that were absorbing Enders in 1947 and 1948 but to demonstrate that he was not exclusively concerned with poliovirus at that time. I would go so far as to say that he wasn’t originally specifically concerned with growing poliovirus in tissue culture. If I am not mistaken, he first tried propagating mumps virus in a tissue-culture setup that he and Tom Weller had devised, and it was only after this work had been successful that he attempted to grow Lansing virus in a similar tissue-culture setup. I want to tell you that, when Enders’ early reports on this latter work

came into the Foundation, it was like hearing a cannon go off. O: Dr. Rivers, I wonder if you would take a moment here to detail the nature of Dr. Enders’ achievement.?

Rivers: Please bear in mind that, until 1949, most virologists believed that it was impossible to cultivate poliovirus in nonnervous tissue. I know that I believed that it couldn’t be done, and I certainly ? Dr. Enders notes that the work in his laboratory was a true collaboration with Dr. Thomas Weller and Dr. Frederick Robbins, and that it is a mistake for the interviewer and Dr. Rivers to convey the impression that the achievements that came out of his laboratory were his alone (private communication).

Immunization against Poliomyelitis—1949-1953 447 wasn't alone; in 1936 Dr. Olitsky and Dr. Sabin proved that it couldn’t be done. I watched that work and I believed it. There was, I

might add, no reason to disbelieve it. Dr. Enders’ achievement in 1949 lay in the fact that he and his coworkers proved the exact opposite when they successfully cultivated Lansing virus (a type 2 poliovi-

rus) in a modified Maitland tissue-culture setup containing nonnervous tissue taken from the skin, connective tissue, muscles, and intestines of human embryos. Now if that wasn’t shooting off a cannon, I don’t know what is. I'll tell you one thing, that report sure as

hell captured everybody’s attention. In the beginning Dr. Enders worked solely with Lansing virus. However, within a very brief period he succeeded in growing Brunhilde virus—a type | poliovirus—in a similar tissue-culture setup. Still

later he grew both viruses in tissue cultures consisting of human prepuces or foreskins. I see you are smiling; perhaps I should take a

minute to explain why Dr. Enders used foreskins in his cultures. Actually, it was difficult to get human tissues because there were just so many human embryos available, and doctors couldn’t go around cutting the skin off people unless they had good reason to do so. Fortunately, babies as well as young boys were being circumcised routinely in Boston hospitals, and Dr. Enders had the foresight to make use of a source of human tissue that in the normal course of events would have been thrown away. It wasn’t easy to use foreskins because they were not sterile and Dr. Enders had to go to a certain amount of trouble to utilize them in his tissue cultures. I would like to empha-

size here that most of Dr. Enders’ work propagating poliovirus in tissue cultures was done with human tissue. It took some years before virologists turned to animal tissues, and in particular monkey kidney tissues, for such work. Once it was discovered that poliovirus could be cultivated in such tissue, it was widely adopted. Monkey kidney tissue was not only more easily available than human tissue; it had the virtue of being free from bacteria, if the kidneys were removed asepti-

cally. It is, of course, true that on occasion virologists ran into monkeys that had TB, but most investigators who used monkeys were

aware of this problem and kept a sharp eye out for such infected ani- | mals. Still later, a number of investigators discovered that some monkey kidneys had simian viruses in them and this alerted polio

448 Chapter 12 workers to still another problem that had to be faced in using these tissues.

There can be little doubt that one of the first people at the National Foundation to recognize the implications of Enders’ work was Harry Weaver. Harry saw in Enders’ reports the first possibility of a practical solution to the problem of producing the large quantities of virus which would be necessary in carrying out a vaccination program. When the Foundation later publicized this hope in a number of news releases, Albert Sabin came down like a ton of bricks on the Foundation and Dr. Weaver. Dr. Sabin believed that such publicity at that time—1950—held out an unwarranted hope for an early vaccine. Fur-

thermore, he was still quite skeptical about the initial reports of Enders’ work. ‘here was good reason for such skepticism on Dr. Sabin’s part. As I mentioned earlier, he and Dr. Olitsky were unable to propagate the Rockefeller Institute’s MV poliovirus in nonnervous tissue: ‘That work was very carefully done, and Dr. Sabin had every right to have faith in it. What he didn’t know, and, of course, had no way of knowing, was that the MV virus had become neurotropic and

could not be cultivated in nonnervous tissue. It wasn’t until 1954 when he tried to reconcile his findings with Enders’ reports that he discovered that the MV virus had mutated and had become neurotropic because of its long passage in monkey brains.* Still later, when Dr. Sabin was seeking to attenuate certain polio strains for his livevirus vaccine using Dulbecco’s plaquing techniques, he once more discovered that on some occasions he would get a mutation that would be strictly neurotropic and would only grow on nervous tissue. I would like to add here that, although the Foundation gave strong and prompt support to Dr. Enders, nobody told him what to do, and he certainly did not restrict his research merely to looking for ways of increasing the yield of poliovirus from tissue cultures. As a matter of

fact, one of the interesting aspects of Dr. Enders’ research at that time was how rapidly and in how many directions it proliferated, and in particular how quickly he applied it to problems of isolation, titration, and typing of poliovirus. For example, within a year of reporting the growth of Lansing virus * A.B. Sabin, ““Noncytopathogenic variants of poliomyelitis viruses and resistance to superinfection in tissue cultures,” Science, vol. 120:357 (1954).

Immunization against Poliomyelitis—1949-1953 449 on nonnervous tissue, Dr. Enders successfully isolated a number of strains of poliovirus by inoculating stool material directly into his tissue cultures. On another occasion, and again very early in his research, he noticed, following the inoculation of his tissue cultures with Lansing virus that there was not only an impairment of tissue metabolism but that his virus-infected cells also failed to exhibit the customary cell migration of normal cells in plasma hanging-drop cultures. Using these phenomena as indices of infection, Enders was soon able to titrate virus samples directly in tissue cultures.

Perhaps one of the most significant early observations that Dr. Enders made was that both Lansing and Brunhilde viruses produced degenerative changes in tissue culture, and that such cytopathogenic effects could be inhibited by use of type-specific immune serum. By this observation, Dr. Enders in effect created a more rapid and certainly less expensive way of typing viruses than was then available. I cite this work, and, by the way, it was by no means the totality of Dr. Finders’ research at that time, to show that he was not exclusively concerned with such problems as increasing the yield of virus through tissue-culture techniques. I do not say that he didn’t work on this problem. He did, and I might add, most successfully. ‘The point I want to make is that he very quickly exploited the implications of his original research. Nobody told him. It came about because he followed his nose or put another way, because he pursued his own imagination and curiosity.

Q: Dr. Rivers, how quickly did other virologists adopt Dr. Enders’ tissue-culture techniques for typing and titering poliovirus?

Rivers: In some instances almost immediately, and I don’t think that one should be too surprised at such a development. ‘Take the problem of typing poliovirus. Up until about 1950, all typing—except

in the case of type 2 poliovirus—had to be done in monkeys. Now, when you begin to do neutralization tests in monkeys and have to use six or more monkeys for each test, the expense very quickly mounts. The tests moreover take some time. It didn’t take virologists long to realize that tissue cultures would permit them to do such tests rapidly

and at a reasonable price. Perhaps the expense of using monkeys

450 Chapter 12 made them realize this sooner than they might have in ordinary cir-

cumstances. Now that I have made that point I should in fairness point out that not all virologists adopted Dr. Enders’ tissue-culture techniques with equal fervor or rapidity. Strangely enough, one of the best laboratories in the country was the slowest to take hold and that was Dr. Bodian and Dr. Howe's laboratory at Johns Hopkins. I have

never been able to quite figure out why they hesitated, but they did delay for almost a year. I know that Harry Weaver remonstrated with them about it, but he never made much headway. Finally, after just

about everybody had adopted tissue cultures, Bodian and Howe joined the parade, but they were a little bit behind the crowd and it took them a while to catch up.

Q: Dr. Rivers, you mentioned the usefulness of Dr. Enders’ tissueculture work for typing polioviruses. Could you tell me what effect this had on the rather long search for more efficient in vitro diagnostic

tests for poliomyelitis?

Rivers: It didn’t stop the search for such tests, if that’s what you mean and, as far as I know, investigators went nght ahead trying to devise flocculation and complement-fixation tests for polio. You must remember that, for a long time, the only methods available to investgators for identifying and differentiating polioviruses from each other and from other viruses were expensive and laborious. For instance, in the old days if you wanted to identify a poliovirus, you would take a monkey which was known, let us say, to have recovered from a Lan-

sing type infection, and you would inoculate it with the virus you wished to identify. If the monkey came down following inoculation, you concluded that the virus was different from the one which caused its original infection. If it didn’t come down, you concluded that the viruses were alike. Another method was to take serum from a known immune monkey, mix it with the virus you wanted to identify, and _ then inoculate the mixture into a susceptible monkey. If the monkey did not come down, you assumed that the serum you mixed with the

virus had neutralized it and made it harmless. If the monkey did come down, you prepared to test the virus with a half a dozen other preparations of immune sera and monkeys until you discovered an

Immunization against Poliomyelitis—1949-1953 451 immune serum that neutralized your virus. No matter which method you used, you needed a great deal of patience and a great many monkeys.

It was this state of affairs which encouraged the search for a good in

vitro diagnostic test for poliomyelitis. I think that many virologists were excited by the possibilities of using John Enders’ tissue-culture techniques for such testing, but it didn’t necessarily follow that if they had been searching for an in vitro diagnostic test they would drop their own work because Dr. Enders had a promising lead. They kept on with what they were doing. For years, Dr. Eugene Roberts at the Hooper Foundation tried to get a good flocculation test for polio. He tried and tried and tried. I remember that in 1950, just about the time that John Enders was developing his own work. Dr. Roberts had

developed an extraordinarily complicated procedure for preparing antigens so he could get certain specific precipitin reactions. Initially, I think he got some positive reactions, but then the work petered out.

I don’t know how many workers over the years tried to devise a complement-fixation test for polio. ‘They also tried and failed, but in

1950 Jordi Casals and Peter Olitsky at the Rockefeller Institute finally did develop a very successful complement-fixation test for type

2 and 3 poliovirus.* ‘That work, by the way, was most ingenious. While working with various neurotropic viruses in Olitsky’s laboratory, Casals had noticed that, if such viruses were propagated in the central nervous system of infant mice, they yielded complementhxation antigens with a higher titer than those usually found in preparations made from the tissues of adult mice. Lansing virus (a type 2 poliovirus), as you know, is the only type which will go in mice. Casals and Olitsky soon discovered, as others had before them, notably Dr. Albert Sabin and Dr. Gilbert Dalldorf, that poliovirus unlike other viruses was nonpathogenic for infant mice, although it was disease-producing in adult mice. Fortunately, this didn’t faze them, and with a great deal of patience they thereupon undertook to adapt in newborn mice the MEF" (type 2) poliovirus that Dr. Olitsky and his associates had previously isolated from tissues which I had given “For an early report and discussion of this work, see Round-Table Conference on a Complement-Fixation Test for the Detection of Poliomyelitis Infection. Rockefeller Institute for Medical Research, New York, April 16, 1951.

452 Chapter 12 him during World War II. By repeated passages from a newborn mouse to a newborn mouse by intracerebral inoculation of brain tissue, they finally succeeded and obtained the antigen with high titer that they were looking for. By doing this, Dr. Casals and Dr. Olitsky in effect gave virologists the one component necessary for a practical complement-fixation test. Complement, as you know, is a substance that is found in all ani-

mal bloods which, when united with a specific antibody, has the capacity to lyse cells. If you took the antigen that Casals got from newborn mice and mixed it with an unknown immune serum and complement, two things might happen. First, if the immune serum was related to the antigen, they would unite and, in the process of uniting, would engage or fix the complement. However, if the antigen

and immune serum had no relation to each other, the complement would remain unengaged. If you later added to your mixture of antigen, Immune serum, and complement, some sheep cells and an antibody against sheep cells, you would find that in the first instance your sheep cells would not be hemolyzed. However, in the second

instance, where your complement was not engaged, your complement would react with the antibody against sheep cells and hemolyze them. I realize that all of this sounds very complex to you, but actually it was a very simple test and proved to be very helpful in identifying type 2 polio. I should add here that today complement-fixation tests

are used very rarely if at all in routine identification tests for poliomyelitis. Virologists rely more on neutralization tests in tissue cultures. They are much cheaper and less time-consuming than com-

| plement fixation tests and, of course, work for all three types of polio as well as ECHOs and Coxsackies. The only time you turn to complement-fixation tests is if there is an absence of cytopathogenic effects in the tissue culture. Then you are kind-of up against it, but

such occurrences are rare. If you think from what I have said that Casals’ and Olitsky’s work on complement fixation was wasted, you would be dead wrong. In recent years the complement-fixation test

has become quite important in identifying many of the new queer arbor viruses that are turning up throughout the world. In many instances, it is the only way we have of identifying them. Casals, by the way, has made this new field in virology his very own.

Immunization against Poliomyelitis—1949-1953 453 Q: Dr. Rivers, when the National Foundation began its typing program in 1948, it appointed a special committee to meet and discuss the various problems that emerged as a result of this program. Many distinguished virologists served on this typing committee among them Dr. Bodian, Dr. Sabin, Dr. Salk, Dr. Francis, and others. Oddly enough, I don’t find your name on this committee, although you served on practically every other committee organized by the Founda_ tion on problems of immunization.°

Rivers: ‘The answer to your question is simple. I just didn’t let myself be drafted for this committee, because I looked upon their work as being of a routine nature. I don’t mean by that that their work was unimportant; on the contrary, they performed a valuable and necessary function. Basically, they had to find ways of getting virologists to do their typing and other tests in a standard way, so that the results of one laboratory could be compared with the results of other laboratories. I just didn’t see the necessity of my being on such a committee. Actually, I can give you one good reason why it was better that I was off of it. I have never been to any medical meeting where I didn’t ask at least one or two irritating questions. ‘The truth is, I might have slowed up this committee in its work by asking such questions, and instead of getting the boys to work together I probably would have driven them apart. The main purpose of the meetings held by this committee was to find ways of getting the boys to work together.

O: Dr. Rivers, if one of the results of the typing program was the establishment of three basic immunologic types of poliovirus, certainly another result was a movement toward standardization— standardization of tissue culture methods, standardization on preparing prototype pools of viruses and prototype pools of antisera. How did virologists react toward this drive for standardization?

Rivers: If you mean did they like it, I can tell you that a large proportion of them didn’t. You must remember that research people are always a little bit peculiar. They are that way or they wouldn't be re| >The Typing Committee was organized on July 10, 1948, and had as members the following physicians: Charles Armstrong, David Bodian, Thomas Francis, Jr., Louis Gebhardt, John Kessel, Charles F. Pait, Albert Sabin, Jonas Salk, and Herbert Wenner.

454 Chapter 12 search people. ‘Their very life is dedicated to looking for new things or

things to be done differently from the way they have been done previously. They are by their nature rebels against tradition or standardization. ‘They were this way a century ago, 50 years ago, 25 years ago, and still are today. Now, if you need to compare the work done in one laboratory with the work done in another laboratory, and have that comparison have any meaning, you have just got to have some kind of standardization. It is a proposition that seems logical and clear on its face, but I want to tell you that it was and still is difficult to get across to researchers immersed in their work. ‘They resent anybody coming into their laboratories telling them how to do their stuff. ‘This was one

of the key problems that the Committee on Typing and later the Committee on Standardization had to face. I don’t believe that it ever became a very critical problem, but it sure as hell was an irritating one. ‘There were a great many arguments; however, if you look at the record, I think that you will find that in the end the committees were very successful in getting the boys to work together the same

way. They might not have been as successful if I had served with them.

O: Dr. Rivers, with the development of tissue-culture techniques and the new complement-fixation tests, did a need arise for specially trained laboratory technicians? Where, for example, did laboratories get technicians to do tissue-culture work? Was there any competition for such help?

Rivers: Most laboratory technicians are trained in the laboratories in which they work. In my own laboratory I always had two kinds of technicians. The first were generally men with at least a high school

education, who took care of my animals and did the heavy work which is sometimes required in a laboratory. ‘he second were welleducated young ladies from either Smith College or Vassar, with a bachelor’s degree in science, who had some knowledge of biology and

chemistry and knew their way around a laboratory. I'll admit that at the Rockefeller Institute I never had any great difhculty recruiting such personnel, and that it probably was more difficult for a laboratory in a small college or the government to get technicians of like ability and background. As far as I know, the problem of getting well-

Immunization against Poliomyelitis—1949-1953 455 trained technicians for polio research did not become acute until we began to make efforts at standardizing laboratory procedures in the early fifties. I remember that at one of the Immunization Committee meetings held by the Foundation Joe Smadel made a statement that reflected that difficulty. I would like to quote it in part here. I see no reason in the world why one should use the same kind of test for all three strains of virus.

[ am thoroughly in favor of going over to tissue-culture method for the Brunhilde type and the Leon type, but with all due respect for the great advance which has been made in the tissue-culture neutralization technique, I certainly would not employ it if I could do a good simple mouse neutralization test. Any person can do the mouse neutralization. You have to have

a well trained technician to do the tissue-culture work, so that I would think it is important to go ahead and get down a good common neutralization test which employs certain simple materials, simple animals that can be accepted as a reasonably good standard test for such work, as has been talked about. . . . The way to get a technique that is going to stand up is to start with a good technique that works well in one laboratory, then agree on certain modifications of that, and then give it to the young people who will work with it for awhile. After about a year, when you have found out all the mistakes that they make, then you have a real test: one that you can give to a PFC in the Army, and with one sergeant looking after him, you can get results of value, and I think that is what you want from this Lansing test—something like that.®

Joe certainly had a point. Any technician can do a mouse-neutralization test. ‘Tissue-culture work always required a well-trained technician—I was even about to add a woman technician. Some women | know would just about jump down my throat for what I am about to say, but I will say it anyway. It’s been my experience that women are

better at tissue-culture work than men are. I think that it’s for the same reason that women are better at taking care of a house or cooking. ‘he truth is that women seem to be willing to do the same thing over every day. Men are not. Tissue-culture work, by God, can get to be pretty dismal, because you have to do the same God-damned thing over and over again, day after day. Unless you do it that way, your results just don’t stand up. You have got to be patient, and it’s been my experience that women have that quality more frequently than men. * Proceedings of the Committee on Immunization, New York, December 4, 1951, pp. 16-17 (National Foundation Archives).

456 Chapter 12 Q: Dr. Rivers, following the work of Dr. Enders and his associates in 1949 polio research developed at such a rapid pace that, in a period of approximately two years, the unspoken wish of 1949 to take steps

to make a vaccine against polio becomes the stated subject of a round-table conference called by the National Foundation in March 1951, at Hershey, Pennsylvania. To refresh your memory of the purposes of this conference, I would like to quote some of the introductory remarks made by Dr. Kenneth Maxcy, who served as chaitrman. This conference is an expression of our mutual interest in poliomyelitis, which goes back many years. As each year has passed, we have approached

more and more closely to our ultimate goal, the prevention of paralytic poliomyelitis. As our knowledge of the epidemiology of the disease has developed, it has become increasingly apparent that there is no expectation of

being able to prevent human exposure to the virus. Even the attempts to postpone exposure may be misdirected.

There is some reason to believe that exposure in early infancy is less likely to be followed by paralysis than exposure in the latter part of in-

fancy or during childhood. There is also some reason to believe that paralytic attacks are somewhat more severe in adults than in children. For the present, therefore, it would seem that efforts directed toward reducing or postponing exposure are not promising. If we grant that exposure to this virus is inevitable at some time during life, then our objective is to provide means whereby every individual may acquire immunity through subclinical infection or antigenic experience without the risk of paralysis and death.

As our knowledge of the immunity mechanism of poliomyelitis has grown during recent years, it begins to appear that this objective is feasible. Experimental work on animals has suggested that any one of a number of procedures might be effectively utilized to this end. The possibilities presented are, briefly, inoculation of infants with poliomyelitis virus inactivated by some method with or without adjuvant, with or without gamma globulin; or with active virus as an avirulent strain or mutant of good antigenic potency, administered by mouth or peripherally, with or without adjuvant, under the protection of passive immunity confirmed by gamma globulin; or by passive immunization with gamma globulin during an epidemic period, when natural exposure to infection is frequent. Variations of these procedures could be amplified.

The time is fast approaching when important questions must be answered; sooner or later the answers to some of these questions can be obtained only through observations on human beings.

Immunization against Poliomyelitis—1949-1953 457 The purpose of this conference is to obtain a group judgment as to important considerations in this respect. Are we justified, on the basis of present-day knowledge, in undertaking limited and well defined experiments on human beings? If not, what further knowledge is needed before undertaking such experiments? *

It is apparent from Dr. Maxcy’s remarks that both methods of active immunization—using inactivated vaccines and_live-virus vaccines—and passive immunization were at that time under consideration by virologists. I would like to turn here to a consideration of some of the problems that existed in regard to active immunization in the spring of 1951.

Rivers: What I am going to say will be somewhat repetitious, but please bear with me. By 1951 Dr. Isabel Morgan had demonstrated beyond a shadow of a doubt that she had been able to immunize rhesus monkeys with formalin-inactivated viruses of all three basic immunologic types to a point where it was impossible to bring down such animals by the most sensitive routes. I need hardly repeat that, up until the time she did her work, most virologists believed that you couldn’t immunize against poliomyelitis with a formalin-inactivated poliovirus. She converted us and that was quite a feat. Isabel, bless her soul, very cautiously refused to say that, because she got such results with monkeys, it could be taken that she would get equally good results with humans. As a matter of fact, she reminded one and all that it was almost impossible to translate her results quantitatively for human use. Now, that is a rule that an experimenter might well keep

in mind, namely, if you want to find what something will do in human beings, you ultimately have to do the test in human beings. You can only go just so far with animal tests alone. In 1950 Howard Howe extended some of Isabel Morgan’s original

observations when he tried to immunize chimpanzees and monkeys with both formalinized inactivated vaccines and live-virus vaccines against all three types of polio. He soon discovered that, while those animals which received formalinized inactivated vaccine could not be prevented from having an alimentary infection and putting out virus in their stools, they nevertheless resisted paralysis upon intracerebral 7 Proceedings of Round-Table Conference on Immunization in Poliomyelitis, Hershey, Pennsylvania, March 15-17, 1951, p. 1.

458 Chapter 12 and oral challenge. Even more interesting were his observations that the antibody responses to all three poliovirus types were within satisfactory limits, and that adjuvants were able to stimulate antibody responses to even very small amounts of formalin-treated material. Although Dr. Howe was aware at the time that little was known about the relative sensitivity of chimpanzees and humans, he thought that

the chimpanzees’ reactions were within a range where it might be feasible to administer formalinized material to children. About a year later, he inoculated between six and a dozen mentally defective children in a Maryland home with formalin-inactivated vaccines and was able to show that the children did develop antibodies against all three polio types. It was an important finding, but no one was in a hurry to give Dr. Howe’s vaccines to all of the children in the United States and for a very good reason—they were made of monkey cord material.®

O: Dr. Rivers, I have a host of questions to ask. How did virologists in 1951 know when an inactivated virus was truly inactive?

Rivers: ‘Today, if you want to know whether a virus is inactivated, you test it in tissue culture. In 1951 if you wanted to know, you tested it by an intracerebral challenge in monkeys. ‘There were, however, a

number of pitfalls in this method. I remember that Dr. Hubert Loring, of the University of California, once inactivated some poliovi-

rus with formalin and found that when he used this material in a dilute state that his monkeys were able to resist an intracerebral challenge. Later he concentrated this same material in an ultracentrifuge and, upon intracerebral challenge, all of his monkeys were brought down. It is plain that his original so-called inactivated virus must have contained some live virus particles. There were still other pitfalls. Because some animals varied in their

susceptibility to poliovirus, a virus that would be inactive in one species might very well be active in another species. ‘hen again, some animals required much larger doses of virus to be brought down than ®H.A. Howe, D. Bodian, and I.M. Morgan, “Subclinical poliomyelitis in the chimpanzee and its relation to alimentary reinfection,” Amer. J. Hyg., vol. 51:85 (1950); H. A. Howe, “Antibody response of chimpanzees and human beings to formalin-inactivated trivalent poliomyelitis vaccine,’ Amer. J. Hyg., vol. 56:265 (1952).

Immunization against Poliomyelitis—1949-1953 459 others, and in such cases a small amount of active virus particles might be present and still have no untoward effect on the test animal. In another test animal, such a small amount of live virus might well cause a paralysis. ‘he point I want to make is that the terms “active” or “inactivated” virus in 1951 was only meaningful in relation to the animal in which it was tested and the manner in which the test was

done. Put another way, if in 1951 you had told me that you were using an inactivated virus in immunizing human beings, you would

have had to convince me that the virus was inactivated as’ far as human beings were concerned.

Q: Dr. Rivers, an examination of some of the papers presented at this round-table conference indicates that not all investigators were addicted to using formalin in inactivating viruses. For example, Dr. George W. A. Dick, then at Johns Hopkins University, tried preparing vaccines with viruses that had been inactivated by ultraviolet radiation or by ultrashort high-speed electron bombardment. He found that the antigenic effectiveness of viruses inactivated by these means compared favorably with those inactivated by formalin. You may remember that I raised this same issue earlier in the context of

the work done by Dr. Albert Milzer and Dr. Sidney Levinson of Chicago.°

Rivers: I will admit that in 1951, and even earlier, virologists were agreed that one could inactivate polioviruses by irradiation or by ultra

short high-speed electron bombardment using a capacitron. Some virologists, like Dr. Carleton Schwerdt, of the virus laboratories at the

University of California, even tried inactivating polioviruses with nitrogen and sulfur mustards. However, most polio workers were of the belief that they could test for inactivation more reliably if the virus was inactivated by formalin, because formalin had been used more frequently in the past in inactivating viruses and, therefore, they had that much more experience to draw upon. ‘This attitude was not

necessarily a mark against using irradiation or other techniques in inactivation. It simply meant that, when virologists were faced with the necessity of making up their minds about using something that in

the long-run would be a key factor in the production of a vaccine

* Proceedings of Round-Table Conference, op. cit., pp. 12-16.

460 Chapter 12 (that was going to be used on a very large number of humans), they chose to rely on experience. You might even say that they were being cautious.

QO: Dr. Rivers, during the course of a subsequent discussion on the inactivation of polioviruses at this conference Dr. Joseph Smadel made the following observation: . . . LT would still like someone to get an answer to the simple question of how many virus particles it takes to produce obvious disease. If you told

me that it took one, ten, or a hundred, then I would say that there is just no point in fooling around with the present material that you have as an inactive vaccine. If you told me that it took a hundred thousand or a million, then I would say that we are on the right track.’°

Rivers: When Dr. Smadel made that point he was simply raising a question of the margin of safety in making an inactivated vaccine. He had every right to make it. Back in the thirties, when he and Dr. Bob

Parker worked in my laboratory on vaccinia virus, they discovered that probably one purified elementary body vaccinia, if placed in contact with a susceptible cell in the skin of a rabbit, would infect that rabbit. You might say that Dr. Smadel had a special appreciation of what could be done quantitatively in determining the size of a dose necessary to infect. If one particle of poliovirus would cause disease in a human, and in the process of inactivation a particle or two of poliovirus escaped inactivation, such particles in an otherwise inactivated

vaccine given to a human being would bring him down. If, on the other hand, it took 150,000 or 300,000 particles of poliovirus to bring

a person down, one or two particles that escaped inactivation were not going to be very dangerous.

O: Dr. Rivers, did virologists in 1951 know how many particles of poliovirus would bring down an animal?

Rivers: I am not sure that, when Dr. Smadel made his remarks, virologists actually knew very accurately how many particles of poliovirus would bring an animal down. ‘They could say that a tenth of acc ora thousandth of acc of a particular mixture of poliovirus would

" Ibid. p. 37. |

Immunization against Poliomyelitis—1949-1953 461 bring down 50 per cent of their monkeys in a given experiment. But they could not tell you how many particles were actually contained in a tenth or a thousandth of a cc. A short time after Joe made his remarks, the development of plaquing techniques by Renato Dulbecco and his associates at the California Institute of Technology made it possible to count particles in tissue cultures. Dr. Dulbecco discovered that the highly destructive activity of poliovirus in cultures of monkey

epithelial cells made little plaques in the culture, similar to those made by phage in bacterial cultures. ‘Through dilution experiments, he soon estimated that each plaque was made by a single virus particle.* It was only after Dr. Dulbecco’s work that it actually became possible for virologists to say with any degree of accuracy how many particles in a particular mixture of poliovirus would bring down their monkeys.

QO: Dr. Rivers, one of the interesting features of the Immunization Conference of March 1951 was that it was not solely concerned with inactivated vaccines. At least one paper, that given by Dr. Hilary Koprowski, devoted itself to the problems of live-virus vaccines.

While the paper itself dealt in detail with rabies vaccines, Dr. Koprowski also spoke later of developing an attenuated nonpathogenic strain of poliovirus useful for immunization purposes.” After that presentation Dr. Howard Howe made the following comment: Dr. Koprowski has already started the ball off at a terrific clip with his

presentation this morning, but I am going to have to take a position which | is different from his in that I do not myself feel that active virus is the answer to our problem. J am expressing my opinion at this point, and I hope

that others will feel free to express theirs as well. . . . It is very hard to show that it provides the extra margin of safety, which I think we must try to insure for all those who are being immunized against this disease. Natural exposure is producing immunity with a paralytic penalty of roughly one in a hundred, or one in a thousand infections, so that the vaccine has to be

pretty safe in order to beat that. . . . It is my feeling that active virus, “ R. Dulbecco, “Production of plaques in monolayer tissue cultures by single particles of an animal virus,” Proc. Natl. Acad. Sci., vol. 38:747—752 (1952). * The first of Dr. Koprowski’s papers was titled “Immunization with modified living virus as exemplified by rabies,” the second was called, “‘A preliminary report on feeding of children with live attenuated polio virus.” See Proceedings of Round-Table Conference, op. cit., pp. 87-98, 155—160.

462 Chapter 12 even though it were possible to produce mutants of all three types which are now known, would be very difficult to justify on a large scale. For that reason, we have put most of our effort in trying to evaluate the results of vaccination with inactivated virus. I think that it is clear now, beyond any doubt that it is possible to immunize animals effectively with inactivated virus preparations.12

How typical was Dr. Howe’s attitude on inactivated versus live-virus vaccines in 1951?

Rivers: I don’t know how typical Dr. Howe’s attitude was, but I do know that he was not the only virologist who thought that way. In 1951 quite a number of virologists, including myself, thought that the first effective vaccine against polio would be an inactivated vaccine. This does not mean that I or anybody else ruled out the possibility of a live-virus vaccine; after all, our experience with smallpox and yellow

fever vaccines certainly pointed in that direction. But in 195] it seemed to me and others that the quickest and safest way we were going to get a vaccine against polio would be to concentrate our efforts on developing an inactivated vaccine. It was not a unanimous opinion by any means. Some virologists believed that the antigenic power of polioviruses was affected when they were inactivated with formalin, while others thought that the immunity obtained by such inactivated vaccines would be too short-lived to be of any real use. Actually, in 1951 and in the years immediately following, there were any number of virologists who devoted themselves to developing a livevirus vaccine against polio. Herald Cox and Hilary Koprowski and 8 Ibid., pp. 222-224. The interviewer must add here that Dr. Koprowski’s second paper had a marked effect on all those present and in particular Dr. Howe. It is noteworthy that the excerpt of Dr. Howe’s remarks quoted in the interviewer's question ends in these words:

I am tremendously interested in Dr. Koprowski’s report of this morning because, in feeding a Lansing-type virus to his unusual group of experimental subjects, he got roughly the same levels of antibody that we have obtained in feeding either the Lansing or the Wallingford strains to chimpanzees, all of which suggests, then, that the human is certainly not Iess—or shall I put it this way—that the human is at least as sensitive a reactor to the poliomyelitis antigen as is the chimpanzee. I think we have also had a little suggestion here at this meeting that as one climbs the ladder of the susceptible animals from the mouse to the rat to the monkey to the chimpanzee, the degree or the facility of antigenic response increases, and that we could expect that the response of man would certainly not be any less than the last of these. I think that Dr. Koprowski’s data are extremely valuable in giving us a bridge

which up to now we have not really had.

Immunization against Poliomyelitis—1949-1953 463 their associates at the Lederle Laboratories in Pearl River, New York,

were certainly among the first to take an active role in developing such an approach. I hesitate to call them the first, because I think that Max Theiler deserves a lot of credit for pointing the way. I have reference here not only to his work in developing a successful livevirus vaccine against yellow fever, but also to his work in developing

an attenuated strain of Lansing virus that successfully immunized monkeys against type 2 polio. A lot of people have forgotten about that work, but I think that it is a good thing to remember it. . Another virologist who worked on the development of a live-virus vaccine against polio was Herbert Wenner of the University of Kansas. As early as the spring of 1952, Dr. Wenner asked the National Foundation for a grant to study the effects of certain attenuated strains of types 1, 2, and 3 polio in human volunteers. As I] mentioned earlier, Dr. Wenner was trained under John Paul at Yale and from 1948 played an important role in the Foundation’s polio typing program along with Jonas Salk, John Kessel, and Louis Gebhardt. He is a quiet, modest individual who doesn’t startle you in conversation; but let me tell you, when he reports a piece of work it generally stands “ There can be little doubt that Dr. Max Theiler was the first to immunize monkeys with an attenuated variant of Lansing type 2 poliovirus, as Rivers says above. ‘There is, however, no evidence that Dr. Theiler ever extended those preliminary experiments to man. The first scientist to report the successful immunization of man against poliomyelitis with a live-virus vaccine was Dr. Hilary Koprowski, then at the Lederle Laboratories, and now director of the Wistar Institute. ‘That work began in 1947 when Dr. Koprowski and two of his associates, Dr. T’. W. Norton and Dr. W. McDermott, isolated a type 2 poliovirus from the blood of a poliomyelitis patient through inoculation of mice. ‘This later gave them the idea of using mouse-adapted virus as a source of an attenuated agent for men. On February 27, 1950, after working out safety tests in monkeys, Koprowski inoculated a six-year-old boy with a live, attenuated type 2 virus. Within the next year, 19 more children were fed the same virus. On March 15, 1951, Koprowski made the first semipublic disclosure of the successful immunization of these children at a meeting On immunization against poliomyelitis at Hershey, Pennsylvania, that was organized by the National Foundation. The first printed account of Dr. Koprowski’s work with a live-virus vaccine did not appear before January 1952. See H. Koprowski, T. W. Norton, and W. McDermott, “Isolation of poliomyelitis virus from human serum by direct in-

oculation into a laboratory mouse.” Public Health Rept., vol. 62:1467 (1947); H. Koprowski, ‘T. W. Norton, and G.A. Jervis, “Studies on rodent-adapted poliomyelitis virus. I. Cerebral resistance induced in the rhesus monkey,” presented at the 51st General Meeting of the Society of American Bacteriologists, Chicago, May 1951; abstract in Bacteriol. Proc. 1951, p. 92; H. Koprowski, G. A. Jervis and T. W. Norton, “Immune responses in human volunteers upon oral administration of a rodent-adapted strain of poliomyelitis virus.” Amer. J. Hyg., vol. 55:109 (1952).

464 Chapter 12 up. In other words, he is a first-rate investigator. It should come as no surprise when I tell you that, when his application initially came be-

fore the Virus Research Committee at the Foundation, it was approved. A short time later, however, the Foundation’s special Immunization Committee became skeptical of the nonpathogenic qualities of his strains, and support for that work was withdrawn. Dr. Wenner was undoubtedly disappointed by this action, but he wisely

accepted it. A year later he got some new attenuated strains of poliovirus that John Enders had developed in tissue culture at Harvard. ‘These were of excellent nonpathogenic quality, and the Foundation very quickly reactivated Wenner’s original grant in this area. From that date to this a portion of Wenner’s work has been devoted to the development of attenuated strains of poliovirus suitable for a live-virus vaccine.

Another laboratory which early devoted itself to the development of a live-virus vaccine was that of Dr. Albert Sabin. Unfortunately, | can’t pinpoint the exact date when Dr. Sabin began to think about the possibilities of a live-virus vaccine against polio. He has always, for example, been a friend of Max Theiler’s, and he certainly didn’t need

anyone to tell him about the implication of Max’s work for such a vaccine. Nobody, for that matter, has ever had to draw Albert a picture of the implications of any virus research. He has always had a mind and imagination of his own. While Dr. ‘Theiler’s work may have

prodded him to think along the lines of live-virus vaccine, I think in the final analysis, it was his own research with the cynomolgous mon-

key which prompted him to investigate the possibilities of oral immunization with modified strains of active poliovirus. I believe that he was fortified in this approach by two important observations. First, he had observed that, when poliovirus was grown in nonnervous human tissue, it showed a decreased pathogenicity for the central nervous system of monkeys. ‘This led him to believe that, by propagating poliovirus in various nonnervous tissues of monkeys, it might be possible to develop strains of poliovirus with different pathogenic quallities. Second, and perhaps equally important, he had observed that not all polioviruses with a high intracerebral pathogenicity were capable

of producing a paralysis or an inapparent infection when given to cynomolgous monkeys orally. As I say, I can’t pinpoint the date when

Immunization against Poliomyelitis—1949-1953 465 he began to think along these lines. I do know, however, that he didn’t ask the National Foundation to support his experiments with live-virus vaccines before the summer of 1952.

QO: Dr. Rivers, I wonder if you would take a moment here to tell me something of Dr. Koprowski’s early work with live-virus vaccines.

Rivers: Again, I am afraid that I can’t tell you when Dr. Koprowski actually began his work with live-virus vaccines. I only know of that work which began when he received some monkey cord containing a strain of Brockman poliovirus from John Kessel’s laboratory in Callifornia. Koprowski took this strain and, with the aid of some of his associates at the Lederle Laboratories, attempted to adapt it to mice and cotton rats. After a number of passages through the brains of cotton rats, Koprowski isolated a strain which, when inoculated intracerebrally into monkeys, seemed to be devoid of pathogenic qualities. He called this mutant strain ‘I'N. It was a most interesting strain: not only did it have nonpathogenic qualities, but upon immunological testing it also turned out to be a Lansing type 2 variant. The Brockman strain is a type 1 polio. Well, I can’t blame Koprowski for that mixup; in all probability, the strain originally got mixed up in Dr. Kessel’s laboratory. The important thing to keep in mind is that the strain was nonpathogenic and was a type 2 variant. A short time later Koprowski gave the TN strain orally to chimpanzees, and when they didn’t come down and showed a good titer of antibodies in the blood,

he and some of his associates were encouraged to test the strain on themselves. I don’t know how many people at the Lederle Laboratories actually took the strain, but again, when nobody came down and when it turned out that they too had antibodies in the blood, Koprowski wrote to the New York State Department of Health for permission to test the effectiveness of his mutant strain on some mentally defective children in a home in upstate New York.

The State Department of Health wrote me and asked what I thought of doing such a test, and I wrote back and told them I was

opposed to it. First, I didn’t think that the safety tests that Dr. Koprowski had done were anything to write home about, and, second, I personally did not approve of using mentally detective children for

466 Chapter 12 such a test. To be sure, other scientists had used mentally defective children for similar tests with inactivated vaccines, and what Koprowski wanted to do was not unusual—you might even say that it was standard practice. Well, I didn’t give a damn about what other scientists did. I would like to make it clear that my attitude had nothing to do with Koprowski. I had such an attitude long before the question of testing inactivated or live-virus polio vaccines ever came up.” For instance, about 20 years ago, some people at the Public Health Research Institute of New York wanted to test what was then a new typhus vaccine on some mentally defective children in Letchworth Village, and they found me bitterly opposed, and I use the word bitterly advisedly.

I think that if someone wants to use adults as volunteers to try out a new drug or vaccine, that is perfectly all right, provided that the

adult has been told about the nature of the disease he is exposing himself to, has been completely informed about the nature of the * Dr. Koprowski makes the following comments on Rivers’ account: Dr. Rivers presents a confused picture of the facts. He cannot be blamed for it because he had very little to do with the group which originally discovered the live-virus vaccine and therefore did not have the facts in hand. After they had fed the live virus to chimpanzees, Koprowski, Norton, and Jervis administered it to twenty children who had no antibodies against the type 2 strain. It was senseless to feed the virus to people with antibodies against type 2, since the results would be of very little value as far as the effectiveness of a vaccine immunization procedure was concerned. Therefore, only two or three people at the Lederle Laboratories actually took the strain after the first study was completed. It was only after the safety and effectiveness of the immunization pro-

cedure was established in a preliminary trial in twenty children that the New York State Department of Health was approached for permission to undertake trials in a state institute for the mentally defective. Officials of the New York State Department of Health advised that a visit to Dr. Rivers might expedite matters. During this visit, Dr. Rivers was generally enthusiastic about the original work which by then had already been reported at the Hershey conference, and he admired the courage of those who were able to take the first step in the right direction. He voiced no opposition to a new trial to be conducted in an institution for mentally defective children, and gave the general impression that he would support this trial wholeheartedly. It is impossible to know what he actually wrote to the officials of the New York State Department of Health, but the negotiations dragged on for such a long period of time that, following a meeting with Dr. Joseph Smadel and Dr. Karl Meyer at the Barbizon Plaza Hotel on January 26, 1952, live-virus vaccine trials were continued not in New York but in California (private communication). Ep. NoTE: For a report on Dr. Koprowski’s test in California, see H. Koprowski, G. A. Jervis, T. W. Norton, and D.J. Nelson, “Further studies on oral administration of living poliomyelitis virus to human subjects,” Proc. Soc. Exptl. Biol. Med., vol. 82:277— 280 (1953).

Immunization against Poliomyelitis—1949-1953 467 agent he is to receive, and has been told the chances for success or failure. If you examine human volunteers, I think that you will find that they generally fall into two classes: they are either prisoners in some state or federal institution, or they are scientists. I don’t even know that you can actually call a prisoner a volunteer. I believe that, although prisoners are usually told that they will get nothing out of volunteering aS guinea pigs, deep down they believe that they may . get a commutation or reduction of their sentence. ‘That’s perfectly all right; the point is, prisoners are generally adults who can weigh the pros and cons of submitting to a test, and if they arrive at a decision to participate in a test, it’s a decision or judgment that they have made. It’s not made for them. Scientists in their research generally try out material on themselves before they give it to other human beings. On at least two occasions I and people who worked with me in my laboratory took experimental

inoculations of material we were working with. About thirty years ago, Bill ‘Tillett and I took a cc of testicular emulsion from a rabbit that was infected with Virus III to see if human beings were suscepti-

ble to the virus. We thought that it was chickenpox virus. Fortunately, we never showed any ill effects from having taken that very sizable dose of Virus III. Bill ‘Tillett and I were doctors, we knew what we were doing; he didn’t have to do it unless he wanted to, and neither did I. ‘The same thing later held true when I and some of my associates took psittacosis virus for purposes of immunization. Again, we knew the nature of the disease, and we had a pretty good idea of the chances of success or failure. An adult can do what he wants, but the same does not hold true for a mentally defective child. Many of these children did not have any mommas or papas, or if they did their mommas and papas didn’t give a damn about them. Aside from their not being free agents, I wasn’t sure that what Dr. Koprowski would find out about his live-virus vaccine in these children would be the

same if it was tested in normal children. For instance, certain men-. tally retarded children—like mongolian idiots—are much more susceptible to infection than are other individuals. John Howland taught me this many years ago, and I believe that it still holds true. My opposition to Dr. Koprowski’s test proved to be ineffective, and in the end of the State of New York did give him permission to hold a

468 Chapter 12 limited test. Approximately 20 mentally defective children received his vaccine. I must in all fairness say that none of these children ever came down with paralytic disease, and all showed a good titer of anti-

bodies in their blood, but it was far from being a conclusive test. Several years later, when Dr. George Dick in Belfast, Ireland, tested Koprowski’s ‘T'N strain and his SM strain, which was a type 1 variant, he discovered that Koprowski’s attenuated strains had reverted to a

relatively virulent state.*° . .

Q: Dr. Rivers, [ would like to pursue this point. When Dr. Koprowski originally gave his paper, no one at the immunization con-

ference raised the question of back mutation, although at one point Dr. Koprowski himself raised such a point peripherally in his discussion of rabies vaccines.

Rivers: To be sure, nobody at the meeting said anything about it, but that didn’t mean, that they didn’t think about it. I'certainly thought about it, and I wasn’t the only smart virologist around. As a matter of fact, by the time Dr. Koprowski gave his paper in 1951, a great many virologists were aware of at least one live-virus vaccine that had back

mutated to a virulent state. At the beginning of World War II, a number of us were concerned that the Germans might try to introduce rinderpest virus and foot-and-mouth disease virus to our cattle.

We did not have these two viruses in our country, and if they had | ever been turned loose they would have worked havoc with our cattle. I don’t have to draw a picture for you of what that would have meant for our supply of beef or milk or butter. It would have been a disaster. Early in the war, Dick Shope, who belonged to my Navy unit at the Rockefeller Institute, was given the job of trying to see whether a livevirus vaccine could be developed against rinderpest. Previously, at* See D.S. Dane, G. W. A. Dick, J. H. Connolly, O. D. Fischer, and F. McKeown,

‘ “Vaccination against poliomyelitis with live virus vaccines. 1. A trial of TN type II vaccine,” Brit. Med. J., vol. 1:59 (1957); “Vaccination against poliomyelitis with live virus vaccines. 2. A trial of SM type 1 attenuated poliomyelitis virus vaccine,” ibid., vol. 1:65 (1957). Dr. Koprowski adds the following observation, “While Dr. Dick’s report was used as an argument at the time for or against a given strain of live virus, we now accept such a phenomenon as a matter of fact since all strains employed today, including those licensed by the U.S. Public Health Service, undergo the same change after passage through the human intestinal tract” (private communication).

Immunization against Poliomyelitis—1949-1953 469 tempts had been made to develop an inactivated vaccine, but they all more-or-less had ended in failure. By passing the virus through chick embryos, Dick finally did develop an attenuated rinderpest virus that could be given to calves. Upon inoculation, the calves would get a lit-

tle rash and develop a slight temperature, but then they would recover and, when tested, show a marked immunity. It was awfully good, and if it had become necessary I believe we would have used it.

But fairly soon after Dick had done his trick, it was shown that his attenuated virus had back-mutated. The question of back mutation is in the picture with all live-virus vaccines. It bothered virologists when they considered Dr. Koprow-

ski’s vaccine, and it bothered them when they later considered Dr. Sabin’s vaccine. I ought to explain that we were not fearful for the

children that, let us say, took Dr. Sabin’s vaccine in the first instance. Those children were probably one hundred per cent safe. We

were concered for the children who would later come into contact with the mutant put out by the inoculated children. Now a lot of what I have said is in the realm of supposition. It is a possibility— however, a possibility that is small. For instance, to date the Russians have inoculated over 100,000,000 children with Sabin’s vaccine and

there is no evidence of any back mutation. If it did back-mutate, it certainly didn’t cause any great catastrophe.

O: Dr. Rivers, we have to this point talked about the various developments in active immunization against polio in the period 1949 to 1951. I would like to direct your attention now to the development of research programs in passive immunization during this same period —specifically the gamma globulin program developed by the Na- _ tional Foundation. I wonder if you can tell me how that program got under way?

Rivers: Properly speaking, the gamma globulin program did not begin with the National Foundation. In essence, it was initiated in the laboratories of Dr. Edwin J. Cohn at the Harvard Medical School.

Edwin Cohn was the younger brother of Alfred Cohn who worked at | the Rockefeller Institute. Unlike his brother who was an M.D. and a cardiologist, Edwin was a Ph.D. and a biochemist, ‘hey were unlike

470 Chapter 12 in other ways. It is no secret that the brothers did not get along very well together. Alfred was an astute, cultured Jew who, in his actions toward other people, was just about the way he ought to have been.

He was a gentleman. Edwin was just the opposite. He was cantankerous and a tough nut. I think that he liked to rough up the other fellow a little bit. I say this at second hand but it’s essentially what Alfred used to tell me about him. No matter what his character was, there can be no doubt that he was also a superb biochemist. Most of Edwin Cohn’s work was concerned with the biochemistry

of proteins, more specifically, the separation of proteins from the complex biological systems in which they occur in nature. When World War II began, there was not enough human blood available , for blood transfusions, and Dr. Cohn was asked by the National Research Council to see if the plasma of animal bloods was suitable for human transfusions. Plasma, as you know, is the liquid remainder of

unclotted blood after red cells and white cells and other formed bodies have been removed. It consists largely of proteins. Cohn got down to work and, with the aid of a brilliant group of colleagues, succeeded in developing a process for separating the proteins of plasma into various fractions like serum albumin, fibrinogens, and globulins of various sorts. Although the use of the plasma of animals for human transfusion turned out to be risky, Dr. Cohn’s research proved to be extraordinarily important, in that it pointed the way for the fractionation of human blood. This fractionation, I might point out, had im-

mediate medical application. The serum albumins, for example, proved useful in the treatment of shock, the fibrinogens and _prothrombin in facilitating clotting and gamma globulin, one of several globulins which were finally obtained, in halting infections.” One of the first investigators to grasp the importance of gamma globulin as an agent for possible use in immunization against poliomyelitis was David Kramer, who was then working in the laboratories of

the State Department of Health of Michigan. I have mentioned Dr. Kramer several times before in other contexts, and I would like to take a moment here to speak of him again. I do this, because, by and

| large, Dr. Kramer has never really received the credit he has deserved * For a detailed account of the history of blood fractionation, see E.J. Cohn, ‘The history of plasma fractionation,” in C.E. Andrus et al. (eds.), Advances in Military

Medicine. Vol. I. Little, Brown, Boston, 1948, pp. 364-443.

Immunization against Poliomyelitis—1949-1953 471 for his contributions to polio research. He was an imaginative investigator and a good experimenter, but somehow he was always on the

edge of things and never quite in the center. I suppose that in part this was due to the fact that he never really had a post commensurate with his talents. During the twenties he worked very closely with Dr. Lloyd Aycock on the Harvard Infantile Paralysis Commission. When that job gave out, he moved on to the Long Island University Medical School in Brooklyn to continue his research in polio. His job there was just as tenuous, and after several years he moved on to the laboratories of the Michigan Department of Health. By the time he reached Michigan he had devoted the better part of twenty years to polio research. From the beginning of its existence the National Foundation supported a great deal of Dr. Kramer’s research. As a matter of fact,

when he first went to Michigan in 1940, the Foundation gave him several grants to develop a chemotherapeutic approach to the polio problem. I remember that in the course of this work he tested the effect of several hundred different chemical compounds on poliovirus with no success. I don’t know whether he was disappointed by those uniformly negative results, but I do know that, at the same time, he was working on problems of chemotherapy, he began to reexamine the prophylactic value of human convalescent serum.

During the early thirties, a number of investigators, among them Dr. William Brebner of the New York City Health Department, and Dr. Joseph Stokes, Jr., of Philadelphia, had made claims that convalescent serum was useful in preventing polio. Unfortunately, however,

their evidence was not conclusive. When Charles Armstrong succeeded in adapting Lansing virus to cotton rats in 1939, Kramer saw a chance of corroborating Dr. Brebner’s and Dr. Stokes’s claims in the laboratory and began to test the usefulness of human immune serum

in preventing experimental infections in cotton rats and mice. As | mentioned earlier, his initial experiments were successful, but no one became excited by them. When Kramer learned of Edwin Cohn’s work with fractions of plasma, he wangled a small supply of human immune globulin from him and began to test the effect on poliovirus. In a very brief time Kramer discovered that the globulin fractions which Cohn had sent him gave marked protection to both cotton rats and monkeys against an intracerebral inoculation of poliovirus. More

472 Chapter 12 important, he learned that his globulin fractions possessed twenty-five

times the amount of neutralizing substance originally found in the plasma from which it was taken. Kramer was so encouraged by his ex-

perimental findings in animals that in 1944 he asked the National Foundation if they would support him in running a small field trial so he could test whether gamma globulin had a prophylactic effect in humans as well.

I suspect that if it had been up to the Foundation alone Dr. Kramer would have been allowed to put on his field trial. At the time, other investigators were also beginning to get very suggestive results of

the protective power of gamma globulin against polio infection in chimpanzees, and it seemed like a good thing to do. Indeed, if I remember correctly, the Foundation finally did-approve Kramer’s re-

quest for a field trial, but unfortunately neither Kramer nor the Foundation was able to persuade the Red Cross of the value of holding such a trial.

You must remember that, during the war, the American Red Cross had charge of collecting blood supplies, and since these supplies were the only source of plasma the Red Cross in effect also controlled the supplies of serum albumins, fibrinogens, and globulins obtained from plasma. Dr. Foard McGinnes, who was then in charge of the blood supply program of the American Red Cross, refused to release the

necessary gamma globulin to Dr. Kramer, on the grounds that the projected field trial was not practical inasmuch as there weren’t enough doctors and nurses available to do the necessary follow-up work required by such a trial. He was, however, willing to release a small amount of gamma globulin so that investigators could carry on further laboratory tests with chimpanzees. In retrospect, I would say that Dr. McGinnes was right. Wartime was a hell of a time to put on a field test even a small one. I don’t think that he was being obstruc-

tive, because a year later, when an opportunity offered to put on a limited test during a polio epidemic in Freeport, Ilinois, Foard sent Tommy Francis a supply of gamma globulin without too much pro-

test.*® :

** It is of interest that Dr. Joseph Stokes, Jr., one of the early proponents of passive immunization in the United States, to this day maintains that it was Dr. Rivers’ opposition to passive immunization that prevented an early field trial with gamma globulin. Both Don Gudakunst and later Harry Weaver assured me that Tom would not lis-

Immunization against Poliomyelitis—1949-1953 473 After the war, the interest in gamma globulin continued not only among virologists but among medical practitioners as well. In 1948, for example, when a polio epidemic hit Houston, Texas, a number of pediatricians in that city gave children in their care a prophylactic inoculation of gamma globulin. I would like to emphasize that these inoculations weren’t given as a test, Later, however, when this experiten to my early pressure for studies on passive immunization in polio, and, since he was the chairman of the committee that decided on grants and no public health authority would move without the assurance of the National Foundation’s approval, all of us, such as David Kramer, who felt that we could save a good many paralytics and a few lives had to wait. The waiting over seven or eight years seemed interminable since those of us in the clinical field saw many more children dying in respirators than did the workers in the laboratories. As Jater proved to be true, we felt a good many could have been saved, and the emotional reaction to this feeling also colored the urgency of our requests and perhaps therefore the stiffening of Tom Rivers’ back. . . . Also . . . the fact that when he espoused a negative point of view he stuck to it with bulldog tenacity —even on numerous occasions contrary to mounting and solid evidence against him— made him often a frustrating experience for younger workers (private communication ). The sharpness of Dr. Stokes’s comments on Dr. Rivers can perhaps best be understood when measured against the hopes he had for passive immunization. (See Appendix D, a confidential memorandum that Stokes presented to the Board of Managers of the Children’s Hospital in Philadelphia on April 24, 1952.) Harry Weaver, the director of research of the National Foundation between 1946 and 1953, offers the following interpretation of the differences between Dr. Stokes and Dr. Rivers: To understand the differing views of Drs. Stokes and Rivers on the possible usefulness of gamma globulin in poliomyelitis, it is important to realize that these differences arose during the early 1940’s. In many ways, Stokes was “ahead of the times” when he first pressed for a test in man of the usefulness of gamma globulin in poliomyelitis. Because knowledge of the pathogenesis of poliomyelitis was evolving so rapidly in the early 1940's, it is to be expected that serious differences existed on such important questions as the portal of entry of the virus; the significance—with respect to development of local and systematic immunity—of the virus in the gastrointestinal tract of both patients with the disease and apparently normal subjects; and the route by which the virus invaded the brain and spinal cord from the outside, and whether or not the virus at any time along this route became exposed to or in contact with poliomyelitis antibodies which may have been circulating in the blood. Also, opinion was divided as to the significance of the large quantities of poliomyelitis antibodies which were found circulating in the blood of patients who were in the early stages of the disease. And we did not know then how many different immunogenic types of the poliomyelitis virus existed, nor whether gamma globulin contained antibodies against each of the different types. Then, too—people being what they are—whenever the suggestion was made to determine the usefulness of gamma globulin in preventing poliomyelitis or the paralytic consequences thereof, an adverse reaction was likely to result, because most investigators believed it was impractical to even think about controlling poliomyelitis through

use of gamma globulin. The arguments in support of this view included the scarcity of gamma globulin, the short duration of protection that could be afforded by a single injection of this product, the enormous size and expense of the effort that would be

474 Chapter 12 ence was analyzed, it seemed that the children who had been inoculated were afforded some protection. In 1950 Dr. William Hammon, who had long been working on immunological and serological responses to polio infections, gave a paper at a conference sponsored by the National Foundation in which he urged that the time had come to put on a field trial to test the effectiveness of gamma globulin as a prophylactic to polio infections.

O: Dr. Rivers, in 1950 there were not many virologists in the United States who were interested in passive immunization against poliomyelitis. What made Dr. Hammon interested in putting on a field trial to test gamma globulin? required to give multiple injections of gamma globulin to each person each year, etc., etc., etc. Perhaps Tom Rivers did have “feet of clay”—who of any substance does not? He may have been a bit slow in the early 1940’s to support a test of the protective efficacy of gamma globulin in poliomyelitis, because he and most other people at that time did not really believe that a poliomyelitis vaccine was in the offing. Therefore, Doctor Rivers was inclined to view any proposal to test the efficacy of gamma globulin as a prelude to promoting this product for the control of poliomyelitis. He believed, and probably tightly so, that the demand for gamma globulin would vastly exceed its supply, and he objected to publicizing a preventive for poliomyelitis which could not be made freely available.

However, in the late 1940’s, when it began to appear to some persons at least that a vaccine against poliomyelitis might be forthcoming, Doctor Rivers was quick to alter his former position and to support a test of the efficacy of gamma globulin, because he believed the answer to this question was a prerequisite to further work on a vaccine. In other words, by the late 1940’s, Doctor Rivers was as desirous as anyone to learn if a susceptible person might be protected against the paralytic consequences of poliomyelitis by the presence of a small amount of antibody which was present prior to the subject’s coming into contact with the virus. If so, the degree of protection afforded should be no less where antibody was induced by injections of vaccine (private communication ). Although it is true that Dr. Rivers was not an enthusiast for passive immunization,

the weight of contemporary evidence is that the major opposition to Dr. Kramer’s proposal for a gamma globulin field trial in 1944 lay with the American National Red Cross and not with Rivers. See, especially, Proposal for a Field Study of the Value of Gamma Globulin as a Prophylactic Agent in Poliomyelitis, July 25, 1944; Memorandum, Donald Gudakunst to Basil O’Connor, August 4, 1944; G. Foard McGinnes, Medical Director ARC, to Donald Gudakunst, August 21, 1944 (Research Immuniza-

tion, Gamma Globulin Field Trials, General, 1944-1951, National Foundation Archives).

* While it is true that Dr. Hammon discussed gamma globulin in its relation to passive immunization at a Round-Table Conference on Gamma Globulin on February 3, 1950, that discussion cannot ‘be construed as a proposal for a field trial.

Immunization against Poliomyelitis—1949-1953 475 Rivers: In part, the answer to that question lies in the personality of Dr. Hammon and, in part, with the development of gamma globulin research during the late forties. I have known Bill Hammon for well over twenty years, at least since the time he began to work with Karl Meyer on problems of encephalitis, and I can say that he is a virologist of distinction. He is also a rather unusual person. He was born of missionaries and to this day has that spirit that missionaries have of trying to sell something. They sell the gospel, he sells medical research. Once Bill Hammon latches on to an idea, he pursues it just as a

missionary might pursue sin. Unfortunately, that attitude of mind sometimes makes it difficult to talk with him, and because of it my feelings about Dr. Hammon have gone up and down. Sometimes | think that he is great, and other times I get so sore at him I don’t respect him at all. But if you push me to it, I will always have to tell you that Bill Hammon has done more than his share in developing virology in the United States.

In 1950 there was ample reason for Bill Hammon to become enthusiastic about gamma globulin. First, gamma globulin was made from pools of blood contributed by many people, and there was little doubt that it contained almost twenty times as much antibody as an equal volume of human serum. What made it even more attractive was the fact that David Bodian, while testing the polyvalent characteristics of polio antibody in gamma globulin in 1949, discovered that it contained antibody in equal titer to all three known types of polio. It had other features as well, perhaps the most important being its success against other virus diseases. Prior to 1950, gamma globulin had

been used effectively by some investigators in the prevention of measles, and Dr. Joseph Stokes, Jr., had already clearly demonstrated that even a small amount of gamma globulin would give protection

against infectious hepatitis. From the foregoing I think you can see why gamma globulin captured Dr. Hammon’s imagination.”° * TD. Bodian, “Neutralization of three immunological types of poliomyelitis virus by human gamma globulin,” Proc. Soc. Exptl. Biol. Med., vol. 72:259 (1949); J. Stokes, Jr., and J. R. Neefe, “The prevention and attenuation of infectious hepatitis by gamma globulin,” J. Amer. Med. Assoc., vol. 127:144 (1945); J. Stokes, Jr., et al. “Infectious hepatitis. Length of protection by immune serum globulin during epidemics,’ J. Amer. Med. Assoc., vol. 147:714 (1951).

476 Chapter 12 O: That’s the positive side of the ledger. Wasn’t it also known that the immunity that gamma globulin might furnish would at best be transitory?

Rivers: That’s true. But please remember that in 1950 there was no vaccine, and the idea of affording protection to humans for even a brief period during an epidemic was attractive.

O: Dr. Rivers, how did the Foundation react to Dr. Hammon’s proposals for a gamma globulin field trial?

Rivers: Negatively. Initially, most members of the Virus Research Committee were not very enthusiastic about Dr. Hammon’s proposals, and it took the Foundation almost two years before it agreed to support a field trial. In the interim the Foundation held several round table conferences with leading virologists to discuss the wisdom

of passive immunization. I can tell you that on more than one occasion the discussion at these meetings became very heated. Most polio investigators in 1950 and 1951—and this included some of our best workers, people like Albert Sabin, Howard Howe, and John Enders —just didn’t think much of gamma globulin as a practical way of protecting against polio. I think that the basic reason for that attitude was that the boys in the know just did not believe that one could give enough gamma globulin to children to bring the antibody titer up to a level where it would be protective. You may remember that several years before Isabel Morgan had demonstrated that she had to get a high titer in the serum of monkeys before they could resist an intracerebral challenge of poliovirus. Although virologists by 1950 knew that poliovirus did not enter humans naturally in the way that Isabel challenged her monkeys, they nevertheless proceeded cautiously because, when they examined large groups of people who had antibodies against polio, they never found any antibody titers near the amount that Dr. Morgan pointed out was necessary for protection. I might add here that there were other findings which encouraged caution. At one of the conferences held by the Foundation, Dr. Gaylord Anderson reported that an analysis of polio cases in Minnesota during the epidemic of 1946 revealed that a substantial number of paralytic

Immunization against Poliomyelitis—1949-1953 477 cases had occurred following the injection of an antigen, and that there was a high correlation between the site of the injection and the site of the paralysis. Even before Dr. Anderson gave his report, several British and Australian investigators had noticed that a number of their

patients had contracted paralytic polio following inoculation against diphtheria and pertussis. ‘This phenomenon was actually not new in 1950. I remember that as far back as 1935, during the Park-Brodie vaccine field trials, several children came down with paralysis of the arm in which the vaccine had been given and that that paralysis had occasioned a great deal of critical discussion. Dr. Anderson’s paper,

however, had the virtue of reminding us that inoculation of an antigen might induce a paralysis which in the natural course of events might not occur, and I can testify that it gave us pause. A short time

: later, these particular apprehensions were reinforced by Dr. Robert Korns of the New York State Department of Health. At a meeting of the American Epidemiological Society in 1951, Dr. Korns reported that an injection of penicillin or a hormone during the polio season was also capable of inducing paralytic polio, although it was an insoluble antigen. That finding threw us back on our heels, because it raised important questions relating to the design of Dr. Hammon’s field trial, in particular, the method of carrying out controls.** Many investigators, including Bill Hammon, felt that if you inoculated your trial group with gamma globulin, it was also necessary to inoculate your control group with a placebo that in appearance looked exactly like the gamma globulin. In ordinary circumstances, I don’t think that anyone would have debated such a procedure. However,

following the Anderson and Korns reports, a number of workers argued that if you inoculated your control group during the polio sea-

son, there was a good chance that some would come down with paralytic polio by the mere act of inoculation, and they urged instead

that the placebo be given by mouth. Some went so far as to argue against using a control group at all. ‘There was one hell of a debate. It was plain to me that once you distinguished the gamma globulin from "1G, W. Anderson, ‘Relation of antigenic injections to incidence and localization of paralysis,” in Proceedings of Round-Table Conference on Immunization in Poliomyelitis, Hershey, Pennsylvania, March 15-17, 1951, pp. 190-210 (includes discussion) ; R. F. Korns, R. M. Albrecht, and F. B. Locke, “The association of parenteral injections with poliomyelitis,” Amer. J. Public Health, vol. 42:153 (1952).

A478 Chapter 12 the placebo you were opening a Pandora's box. I could just see thousands of mommas and papas of those children who got the placebo descending on the Foundation asking why their children didn’t get the gamma globulin. I also didn’t know how anyone was going to prevent a local physician from giving gamma globulin on the q.t. to children who got the placebo. It would have balled up the field trial good and proper.

O: Dr. Rivers, by your last statement you seem to be raising an ethical problem. How about the ethics of giving a placebo in the first place?

Rivers: ‘The question you ask is not new and Comes up every time a

test is given. Essentially you are asking me, what right does an investigator have in withholding from some children something which he thinks might do some good. ‘The answer is clear. If we were certain before the field trial that gamma globulin would be of help, then it is plain that we would have had no right to give any child a placebo. The point, however, is that we were not certain and, unless we ran a test with adequate controls, we would never know whether we were right or wrong. In the circumstances, I think that if we hadn’t given a placebo we would have been unethical.

QO: Dr. Rivers, I don’t want to disturb the trend of your thought, but I think that it might be helpful at this point if you could briefly outline the specific purpose of Dr. Hammon’s field trial.

Rivers: I think that basically all Bill Hammon wanted to do was to put on a test whereby he could determine whether a given dose of gamma globulin could prevent paralytic polio before exposure to, or before the onset of, the illness. I do not believe that he was primarily concerned in these trials with discovering whether gamma globulin would interfere with inapparent or subclinical polio infections. I don’t want to be misunderstood. | am not saying that he wasn’t interested

in this problem—actually he had to be because, if gamma globulin did interfere with subclinical infections, it might also have interfered with the process of subsequent active immunity. All I am trying to

Immunization against Poliomyelitis—1949-1953 479 say is that this problem was secondary to the original purpose of the field trial, which was to discover whether a given dose of gamma globulin would prevent paralytic polio. What that dose was, no one at that time knew. To be sure, there had been previous animal tests, but

Dr. Hammon felt very strongly that it was almost impossible to extrapolate the amount of gamma globulin needed for man from the dosage per pound found necessary to protect a monkey against an intracerebral injection of virus. For one thing, the route of experimental infection in monkeys was not necessarily the route of natural infection in man; for another, the severity of the disease in monkeys was ~ greater than it was in man. Hammon, therefore, argued that at best an arbitrary dosage would have to be selected. ‘The question was, how much?

Some investigators following Dr. Joseph Stokes’s reports that a small amount of gamma globulin would protect against hepatitis, urged that the dose be small. Dr. Hammon himself was inclined to give a relatively large dose instead of a small one. But I think it should

be kept in mind that most investigators were agreed that the dose could not be above 10 cc. In the end, Hammon divided his children into three weight groups. To the first, which ranged up to 35 pounds, he gave 4 cc; to the second, which ran from 36 to 60 pounds he gave 7 cc; and to all those above 60 pounds he gave 10 cc. Heck, he couldn’t have given much more without having a first-class revolt on his hands. I don’t think there is a kid in America who would have stood, let us say, for an inoculation of 10 cc in each buttock without complaint—it just would have been too damn painful, and in the end it would have made the trial impractical. After the first day of such an inoculation, the kids would have gone into hiding.”

O: Dr. Rivers, how far did the Foundation go in designing the

gamma globulin field trials? |

Rivers: Let’s get one thing straight. The gamma globulin field trials were designed by Bill Hammon. It is true that the National Foundation held a number of conferences to discuss the field trials and that 2 For discussions of the problems attendant on the formulations of a field trial for gamma globulin, see Proceedings of the Round-Table Conference, op. cit. Minutes of a meeting of the Committee on Immunization, May 17, 1951; ibid., July 6, 1951.

480 Chapter 12 everybody and their aunt at these conferences made suggestions about

placebos, dosage, and a hundred other problems that haven’t been mentioned, but they were nothing more than suggestions. In the final analysis, the field trial was carried out according to the specifications drawn up by Dr. Hammon. It has never been the policy of the

Foundation to tell an investigator how to do an experiment. The Foundation could turn down a man’s proposals, or they could accept a man’s proposals but, once they accepted, they let him alone, which is as it should be.

QO: Dr. Rivers, how did you feel about the gamma globulin field trials?

Rivers: That’s easy, I supported them. During the last conference called by the Foundation to discuss the feasibility of putting on a gamma globulin field trial, there was a hell of a debate. If you will examine the minutes of that conference, you will find that at one point I got up and made a statement that on its face sounds idiotic. “Gentlemen,” I said, “let’s throw scientific discussion out of the window, and let’s do the experiment.” After several meetings of discussing Dr. Hammon’s proposals backward and forward, I had become convinced that we could talk about them for another ten years and still not reach a conclusion. Under the circumstances I felt that the only way to reach a conclusion was to put the experiment on—I was probably influenced in making my statement by Sir Francis Bacon who is once reputed to have said (at least everybody quotes him as saying), “Don’t think—experiment!” I like the sentiments of that statement,

except I have always felt that he should have said, “Experiment,

but for God’s sake don’t stop thinking.”* I am appalled by the idea of doing an experiment without thinking. Now why did I support the trials? I want to make it perfectly clear that I did not support them because I was interested in using gamma

globulin as a public health measure. I never thought that. I did sup*° Dr. Rivers is mistaken here. The sentiments on experimentation which he ascribes to Bacon were made by John Hunter in a letter to Edward Jenner, August 2, 1775. “I thank you for your experiment on the hedgehog; but why do you ask me a question by way of solving it? I think your solution is just; but why think—why not try the experiment?” The letter is cited in John Baron, The Life of Edward Jenner M.D. Vol. 1. Henry Colburn, London, 1838, p. 33.

Immunization against Poliomyelitis—1949-1953 481 port them because I felt the trials might furnish virologists with information that would be helpful in making a vaccine. By 1951 virologists had discovered a number of things that made a vaccine a distinct pos-

sibility. First, Isabel Morgan had already shown that formalinized inactivated poliovirus could be used for immunization purposes; second, John Enders had demonstrated that poliovirus could multiply in nonnervous tissue; and, third, the immunologic typing program cartied on by the National Foundation was rapidly coming to the conclusion that there were three major immunologic types of poliovirus.

At that time, however, we still did not know whether poliovirus reached the central nervous system from the portal of entry by way of

the nerves or the blood stream. If it traveled by way of the nerves, most virologists were resigned to the fact that protection could only be achieved by a high antibody titer, similar to the one indicated by Isabel Morgan. If, on the other hand, it traveled by way of the blood stream, then the titer of antibody could be much smaller. One of the

cine. }

crucial things we had to know was whether a low antibody titer would

protect; if it did, then by gosh we had a possibility of making a vac Now, whether other people on the Foundation’s Immunization Committee wanted to know that, I just couldn’t say. I talked about it, but whether they ever heard me I don’t know. You can talk to a guy until you are blue in the face, but it doesn’t necessarily follow that he hears a word you say. I can’t say that everybody on the Immunization Committee appreciated my reasons, but the fact is the entire committee joined with me in approving the field trials.

QO: Dr. Rivers, would you go so far as to say that your statement, ““Let’s throw scientific discussion out of the window and do the experiment” carried the day for the field trial?

Rivers: It’s hard to say. I think that by the last meeting everybody realized what I had and had about reached the same conclusion. It wasn’t difficult; heck, we had been discussing the question for almost two years. I don’t think that I was all by myself in calling for a field trial. I just happened to shoot my mouth off a little bit sooner than the others. Let’s say that something that was bound to occur was

482 Chapter 12 brought to pass a few minutes sooner by my statement. That’s the only credit I will take.

The first gamma globulin field trial was put on in Provo, Utah, early in September 1951, during an incipient epidemic of polio.” Properly speaking, the Provo trial cannot be considered a field trial, because it was not made on a scale large enough to give statistically valid results. Actually, it was a pilot study to work out the kinks and problems that Dr. Hammon was likely to run into putting on a largescale test. If memory serves, a little more than 5000 children received gamma globulin and the placebo. Yet, in spite of its size, the results that emerged from this test were suggestive and seemed to indicate |

that a small amount of antibodies would protect against paralytic polio. I would say that the significance of this finding was immediately and independently appreciated by Dr. David Bodian at Johns Hopkins and Dr. Dorothy Horstmann at Yale. They assumed that, if Dr. Hammon’s findings were valid, it meant that the poliovirus _ traveled from the portal of entry to the central nervous system by means of the blood stream, and they began to search for a viremia. If I remember correctly, they fed cynomolgous monkeys and chimpanzees poliovirus and after several days collected blood specimens from these animals and tested them for the presence of poliovirus. After some search, they discovered virus in the blood between the time of

feeding and paralysis. Suffice it to say, if they had waited for the paralysis to occur they never would have found evidence of viremia.” Most of the investigators who had previously looked for virus in the blood were unsuccessful because they examined the blood of animals and people who had already become paralyzed. Once Dr. Bodian and Dr. Horstmann learned that viremia in animals occurred very early in the disease, they began to look early in human beings as well and soon discovered viremias in abortive cases of polio. ‘The interesting thing in all of this is that, several years before Dr. Bodian and Dr. Horstmann “The Provo Field Trial was held on September 4-7, 1951. For a detailed discussion see W. McD. Hammon, L.L. Coriell, and J. Stokes, Jr., “Evaluation of Red Cross gamma globulin as a prophylactic agent for poliomyelitis. 1. Plan of controlled field tests and results of 1951 pilot study in Utah,” J. Amer. Med. Assoc., vol. 150:739 ares Bodian, “A reconsideration of the pathogenesis of poliomyelitis,” Amer. J. Hyg., vol. 55:414 (1952); D. Horstmann, “Poliomyelitis virus in blood of orally infected monkeys and chimpanzees,” Proc. Soc. Exptl. Biol. Med., vol. 79:417 (1952).

Immunization against Poliomyelitis—1949-1953 483 confirmed the phenomenon of viremias, a number of other workers had discovered poliovirus in the blood of experimental animals and

human patients but either did not follow up their findings or else drew the wrong conclusions from their observations. For instance, as early as 1941, Albert Sabin, after feeding some cynomolgous monkeys poliovirus, observed a viremia but assumed, as sometimes occurs in

other virus diseases, that during active multiplication in certain tissues the virus may be eliminated in the blood stream. It puzzled him and he ruminated about it, but he didn’t follow it up. In his defense, I should say that a war was going on and he had a hell of a lot of other things to think about. An even more notable case was that of Dr. Joseph Melnick. In 1946 Dr. Melnick, with the assistance of Dr. Robert Ward and Dr. Dorothy Horstmann, examined the blood of 111 polio patients and detected poliovirus in the blood of one patient. If you examine the clinical history of this patient, you will find that the blood was taken very early in the infection—I think several hours after the onset of symptoms, and certainly before paralysis set in. Dr. Melnick took the lone case to be unimportant and certainly did not look on it as showing any necessary factor in the pathogenesis of the disease in man. You must keep in mind that Dr. Melnick’s work was not done in a manner to pick up viremia—most of his patients, as I remember, were examined and bled after paralysis set in, and by that time it was, of course, too late to discover a viremia. In the circumstances, I can’t blame him for looking on his one case as an aberra-

tion. I don’t know why the discovery of a viremia didn’t hit all investigators in the face; the fact remains that it didn’t, and I suspect that there are many discoveries in science that are overlooked simply because scientists don’t always appreciate what they see. Hell, look how long it took us to integrate ether into surgical procedures, or for

obstetricians to learn how to wash their hands before delivering a baby. The evidence was there for everybody to see but you know, it’s

not the seeing, it’s the appreciation of what you see, that is important.?® 6 See also A.B. Sabin, “Studies on the natural history of poliomyelitis (Bela Schick Lecture) ,” J. Mt. Sinai Hosp., vol. 11:185 (1944), especially remarks on pp. 191-192; R. Ward, D.M. Horstmann, and J. L. Melnick, “The isolation of poliomyelitis virus from human extra-neural sources. [V. Search for virus in the blood of patients,” J. Clin. Invest., vol. 25:284 (1946). Dr. Koprowski in 1947 also demonstrated viremia in a

484 Chapter 12 Q: Dr. Rivers, you mentioned earlier that the Provo trial was a pilot study. When was the first large-scale gamma globulin field trial put on?

Rivers: Actually, there were two large field trials after Provo; one was held in Houston, Texas, and the other in Sioux City, Iowa.” Although close to six times as many children were inoculated with gamma globulin and placebos in Houston as in Provo, the tests did not have the validity they should have had, simply because the doctors and the public in Houston did not play the game according to the

rules. What happened was that during the trial many doctors gave their patients inoculations of gamma globulin on the g.t. and, while it didn’t do the patients a hell of a lot good, it bollixed up the results of

the trial good and proper. I hate to say this about the doctors in Houston, but they shouldn’t have done this. ‘They thought they were doing good, but they weren't.

QO: Dr. Rivers, what do you do when you are running a field trial and you find that doctors are not following instructions?

Rivers: I'll tell you what you do—you just go ahead and finish the trial and charge it up to profit and loss. You keep your mouth shut because it never pays to make the medical profession mad at you. When all is said and done, a family will trust and believe the family physician more than it trusts or believes a scientist who is connected with an institute or a foundation, no matter how eminent he may be. The scientist, after all, is a person they have never seen or met. There might be a story about him in the local newspaper, but, hell, that is no competition for the family physician who tends the family in sickpolio patient through inoculating mice. H. Koprowski, T. W. Norton, and W. McDermott, “Isolation of a poliomyelitis virus from human serum by direct inoculation into a laboratory mouse,” Public Health Rept., vol. 62:1467 (1947). * ‘The gamma globulin field trials in Houston, Texas, ran from July 2 to 12, 1952. The trial in Sioux City, Iowa, ran from July 17 to 22, 1952. W. McD. Hammon, L. L. Coriell, and J. Stokes, Jr., “Evaluation of Red Cross gamma globulin as a prophylactic agent for poliomyelitis. II. Conduct and early follow up of 1952 Texas and IowaNebraska studies,” J. Amer. Med. Assoc., vol. 150:750 (1952); W.McD. Hammon, et al., “III. Preliminary report of results based on clinical diagnosis,” J. Amer. Med. Assoc., vol. 150:757 (1952).

Immunization against Poliomyelitis—1949-1953 485 ness and times of crisis, and who is frequently looked up to as being infallible. You don’t raise hell with the family doctor, no matter how justified you think you may be, because if you do, you quickly find yourself in trouble with the public. ‘The National Foundation, so far as I know, never said anything about the Houston experience. Actually, it wasn’t until Dr. Hammon put on his field trial in Sioux City, Iowa, that we definitely learned that a small dose of gamma globulin (calculated at 0.14 cc per pound of body weight), given intramuscu-

larly into the buttock, would give children temporary protection against paralytic polio.

If the gamma globulin field trials had stopped after Sioux City, everything would have been all right, because to that point they had proven to be extraordinarily valuable and had taught virologists a great deal. But damn it, in 1953 the National Foundation, in collaboration with the National Research Council, decided to put on another trial to test gamma globulin as a public health measure by giving it to family contacts. Now I want to get something off my chest. When

Bill Hammon originally put on the gamma globulin field trials in Provo, Houston, and Sioux City in 1951 and 1952, it was done for the specific purpose of discovering whether a given dose of gamma globulin could prevent paralytic polio—and nothing more.

~ In 1953, however, Bill turned around and agreed to test gamma | globulin as a public health measure by giving it to family contacts, and I tell you frankly I hold this decision against him. In 1952 Bill Hammon, I, and a hell of a lot of other virologists believed that once you had an index case of polio in a family, the chances were that the whole family was infected, and giving gamma globulin to that family would not prevent polio. For a reason I still can’t appreciate, Bill allowed Alex Langmuir to talk him out of this position. I don’t even know why Dr. Langmuir did this, because ordinarily he is a pretty smart apple and has on many occasions, too numerous to mention, demonstrated that fact. It mystifies me that he was so far off base on this, but he succeeded in persuading Bill Hammon, and | then made it

my business to try to talk Mr. O’Connor out of giving the support of , the National Foundation to this new test. I told him as bluntly as I could that I thought this new test would in all probability be a waste of time, money, and effort. He heard me out and then went along with

486 Chapter 12 Dr. Langmuir and Dr. Hammon. I'll say this, 1 don’t think that Mr. O’Connor was dumb in the sense that he didn’t know what he was doing. I think he believed me when I told him that giving gamma globulin to family contacts would do little if any good. Actually, | don’t believe that he looked upon this test as a scientific question. By 1953 he realized that a vaccine was in the offing and that it was only a matter of time before we had one in hand. I think he was trying to buy time. I can’t say for sure, because he never confided his reasons for supporting this particular test. | am not saying by this whether Mr. O’Connor did nght or wrong. I am in no position to judge, because I know nothing about how to handle the public. Mr. O’Connor does. I can only tell you that I advised him against supporting this particular test.°* QO: Dr. Rivers, how often did Mr. O’Connor override the judgment of his scientific advisors?

Rivers: Mr. O’Connor did not override the judgment of his scientific advisory committees—he believed and trusted them. I should point out that in this particular instance Mr. O’Connor did not bring the Virus Research Committee together to advise him; instead he counseled with various scientists both inside and outside the Founda-

tion. I suppose that because he acquired his advice in this way, he never actually felt that he was overriding the judgment of his Virus Research Committee. You must remember that a committee of the National Research Council told him the test was perfectly feasible. *° There can be no doubt that Rivers opposed the program carried out in 1953 to use gamma globulin as a prophylactic measure against paralytic poliomyelitis. However, he basically refuses to acknowledge that the actual purpose of the program was to use gamma globulin as a public health measure against the disease rather than as a test to discover its efficacy. Moreover, Dr. Rivers overlooks the fact that there were sharp differ-

ences between the U.S. Public Health Service and The National Foundation for

Infantile Paralysis as to how the gamma globulin was to be used. Initially the Public Health Service wanted to restrict the administration of gamma globulin to family contacts. The Foundation, on the other hand, urged that the gamma globulin be administered on a community wide basis to abort impending epidemics. After some debate, the Foundation’s suggestions were incorporated into the test program, and it was decided to allocate the major portion of the available supply of gamma globulin to communitywide prophylaxis. For detail on the evolution of the gamma globulin test program of 1953, see folders on Gamma Globulin, U.S. Public Health Service, 1953-1954 (National Foundation Archives).

Immunization against Poliomyelitis—1949-1953 487 Hell, if I bothered him too much, he could always turn around and

say, “I’om, the National Research Council says to do it. You don’t : think you are better than they are.” He could give me an argument, and I frankly wasn’t going to look for a hassle with him. I'll tell you one thing, I didn’t have to wait for the results of that test to know that they wouldn’t come up with anything. Pll admit that to this day I have never bothered to read the final report of that test. It’s written up somewhere. You read it and if it proved anything I’ll eat it for lunch tomorrow.”® ” An Evaluation of the Efficacy of Gamma Globulin in the Prophylaxis of Paralytic Poliomyelitis as Used in the United States, 1953. Report of the National Advisory Committee for the Evaluation of Gamma Globulin in the Prophylaxis of Poliomyelitis, Public Health Monograph No. 20, 1954.

CHAPTER l 3

Prelude to the Salk Vaccine But my purpose here is to doo theym good that haue moste nede, that is to saye, children: and to shewe the remedies that god hath created

for the vse of man... .

Thomas Phaire, The Boke of Chyldren, 1545

QO: Dr. Rivers, on January 23, 1953 the Committee on Immunization of the National Foundation held a special meeting at Hershey, ‘ Pennsylvania, to examine the reports made by two young scientists. One of these was Dr. Jerome Syverton, the other was Dr. Jonas Salk.?

Rivers: I have told you something about Jerry Syverton before. For now, let me say that when Dr. Enders and his associates succeeded in propagating poliovirus in nonnervous tissue in 1949, Dr. Syverton set himself the task of trying to extend that work by developing pure strains of human and monkey extraneural cells in vitro. In the beginning he had little success. However, after about two or three years of experimentation, he and an associate, Dr. William Scherer, succeeded in propagating all three known types of poliovirus in morphologically pure cultures of monkey testicular fibroblasts maintained in a series. A short time later they succeeded in repeating this work with a strain of human malignant epithelial cells called HeLa cells. These are very interesting cells, and perhaps I ought to take a min-

ute or two to tell you how they were found, because they have since become important to people engaged in cancer research. Originally HeLa cells were discovered in the tissue of a Negro woman who was * Minutes of the Meeting of the Committee on Immunization, The National Foundation for Infantile Paralysis, January 23, 1953.

488

Prelude to the Salk Vaccine 489 operated on for a cancer of the cervix sometime during World War II. Later, they were named in honor of this patient. So far as I know, the initial biochemical and cytological studies of Hela cells were done by Dr. George Gey of the Johns Hopkins Medical School, and it was he who supplied Dr. Syverton with his first strain. ‘lhe achievement of Syverton and his coworkers rested on the fact that they dis-

covered that Hela cells could be used effectively for the detection and quantitation of poliovirus as well as its cultivation.

Syverton’s work was beautifully done and created a great impression on the Immunization Committee, but there was serious doubt on the part of many virologists that it would be feasible to use HeLa cells to produce virus for a potential vaccine. John Enders best expressed that doubt when he said that he wouldn’t want to use cancer cells as the basis for any vaccine, on the grounds that, since investigators at that time didn’t know the cause of cancer, it was extremely unwise to inject any elements cultivated in HeLa cells into people until such answers were forthcoming. Later Joe Smadel and I talked about Syverton’s work at great length and came to the same conclusion, although for different reasons. Unlike Dr. Enders, we felt that if the proper precautions were taken to filter the HeLa cells from the tissue cultures before the virus was used in a vaccine, it would be perfectly safe to use such virus. However, we didn’t believe that the public would take a polio vaccine if it discovered that such a vaccine was made from viruses cultivated in tissue cultures of malignant cells. We believed that such a public attitude would not only be natural, it would also be right. Hell, if I was completely ignorant of what went on in science, I wouldn’t take such a vaccine. In spite of this I don’t want you to make any mistake about the importance of Dr. Syverton’s work. Although investigators couldn’t use HeLa cells for the production and harvesting of poliovirus, they could use such cells immediately and profitably in the laboratory for diagnostic purposes.

O: Dr. Rivers, how much of a problem was it in 1953 to produce

poliovirus in sufficient quantity to make a polio vaccine? | would go so far as to say that, by the time Dr. Syverton had reported

Rivers: I don’t believe that it was much of a problem in 1953. I

490 Chapter 13 his first success in 1952, Raymond Parker at the Connaught Laborator-

ies in Toronto had already taken an important step in solving the problem of producing poliovirus in large quantities in tissue cultures. I have known Dr. Parker for a long time. He is a Canadian by birth and received a good deal of his scientific training at Yale and at the Kaiser Wilhelm Institute in Berlin. I first met him during the early thirties

when he was associated with Alexis Carrel at the Rockefeller Institute. I don’t know how much the latter association contributed to his knowledge of tissue culture work, but there can be no doubting that he was expert in this area. In 1951 Dr. Parker and some of his associ-

ates at the Connaught Laboratories devised a synthetic medium, know as mixture 199, as a nutrient for tissue cultures. It was soon discovered that, when this medium was substituted for the traditional Hanks solution and ox serum filtrate as a nutrient in tissue cultures used to cultivate polioviruses, such cultures could also produce large amounts of poliovirus without the presence of foreign serum. ‘That

work caught Harry Weaver's attention, and in 1952 the National Foundation gave the Connaught Laboratories a special grant to see if

they could adapt tissue-culture techniques to the production of polioviruses in large quantities. Dr. Andrew Rhodes carried that pilot study through very successfully, and when the Salk vaccine came to be produced commercially the Connaught Laboratories were initially chosen to grow poliovirus for American pharmaceutical houses.

Q: Dr. Rivers, before we begin to talk about Dr. Salk’s work, I wonder if you would tell me when you first met him.

Rivers: I first met Jonas Salk in 1940 when he was an interne at the Mt. Sinai Hospital in New York. At the time he and Tom Francis, who had been his professor of bacteriology at the New York University Medical School, had come to the Rockefeller Institute as guest investigators to study the use of ultraviolet light in inactivating influenza virus. I remember that they received much help in this project from Dr. George Lavin. However, I myself saw little of them at this time. I only met Dr. Salk casually and knew little about him save that he was a bright youngster who worked with Dr. Francis. You may re-

member that, when Dr. Francis was appointed professor of epr-

Prelude to the Salk Vaccine 491 demiology at the School of Public Health at Michigan, in addition to his research he also undertook the obligation of developing a training program for young virologists.

In 1942, after Dr. Salk had finished his interneship, he took advantage of this program, and under a fellowship established by the National Foundation resumed his virus studies with Dr. Francis.’ | would like to emphasize here that although Francis’s laboratory spent , a good deal of its time studying poliomyelitis, in the beginning Salk did not work with poliovirus. Instead, Dr. Francis put him to work on influenza and, in particular, purifying and concentrating the various strains of influenza virus for future use in a vaccine.® ‘That work absorbed Salk and was later continued under the auspices of the Influ-

enza Commission of the Armed Forces Epidemiological Board. In 1951 it culminated in his development of an inactivated vaccine, pre-

pared with adjuvants, against both Influenza A and Influenza B strains of virus. I was a member of the Armed Forces E,pidemiological Board, and I can tell you that the vaccine that Salk prepared with adjuvants was a damned good vaccine. It was by no means the first inac-

tivated influenza vaccine ever to be developed—Frank Horsfall, for example, had developed a heat-inactivated vaccine against influenza several years before—but it was one of those that pointed the way to establishing immunization against influenza with an inactivated vaccine as a valid procedure in military medicine.* I would like to add * Technically, Salk’s grant was made by the National Research Council, but the funds for the grant program were supplied by The National Foundation for Infantile Paralysis. * Dr. Francis notes, ““The work I ‘put’ Dr. Salk on was at first his own fellowship request regarding local antibody formation. The influenza work had always been supported by the Commission on Influenza. The purifying and concentrating work was not an assignment but was done in conjunction with my own vaccine objectives and commitments’ (private communication). * Dr. Rivers here has telescoped a series of separate events relating to the making of vaccines against influenza. In 1942 Dr. Francis and his staff at the University of Michigan helped perfect an inactivated vaccine against influenza. Subsequently that vaccine was tested in a well-designed study in the ASTP units of a number of universities by a large group of investigators afhliated through the Commission on Influenza. ‘This study confirmed the high effectiveness of the vaccine, and in 1945 it was used throughout the U.S. Army. Dr. Salk took part in this study. When Dr. Salk later moved to the University of Pittsburgh he continued his work on influenza and in 1951 prepared an adjuvant vaccine against influenza. This vaccine is the one that Dr. Rivers has reference to. See Members of the Commission on Influenza, Army Epidemiological Board, ‘‘A clinical evaluation of vaccination against influenza,” J. Amer. Med. Assoc. vol. 124:982 (1944); J. E. Salk, H. E. Pearson, P. H. Brown, and T. Francis, Jr., “Protective effect of vaccination

492 Chapter 13 that the problem that Salk faced—in providing an inactivated vaccine

to evoke a high level of antibody and to maintain an antibody titer above the critical level required for immunity against influenza was strikingly similar to the problem he later faced in preparing an inactivated vaccine against polio.

I actually came to know Dr. Salk better after his laboratory at the University of Pittsburgh agreed to participate in the National Foundation’s program for typing poliovirus. Harry Weaver, who played a key role in organizing that program for the Foundation, was very much impressed with Salk and communicated his enthusiasm about

his work to the Virus Research Committee. [ know that on more than one occasion he sang his praises to me. It was because of his work typing polioviruses that Salk began to turn up at the conferences held by the Foundation on problems of immunization. I must say that although Dr. Salk was respectful of his elders—which one might expect of a youngster—he nevertheless gave a good account of himself

in the give-and-take that distinguished these affairs. As a matter of fact, if you had a thin skin it was not a good idea to attend these conferences because no one was ever spared. Hell, if you presented a paper or got up to talk, you had to be prepared to be ripped apart. It didn’t matter who you were: if you got up to talk you were a fair target. ‘That was the function of these meetings—it was to examine results and test ideas. Why should anybody be sacred? In 1950, when a number of refinements in typing poliovirus made it feasible to cut back the number of laboratories exclusively working against induced influenza B,” Proc. Soc. Exptl. Biol. Med., vol. 55:106 (1944); J.E. Salk, M.L. Bailey, and A. Laurent, “A safe immunologic adjuvant for enhancing the height and persistence of antibody response to influenza virus vaccines in man,” J. Clin. Invest., vol. 30:669 (1951). Although Dr. Rivers is correct when he credits Dr. F. L. Horsfall, Jr., with being among the first to produce an inactivated vaccine against influenza, Horsfall was by no means the first to work on problems of a vaccine against influenza and was preceded by several years in this activity by a number of American and British investigators. For further details, see A. Chenoweth, et al., “Active immunization with the viruses of human and swine influenza,” Amer. J. Diseases Children, vol. 52:757 (1936); J. Stokes, Jr., et al., “Vaccination against epidemic influenza with active virus of human influenza,” Amer. J. Med. Sci., vol. 194:757 (1937); C.H. Andrewes, and W. Smith, “Influenza: Further experiments on the active immunization of mice,” Brit. J. Exptl. Pathol., vol. 18:43 (1937); F.L. Horsfall, Jr., et al., “Studies on the efhcacy of a complex vaccine against influenza A,” Public Health Rept., vol. 56: 1863 (1941). The problem of influenza is superbly reviewed by R. E. Shope, “Influenza, history, epidemiology and speculation,” Public Health Rept., vol. 73:165 (1958).

Prelude to the Salk Vaccine 493 on typing problems, Harry Weaver encouraged Dr. Salk—whose laboratory you may remember was one of four engaged in typing work—to submit an application to the Foundation for developing a new research program in immunization for his laboratory. He didn’t have to prod too hard, because within a very short period of time, Salk submitted a first rate program to the Virus Research Committee for consideration. The interesting thing about this application is that if you examine it, you will find that Salk initially was far more concerned in searching for nonpathogenic live-virus strains of polio that

could induce immunity than he was in an inactivated vaccine. I would go so far as to say that one of Salk’s secondary projects in passive immunization—one that involved the oral administration of

antibody derived from the yolk of eggs laid by hens previously immunized with all three types of poliovirus—probably absorbed him more in the beginning than working on an inactivated vaccine.® Within a year after starting his new program, Dr. Salk shifted the focus of his attention to study the effect of formalin-inactivated vac-

cines. I think that the impetus for the shift came from two sources. The first was his success in preparing an inactivated vaccine with adjuvants against influenza, and the second was the rapid development of tissue-culture work in his laboratory. The latter development not only allowed him to cultivate polioviruses for his vaccines but also allowed him to undertake quantitative estimations of virus and antibody. It’s easy in the saying, but actually Dr. Salk had to surmount a great many technical problems in order to prepare an inactivated vac-

cine against polio. For instance, although it was known how much formalin was necessary to destroy the infectious nature of poliovirus, no one at that time knew how much in excess of that amount poliovirus could tolerate and still be antigenic. Another typical problem was the necessity of studying the extent to which a virus suspension could be diluted and still induce antibody formation when mixed with adjuvants. Within a year, however, Salk and his associates solved these and other problems. Perhaps one of Dr. Salk’s most significant technical achievements during this period was his extension of techniques for cultivating all *Jonas Salk, Grant Application to The National Foundation for Infantile Paralysis,

July 20, 1950 (CRBS #105, University of Pittsburgh, 1950, National Foundation Archives).

494 Chapter 13 three types of poliovirus in roller-tube cultures of monkey testicular

and kidney tissue. I say this because in the end it was these techniques which supplied him with the material of high antigenic content—especially when combined with an adjuvant—which he needed for his inactivated vaccine. No scientist works alone, and | would like to stress here that some of Dr. Salk’s success in the area of cultivating poliovirus owes much to Dr. Syverton and his team at the University of Minnesota, and to Dr. Charles A. Evans and his associates at the University of Washington for their pioneer efforts in grow-

ing neurotropic viruses in extraneural animal tissues. Be that as it may—by the end of 1951 Dr. Salk was able to demonstrate that he could successfully immunize monkeys against polio by inoculating them intramuscularly with tissue-culture fluids treated with formalin ~ and emulsified with mineral oils. In fact, it was this success which encouraged him in the spring of 1952 to test the effect of his inactivated

preparations on a limited group of children at the D.'T. Watson - Home for Crippled Children just outside Pittsburgh and at the Polk State School at Polk, Pennsylvania.

I think that I should take a moment to tell you something about these tests. First, all of the children who were inoculated at the D. T. Watson Home were paralytic victims of recent polio epidemics. With the exception of one small group, all of these children were inoculated intradermally with formalin-inactivated tissue culture fluids, in aqueous solution, containing the virus responsible for their original infection. ‘The purpose of this test was to learn whether inoculation of such material would act as a booster. The second test was different both in purpose and in the nature of the children tested. ‘The children at the Polk State School were mental defectives who previously, as far as was known, had not had paralytic polio. ‘Those children were inoculated intramuscularly with small amounts of formalin-treated tissueculture fluids containing all three immunologic types of poliovirus emulsified with mineral oils. ‘The purpose of this test was to see if such a vaccine could in fact induce antibody formation in humans. I must say that the initial results of these limited human tests car-

ried a great deal of promise. For instance, the children at the Polk State School who received small doses of inactivated preparations with

adjuvants demonstrated antibody formation for all three immuno-

Prelude to the Salk Vaccine 495 logic types of poliovirus, while the children of the D.'T. Watson Home, who were inoculated with inactivated preparations without an adjuvant, showed antibody formation to type 2 polio. In either case, the data for the level and persistence of antibody fortified the conviction that it was possible to approximate the immunologic effect of the natural disease with an inactivated vaccine. Actually, one of the purposes of the Conference on Immunization in January 1953—which you mentioned earlier—was to give virologists a chance to examine the early results of Dr. Salk’s tests.

Salk’s report? |

QO: What was the reaction of those present at the conference to Dr.

Rivers: Unfortunately, I can’t answer that question firsthand, because I was unable to attend that particular conference. What I know of it comes from a subsequent reading of the minutes of the confer-

ence. However, I will say that you can’t read the minutes without feeling that those present were impressed with Dr. Salk’s achievement. ‘This doesn’t mean that they accepted everything he said, lock,

stock, and barrel—not by a long shot—and I can tell you that they put Jonas through his paces. Some of those present were doubtful that immunization with formalimized vaccines would give antibody levels higher than that produced by a natural infection. Others were skeptical of the use of adjuvants. Many adjuvants at that time were produced commercially and had toxic components that caused rather severe local reactions when given intradermally. Still other virologists were worried about the possibility of organ damage caused by inoculating people with material derived from monkey kidney tissue. They examined Jonas closely—that’s not surprising—these boys would have questioned their own mothers if they were foolhardy enough to give a paper at a conference.

When the problem of whether Dr. Salk’s results warranted his carrying out a field trial later that spring was brought up, a wide variety of opinion was expressed. Dr. Smadel got up and asked, “When are you going to do your Provo test?’”’ Dr. Smadel was bold and at this point, I would say, was even out in front of Harry Weaver. From the January meeting forward, Dr. Smadel consistently preached “‘to get

496 Chapter 13 going and hold a field trial.” Dr. Tommy Turner of Johns Hopkins was another who felt that, if an inactivated vaccine could be produced under rigid standards of safety, an early field trial was warranted. Dr. Sabin on the other hand, counseled against holding a field trial. Like some others at the conference, he too was concerned about the use of

adjuvants and the organ damage that might be caused through the use of monkey kidney material. He particularly urged that more work

be done with animals and even suggested that antibody surveys be made in representative communities. Albert not only looked directly at the question, he looked around it and examined every possible facet, including a few theoretical facets that didn’t occur to others. A number of other virologists, while impressed with Dr. Salk’s results, were at that time simply against the idea of holding a field trial of the

nature of the Provo, Utah, gamma globulin tests. These recommended that Dr. Salk extend his clinical studies on a more limited basis than that suggested by a field trial. Dr. John Enders fell into this

category. I think that it might be helpful if I quoted some of the remarks he made at that time. I am afraid that I can’t quite agree with Dr. ‘Turner if he uses the term “Provo experiment.” I don’t think that we are ready for it. I think, if we do such a thing, it would mean that we would go off half cocked.

What I have heard here makes me think that, first of all, we haven’t decided on the strain of virus that is most suitable to use yet. Dr. Salk is not quite satished with his test for safety in respect to the virus. Further work should be done on that, and careful work. The mode of vaccination,

the route and type of vaccination, adjuvant or no adjuvant, intradermal against intramuscular—we haven’t enough data to decide which to use on a scale of this magnitude. Those are a few of the points that it seems to me we have made a lot of progress on with respect to solving them, but we haven’t got the answer yet, and J don’t think that a large scale experiment should be undertaken until those things have been worked out on smaller groups such as Dr. Salk has already used.

I would suggest more experimentation along the same lines that he is doing so admirably at the moment, and not enter into a large experiment which will inevitably he connected with a lot of publicity and may jeopardize the entire program. I don’t see that we are prepared to go into it in the time that we have at our disposal. I would be very strongly against any thing of the Provo sort this year.® * Minutes of the Meeting of the Committee on Immunization, The National Foun dation for Infantile Paralysis, January 23, 1953, pp. 237-238.

Prelude to the Salk Vaccine 497 I would like to add here that at no time during the conference did Dr. Salk push for a field trial. As a matter of fact, like Dr. Enders, he too spoke of extending his clinical studies, rather than doing a field trial on the order of Provo. He was very cautious. After this canvas of opinion—and believe me when I say that everybody spoke his mind —the conference adjourned. As far as I know, at no time did the conference take a formal vote on whether to do a field trial or not. That was not its purpose. Several days after this conference, Harry Weaver met with me to discuss further the pros and cons of doing a field trial

later that spring. It was not an easy matter. The dilemma that we faced is perhaps best expressed in a memorandum that Harry Weaver prepared for Mr. O’Connor following our meeting. I would like to quote a part of it here:

During the past several months very considerable progress has been made toward the development of a safe and effective vaccine for poliomyelitis. In fact, one of our grantees has developed a vaccine which, when injected intramuscularly, stimulates production of all three poliomyelitis

antibodies in amounts that should be adequate to protect against the paralytic consequences of an infection with the virus. This vaccine already has been injected into 161 individuals without any untoward effects that were discernible.

The practice of medicine is based on calculated risk. Where the risk is known, the physician elects to follow the course that provides the greatest benefit with the least risk of incurring any untoward effects.

It is impossible at this stage of development to predict the degree of efficacy on the one hand, and the degree of safety, on the other, of the poliomyelitis vaccine that has been developed. These questions can only be determined after injecting relatively large numbers of human beings.

There is no question of the facts that with additional research: (1) A still more effective poliomyelitis vaccine could be produced; (2) We would

be better informed as to the kind and frequency of untoward effects that

might result from the use of the vaccine; and (3) We would be better in- . formed with respect to the best route of inoculation, and the best time for

administration, of the vaccine to obtain maximal protection against para- | lytic disease... . If such research is carried out, a very considerable amount of time will elapse before a poliomyelitis vaccine is made available for widespread use; with the result that, in the interim, large numbers of human beings will develop poliomyelitis who might have been prevented from doing so had the vaccine been made available at an earlier date.

498 Chapter 13 It seems to many of us that we have come to a stage where the future course of our work must be governed by both scientific and sociological considerations. At the request of Dr. Thomas M. Rivers, Director of the Hospital of the Rockefeller Institute for Medical Research, I am calling a meeting of leaders in both these fields. During this meeting we will review the status of the poliomyelitis vaccine as of the day of the meeting; attempt to weigh the consequences of moving into the field too rapidly on one hand, as contrasted with postponing field work on the other; and to give the investigator the benefit of our thinking regarding the future course of action he should follow.”

I would like to underscore here our purpose in broadening the base of the new conference to include participants other than virologists. At that time the problem of human experimentation was in the public eye for a wide variety of reasons. For instance, in September 1952, Pope Pius XII had given a speech at the First International Congress on the Histopathology of the Nervous System in which he outlined the Roman Catholic Church’s position on the moral limits of human experimentation for purposes of medical research. ‘That speech had a very broad impact on medical scientists both here and abroad.® At the very same time, the American Medical Association was also trying to sketch principles to guide scientists on the use of human subjects in medical experimental work. ‘This particular attempt was made in

response to the death of three prisoners from infectious hepatitis following a series of experiments in a federal penitentiary designed to discover a method for making whole blood and plasma safely.

Well, how would you weigh those deaths? Would you have stopped the experiments, or would you have continued them? I feel free to ask you these questions, because I was faced with them as a member of the Armed Forces Epidemiological Board. I can tell you now that they weren’t easy to decide. For one thing, there was no settled code or standard to which one could refer regarding such experiments. To be sure, a number of statements on human experimentation had been made at the Nuremberg War Crimes trials. Unfortunately, however, these statements were not clearcut and in some in7 Memorandum, Harry Weaver to Basil O’Connor, January 30, 1953 (Folder, Vaccine, Polio, Salk: Development and Promotion, 1952, National Foundation Archives).

*Dr. Rivers had been much impressed with Pope Pius’s speech, “The Moral Limits of Medical Research and Treatment,’ and later sent his annotated copy to Basil O’Connor (see T’. M. Rivers to Basil O’Connor, January 29, 1953, folder, personal correspondence, 1953, Rivers papers).

Prelude to the Salk Vaccine 499 stances were even contradictory. I will say this, that in the end the Armed Forces Epidemiological Board voted to continue with the whole blood and plasma experiments in spite of their hazardous nature,

because at that time thousands of people were dying annually of infectious hepatitis following blood transfusions and the injection of plasma. I don’t mean by this to compare the dangers of those experiments with tests of Dr. Salk’s polio vaccine—I only want to stress that the general question of human experimentation was one of the key questions that had to be considered in extending Dr. Salk’s tests on the scale of a field trial. Another important reason for broadening the base of the conference was to share the responsibility with Dr. Salk for conducting a field trial if a decision to go ahead was finally reached.

Q: Dr. Rivers, | would like to pursue with you the problem of sharing responsibility with Dr. Salk.

Rivers: Before I answer your question I would like to emphasize once more that Dr. Salk was very cautious about extending his clinical tests to field-trial status during the spring of 1953. I think that his at-

titude was nowhere more apparent than in the comments he made during the special February meeting called by the Foundation. For instance, at one point a discussion that Dr. Salk began on safety tests became so bogged down in detail that it got Dr. Smadel sore. “Look,” Joe said, “if we’ve got something good enough to work on, let’s quit fooling around with minutiae and get down to work. If every vaccine that was ever used on humans was put through half of this, we never would have had any preventive measures at all, because no one would have bothered with them.” I felt like Joe. I was sure that Jonas had an inactivated vaccine that was safe for children. If I didn’t think that, I never would have allowed the Foundation to use my name to call the February meeting. I can tell you that if I had a kid I wouldn’t have

hesitated for one minute to inoculate him at that time with Salk’s vaccine. Damn it, do you know that at this meeting, Salk wouldn’t even call his vaccine a vaccine; he kept calling it an inactivated prepa-

ration. Now, what I have just said doesn’t mean that I was ready to run off half-cocked for a field trial in the spring. It simply means that,

500 Chapter 13 like Samuel Johnson, I realized that nothing would ever be accomplished if we waited to overcome all possible objections.

The basic problem that I and others at the February meeting faced was to decide what measures were necessary to test the safety and

eficacy of Dr. Salk’s vaccine. Now that sounds more complicated than it actually was, because at that particular point the problem of safety was paramount, all other problems such as efficacy were actually secondary. Believe me, when you deal with a vaccine, the first

question that you ask is, “Is it safe?” and if it isn’t you stop right there; you don’t even bother to ask any other questions. In the end we

decided that it wasn’t feasible or necessary to hold a field trial that spring to establish the safety of Salk’s vaccine. Instead we recommended that between five and six hundred children in Alleghany County, Pennsylvania—the site of Dr. Salk’s laboratory—be inoculated with the vaccine well before the onset of the polio season. ‘The limitation on time was important and was made because we wanted to avoid the vaccine’s being blamed for incidents of polio that had nothing to do with the vaccine. You know, occasionally a person will drop dead if you only stick him with a sterile needle. We just wanted to avoid as many untoward, accidental incidents as was humanly pos-

sible. It was felt that these inoculations, plus the 161 children that Dr. Salk had previously inoculated at the D.'T. Watson Home and the Polk State School, would furnish important evidence about the safety of the vaccine in humans. It was contemplated, moreover, that after the polio season—the late fall and winter—such inoculations would be continued in a sufficient number of communities to furnish more data which later might be helpful in evaluating the safety and effectiveness of the vaccine before large-scale trials were undertaken in 1954. These recommendations marked the first step taken for sharing responsibility with Dr. Salk.’ ‘The second involved sending a letter to the Journal of the American Medical Association. ‘The circum-

stances were these. |

Before the February meeting, it was known that Dr. Salk had submitted an article to the Journal of the American Medical Association describing the initial results of the early tests of his vaccine on chil®See also Minutes of Meeting of The National Foundation for Infantile Paralysis, February 26, 1953.

Prelude to the Salk Vaccine 501 dren. That article was scheduled for publication late in March of 1953.” The great fear that existed at the Foundation and elsewhere was that the appearance of the article would create a public demand

for the vaccine, and that great pressure would subsequently be brought to bear on both Dr. Salk and the Foundation for the immediate release of the vaccine. ‘T’o counter that anticipated pressure, I suggested that the meeting join with me in writing a letter to the Journal embodying the recommendations we had earlier made to Dr. Salk for the development of procedures for testing the safety of his vaccines, and in particular to explain the need for such procedures. A long letter was drafted and, after some changes of phraseology, was signed by all those present at the meeting and sent off to the Journal. It was a good letter, but frankly I don’t think that it would have amounted to a hill of beans if the people present at the meeting hadn’t agreed to join with me in signing it. ‘"hese people were eminent in the world of science, government, and education—their names meant something

and afforded protection, because people would stop and listen to them. Believe me when I say that no one in the wide, wide world would have paid any attention to that letter if I had signed it alone.

O: Dr. Rivers, what was the reaction of the American Medical Association to the letter?

Rivers: As far as I know, there was no reaction at all, except that the Journal published the letter in the issue following the publication of Dr. Salk’s article. Dr. ‘Thomas P. Murdock, who was a member of the Board of Trustees of the American Medical Association, and Dr. Austin Smith, who was then serving as editor-in-chief of the Journal, had a great deal of sympathy for the problems involved in developing

a vaccine against polio, and they saw to it that the letter was published. In all fairness, I should add that the Journal also published an editorial underlining the purpose of the letter." However, the AMA 7? Dr. Rivers’ reference here is to J. E. Salk, “Studies in human subjects on active immunization against poliomyelitis. A preliminary report of experiments in progress,” J. Amer. Med. Assoc., vol. 151:1081 (1953). “1 Editorial: “Research on a vaccine for the prevention of poliomyelitis,’ J. Amer. Med. Assoc., Vol. 151:1194 (1953). The letter signed by Dr. Rivers and others appeared in the same issue, on p. 1224.

502 Chapter 13 itself did nothing more. ‘They certainly didn’t do what they later did for Albert Sabin. Recently, as you know, the House of Delegates of

the AMA endorsed the use of the Sabin live-virus vaccines.? That decision, by the way, marked the first time that the AMA has taken such action, and I can assure you that they didn’t do anything comparable for Jonas Salk. ‘They published his paper, sure, but if the vac-

cine had turned out badly I believe that the Journal would have turned around and said, “There was no evidence from the paper we received that the vaccine was dangerous—the fault resides with the author of the article.” ‘That is a set policy. ‘The AMA never takes any blame—and they shouldn’t—for articles published in their Journal. QO: Dr. Rivers, in May of 1953 the National Foundation organized a special Vaccine Advisory Committee to advise the Foundation with respect to the field trials of the Salk vaccine. Why was this necessary when the Foundation already had in being a special Immunization Committee composed of the leading virologists in the country? *°

Rivers: The Immunization Committee, as you say, was made up of distinguished virologists. I would like to add that many—although not all—were also grantees of the Foundation, and each of these in one way or another had a special stake in the polio research then in progress. As is natural, each man’s opinion was a bit biased in favor of what he was doing, especially when it came to a question between his

work and that of another. Now as far as the work of the Immunization Committee went, that bias didn’t matter one whit, because the basic function of the Immunization Committee was to discuss and examine the research that was then in progress. The committeemen presented papers, listened to one another, or fought with one another. 2 Dr. Rivers here has reference to the report, The Present Status of Poliomyelitis Vaccination in the United States, which was approved by the House of Delegates of the American Medical Association on June 28, 1961. 18'The Vaccine Advisory Committee was formed on May 25, 1953. The Immunization Committee of The National Foundation for Infantile Paralysis was created in Apmil 1951 and met for the first time on May 17, 1951. Its original members were David Bodian, John Enders, Thomas Francis, Jr., William McD. Hammon, Howard Howe, John R. Paul, Andrew J. Rhodes, Albert Sabin, Jonas E. Salk, Joseph Smadel, ‘Thomas Turner, and Antonio Ciocco. At various times other experts were invited to join with the Immunization Committee in its conferences and meetings.

Prelude to the Salk Vaccine 503 They were frequently called together so that they and the Foundation could learn what was going on, but they were never an executive committee, and they never had any power to act one way or another. I know that what I have just said is not exactly the view that many

members of the Immunization Committee had of their functions, and some would strongly disagree with my interpretation. Some members always thought that their responsibilities transcended mere discussion, and when the Vaccine Advisory Committee was formed they felt that they were being bilked out of making decisions on the Salk vaccine. I tell you this because I want it clearly understood that some members of the Immunization Committee resented the organization of the Vaccine Advisory Committee. ‘They didn’t keep their feelings secret; as a matter of fact, they were pretty vocal about it. I would like to add that this resentment was not limited to decisions about the Salk vaccine and was revived from time to time, especially when executive decisions had to be reached about live-virus vaccines and orphan viruses. Now I will tell you why Mr. O’Connor created the Vaccine Advisory Committee and the reason why I agreed with him. Mr. O’Connor designed the Vaccine Advisory Committee as a small executive committee whose duty it was to inform the Foundation what was going on, scien-

tifically speaking, and to devise a program for action in developing a vaccine. We didn’t think that it would be proper for anybody who had a personal stake in immunization research—whether it was Salk,

Sabin, or anybody else for that matter—to be allowed to vote for anything. We thought that such decisions were best arrived at by disinterested people who were not necessarily virologists. The com-

mittee that was eventually organized met those requirements. It was made up of Dr. David Price, Dr. Thomas Murdock, Dr. Ernest Stebbins, Dr. ‘Thomas Turner, Dr. Norman Topping, Dr. Joseph Smadel and myself. Some of these names are already familiar to you —TI have previously spoken of Smadel and Stebbins and Turner—

but I will say something of the others. David Price was then the Assistant Surgeon General of the United States, ‘Thomas Murdock was a practicing physician and a member of the Board of Trustees of the American Medical Association, and Norman Topping, who was then Vice President of Medical Affairs of the University of

504 Chapter 13 Pennsylvania, had previously had a long and distinguished career in the U.S. Public Health Service.

Q: Dr. Rivers, most of the members of the committee that you have described seem to have had a larger experience in public health than in virology. As far as I can see, only Dr. Smadel and yourself had previously done laboratory work with viruses.

Rivers: ‘That’s true; however, I think that you ought to keep two things in mind. First, as I indicated before, the problems of the Salk vaccine involved matters of public policy and were not restricted to problems of virus research. Second, people like Price, ‘Turner, Stebbins and Topping were trained public health men and previously had been closely associated in research involving the epidemiology of polio. More important, they were people who were accustomed to examining and weighing scientific evidence. They didn’t have to be virologists to reach a judgment about the Salk vaccine—hell, if they needed a virological viewpoint, Joe Smadel and I were fully capable of

supplying a disinterested opinion. I can tell you quite frankly that | would not have served on a committee where some of the members were people who had a personal interest in either an inactivated or a live-virus vaccine. I have always had the conviction that Mr. O’Connor was right in organizing the Vaccine Advisory Committee—if he hadn’t, I probably would have tried to persuade him to form such a committee.

Q: Dr. Rivers, were there any changes in the personnel of the Vac-

cine Advisory Committee during the consideration of the Salk vaccine?

Rivers: ‘There were two changes. In the fall of 1954, a little over a year after the committee was first organized, Dr. Murdock resigned. Tom Murdock was one of the nicest and fairest men I ever met. He didn’t know anything about viruses particularly, but he could listen to evidence and reach a decision. He didn’t always vote the way I voted, but that made no difference. Plenty of people didn’t think the way I thought. I should make it clear here that this resignation had nothing

_ Prelude to the Salk Vaccine 505 to do with policy. During the summer of 1954, Tom began to have terrible pains in his chest, and upon examination it was discovered that he had an aneurysm of the thoracic aorta. The pain became so bad that his doctor finally advised an operation and it was then that he resigned from the committee. The operation was successful and Dr. Murdock lived for some years afterward. However, although he still took a keen interest in Foundation matters, he could never carry on as actively as he had before the operation. The second person to resign from the Vaccine Advisory Committee was Joe Smadel. Again, the resignation had nothing to do with policy.

Joe, in addition to his regular work as chief of the Virus and Rickettsial Laboratories of the Army, was asked in the winter of 1954 to undertake a special assignment by the government, and he discovered that he just didn’t have enough time to meet all of his obligations, so

he resigned from the committee. However, as you will see, he still continued to play an active role in working on problems relating to the production of the Salk vaccine. I hated to lose Joe, but fortunately we got an excellent replacement in Dick Shope.

O: Dr. Rivers, wasn’t Dr. Shope’s experience mainly in animal pathology?

Rivers: ‘The first thing to remember about Dick Shope is that he is an M.D., and the second is that there are few people in the country who can match his general knowledge of virology. It is true that Dick interests himself in veterinary problems, but it would be a mistake to assume that because of this he has less reverence for human life. Pigs or men, Dick Shope has a reverence for life. I can tell you that when he prepared his influenza vaccine for hogs he wasn’t ready to lose one

hog. Safety was ingrained in him. Oh, I know that you have heard some people say that Dick Shope likes his hogs better than he likes some human beings—hell, I can’t say that I blame him for that. O: Dr. Rivers, previously you described Dr. Weaver's role in developing the Salk vaccine. Did he play any part in planning the field trials to evaluate the vaccine?

506 Chapter 13 Rivers: I would like you to bear in mind that the Vaccine Advisory Committee did not at any time have any administrative responsibilities for carrying out the field trial. ‘Those responsibilities were Foun-

dation responsibilities and in the beginning they fell on Harry Weaver’s shoulders. I must say that Dr. Weaver never shirked these

responsibilities. On the contrary, I think that he embraced them. Long before the Vaccine Advisory Committee ever met, he set about to develop plans for a field trial. For instance, almost the first thing he did was to reorganize the Medical Research Division of the Foundation so that it could become the instrument for holding the trials. As a part of that reorganization, he persuaded Dr. Joseph Bell of the U.S.

Public Health Service to take a leave of absence and come to the Foundation to help him develop epidemiological programs for evaluating the vaccine. I believe that Dr. Weaver planned for Dr. Bell, to eventually be the scientific director of the field trial under his imme-

diate jurisdiction. I don’t know the full ins and outs of subsequent developments, as I wasn’t an employee of the Foundation at the time, but I do know that, just about this time, Weaver got into one hell of an administrative hassle with Hart Van Riper, who was medical director of the Foundation and Weaver’s boss. It’s no secret that the two men didn’t get along very well together. They had fought before this on a variety of issues. Dr. Van Riper was a good pediatrician, but that was about the end of it. Research was just outside of his ken. Dr. Weaver, on the other hand, was a smart, ageressive hombre who knew a great deal about research and the Salk vaccine in particular, and, as I say, wasn’t loathe to push his ideas and assume responsibility for the trial. When Weaver began to reorganize his department, the two clashed. Van Riper claimed that Weaver was going over his head in getting things done, and Weaver claimed that

Van Riper was thwarting his plans for the trial. When Melvin Glasser, who had previously worked very closely with Mr. O’Connor

in the International Red Cross, was hired by the Foundation as assistant administrative director, to coordinate the work of the field trial and other departments of the Foundation, Weaver looked upon the appointment as an expression of a lack of confidence in his ability to plan and carry out the trial and soon afterward resigned.** I will 44 Dr. Weaver resigned his post on August 29, 1953.

Prelude to the Salk Vaccine 507 say this. I personally hated to see Weaver leave, and so for that mat-

ter did Mr. O’Connor. Mr. O’Connor was always very fond of Weaver, and his resignation didn’t affect Mr. O’Connor’s opinion of him one bit. ‘They are friends to this day. The moral should be plain: if you have occasion to fight with your boss, you must also be prepared to leave your job.

QO: Dr. Rivers, how did Dr. Weaver’s resignation affect the development of the field trial?

Rivers: If you mean, did it slow things up, the answer is no. Henry Kumm, who had joined the Research Division of the Foundation a year or two before Weaver's resignation, was appointed director

of research in his place. Dr. Kumm was very knowledgeable about research and particularly well trained in public health, having served for many years as a field officer for the International Health Board of the Rockefeller Foundation in Central and South America. I would go so far as to say that Weaver’s resignation did not immediately affect Dr. Bell either. As a matter of fact, after Weaver left, Bell was formally appointed scientific director of the field trial, and as such was charged with formulating and administering policies and plans for all aspects of the field trial. ‘To help him in this work,

Dr. Thomas Dublin, who was actually hired by Weaver, was appointed as Bell’s deputy.

QO: Dr. Rivers, one of the keys to understanding the subsequent development of the vaccine field trials are the plans that Dr. Bell initially developed for the trial.” Before we discuss these plans, I wonder if you could tell me something about Dr. Bell.

Rivers: At the time that Dr. Bell was hired by Harry Weaver, he was chief of the Epidemiological Unit of the Microbiological Insti* Joseph Bell, Outline of Considerations and ‘Tentative General Plans for an Epidemiological Field Trial of a Poliomyelitis Vaccine, September 8, 1953 (folder, Vaccine, Polio, Salk: Development and Promotion, September 1953, National Foundation Ar-

chives); Summary of a Proposed Plan for a Field Trial, October 1, 1953 (folder, Vaccine, Polio, Salk: Development and Promotion, October 1953, National Foundation Archives).

508 Chapter 13 tute of the National Institutes of Health. He had had a long-time interest in preventive medicine and was widely known as an expert in the epidemiology and prevention of childhood diseases. More particularly, he knew a great deal about vaccines. For instance, Bell was the first to show that alum-precipitated pertussis vaccine gave real protection against clinical whooping cough in children. In the area of

epidemiology, it was his study of an outbreak of O fever in Los Angeles which led the way to the prevention of that disease by demonstrating that the fever was practically confined to the consumers of raw milk from infected cows or to people who lived or worked near infected dairies. Just before coming to the Foundation, Bell also made an important contribution to understanding the epidemiological aspect of Coxsackie viruses in human disease. [ tell you all this to

underline that Dr. Bell was a good choice for the job that Harry Weaver had in mind. He subsequently proved his worth to the Foundation in a number of ways. ‘To my mind, one of the very early impor-

tant contributions that he made to the design of the field trials involved the use of adjuvants in the Salk vaccine.

You may remember that, when Dr. Salk carried out his early tests in 1952 and 1953, several groups of children were inoculated with a vaccine that was emulsified in mineral oils for the specific purpose of enhancing their antibody titers. ‘hese tests were very successful, and initially Salk believed that one dose of an adjuvant vaccine would be sufficient to immunize children. While it is true that many adjuvants were known to be irritating, Salk’s experience—he had participated in inoculating soldiers with an inactivated influenza vaccine emulsified in mineral oil without undesirable reactions—fortified his conviction that it was possible to remove the reactive impurities of commercially produced adjuvants. As a matter of fact, he spent a good deal of time during the summer of 1953 looking for better adjuvants.

I believe that the Vaccine Advisory Committee would have gone along with a vaccine prepared with adjuvants, if it hadn’t been for Dr. Bell. Bell had discovered that, when the influenza vaccine prepared with adjuvants was given to children, they showed a reaction that was quite different from that manifested by adult soldiers. In the case of children, such vaccine proved to be irritating, and a substantial number of children developed swollen painful arms and running abscesses that took months to heal. When the Vaccine Advisory Committee

Prelude to the Salk Vaccine 509 received Bell’s report, we decided against using an adjuvant vaccine. | remember that when we later asked Salk whether he could do with-

out an adjuvant, he replied that he could and intimated that two or more doses of an inactivated saline vaccine would probably give the same result as one dose of an adjuvant vaccine. However, no one at that time actually knew how those injections should be spaced, and Salk himself suggested that studies be instituted to discover the re- . quired interval for optimal effect in giving such a vaccine. I think that

it is fair to say that the decision to use multiple inoculations of a saline-inactivated vaccine in the field trials in part stems from Bell’s

: report. Looking back, I would have to admit that I still don’t know whether an adjuvant in Salk’s vaccine would have caused the trouble that Bell described. I say this, because the Salk polio vaccine is not as irritating a vaccine as the influenza vaccine, and to this day I wish we had inoculated several thousand kids with an adjuvant vaccine to test

Dr. Bell’s contention. I can only say that at that time the Vaccine Advisory Committee was primarily interested in being bloody-well certain that the vaccine that the children got in the trial was as safe and nonirritating as could possibly be made.

Q: Dr. Rivers, didn’t Dr. Bell make other recommendations? Rivers: Indeed he did, and I certainly didn’t mean to imply by this ' short review that Dr. Bell’s recommendations concerning the use of an adjuvant vaccine were the only recommendations he made. Actually, when Bell first came to the Foundation he developed a very detailed model for holding the field trials. At the time he drew up this model, he was particularly concerned with determining whether the Salk vaccine—which was then a laboratory prepared product—could be consistently and uniformly reproduced by pharmaceutical houses on a scale suitable for mass immunization. As a good epidemiologist,

he also wanted to know whether the vaccine impaired the natural spread of polio infection, and whether the neutralizing antibodies induced by the vaccine protected children against naturally occurring paralytic disease. I would say that these questions constituted Bell’s major objectives. To achieve these objectives he recommended that two strictly com-

510 , Chapter 13 parable groups of children of school age be chosen and that one group be inoculated with Dr. Salk’s vaccine and that a second control group

be inoculated with inactivated influenza vaccine. If [I am not mistaken, he originally suggested that both the polio and control influenza vaccine be given to children in the first and second grades, that no vaccines be given to third and fourth grades, and that both vac. cines be given to fifth and sixth grade children. He further suggested that, before the field trials actually began, Dr. Salk institute limited trials with commercially prepared vaccines in about 5000 children in

Alleghany County as a precautionary safety test. | No one had any quarrel with Dr. Bell’s suggestions for limited safety tests with commercially prepared vaccines, but one hell of a fight developed over the question of using an injected control group, and in particular over using influenza vaccine as a placebo. The Vac-

cine Advisory Committee, for example, thought that the placebo should be a normal saline solution. ‘That didn’t suit Bell. He claimed that it would be more ethical to give the control group influenza vaccine because it would do them some good while the saline solution would do no good at all. I don’t really know how far Bell was actually concerned with ethics; I think that it would be closer to the mark to say that as a public health man he saw the held trials as an opportunity to collect data about the effect of influenza vaccine in children, without too much extra effort and expense. In other words, he saw a chance of killing two birds with one stone. Dr. Salk on the other hand was very unhappy with Dr. Bell’s recommendations, so unhappy that a week or two after the Vaccine Ad-

visory Committee first discussed Bell’s recommendations he presented the committee with an alternative proposal for carrying out the field trial. ‘The nub of Salk’s proposal was that a narrow age band of the child population in specific communities—children in the second grade—be inoculated with the test vaccine, and that, instead of inoculating a control group with influenza vaccine, uninoculated chil-

dren in the first and third grades of these same communities act as observed controls. Salk’s proposal found favor with many people in the Foundation, because the use of nonvaccinated controls seemed to confer substantial administrative benefits in running the field trial. For one, under the Salk plan the manpower and time available for

Prelude to the Salk Vaccine | 51] vaccination would be concentrated on giving the vaccine and not be divided between giving the vaccine and the control substance. Second and perhaps even more important, the plan seemed to point a path that would avoid the difficulties that many feared would arise in en-

suring that three identical injections of either the test or control vaccines would be given to the same individuals. Further, many felt

that, by avoiding control injections, the localization of paralysisprovoking effect that sometimes occurred by the mere act of inoculation could be avoided. The question of injected versus observed controls was argued be-

fore the Vaccine Advisory Committee not once but many times throughout the fall of 1953. It was never a tea party argument and the fur flew more than once. Dr. Bell was a good fighter and he was not a dumbbell. It’s true that he was a hard guy to get along with, but, by the same token, some of the people at the Foundation were also hard to get along with. In the midst of these arguments Bell decided that he had had enough and resigned and went back to his old post at NIH.*® In case you are wondering, I can tell you right now that Bell’s resignation did not end the debates over the design of the field trials. Although the Vaccine Advisory Committee did not go along with all of Bell’s recommendations, it did favor his orthodox plan for an injected control over Salk’s plan for an observed control. I remember that several weeks after Bell left the Foundation the Vaccine Advisory Committee met in a special session to discuss this problem once more.

At that time, commercial production of the vaccine was lagging and it seemed highly doubtful whether it would be administratively possible to put on a controlled trial of the size that the Vaccine Advisory Committee had originally deemed necessary. The committee

faced an unhappy dilemma. With the production of the vaccine lagging, if the Foundation ran a limited controlled trial, it also ran the risk of coming up with answers that would not be useful. We all believed that the Foundation had to put on a field trial in the spring of 1954; if it didn’t, the lid would be off and the following year everybody and his aunt would be trying out their own vaccines unless the Public Health Service could put a muzzle on them. It was nothing we *° Dr. Bell resigned on October 31, 1953.

512 Chapter 13 could count on, and in the circumstances we thought it might be more feasible to go along with the alternative plan developed by Dr.

Salk.” I think it is fair to say that, from the middle of November 1953, the Foundation was prepared to run the field trials under Salk’s plan and had even started the ball rolling in that direction. However,

early in December, not more than two or three weeks later, everything stopped as the Foundation reexamined once more whether it was proper for it to conduct the field trial under its own auspices. At that time it was decided that the evaluation of the vaccine had best be done by a scientist outside the Foundation, and Tom Francis at the University of Michigan was chosen to do the job. ‘That choice, | might add, changed the design of the field trial once more.

O: Dr. Rivers, before we discuss Dr. Francis and the new design of the field trial, I would like to ask you whether the government played any role in planning the field trials.

Rivers: I don’t know that I can answer that question in a clean-cut way. If you mean did the government know what was going on, the answer is yes. Dr. David Price, who was then the Assistant Surgeon General of the United States, and Joseph Smadel, who was then Chief of the Department of Virus and Rickettsial Diseases at the Walter Reed Army Center, were both members of the Vaccine Advisory Committee and participated in the various discussions and decisions made by the committee. One of the early decisions that we made directly involved NIH in the field trials. Initially, the Vaccine Advisory Committee was concerned about the safety of commercially produced vaccine and decided that, before such vaccine was passed for use in the field trials, it would have to pass safety tests in three different laboratories—the producer’s laboratory, Dr. Salk’s laboratory, and the Division of Biological Control at NIH. Later the Foundation signed a formal agreement with NIH that the Division of Biological Control would independently test all batches of Salk vaccine prior to the field trials for safety, potency, and sterility. As a matter of fact,

the Foundation even agreed to supply monkeys to NIH for such safety tests. “ Dr. Rivers has reference to a special meeting held of the Vaccine Advisory Committee on November 13, 1953 in New York.

Prelude to the Salk Vaccine 513 Designating three different laboratories to do safety testing did not end the problem, because the Vaccine Advisory Committee soon discovered that it was quite a problem to achieve uniformity in safety testing commercially produced vaccine. It was a problem because the previous direct experience of these laboratories with poliovirus varied. For example, prior to this time the Division of Biological Control at NIH had very little experience with the clinical manifestations and histopathology of polio in monkeys. I will give you an example of

what I mean. In the beginning of safety testing commercially produced Salk vaccine, a certain batch of vaccine which had passed the safety tests at Parke-Davis was sent to NIH for further testing. It didn’t take long before the Division of Biological Control informed the Vaccine Advisory Committee that that particular batch of vaccine was causing polio in monkeys. In the circumstances, I hurried down to Washington with David Bodian. I invited Dr. Bodian to come along because he probably knows more about what takes place in man and monkeys when they are infected with poliovirus than any other person in the United States. Polio, like yellow fever and other virus diseases that attack the central nervous system, leaves a rather characteristic distribution of lesions following infection. Dr. Bodian

examined the sections of the spinal cords of monkeys that NIH claimed had come down with polio and discovered that the so-called polio lesions were in fact old dengue-virus lesions. ‘The monkeys, which had come from the Philippines, had apparently been previously infected with dengue virus and had recovered. I tell this story not to cast any reflection on the Division of Biological Control. The people who worked in that divison were first rate. I just want to underscore that at that particular time they lacked experience in the histopathology of polio. Subsequently, Dr. Bodian, as well as other grantees of the Foundation who were well versed in this area of polio research,

educated the personnel at NIH, as well as the personnel at the laboratories of pharmaceutical houses, so that they could cope with the clinical and histopathological problems of polio that came up during safety testing.

QO: Dr. Rivers, if developing uniform testing procedures was a problem, how much of a problem was it to get pharmaceutical houses to

produce the vaccine commercially in a uniform manner? Did the

514 Chapter 13 Vaccine Advisory Committee have any function in overseeing the production of the vaccine?

Rivers: Most of the poliovirus that was originally used in the vaccines for the field trial was initially grown in the Connaught Laboratories in Canada and then shipped by truck to Parke-Davis and Com-

pany in Detroit to be inactivated and prepared as a vaccine. There was a great deal of red tape in getting such virus into the United States because it was infectious material, and special passes had to be obtained from Quarantine Control of NIH to carry the virus over the

border. Later, Dr. Salk’s laboratory at the University of Pittsburgh also undertook to grow poliovirus, and other pharmaceutical houses such as Eli Lilly, Cutter, Wyeth, and Pitman-Moore, joined ParkeDavis in preparing the vaccine. All the firms charged with producing the vaccine were guided in that production by a detailed set of requirements and specifications. ‘hese covered production of the virus, safety tests in animals and tissue culture, potency tests, and even included such general things as methods of labeling and dating the vac-

cine. Let me emphasize that the key to uniformity in commercial production as well as safety testing of the vaccine were these requirements and specifications. ‘Their preparation was the work of several hands. When the decision to hold a field trial was reached, Dr. Salk undertook to revise the original specifications he had used in producing the vaccine in his laboratory for large-scale commercial production. In the summer of 1953 he gave the Vaccine Advisory Committee his revision.'* However, as the commercial production and safety testing of the vaccine developed that fall, the revised requirements and specifi-

cations were further modified. We waited a while and then asked Jonas to put the new modifications down in a more permanent form. He was working in the laboratory continually during this period, and he just never got around to doing what we asked. As the fall wore on we began to badger him. I would like to explain that writing such specifications was not a little chore. You don’t write up specifications for a vaccine in a para*® See J. Salk, Specifications and Minimal Requirements for an Experimental Poliomyelitis Vaccine August 26, 1953 (folder, CRBS #105, University of Pittsburgh, July 1953, National Foundation Archives).

Prelude to the Salk Vaccine 515 graph or a page. You have to spell out everything and you can take nothing for granted, because if anything later goes wrong you can’t turn around and say to the commercial producer, “Why, any damn fool knows that you should have done thus and so.” Everything has to

be put down, the i’s dotted and t’s crossed. We kept pushing Jonas until, at one Advisory Committee meeting held in Pittsburgh, Joe Smadel climbed his back and insisted that there had to be a cut-off

- point if the requirements and specifications were ever going to be written. Joe was so annoyed that before he realized what he was saying he about half-way volunteered to do the job himself. The com-

mittee didn’t give him a chance to reflect and accepted then and there. Later, Salk sent Smadel a copy of the requirements and specifications that he had worked out, and during Christmas week of 1953

Smadel and Dr. William Workman of the Division of Biological Control at NIH rewrote and revised them to the satisfaction of the Vaccine Advisory Committee. From time to time in 1954, Salk, in collaboration with Workman, added a number of amendments and appendices, but basically the redrafted specifications and requirements which Smadel and Workman set down guided the commercial production and testing of the Salk vaccine.”® You asked whether the Vaccine Advisory Committee was ever bur-

dened with overseeing the production of the vaccine. The answer to that is no. Although the committee was concerned about how the vaccine should be made and tested, it was never directly responsible for guiding and overseeing the actual process of production. ‘The person in the Foundation with that responsibility was Dr. G. Foard Mc-

Ginnes. I have spoken of McGinnes before with reference to the gamma globulin program. Let me add here that originally McGinnes

had been trained in public health at the Johns Hopkins School of Public Health, and, before coming to the Foundation, had had a very wide experience in public health administration, including service in the Tennessee State Department of Health, and as national medical director of the American Red Cross. In the latter post, McGinnes had 7° See J. Salk, Specifications and Minimal Requirements for an Experimental Poliomyelitis Vaccine. Working draft of first revision, November 25, 1953; and especially Joseph Smadel to T.M. Rivers, December 28, 1953; T.M. Rivers to Joseph Smadel, December 30, 1953; and Joseph Smadel to T.M. Rivers, January 26, 1954 (folder, personal correspondence, 1953-1954, Rivers papers).

516 Chapter 13 worked for a time under Mr. O’Connor and they got to know and like one another—so much so that, when Mr. O’Connor later left the Red

Cross, he persuaded McGinnes to become a consultant for the National Foundation on problems of patient care. In this position he actually served as a liaison man between the Foundation, the U.S. Public Health Service, and various medical organizations and phatrmaceutical houses. He maintained an office in Washington and just about knew and worked with everyone. I would say that Foard was an

A No. 1 politician, and I don’t mean to use the word in a derogatory sense—I just mean that he was able to get things done. When the Foundation began to plan the field trials, Mr. O’Connor decided to make McGinnes responsible for getting the vaccine into

production. He hit the nail on the head, because McGinnes again proved wonderfully adept in getting the various people and companies associated with making the vaccine to work together. If that job had been left up to me, it probably would never have been done. I'll tell you why. I am a rough fellow and I didn’t give a damn how pharmaceutical companies were going to meet the requirements for pro-

ducing vaccine so long as they met them. Can you imagine what would have happened if I had done the telling instead of Foard McGinnes? Foard had a way of telling people what to do without getting them mad. If I had told them, they would have gotten mad and closed up shop. Don’t ask me how he did it, because I don’t know. I do know this, I wouldn’t have had his job if you had paid me. QO: Dr. Rivers, did you ever have occasion to tell people off about the Salk vaccine? I raise the question because in one sense the Vaccine Advisory Committee seems to have been designed for meeting and coping with criticism made of the vaccine.

Rivers: ‘That, of course, was not the immediate or specific purpose of the Vaccine Committee, but I will admit that on several occasions we did answer criticisms made of the vaccine both before and during the field trials. Actually, several months before the field trials were held, some members of the medical profession began sniping at the vaccine. I’ll tell you of one such incident because it involved me personally. Sometime early in the fall of 1953, Dr. Salk gave an address

Prelude to the Salk Vaccine 517 at the annual meeting of the American Academy of Pediatrics on his vaccine. His talk was well received and later during the course of the

meetings, the Academy adopted a special resolution supporting the projected field trials. I think that it might be helpful if I quote that

resolution here. | :

When and as it becomes possible to extend studies on immunization of children against polio by means of killed vaccine, the American Academy of Pediatrics wishes to extend to the National Foundation and its cooperating investigators the professional support and cooperation of its entire membership.

I was a member of the Academy of Pediatrics and, although I didn’t attend this particular meeting, I thoroughly approved the resolution. However, not all members felt the same way. About a month after that meeting, Dr. C. Henry Kempe, who was then an assistant professor of pediatrics at the University of California Medical School, wrote a very hot letter to Aims McGuinness, Chairman of the Com-

mittee on Immunization and Therapeutic Procedures of the Academy, urging that the Academy withdraw its endorsement of the field trials. In Dr. Kempe’s view the Salk vaccine at that time was potentially unsafe and of undetermined potency, and as far as he was concerned had been insufficiently tested for a mass field trial. He seemed to believe that there was a reluctance on the part of virologists to go on record against the field trial plans of the Foundation, and he urged Dr. McGuinness to canvass leading virologists for their opinions in this matter. Dr. McGuinness then sent that letter to me and to sev-

eral other virologists and asked us if we cared to make any comment.” I can’t say that I thought much of Kempe’s letter. Mind you, he was no slouch, and although he was still a youngster, he did have a reputation for knowing a good deal about smallpox and the reaction of children to smallpox inoculations. Don’t ask me why he wrote that particular letter because I don’t know. The only thing that comes to mind is that he might have been impressed with reports that Albert Milzer and Sidney Levinson of Chicago had made that they couldn’t °C. Henry Kempe to Aims McGuinness, November 27, 1953; Aims McGuinness to T.M. Rivers, December 26, 1953; T.M. Rivers to Aims McGuinness, December 29, 1953 (folder, personal correspondence 1953, Rivers papers).

518 Chapter 13 inactivate poliovirus using Salk’s methods of inactivation with formalin. Those charges created a great furor, because both Dr. Milzer and

Dr. Levinson were highly respected workers. I remember that Dr. Hart Van Riper was so upset that he went to the trouble of asking Dr. Salk to prepare a rebuttal. It never bothered me, first, because other laboratories which followed Salk’s instructions carefully succeeded in inactivating poliovirus, and, second, because I always believed that Dr. Milzer and Dr. Levinson’s private interest in inactivating poliovirus by irradiation blinded them to the usefulness or efficacy of using other techniques for purposes of inactivation.** Several weeks before I received Dr. Kempe’s letter from Dr. McGuinness a special meeting of the Vaccine Advisory Committee was called to advise Mr. O’Connor whether the Salk vaccine at that time was safe and ready for the field trial. I remember this particular meeting very vividly because Mr. O’Connor invited a special group of leading pediatricians and virologists—people like Rusty McIntosh, Horace Hodes, and ‘Theodore Senn—to aid the committee in its delibera-

tions.?2 Mr. O’Connor often acted like that when he was about to take an important step, because he always wanted to be doubly sure that the ground he was going to walk on was firm. At that meeting the committee reviewed with Dr. Salk all of the protocols and proce-

dures for producing and inactivating poliovirus in preparation for making a vaccine, and came to the conclusion that he had in fact provided exacting safeguards for the safety of the vaccine. Later, we formally expressed these views in a letter to Mr. O’Connor.” I tell you this because, when the question of Dr. Kempe’s letter came up, Mr. O’Connor did not depend on the letter we had sent him earlier, but *1 "This debate broke out following the presentation of a paper by Milzer at a meeting of the American Public Health Association in Chicago on November 10, 1953. Later Milzer retracted a portion of his statement; however, the paper itself was subsequently published. A. Milzer, S.O. Levinson, H.J. Shaughnessy, et al. “Immunogenicity studies in human subjects of trivalent tissue culture poliomyelitis vaccines inactivated by ultraviolet irradiation,’ Amer. J. Public Health, vol. 44:26 (1954). For the furor caused initially by the paper see The New York Times, November 11, 1953, and The New York Herald Tribune, November 11, 1953. 2 Rivers once again has reference to the special meeting of the Vaccine Advisory Committee held on November 13, 1953, in New York.

Vaccine Advisory Committee to Basil O’Connor, December 3, 1953 (folder, Vaccine, Polio, Salk: Development and Promotion, December 1953, National Foundation Archives).

Prelude to the Salk Vaccine 519 instead convened the Vaccine Advisory Committee in a special meeting for the express purpose of answering Dr. Kempe’s criticism. I have

the letter that the committee finally sent to Dr. McGuinness, and I would like to read it here because it answers in a detailed way many of

the criticisms which were made of the Salk vaccine before the field trials. February 4, 1954 Dear Doctor McGuinness: The undersigned Committee on Vaccination which was chosen to advise ‘The National Foundation for Infantile Paralysis regarding the field trials

this coming summer has received a copy of Doctor Kempe’s letter from you. ‘Ihe Committee members have individually considered this letter, and have jointly prepared this reply following a full discussion of its contents at a meeting of the entire Committee which was held in New York City on February 1, 1954. Doctor Kempe points out in his letter that other organizations, such as the American Public Health Association, have not passed resolutions comparable to those passed by the American Academy of Pediatrics. A member

of this Committee who is also a member of the Executive Board of the American Public Health Association assures us that the failure of the Executive Board of the American Public Health Association to enact such a resolution was based not on any question of the validity or safety of the proposed vaccine field trials, but upon an established policy of that Associa-

tion not to enter into active endorsement of any specific study of this nature.

Taking up the questions as Doctor Kempe lists them, the Committee would like to state that vaccine used in the field trials has been and is being prepared in accordance with procedures acceptable to this Committee and acceptable as minimal requirements by the Laboratory of Biologics Control of the National Institutes of Health, United States Public Health Service.

It is the opinion of the Committee that the methods of preparation and . testing provide adequate safeguards as to the non-infectivity of the vaccine insofar as animal and other laboratory studies of a practical nature can be expected to safeguard such procedures. ‘The Committee has satisfied itself

that every reasonable safeguard possible has been incorporated in these standards. A copy of these standards is attached.

Prior to the initiation of the larger field trial an initial group of 5000 children will have received the vaccine, 2500 the vaccine produced in Doctor Salk’s laboratory, 2500 the vaccine produced commercially. In addition

to the tests as set forth in the minimal requirements, for each lot of vac-

520 Chapter 13 cine a group of children will be inoculated and serological studies made to establish antigenic effectiveness of each batch. The second question raised by Doctor Kempe concerning the evidence of antigenicity of the aqueous vaccine is also of importance. He has suggested that available published data concerning the number of children who have received the aqueous vaccine and whose sera have been titrated for antibody levels is limited. However, additional unpublished information has been made available to this Committee as to the consistency of the antigenic response to aqueous vaccine, and other extensive work is in progress to confirm this point. We have assurance that the sera of a minimum of 100 from each of the two groups referred to above in the trial run will be titrated for antibody to establish the comparability of the mass produced vaccine with that produced in Doctor Salk’s laboratory. Animal tests already demonstrate that both products are equally antigenic. The minimum standards for production of the vaccine require that there be no more than two periods of incubation with formalin in a concentration of 1:4000. There is no appreciable change in antigenic activity during this limited period of formalinization. To assure antigenic potency of the

final product the minimum standards require that the vaccine elicit an antibody titer of at least 1:8 when tested in monkeys, and it must also show an antigenic response in human beings.

Treatment of the virus with formalin 1:4000 is carried out in the range pH 6.9 to 7.1. Experience has demonstrated no difficulty in maintaining

the pH within this range. However, should any circumstance prevent proper inactivation of the virus, the rigorous safety tests which the finished vaccine is required to meet, would detect residual living virus.

Although it might be feasible to concentrate the virus particles of the finished vaccine to increase the sensitivity of a test for residual living virus,

the Committee believes the procedure as indicated in the attached standards by which inactivation time is carried beyond the point of disappearance of live virus, provides an adequate margin of safety.

The method of inactivation of the virus as set forth in the attached minimum standards has been duplicated by at least three commercial manufacturers of biologicals. Members of the Committee have, in addition, communicated with a number of laboratories experienced in the field and with one single exception have been advised that it is possible to reproduce Doctor Salk’s methods. The single exception referred to above was reported at the annual meeting of the American Public Health Association in New York on November 10, 1953, and received wide publicity through the press. Those who made that report have since indicated that they had not carried out Doctor Salk’s techniques in detail and they have retracted

their statement'that the techniques could not be successfullv duplicated. With reference to the total nitrogen, according to the minimal requirements for the finished vaccine the batch of filtered tissue culture fluid will

Prelude to the Salk Vaccine 521 be considered suitable for further processing if it contains less than 0.35 mgm. per ml. of total nitrogen, 0.20 mgm. per ml. of amino nitrogen and 0.02 mgm. per ml. of protein nitrogen. It may be noted that synthetic nutrient fluid mixture 199 itself (without kidney cells or virus) contains approximately 0.25 mgm. per ml. of total nitrogen and 0.12 mgm. per ml. of amino nitrogen.

The important practical question, however, is whether the minimal amounts of monkey kidney protein present in the vaccine is in fact harmful to the persons receiving the vaccine. E:vidence indicating that it is not harmful is derived from the observations in over 700 persons thus far vaccinated by Doctor Salk, in whom no ill effects attributable to kidney damage have been observed. In addition, intensive studies are being made on the serological responses

of human beings to this vaccine from the standpoint of the possible development of antirenal substances. ‘The results thus far indicate that antirenal substances are not evoked by the vaccine which, in turn, suggests either

that monkey kidney material is present in very small amounts, or that which is present is not highly antigenic. The Committee and Doctor Salk are fully cognizant of this problem and if any untoward effects are subsequently noted they can be relied upon to take appropriate steps, ‘The vaccine in terms of antigenic capacity has been tested and has been found to be stable for many months. Animal potency tests have been developed and are being employed so that one batch of vaccine can be compared with other batches. Such tests will be made before the vaccine is released for mass trial. For such tests sera from monkeys receiving three doses of vaccine at weekly intervals must have neutralizing titers of at least 1 to 8 when drawn one week after the third dose of vaccine. In addition, tests for antigenic potency of each lot will be made in human beings. It is true that the early available data, March, 1953, were based on the adjuvant type vaccine. ‘The report in Pediatrics, November 1953, was based upon experience with both adjuvant and aqueous vaccine. Since then, information has become available to the Committee on antibody response to aqueous vaccine in children as well as certain animals. Of course, the animals had had no previous experience with the antigen, as was true with many of the children. ‘The response in both was entirely satisfactory and

these data will be published soon. '

The mass field trials as recommended by the Committee will now consist primarily of studies with injected controls and with an adequate sampling of children for pre- and postvaccination antibody titers.

In addition to answering the quesions specifically raised by Doctor Kempe, there is enclosed a statement made by the Vaccine Committee which will be sent to a number of scientific and medical publications, along with a copy of the minimum requirements. The Vaccine Committee sincerely hopes that the answers given in this

522 Chapter 13 communication will be found satisfactory by the Immunization Committee of the American Academy of Pediatrics. Sincerely‘yours,

Tuomas M. RIvers, M.D., Chairman

Committee Members ‘THomMasS P. MuRDOCK, M.D.

Davin E. Prick, M.D. JosepH E. SMADEL, M.D. ERNEST L. STEBBINS, M.D.

NorMan H. ‘TOoprinc, M.D. THomas B. TURNER, M.D.

QO: Dr. Rivers, this might be a good place to discuss in greater detail

some of the problems that came up in producing the Salk vaccine. For instance, wasn’t there a substantial problem in choosing the various strains of poliovirus used in the vaccine?

Rivers: It is true that that was an important problem, but in the main it was restricted to making a choice of the type | strain that we were going to use; making a choice of the type 2 and type 3 strains was not too difficult. All of the strains picked for the vaccine were originally chosen by Dr. Salk. ‘That shouldn’t be too surprising. Remember, through his participation in the poliovirus typing program, Salk had acquired a rather unique and substantial knowledge of the quality and characteristics of the various polio strains isolated in the

United States. He knew what each and every one could do, and initially he chose the Mahoney as his type | strain, the MEF" as his type 2 strain, and the Saukett as his type 3 strain. I should add here that the three strains as finally used in the vaccine were monkey kidney tissue-culture adapted strains. Now, not all polio strdins within a given type are alike, and virologists have known for a long time that some are certainly more antigenic than others. We don’t know why this is so; we only know that it

is so. For instance, although the Mahoney strain is a very virulent type 1 strain, it is nevertheless one of the best type | strains for making antibodies. ‘The Parker strain, which is a less virulent type | strain and does produce antibodies fairly well, still cannot make antibodies

Prelude to the Salk Vaccine 523 as well as the Mahoney strain. From the beginning, a number of virologists opposed using the Mahoney strain in the vaccine, and for a long time the Vaccine Advisory Committee held off in giving final approval to the use of the Mahoney strain. It got so that almost every letter I received from Joe Smadel during the fall of 1953 would ask, “When are you going to pick the goddamn strain?” Joe was anxious to standardize the strains so that various laboratories could plan their serum neutralization tests and other necessary diagnostic procedures. In the end we wound up okaying the Mahoney strain in spite of the

fact that it was virulent. We chose it because it had excellent antigenic qualities. Most of the polio at that time was type | polio and the Vaccine Advisory Committee wanted a vaccine with a good antigenic type | strain in it. I think that we did the right thing, although not everybody at the time agreed with that choice.** Since then, any number of virologists have from time to time wondered out loud whether we should keep the Mahoney strain in the vaccine. ‘The British, for example, use an attenuated Brunhilde strain developed by John Enders and his associates in their inactivated vaccine. However, in the United States most producers, with the exception of Merck, Sharpe, and Dohme, who use the Parker strain, still make the Salk

vaccine with the Mahoney strain. They haven’t switched to other strains because the evidence from the field is that the Mahoney strain has excellent antigenic qualities, and I expect that they will never give it up.

Q: Dr. Rivers, when Dr. Salk presented the results of his early tests with his vaccine to the Immunization Committee in January 1953, Dr. Smadel and Dr. Sabin both raised the question whether the vaccine would cause damage to human kidney tissue.”°

Rivers: ‘That was an important question and Dr. Smadel and Dr. Sabin—and there were others too—had every nght to raise it, and | * David Bodian of the Johns Hopkins Medical School to this day believes that a ‘serious error was made by the Vaccine Advisory Committee in selecting type 1 Mahoney strain for the Salk vaccine. He maintains that this choice did more to antagonize the Committee on Immunization than any other action taken in the making of Salk vaccine (private communication). ~” Minutes of the Meeting of the Committee on Immunization, op. cit., pp. 197-198.

524 Chapter 13 will tell you why. The polioviruses from which the Salk vaccine was made was cultivated in tissue-culture media made up of minced mon-

key kidney tissue suspended in Raymond Parker’s solution 199. Sometime during the early thirties a Japanese investigator named Masugi took rabbits and ducks and immunized them with rat kidney material. Subsequently, he bled those animals and when he put their serum into rats he discovered that the rats showed marked change in

the output and character of their urine, developed ascites and had other symptoms of nephritis. Some years later, Dr. Smadel and Dr. Farr at the Rockefeller Institute repeated Dr. Masugi’s work with great care, and produced beautiful examples of nephrotoxic nephrosis in laboratory animals. The members of the Immunization Committee and the Vaccine Advisory Committee were well aware of this work

and its implications, although nobody at that time had been able to produce lesions in the kidneys by injecting kidney tissue directly into laboratory animals. In his early tests, Dr. Salk had not elicited any evidence of monkey-

kidney-protein sensitivity in the children he had vaccinated, but to be doubly sure the Vaccine Advisory Committee asked Manfred Mayer,

an immunochemist at the Johns Hopkins Medical School to study the problem independently. The results of Dr. Mayer’s study were equivocal. Although he found that children who were vaccinated with

Salk vaccine had an absence of complement-fixing antibody to monkey-kidney antigen, he couldn’t actually tell us whether the children formed such antibody, because there was a very remote possibility that the antibody might have become fixed in their kidneys and thus screened from their blood streams. To exclude this remaining small possibility, the Vaccine Advisory Committee asked Dr. Salk to do kidney function tests on the children then being inoculated in Alleghany County preliminary to the field trials. It was not a simple matter. First, this particular test required a control group, because there was always a possibility that when you inoculated several thousand kids, one or two might come down with a

glomerulonephritis or other things that had nothing to do with the vaccine. Second, all of the children had to be looked at clinically and their bloods and urines carefully examined. At the very least, it was

time consuming. To help Salk, the Vaccine Advisory Committee

Prelude to the Salk Vaccine 525 asked Dr. Robert Korns of the New York State Department of Health, who was then acting as a deputy to Dr. Francis in setting up the field trials, to go to Pittsburgh to supervise the clinical examination of all children who were absent from school for three or more days following vaccination with the Salk vaccine. Those tests were

carried out meticulously and in the end proved that any fears we might have had about monkey-kidney-protein sensitivity were groundless.°°

O: Dr. Rivers, early in 1954 workers at the Connaught Laboratories in Toronto discovered B virus in some lots of monkey kidney tissue, and some investigators in that laboratory became quite concerned about the implication of that discovery for the production and use of Salk vaccine.”

Rivers: It agitated some of them all ght, although for the life of me I don’t know why. I am not saying that B virus wasn’t a dangerous

virus. | have known about B virus since Albert Sabin isolated and named it following the death of Dr. William Brebner from a monkey bite back in 1932. I am saying that it didn’t constitute a very great hazard in the production and use of polio vaccine. For one, B virus is very easily demonstrated by injecting material into rabbits. Rabbits are very susceptible to the virus and even a very small amount will bring a rabbit down. For another, as a rule B virus is much more susceptible to formalin than poliovirus and it is easily inactivated. I knew that and other virologists knew that, and it has always been my feel-

ing that the people at the Connaught Laboratories should have known that: To be perfectly fair, not everybody at the Connaught Laboratories was upset by the discovery of B virus. Dr. Robert DeFries, who was then director of the laboratory, took the discovery in stride. If it had been left to him, I seriously doubt whether any fuss would have been made at all.

The person who really agitated the question was Dr. Clennel E. Van Rooyen. Dr. Van Rooyen was a Canadian by birth who before World War II had achieved an international reputation as a virologist 6 The tests were carried out from December 1953 through April 1954.

Robert DeFries to Hart Van Riper, February 8, 1954 (folder, CRBS Appr. #19, Connaught Laboratories, 1954, National Foundation Archives).

526 Chapter 13 by publishing a large, compendious textbook called Virus Diseases of

Man in collaboration with Dr. Andrew J. Rhodes, one of his colleagues at the University of Edinburgh. After World War II, Van Rooyen returned to Canada and took a post as director of research at the Dufferin division of the Connaught Laboratories. Van Rooyen’s opinions carried great weight in ‘Toronto, and when he began to voice his concern about the discovery of B virus in monkey-kidney tissue there were repercussions in New York, and Mr. O’Connor decided that it would be wise to call a special meeting to discuss the problem. Mr. O’Connor’s action in calling the meeting is understandable. The Connaught Laboratories was a key to the production of poliovirus and any problem that affected that production would, of course, have had serious repercussions on the field trial which was then just about ready to get under way. A meeting was arranged *° and a spe-

cial delegation composed of Dr. DeFries, Dr. Van Rooyen, Dr. Rhodes, Dr. Fraser, and a lawyer from the University of ‘Toronto came to New York on behalf of the Connaught Laboratories. Mr. O’Connor, Henry Kumm, Hart Van Riper, and I appeared on behalf of the Foundation. In this particular instance I told Mr. O’Connor that it would be unnecessary to convene the Vaccine Advisory Com-

mittee. The meeting, as I remember it, went very smoothly. Van Rooyen raised his questions and I tried to answer them. In substance I said what I told you earlier. I don’t think that I had much trouble convincing DeF ries, Fraser and Rhodes that B virus wasn’t a grave problem, but it did take me the better part of a day to do it. Later I belie¢ve the Connaught people sent the B virus they had isolated to John Enders so that he could compare it with some unknown monkey viruses that Dr. Robert Rustigian had earlier isolated in Chicago. In the course of that work Dr. Enders confirmed my contention that B virus was easily inactivated by formalin. ‘To sum up, I would say that B virus never really interfered with the production and use of Salk vaccine. At best, it was a tempest in a teapot. There were any number of such troublesome incidents before the field trials got under way. One that I remember very well was brought

about by a report made by Dr. Fred Stimpert, who was director of microbiological research at Parke-Davis and the man who had the responsibility for producing Salk vaccine for that company. In brief, *® This meeting was held on February 10, 1954.

Prelude to the Salk Vaccine 527 Dr. Stimpert reported that during the course of some safety tests, he inoculated some tuberculin-sensitive guinea pigs with material from a recently produced lot of Salk vaccine and discovered that the animals had developed positive reactions. He interpreted these reactions to mean that that particular lot of vaccine either had tuberculin in it or had a substance which was biologically indistinguishable from tuberculin. It was a grave report and when it reached the Foundation it just about set everybody off. Mr. O’Connor was so upset that he came to my office at the Rockefeller Hospital to discuss the report. It was one of the few times in my long association with Mr. O’Connor that

he made that trip. ‘There was no doubt that the matter had to be cleared up. If that report had ever become public before the Foundation had an answer, there would have been the devil to pay. A number of investigators who had been called on the telephone suggested

that there was a possibility of a nonspecific false positive result. Others thought there might have been a contamination in the laboratory. They were certainly reasonable suppositions, but they had to be tracked down and nailed. What we needed was somebody who knew about the tuberculin reaction in guinea pigs. Luckily, such a person worked at the Rockefeller Institute. I am speaking here of Mermill

Chase. Early in his career Dr. Chase had worked with Karl Landsteiner, and it is not hyperbole to say that Merrill Chase probably knows more about hypersensitivity reactions in guinea pigs and other laboratory animals than anybody else in the United States or, for that matter, the world. I asked Merrill to check Dr. Stimpert’s findings, and he got right down to work. He is much like Landsteiner when it comes to investigation—he is all business. In a little under two days, he demonstrated that Stimpert’s results were incorrect and that the so-called tuberculin reactions occurred in control animals as well as in

tuberculin-sensitive animals. He eventually traced the reaction to merthiolate, a mercury containing compound which was used as a preservative in the vaccine. That settled the matter, but I can tell you that before Dr. Chase’s report was made, a hell of a lot of people were unsettled.

O: Dr. Rivers, material in the National Foundation files indicate that in 1954 you heard a rumor that Dr. Sven Gard of Sweden was cultivating poliovirus in human embryonic tissue preparatory to mak-

528 Chapter 13 ing a vaccine against polio. I raise the issue because the news apparently upset you.”

Rivers: You are damn right, I was upset. I wasn’t upset at the fact that Dr. Gard was undertaking to make a vaccine; I was upset because

he was cultivating the virus for that vaccine in human embryonic tissue. I believed that by doing that he had a good chance of picking up hepatitis virus. ‘This, by the way, is one of the reasons why nobody in this country will approve a vaccine made by such techniques. Sven Gard is a first-rate investigator and, while I have no doubt that he was

concerned about hepatitis virus, I do not believe that he was as impressed with the harmful effects of the virus as investigators in this country. We had that attitude because we had quite a big mouthful of hepatitis during World War II. Hepatitis is a disease that doctors used to call catarrhal jaundice, and at one time it was believed that the disease was caused by mucus blocking the main bile duct of the liver. However, early in World War II we learned that the disease was

really caused by a virus, when a hell of a lot of boys in the service came down with hepatitis following inoculation with yellow fever vaccine that had human serum in it. Many died. ‘That experience had a profound effect on me, and since then I have always balked at anyone’s taking a chance on having human serum or human tissues in a polio vaccine, period.

Since we are talking about hepatitis, I would like to talk about another aspect of the hepatitis problem, because it later became important in the administration of the vaccine during the field trials. After World War II there was a serious outbreak of hepatitis among soldiers stationed in Germany, and John Paul was sent by the army to investigate the epidemic. He soon discovered that this particular epidemic had its origin in the fact that needles of hypodermics were not properly sterilized following routine inoculations. Dr. Paul’s experience alerted the Vaccine Advisory Committee to still another hepatitis hazard, that of inadvertently transmitting the virus during routine inoculation with polio vaccine. I don’t mind telling you that before the field trials were put on, I was more concerned that children * News release on Gard vaccine, April 9, 1954 (folder, Sven Gard, Public Relations Files, National Foundation Archives); T. M. Rivers to Fritz Buchtal, February 11, 1955 (folder, personal correspondence, 1955, Rivers papers).

Prelude to the Salk Vaccine — - 529 might come down with hepatitis than I was with the possibility of their coming down with polio because of live virus in the vaccine. I’ll tell you why. When a doctor injects anyone with formalinized material, he is always afraid that he might put it directly into the vein causing convulsions and other complications. To avoid such a possibility,

he usually pulls back on his needle to see if he is going to get any blood. Nine-hundred-and-ninety-nine times out of a thousand, he doesn’t get any blood and he continues giving his injection. However, when he pulls back, he sometimes also pulls back a little juice from the subcutaneous and muscular tissues, and on occasion even a little

blood from a small blood vessel. If the person being injected has hepatitis virus, there is an excellent chance that this procedure has contaminated the needle, syringe, and contents of the syringe with hepatitis virus. You must bear in mind that even an infinitesimal amount of hepatitis virus from such juice or blood will suffice to contaminate, and if the proper precautions are not taken the next person inoculated with these materials can become infected with hepatitis. Before the field trials, the Vaccine Advisory Committee worried a

great deal about this hazard until Henry Kumm reminded us that, when yellow fever vaccine was given in South America, hepatitis never became a problem because the physicians giving the vaccine

were instructed not to pull back on the needle. Later, when the Foundation prepared a handbook of instructions for those participating in the field trials, similar directions were given to physicians, and a special point was made of instructing personnel to autoclave all needles and syringes for a period of at least twenty minutes following their use in inoculating children.

Q: Dr. Rivers, you just mentioned that you had no great fears that live virus would turn up in the Salk vaccine. Yet just before the field trials got under way Dr. Hart Van Riper, the medical director of the National Foundation, made a public announcement that four batches of commercially produced Salk vaccine had to be discarded because of the discovery of live virus in these batches. Could you tell me the procedures which the Vaccine Advisory Committee followed before they released the Salk vaccine for use in the field trials? °° °° Hart Van Riper, News release, April 5, 1954 (folder, Vaccine, Polio, Salk: Development and Promotion, April 1954, National Foundation Archives).

530 Chapter 13 Rivers: Although it is true that live virus was found in four batches of commercially produced vaccine, in each case the Vaccine Advisory Committee found that the companies involved had not followed the procedures for inactivating the virus as carefully as they should have. In each instance the live virus was discovered in the safety testing. As I mentioned earlier, all batches of commercially produced Salk vaccine were tested independently in three laboratories—the producer’s laboratory, the laboratory of the Division of Biological Control of the National Institutes of Health, and Dr. Salk’s laboratory. ‘These tests were uniform for all laboratories and set out in detail in the minimum requirements and specifications for making the vaccine. I would like to quote a portion of the specifications for safety testing in monkeys here verbatim. Final Vaccine Test for Active Virus in Monkeys: A formaldehyde neutralized sample of the final vaccine without added preservative is inocu-

lated intracerebrally in 1.0-ml amounts into each of 12 rhesus or cynomolgous monkeys and intramuscularly in 10-ml amounts into 6 healthy cynomolgous monkeys. The intracerebral inoculation consists of 0.5 ml into the thalamic region of each hemisphere and the intramuscular inoculation of 2.5 ml bilaterally into the gastrocnemius-soleus and the biceps muscles. ‘he monkeys are observed for 28 to 33 days and symptoms suggestive of poliomyelitis are recorded. At least 8 of the intracerebral test monkeys and at least 4 of the intramuscular test monkeys must survive the test period. Histopathologic examination is made of all monkeys which die or survive the test period. The lot of vaccine is considered satisfactory if no lesions suggestive of poliomyelitis are present. If minimal inflammatory lesions of questionable significance are present in one or more monkeys an enlarged sample of sections from these animals may be examined, but the lot of vaccine is not considered satisfactory unless the enlarged sample permits reclassification into the negative category of no lesions suggestive of poliomyelitis.*1

I read this specification to you, because I think it is fair to say that in the beginning not all virologists were satisfied with safety tests in monkeys alone and some requested additional tests in chimpanzees. | remember that at one point, when the requirements were being discussed at a meeting of the Immunization Committee, Howard Howe * From Minimum Requirements, Poliomyelitis Vaccine. First revision, April 12, 1955, p. 3 (folder, Salk Vaccine Requirements, Rivers papers).

Prelude to the Salk Vaccine 531] of Johns Hopkins suggested that the vaccine be safety-tested by inoculating chimpanzees intraspinally. The Vaccine Advisory Committee

did not accept that particular suggestion not only because it would have taken the U.S. Mint to conduct such tests, but also because the committee believed that chimpanzees like men were less susceptible to poliovirus than monkeys. In other words, while it is easy to bring a monkey down with an intraspinal inoculation of poliovirus, it is more

dificult to bring a chimpanzee down by such a technique, because chimpanzees are more resistant to poliovirus than monkeys are. The committee felt that in dealing with an inactivated vaccine an intracerebral inoculation of poliovirus in monkeys was a severe enough test. I do not believe that that particular safety requirement for the Salk vaccine was ever modified, although it is true that other safety tests were later added to the orginal requirements.

QO: Dr. Rivers, I take it that when the Salk vaccine passed the safety tests in all the laboratories it was released for use in the field trials.

Rivers: No indeed. After a particular batch of vaccine passed the safety tests in all three laboratories, all the protocols of production and safety testing were sent to Dr. Theodore Boyd in the Division of Research at the National Foundation. Dr. Boyd then checked all the production records—the amount of protein, pH, temperatures, and so forth—against the minimum requirements and specifications and very carefully noted if there were any differences between the two. The

pharmaceutical houses, as near as | can make out, put down their findings honestly and scrupulously. When Dr. Boyd completed his analysis he would send me all the records and his notes for final approval. By ad hoc agreement with NIH, I would only release vaccine for use when a certain number of consecutive batches of vaccine from a particular producer met all of the production safety and potency requirements. I forget now the exact number of consecutive batches

that had to be passed but the important thing to remember is that they had to be consecutive batches. I would not release a single batch on its own. There was quite a hassle about this, so keep it in mind. I

will say this, the vaccine that I finally approved might have a little more protein than the specifications allowed, or the pH might be 7.1

532 Chapter 13 instead of 7.2, or the temperature for inactivation might have varied and not been just so. My final decision to pass the vaccine always hinged on whether the safety tests in all three laboratories showed that no live virus was present. I could always depend on Dr. Boyd to bring to my attention any factor that didn’t quite hit the mark. QO: Dr. Rivers, was Dr. Boyd a virologist?

Rivers: No. ‘Theo Boyd is a physiologist—and a damn good one. He studied physiology with old Ajax Carlson at the University of Chicago. I don’t know what he did immediately after he got his degree,

but I do know that before he came to the National Foundation he was a professor of physiology at the Loyola University Medical School

in Chicago. Boyd is an extremely unusual person, and I suspect that the only reason he hasn't reached a pinnacle in science is that he is one of those rare people who is not concerned about himself. There are not many like that around, you know. Although Boyd has never worked with viruses in the laboratory, he is probably one of the best informed men about virology in the country, and to my mind knows a great deal more virology than a lot of so-called virologists. Not only is his knowledge accurate, he uses it in an accurate manner. One of the best measures that I know of Boyd’s scholarliness is a review that he

wrote On immunization against polio. That review was so good that the Bacteriological Reviews published it as a special supplement to one of its numbers.” ‘To my knowledge, the Society of American Bacteriologists had never before or since accorded such an honor to a physiologist. I think you can see from what I have said why I could depend on Theo Boyd. Hell, I still depend on him. Today he is director of the Division of Research at the Foundation.

O: Dr. Rivers, what was the attitude of NIH to the field trials, given the discovery of live virus in several batches of commercially produced vaccine?

Rivers: Just before the Vaccine Advisory Committee gave its final approval to the use of the vaccine in the field trials, we held a meeting 2 'T Boyd, “Immunization against poliomyelitis,” Bacteriol. Rey., vol. 17:339 (1953), also later issued as a special supplement.

Prelude to the Salk Vaccine 533 in Washington with NIH to review the protocols of all the vaccine produced up to that time.** I will tell you plainly that Dr. James Shannon and Dr. Victor Haas of the U.S. Public Health Service at that time were against passing the vaccine. As a matter of fact, Dr. Haas said that in his view the vaccine was dangerous and that he would not give it to his own children. When Dr. Shannon presented statistics to prove that commercially produced vaccine was unsafe, | just about hit the ceiling. It was apparent to me and other members of the Vaccine Advisory Committee that the batches of vaccine that contained live virus were due to faulty production techniques, and that, if the producers followed the requirements and specifications which were laid down, a perfectly safe vaccine could be and was made.

Let me give you an example of what I mean. During the process of inactivation in one of the companies—I am not going to tell you its name—live virus was passed from one tank connected on its underside with a pipe and pitcock to another tank. The virus was inactivated in the second tank and when inactivation was completed passed through the pipe back to the original tank. ‘The only trouble with that procedure was that nobody had bothered to clean the pipe or the first tank after the live virus had been siphoned off to be inactivated. No wonder there were batches of vaccine with live virus.

Here Jim Shannon was counting statistics, and statistics had noth-

ing to do with the case. I got madder than hell. Luckily, Dave Bodian , was there and he came to my rescue. Dave in his quiet manner polished off everybody pretty thoroughly, but the meeting dragged on

until we finally agreed that other people ought to be brought in the next day to join the deliberations.** After the meeting, Mr. O’Connor took me aside and said, ““T'om, I want you to go back to New York The meeting was held on April 24 and 25, 1954, in Washington. An agreement between the National Foundation and NIH was signed on April 25, 1954 (folder, personal correspondence, 1954, Rivers papers). ** Dr. Bodian points out: “Rivers is less than fair to Shannon here, since Shannon’s

statistical point became the basis for the requirement that a given number of consecutive lots must be clean before any one of them can be passed. Earlier Rivers emphasizes this as one of his major requirements in accepting batches for the field trial, but the device was Shannon’s. My only accomplishments at this meeting, which I attended as consultant for the National Foundation, were to dispel the unwarranted fear of nonspecific brain lesions in monkeys, and to support Shannon's idea for certifying batches of vaccines” (personal communication).

> 34 Chapter 13 tonight and cool off. Forget the meeting tomorrow, come back tomorrow night.” I was hot under the collar, but I took his advice and went

back to New York, and I suppose that I did cool off a little bit. The next day the new people who were brought in suggested that producers had to submit a certain number of consecutive batches of vaccine that passed all the safety tests before any one batch would be passed for use in the field trial. After that meeting Mr. O’Connor, anticipating that the Vaccine Advisory Committee would now approve the vaccine for use in the field trials, drew up a series of recommenda-

tions signifying that approval. When I returned to Washington that evening, he showed me the recommendations that he had drafted and then made me sit down with him to polish and rephrase them. The next morning the Vaccine Advisory Committee met, and after reviewing the discussions held at NIH approved the use of the vaccine for the field trials. When everybody had signified approval of the vaccine, Mr. O’Connor produced the recommendations that we had worked on the night before. I sat back and watched. You know how people are—they made several changes,—nothing important, and then everybody signed. Later, these signed recommendations were sent over to NIH and they issued a statement that our recommendations were sound and that the National Foundation was justified in holding the field trial.

Q: Dr. Rivers, earlier you mentioned the selection of Dr. Thomas Francis as director of the field trial. Can you tell me how he came to be chosen?

Rivers: As I told you before, originally, the Foundation planned to evaluate the vaccine under its own auspices. However, when Joseph Bell resigned his post as scientific director of the field trial, the Vaccine Advisory Committee and a number of state health officers took the opportunity to urge the Foundation to reconsider its original plan.

. We all felt that it would be wiser to have the evaluation of the vaccine made by a scientist outside the Foundation and preferably one connected with a university. Although I cannot now pinpoint the exact date when the Foundation began to look for such a scientist, |

do remember that I consulted a number of times with Hart Van

Prelude to the Salk Vaccine 535 Riper about such a person late in November and early December of 1953. My first recommendation was that the Foundation try to get Dr. Francis Schwentker then a professor of pediatrics at Johns Hopkins and a very smart fellow to do the job. Van Riper took my advice

and made him an offer but he turned it down. Thank God that he did. If he had accepted, I think that the trials might have ended disastrously. I say this because at the time the offer was made Dr. Schwentker was seriously ill—I didn’t know about it—and a short time later he committed suicide.

After Schwentker’s refusal a number of other names were thrown in the hopper. I can’t honestly say now who first mentioned Tommy Francis’s name. I do know that, once his name was mentioned, Dr. Van Riper made immediate overtures to him. It wasn’t easy. At the time Francis was on a sabbatical leave in Europe and it took more than one cablegram to bring him back to this country. When he returned he spoke to Van Riper and then came to see me at the Rockefeller Institute. Francis must have spent about a half a day pacing up and down my office discussing the various aspects of the offer that Van Riper had made to him. I have known ‘Tommy Francis for over twenty-five years. He is an extraordinarily intelligent man, but he does

have a hell of a time making up his mind. He certainly had qualms about taking on this job. First, although evaluation of the vaccine fitted in with his interests in epidemiology and study of disease control, he didn’t consider it research. I think that in part his fear here was that, if he undertook to do the evaluation, it might result in the Foundation’s discontinuing its support of the research grants he was then working under. ‘There was, of course, no such jeopardy, but he thought of it all the same. I don’t know if I have made myself clear. Uhe thing I would like to emphasize is that Dr. Francis wanted assurances from the Foundation that this new job would not in any way jeopardize or interfere, even

for a brief period, with the continuity of his research interests. Perhaps his greatest qualm, when he spoke to me, related to the thenannounced design of the field trial. Briefly, Francis had serious reservations about doing an evaluation based on observed controls alone. He firmly believed that the most effective procedure for measuring

the effect of the vaccine was through studies based on an injected

5 36 Chapter 13 control. While he was willing for the evaluation to be based in part on an observed control, he was adamant that the integral and major part of the field trials had to be based on an injected control. Actually, this was not as much of a problem as Francis thought it would be, because by the time he was approached to evaluate the vaccine a substantial number of state health officers had indicated to the Foundation that they preferred injected control studies to be made in their states. ‘That battle was won even before Dr. Francis stated his position.®°

Many scientists, when they receive a grant or undertake a job for a

foundation or government, are very sensitive about what freedom they will have in carrying out their work. Dr. Francis was no different. He wanted assurances that a special evaluation center would be set up at the University of Michigan and that he and the center would have complete control over all the collected data, codes, and rights of publication. I was amused by this, because I didn’t think that the Foundation wanted it any other way. I was, of course, right. In the end, the

Foundation agreed to all his demands and an open-end grant was made to the University of Michigan to establish a special evaluation center to carry out the study.

O: Dr. Rivers, signing an agreement is one thing, living with it is quite another. Was there any conflict between Dr. Francis and the Foundation in carrying out the field trials?

Rivers: If you mean, did the Foundation bother Dr. Francis in the running of the field trials, the answer is no. On the contrary, there was

a good deal of cooperation between the two. For instance, when it

came to choosing those areas best suited for holding the trials, Gabriel Stickle of the Foundation’s statistical department helped Dr. Francis and his associates choose the counties most likely to experi*5 Although Dr. Rivers is correct in saying that many state health officials preferred

injected control studies, his belief that the battle was won before Dr. Francis stated his position is incorrect. Dr. Francis engaged in negotiations on this and other points with the Foundation for almost a month before accepting responsibility for the trials. See Hart Van Riper to Thomas Francis, Jr., December 10, 1953; Hart Van Riper to Basil O’Connor, January 13, 1954; Thomas Francis, Jr., to Basil O’Connor, January 25, 1954 (folder CRBS Appr. #19, University of Michigan, 1953, National Foundation Archives).

Prelude to the Salk Vaccine 537 ence epidemic conditions during the trial with a great deal of accuracy. The intricate reporting forms used in gathering statistics for the evaluation was in part the work of still another Foundation staff member, Dr. ‘Thomas Dublin.** Actually, I can’t begin to detail the hundreds of ways in which the Foundation cooperated with Francis, save to say that such cooperation ranged from sending him detailed reports of polio admissions in hospitals throughout the country to recruiting professional personnel to do muscle evaluations. In my view, one of the Foundation’s most important contributions prior to the holding of the trials was to call a series of conferences with its grantees so that they could discuss with Francis the problems involved in taking blood samples and standardizing laboratory procedures for virus recovery, preparing antisera, and doing serum neutralization tests. Come to think of it, it is wrong merely to stress the cooperation between the Foundation and Francis. Most of the virus laboratories in the country cooperated as well. They knew that one man and one laboratory couldn’t do the work alone and they willingly took on the

many laboratory burdens that had to be done. John Paul and Joe Melnick at Yale, Herbert Wenner at the University of Kansas, Edwin Lennette at the University of California, Howard Shaughnessy at the State Health Department of [linois, Dave Bodian and Howard Howe at Johns Hopkins, John Enders at Harvard, Morris Schaefter at the government laboratories in Montgomery, Alabama—and there were others—all did their share and more. You can take it from me if these boys had not cooperated there wouldn’t have been a successful field trial. 86 Rivers’ statement on the role of Gabriel Stickle and Thomas Dublin, Jr., in the preparation of the Salk vaccine field trials should be amended. Although Stickle helped in the selection of the counties used in the field trials, his work was adjunct to that of the Vaccine Evaluation Center at the University of Michigan. Again, although both Mr. Stickle and Dr. Dublin helped in the preparation of some of the reporting forms later used in the field trials, these forms were drafted to specifications drawn up by Dr. Francis. Later they were revised and modified by Francis. The final decision as to use was at all times the responsibility of Francis and his associates at the Vaccine Evalluation Center at the University of Michigan.

CHAPTER l 4 |

Salk Vaccine and Sabin Vaccine—1954-1958 Thirty years ago Franklin D. Roosevelt had a tremendous dream—a

. dream that the public could and would participate with scientists in lifting a fear from the minds of mothers and fathers and children, not only in the United States of America, but all over the world. If we think of the solution of the problem of paralytic poliomyelitis in terms of eliminating one fear besetting the people of the entire world, the activity we have conducted takes on even greater significance. Basil O’Connor, An Address on the Occasion of the Presentation of the Francis Report, April 12, 1955

Q: Dr. Rivers, what impact did the development of the Salk vaccine and the field trials have on the other research that the National Foundation was then supporting?

Rivers: ‘That support went on. The Virus Research Committee and Mr. O’Connor always understood the necessity for maintaining continuity in polio research, just as they always understood the need for supporting basic research in virology. If you will examine the grants approved by the Virus Research Committee during this period, you will find that more than half were devoted to basic virus research. For instance, during this period Barry Commoner received several grants to develop his investigations of the biochemical mechanisms which govern the synthesis and reduplication of tobacco mosaic virus. Linus Pauling received support to investigate by means of x-ray diffraction the structure and molecular composition of plant and animal viruses. Earl Evans was given several grants to continue his investigation of 538

Salk and Sabin Vaccines—1954—1958 539 the biochemistry of bacteriophage. ‘There were, of course, many other grants of a similar nature. I only cite these as typical examples. Now, I am not saying that investigators weren’t worried about their support —they were. Hell, I received letters every other day in 1954 and 1955 asking me whether the Foundation would continue to support this or

full. |

that work. There were trepidations, and [ will admit that on several occasions during this period not everybody got the exact sum of money they put in for, but in most cases support was generous and

Let me reemphasize: although the Salk vaccine had been developed and was then being tested, if an investigator had an important lead about the fundamental nature of poliovirus and needed support to continue his research—vaccine or no vaccine—he was supported.

Let me give you an example of what I mean. Sometime in 1954, Gregory Schwartzman, an investigator at the Mt. Sinai Hospital in New York, discovered that when he injected poliovirus into hibernat-

ing hamsters, the virus located itself in brown fat but did not pene trate the central nervous system. Initially, Dr. Schwartzman wondered whether poliovirus remained in the brown fat of the hamsters in a latent state. Later, when brown fat was discovered in humans, he thought the persistence of poliovirus in the brown fat of a person who had been infected and had recovered might well be a source of spreading the virus at a later time. It was an interesting finding, and when Dr. Schwartzman asked us to support his investigations we did so. Nothing of any great significance came out of this research, but that doesn’t mean that it wasn’t worthwhile. ‘Today the problem of brown fat is being pursued by Dr. George Dempster of the University of Saskatchewan and something may come out of it yet.

O: Dr. Rivers, I would like to pursue the question of research on another level. What, for example, was the attitude of the Foundation at this time toward supporting the development of other vaccines? Rivers: I take it that you want to speak about Dr. Sabin. *G., Schwartzman, “New aspects of pathogenesis of experimental poliomyelitis,” J. Mt. Sinai Hosp., vol. 21:3 (1954).

540 Chapter 14 O: Yes. Dr. Rivers, when did the Virus Research Committee become aware that Dr. Sabin was on the point of developing a live-virus vaccine?

Rivers: It is difficult to say. My own impression is that I and other members of the Virus Research Committee became aware of Dr. Sabin’s progress along these lines sometime during the fall of 1953.

At that time, Sabin reported to the Foundation that he had succeeded in transforming all three types of poliovirus to avirulent variants by making repeated passage of large amounts of poliovirus in tissue cultures. Initially, these tissue cultures contained virulent as well as avirulent strains. However, Sabin indicated that by utilizing terminal dilution techniques, he was able to segregate relatively stable

variants. Later, when he inoculated monkeys intracerebrally with these variants, he found that they did not cause any lesions or paralysis. Dr. Sabin’s report dovetailed very nicely with what other investigators had found. In 1952, for example, John Enders and his associates at Harvard had produced an avirulent Brunhilde type | poliovirus

by passage in nonnervous tissue culture.” If I am not mistaken, Finders even sent this attenuated strain to Sabin for experimental purposes. In 1953, Joe Melnick at Yale, in an effort to extend the work of the Enders group—using techniques similar to those used by Dr. Sabin—independently, and I would say almost simultaneously

with Sabin, also succeeded in developing polio strains with a decreased virulence.* In the circumstances, I think you can appreciate

why I and others thought that Sabin’s work was promising. You would do well, however, to keep in mind that much was then still unknown. For example, Sabin at that time didn’t know anything about the genetic stability of the variant strains he had developed. He didn’t know the conditions under which poliovirus could be regularly cultivated in an avirulent form. Nor did he know whether there existed in nature avirulent strains that were better than those he had produced in the laboratory. *J.F. Enders, T.H. Weller, and F.C. Robbins, “Alteration in pathogenicity for monkeys of Brunhilde strain of poliomyelitis virus following cultivation in human tissue,” Fed. Proc., vol. 11:462 (1952). °J.L. Melnick, “Variation in poliomyelitis virus on serial passage through tissue cul. ture,” Cold Spring Harbor Symp. Quant. Biol., vol. 18:278 (1953).

Salk and Sabin Vaccines—1954-1958 541 During the winter of 1953 Dr. Sabin made a special trip to New York to ask Henry Kumm and myself whether the Foundation would } allow him to change the research program he had originally proposed for his grant so that he could develop his new leads. I can tell you that

he didn’t have to twist my arm or Henry Kumm’s. The Virus Research Committee very readily agreed to the change, and I saw to it that he was given a special supplementary grant so that he could continue his new research without any delays.

Q: Dr. Rivers, how rapidly did Dr. Sabin’s research develop?

Rivers: I would say, very rapidly. Dr. Sabin, you know, has never been a slouch in exploiting a promising lead. In the spring of 1954, just when the Salk vaccine field trials were about ready to get under | way, Sabin discovered that there was considerable variation in the immune response of both monkeys and chimpanzees to his new mutant viruses. He found, for example, that when he inoculated monkeys intracerebrally with these mutants he could not produce any paralysis or lesions in the central nervous system. On the other hand,

if he inoculated monkeys intraspinally with these same viruses he could produce a paralysis. Sabin called these mutants “spinal variants.” ‘The interesting thing about these “variants” was that they seemed to possess an afhnity for certain neurones, and, for some reason, in the process of multiplication they only seemed to produce a small number of infectious particles having neurotropic properties. Sabin soon discovered that when these “variants” were inoculated intraspinally in chimpanzees none of his animals would come down with paralysis. Chimpanzees like men are less susceptible to poliovirus than monkeys, and these results fortified Sabin’s conviction that he had finally isolated mutant strains of poliovirus which could be candidates for experimental tests in man.* * A.B. Sabin, W. A. Hennessen, and J. Winsser, “Studies on variants of poliomyelitis virus. Experimental segregation and properties of avirulent variants of three immunologic types,” J. Exp. Med., vol. 99:551 (1954); A.B. Sabin, “Characteristics and genetic potentialities of experimentally produced and naturally occurring variants of poliomyelitis virus,” Ann. N.Y. Acad. Sci., vol. 61:924 (1955). For an excellent review of the process of Sabin’s research during this period, see also A.B. Sabin, Immunity in Poliomyelitis, with Special Reference to Vaccination. World Health Organization Monograph Series,

No. 26, pp. 297-334 (1955).

542 Chapter 14 Late in March 1954 Dr. Sabin approached the Foundation for permussion to test these mutants in children. ‘Uhe request was passed on to the Vaccine Advisory Committee, and we postponed action on

it until we had a chance to talk to him personally. We had a lot of questions to ask, particularly about the possibility of reversion to viru-

lence of these mutants, and just didn’t feel that it would be wise to extend his experiments at that time. When he learned our decision, he just about went up like a skyrocket. He came to see me in New York and after some discussion | finally persuaded him to postpone

his request until the fall. He agreed but I don’t want anybody to think that he was happy. He wasn’t. I don’t think that he was particularly angry with me then, but very shortly thereafter he got sore as hell at me. Pll tell you why. A few weeks after the Vaccine Advisory Committee had tabled his request to extend his experiments to human subjects, Dr. Sabin asked

the Foundation for 1000 monkeys to push his animal experiments forward. I don’t remember now just how many monkeys Sabin used in his experiments during the spring of 1954, but it was well over 1000. When Dr. Kumm brought me a request for another thousand monkeys, I put my foot down and said no. I said other things too. I just didn’t think that he needed that many monkeys, and I felt that he could accomplish what he wanted to do with a smaller number.

I would like to take a moment here to say a word or two about monkeys, because they constituted quite a problem at that time. As I mentioned earlier, getting monkeys from India and elsewhere was so

dificult that in 1952 the Foundation opened a monkey farm at Okatie, South Carolina, for the specific purpose of supplying grantees with enough healthy monkeys to carry on their research. ‘The mon-

keys that were captured in India were frequently in poor shape; if they weren’t in poor shape when they were caught, they soon deteriorated because of crowded quarters and poor feeding. If one monkey came down with diarrhea, it wasn’t too long before the rest would come down as well. The same held true for TB. Although the farm at Okatie made particular effort to condition the monkeys in their care,

it was not unusual for the Foundation to receive complaints from laboratories that the monkeys they had received had to be discarded because of illness. During the Salk vaccine field trials, the Foundation

Salk and Sabin Vaccines—1954—1958§ 543 had the added burden of supplying monkeys to commercial firms pro-

ducing Salk vaccine and to the government laboratories testing the vaccine. The supply of monkeys became so tight at the time of the trials that vaccine producers began to complain that they didn’t have enough monkey kidney tissue to cultivate poliovirus. Luckily, Dr. Melnick later rescued us from that difficulty by devising a method to increase the number of cultures which could be made from a given amount of monkey kidney tissue. What he did was to take a monkey kidney, snip it into small pieces and suspend it in a solution containing trypsin in a large Ehrlenmeyer flask. ‘The trypsin had a disintegrat-

ing effect on the bits of kidney tissue and they soon separated into individual cells. When they reached this state, Melnick siphoned them from the flask, plated them on the surface of another flask, and covered them with a nutrient medium. Under these new conditions, monkey kidney cells multiplied very rapidly and were easily harvested.

Many commercial houses later adopted this method for growing poliovirus.°

, I tell you about the monkey problem in this detail because I want you to understand why I turned down Dr. Sabin’s request for a thou-

| sand monkeys. ‘The fact that I turned him down did not mean that I wasn’t enthusiastic about his work. I was, and I said so privately and publicly. ‘This is not a story. If you examine the paper that I gave on the progress of immunization at the Third International Poliomyelitis Conference in Rome in September 1954, you will find that I devoted a good part of my talk to summarizing Sabin’s research to that date. I certainly didn’t mind telling an international audience at that time, “This work is exciting and should be continued vigorously but with

caution.” I tacked on the word caution, because I felt that a lot of questions still remained to be answered. I was particularly concerned

at that time with the stability of the mutant strains that Sabin had developed. °>G.L. Morann and J. L. Melnick, “Poliomyelitis virus in tissue culture. VI: Use of kidney epithelium grown on glass,” Proc. Soc. Exptl. Biol. Med., vol. 84:558 (1953). The technique of trypsinization was initially developed by Dr. Peyton Rous at the Rockefeller Institute in 1916. Simultaneously with Dr. Melnick, Dr. A. W. Frisch developed a similar technique, using monkey testicular tissue. See A. W. Frisch and V. Jentoft, “Use of trypsin in preparing subcultures of monkey testicular tissue,” Proc. Soc. Exptl. Biol. Med., vol. 82:322 (1953).

| 544 Chapter 14 Q: Dr. Rivers, there is evidence that, during the summer and fall of 1954, Dr. Sabin felt so frustrated that he contemplated going to other foundations for support of his research.® Given his feelings, I can’t understand why he came before the Virus Research Committee in the fall of 1954 to ask for permission to conduct limited trials with his

live viruses among the prisoners at the Federal Penitentiary at Chillicothe, Ohio.‘ Was it in any way necessary for him to obtain such permission from the Virus Research Committee?

Rivers: The truth is that Dr. Sabin never needed any outside support. He was getting all the damn support he needed and more from the National Foundation. He was impatient and, as far as I am concerned, that was his major problem. I remember that in the fall of 1954 he submitted an application for a supplementary grant to the Foundation and asked for immediate action. When Henry Kumm brought the application to my attention, I tabled it for about three months. ‘The Virus Research Committee did not have a formal meeting scheduled at the time I received the application, and getting im- _ mediate action would have meant submitting it to a mail vote. On that voting it always took a unanimous vote to pass. One vote could have stopped that application, and believe me when I say that there were always one or two guys on the committee who were willing to throw a monkey wrench into the works. Why risk a refusal? In this particular instance, I arranged for a reallocation of the balance of funds in Sabin’s original grant so that he could use it as a temporary source of credit. All Sabin could see was that he wasn’t getting what he had asked for.

As for the second part of your question, I think that Dr. Sabin was just acting wisely when he asked the Virus Research Committee for

permission to conduct tests with the prisoners at Chillicothe. Although it is true that he could have asked the prison authorities for such permission on his own, he knew that he didn’t stand a chance of

getting it without our help, because the authorities would have turned around and asked him what we thought. They knew of our existence. Why should they stick their necks out and make an impor° See, particularly, Memorandum from Henry Kumm, April 19, 1954 (Kumm memoranda, 1954, National Foundation Archives). 7 Albert Sabin to H. M. Janney, medical director, Federal Bureau of Prisons, November 19, 1954 (copy in folder, Personal correspondence, 1954, Rivers papers).

Salk and Sabin Vaccines—1954-1958 545 tant decision like that without having it protected by the advice of a committee of scientists who had long worked in the field? By asking us first, Sabin was saving time. We didn’t hold him up. Actually, he wasn’t going to do a hell of a lot. If I remember correctly, he initially planned to test his strains in about thirty prisoners. Previously he had fed his strains to a few people in Cincinnati with very good results. The committee knew that his mutant strains were far less virulent than those one would ordinarily meet in nature. We also knew that even if he took a type 1 Mahoney strain and fed it to thirty prisoners, he could probably get away with it.

QO: Dr. Rivers, had Dr. Sabin himself taken his viruses at this time?

Rivers: Oh, yes. Most scientists in his position would have done the same. Dr. Salk, for example, took his own vaccine and inoculated his wife and children with it long before the field trials. It’s not that one expects to learn a lot by taking such material—onie guy or his family proves nothing. But in the circumstances, someone was bound to ask him, “Dr. Sabin, have you taken your vaccine?” I know that if anyone ever came up to me and asked me to take an untried vaccine, I'd ask, “Have you taken it?” and, by God, if that person said No, I'd tell him to go to hell. This would be the reaction of most anybody, I think. Since the question of this early trial has come up, let me say that in

the winter of 1954-55, Dr. Sabin fed his mutant viruses to the prisoners at Chillicothe with great success. All the prisoners developed immunizing alimentary tract infections, no viremias were discovered, and no clinical illness resulted.

O: Dr. Rivers, I would like to change our focus at this point and turn to an examination of the Salk vaccine during this same period— the winter of 1954. Isn’t it true that some months after the Salk vaccine field trials were held the government and several commercial producers discovered that several batches of Salk vaccine which were in storage were losing their potency? ° ®* See, especially, telegram, Jonas Salk to Basil O’Connor, November 8, 1954; memorandum from Jonas Salk, November 12, 1954; William G. Workman to Basil O’Connor, November 23, 1954; Thomas Rivers to William Workman, November 23, 1954 (folder, Vaccine, Polio, Salk: Development and Promotion, November 1954, National Foundation Archives).

546 Chapter 14 Rivers: ‘That's true and it involved the Foundation and Dr. Salk in

quite a hassle with NIH. | Let me begin by saying that the government has long required commercial producers to put preservatives in the vaccines they manu-

facture. ‘hese preservatives are not made to kill anything, because they are not strong enough to kill; they are merely added as a way of preventing bacteria or molds, which may have gotten into the vaccine during manufacturing or storage, from multiplying. Merthiolate was added to the Salk vaccine as just such a preservative. When the Salk

- vaccine was originally prepared for the field trials, it was used so promptly that little if any of it was ever stored. However, once the trials were over, surplus vaccine was stored for future use, and it was these batches of vaccine which were later discovered to have lost their potency. Examination very quickly revealed that the merthiolate was responsible and, in the circumstances, there was nothing to do but to

get rid of it. It was at this point that the trouble began. The government took the position that since the Salk vaccine used in the field trials contained merthiolate, they would in the future be unable to license Salk vaccine without merthiolate unless they had additional evidence of the safety of such a modified product. ‘That po-

sition got me sore as hell, and [ll tell you why. First, when the merthiolate was added to the vaccine, it was added as a preservative and never as a factor in relation to the safety of the vaccine. Second, the safety tests of the vaccine were determined long before the addition of merthiolate as a preservative. ‘The Vaccine Advisory Committee was certain that the elimination of merthiolate would have no effect on the safety of the vaccine and wrote a letter to that effect to

Dr. Sebrell and Dr. Workman at NIH. They, however, remained adamant. In part, I think they were caught by their own rules of procedure. The government has always required commercial producers to sub-

mit clinical evidence of the safety of their products. For example, when a commercial house makes vaccinia virus to protect human beings against smallpox, they have to test every batch in a certain number of unvaccinated children and nearly all, if I am not mistaken,

have to have primary takes. In this instance, Dr. Workman wrote back to the Vaccine Advisory Committee and said that he wanted

Salk and Sabin Vaccines—1954-1958 547 each of the producers to submit clinical evidence of the safety of the Salk vaccine they produced without merthiolate in at least 2000 individuals. For six commercial firms at that point to conduct safety tests on their own in 12,000 individuals would have been well nigh impossible without disrupting production. Everybody got sore—me, the Foundation, Dr. Salk, Dr. Workman, and Dr. Sebrell. We had a hot correspondence for a while. However, in the end we got together and worked out a compromise plan. Since the Foundation had contracted for nine million doses of Salk vaccine from the commercial producers, NIH agreed that Dr. Salk would be allowed to safety test representative batches of vaccine made without merthiolate from each of the producers in from 5000 to 8000 children so as to satisfy the clinical evidence that NIH required.

QO: Dr. Rivers, during the winter of 1954 and the early spring of 1955, a number of articles appeared in newspapers and magazines on Dr. Francis’s evaluation of the Salk vaccine.

Rivers: I never bothered about such reports. Whenever there is anything important going on, you always see such reports in the newspapers. ‘hey are called leaks. ‘There are honest-to-God leaks and there are just plain manufactured leaks. Both kinds went on here.® To this

day, I don’t know which was which, because I never paid any atten~ tion to them. I didn’t ask Dr. Francis if they were so, because | didn’t want to embarrass him. Heck, if he was to tell me that a statement was correct or incorrect he would in effect be giving me information

that I had no right to have. Why bother him? [ knew that when Francis got through with his work he would give us answers and that would be that. Personally, I had every reason to believe that his report would be favorable. I had watched the development of the vaccine from its inception. I was sure that it was safe, and I also believed that it was effective; the only thing I didn’t know was how effective. O: Dr. Rivers, did you or the Vaccine Advisory Committee play any part in planning where and when the Francis report was to be given? * Dr. Francis takes exception to this statement by Dr. Rivers and points out that there were no leaks from the Vaccine Evaluation Center nor was any information given to anyone (private communication). The same point is made in a contemporary news report in I'he New York Times, April 1, 1955, p. 19, column 1.

548 Chapter 14 Rivers: [ had nothing to do with that kind of planning, and I can tell you that it was never a function of the Vaccine Advisory Committee. I do know that early in February 1955 Dr. Francis told Mr. O’Connor that he expected to finish writing his report by the end of March. In the beginning, Mr. O’Connor thought it would be nice if the report could be made public at the National Academy of Sciences in Washington. However, Dr. Bronk, who was then the president of the Academy, indicated that, since the National Academy had never before participated in such a function, it was unlikely that the members of the Academy would approve of such a step. It was then de-

cided that, since the evaluation had been carried out under the auspices of the University of Michigan, the report should be made public from Ann Arbor. The final choice of a date was fortuitous. Originally, Francis had expected to finish writing the report by the end of March; later, however, he informed the Foundation that he couldn’t have the report before April 8th or 9th. At that point, the suggestion was made that the report be given on April 12th, the anniversary of President Roosevelt’s death. There could be no quarrel with that decision. What if the report was delayed for three or four

days? President Roosevelt had been the founder of the National Foundation; Mr. O’Connor had been one of his closest friends—hell,

they started everything—without them there would have been no Foundation and | dare say no vaccine. Why shouldn’t the report be given on that day? It was fitting.””

QO: Dr. Rivers, do you remember going out to Ann Arbor?

Rivers: Yes. I started out alone, but when I boarded the Wolverine to Detroit | met Harry Weaver. Mr. O’Connor had invited him to * On the choice of date for presenting the Francis report, Dr. Francis makes this observation:

The choice was made by my staff and me with no knowledge that any political significance attached to the date. The decision was made at Ann Arbor in a conference that we had with university public relations personnel, and members of the Evaluation Center. It was made only because we couldn’t get finished as earlier expected. The only angle was that the public relations people thought Tuesdays were to be preferred. The statement that a suggestion was made that it be done on the anniversary of President Roosevelt’s death is not correct. We didn’t know the relationship until after the decision was made (private communication ).

Salk and Sabin Vaccines—1954-1958 549 the meeting, and we had a nice time together on the train reminiscing. It was only when we arrived in Detroit that I realized that a lot of other people were going to the same place. 1 don’t mind telling you that there were a few things about the meeting that I didn’t like,

and that I am sure the University of Michigan didn’t like. Inaword, the newspaper people and photographers created a madhouse. I don’t know when I have seen such wild people. ‘Talk about putting frosting

on the cake, these boys and girls put Christmas trees on with the frosting. It is true that never before had there been a scientific trial of the scope of the vaccine field trials of 1954. It can also be said that the report that Dr. Francis gave of the results of that trial deserved the attention it got, but it always rubs me the wrong way when something like the madhouse at Ann Arbor happens. Newspaper people say that if it wasn’t for public support there wouldn't be any scientists

and that the public have a right to know what’s going on. I can’t argue with them too much if they want to tell the people what scientists are doing, except that I wish that they would put it on a little bit thinner, and not quite so thick. I don’t think that there is any need for me here to recapitulate all of Dr. Francis’s findings save to say that he reported that the vaccine as used in the field trials was 60 to 70 per cent effective in preventing type 1 virus positive paralytic cases, and 90 per cent and more effective in preventing paralytic cases of type 2 and type 3 polio. If anyone is interested in all of the details and figures, they can always turn to the final report which Francis published in 1957, After Dr. Francis gave his presentation he turned the report over to me and I made an appropriate little say-so. ‘Then came the speeches.

Mr. O’Connor made a speech, Alan Gregg made a speech, Dave Bodian made a speech, and Bill Workman made a speech. Then late in the afternoon Jonas Salk made a speech, and that speech got me sore. When the field trials were put on, children were given three doses of vaccine several weeks apart. The Vaccine Advisory Committee suspected that it could probably get better results if the inoculations were spaced differently but, unfortunately, it had not time to experiment. ‘The field trials did not begin before April and in some parts of the country like the South and Southern California, polio frequently made its appearance long before the summer. As a result

550 Chapter 14 we did the next best thing—we decided to get an optimum amount of

vaccine into the kids before the polio season began and asked Dr. Francis to give the inoculations several weeks apart. | am not saying that, when Dr. Salk reported at Ann Arbor that he got a higher antibody titer when he gave the first two doses a few weeks apart and the third dose seven months later, he was wrong. On the contrary, he was

right. I am saying that he should not have made that particular speech on that occasion. ‘lo my mind, it was an implied criticism of the way Francis had run the field trials, and nothing should have detracted from the kudos that Tommy received that day. Dr. Francis’s evaluation of the Salk vaccine was a superb achievement." QO: Dr. Rivers, had you or the Vaccine Advisory Committee decided before the report what effectiveness would be acceptable?

Rivers: I think that I can honestly say that I and the other boys had not made up our minds one way or the other. However, Mr. O’Connor had made up his mind a long time before. I know because, while plans were being made for the Third International Conference on Poliomyelitis during the summer of 1954, Mr. O’Connor indicated to me that if the vaccine only proved 25 per cent effective, he still would

advise everyone to take it. He felt that anything that would prevent even a small number of paralytic cases was worth while. I could understand that; I think that anyone who has ever seen a paralyzed kid could understand that. ‘The figures that Francis later presented on the effectiveness of the vaccine were, of course, eminently acceptable to the Vaccine Advisory Committee. Actually, Francis initially underestimated the effectiveness of the vaccine, because some of the batches

of vaccine which were used in the trials were for one reason or another not as good as they might have been. } As soon as Dr. Francis finished giving his report, a special commit“ The schedule of inoculations of vaccine during the field trials were at 0, 1, and 5 weeks or at 0, 7, and 35 days. The decision as to the schedule of administration of the vaccine was made by the Vaccine Advisory Committee of The National Foundation for Infantile Paralysis in collaboration with Dr. Jonas Salk and Dr. Francis and his associates in the Vaccine Evaluation Center. See 'T. Francis et al., Evaluation of the 1954 Field Trial of Poliomyelitis Vaccine: Final Report. Poliomyelitis Evaluation Center, Department of Epidemiology, School of Public Health, University of Michigan, April 1957, pp. 36-38.

Salk and Sabin Vaccines—1954-1958 551 tee met in Ann Arbor and recommended that the Secretary of Health, Education, and Welfare, Mrs. Oveta Culp Hobby, license the manufacture of Salk vaccine. She did. However, certain details remained to be taken care of—one of these related to the potency-titer

requirement. Several days after the Ann Arbor meeting, a special committee, of which I was a member, met with officials of NIH in Washington and agreed to lower the original potency titer required for the manufacture of Salk vaccine. If we hadn’t done this, I doubt whether we would have had a vaccine. Some people have since ques-

tioned our good sense in doing this, but the fact remains that the original potency-titer requirement was too high for commercial houses to meet and still have a vaccine that would be available at a price that the public could stand. There are times when you can set too high a standard. I think that’since the standard that we set holds

to this day, we perhaps did the right thing to lower it a little bit.” Q: Dr. Rivers, soon after the acceptance of the Francis report and the government’s licensing of commercial producers, the production and distribution of the Salk vaccine seemed to degenerate into a state of chaos. How involved was the Foundation in these matters?

Rivers: While the field trials were being held, Mr. O’Connor and I frequently talked about what the Foundation should do about the vaccine after the Francis report was made. These were not formal talks in any way and took place at odd moments in the backs of automobiles and in airplanes while we were traveling together. I can’t even tell you now how often we spoke about this problem, but I can tell you that we finally reached the conclusion that, when and if the vaccine was licensed, the production and distribution of the vaccine should become the government’s business and the Foundation should wash its hands of these particular problems. After all, the Foundation

had helped develop the vaccine, had helped lay down the rules and regulations for safe and effective commercial production, and had in fact done everything possible to get the government to like what was done. At this point it could do little more. “ Dr. Bodian points out that the potency requirements were subsequently raised, but . that this was not known except in the “trade” (private communication).

552 Chapter 14 QO: Dr. Rivers, in the period following licensing, did the government call on the Vaccine Advisory Committee for advice or help?

Rivers: No. Actually, there was no reason for it to do so. When the government licensed commercial production, NIH appointed its own committees of experts, and when problems came up it went to them rather than to a committee originally organized by the Foundation. Q: I raise the question because, a scant two weeks after the presentation of the Francis report, a number of cases of paralytic polio occurred among children inoculated with vaccine produced by the Cutter Laboratories. I wonder if you would speak with me about the Cutter incident.*®

Rivers: I don’t think that it’s proper for me at this time to discuss the Cutter incident, because, as you know, several suits which were later brought against the company are still being adjudicated. But I will say this: when I first learned about the Cutter cases, I was extremely disturbed, because I believed that if the vaccine was made and tested as had been done before and during the field trials, it was perfectly safe. I still believe that.

O: Dr. Rivers, it is a matter of public record that, following the first reported cases of polio among children who had been inoculated with batches of vaccine produced by Cutter, Dr. Leonard Scheele, then the Surgeon General of the United States, withdrew the Cutter vaccine from the market and temporarily suspended all inoculations with commercially produced vaccine, pending retesting. He also called meetings with nongovernmental virologists. Did you take part in any

of these meetings? :

Rivers: I attended only one such meeting. However, I do not now remember exactly when it took place.** It’s strange that I don’t re8 For a contemporaneous analysis of the polio cases that arose as a result of the administration of Salk vaccine between April 22 and May 27, see Public Health Service, Technical Report on Salk Poliomyelitis Vaccine. Washington, D.C., June 1955 (mimeographed). “4 Following the Cutter incident, Surgeon General Leonard A. Scheele called a meeting of scientific experts on April 29-30, 1955 to discuss the Salk vaccine. ‘This group

Salk and Sabin Vaccines—1954-1958 553 member that, because several things occurred at that meeting that still stand out in my memory. The first was the testimony of Herdis von Magnus. Dr. von Magnus was a member of the Serum Institute of Copenhagen and was specially flown to the United States from Denmark so that she could tell the meeting about the Danish experience in manufacturing and using Salk vaccine. I should perhaps explain that at that time the Serum Institute, under the direction of Dr. Prebend von Magnus (Herdis von Magnus’s husband), was making Salk vaccine for the Danish vaccination program against polio.*® Dr. von Magnus told us that the Serum Institute followed all the specifcations and requirements which guided commercial producers in the

United States, save that they used Brunhilde instead of Mahoney poliovirus as the type 1 strain in their vaccine. However, she was adamant that when the vaccine was made according to specifications, it was perfectly safe, and that to her knowledge no cases of paralytic

polio had occurred in Denmark as a result of inoculation with the vaccine.

That testimony was to the point. I can’t say the same for the fight | initially contained eleven members: David Bodian, John Enders, ‘Thomas Francis, William Hammon, Edwin Lennette, Foard McGinnes, Howard Shaughnessy, John Paul, Albert Sabin, Jonas Salk, and Joseph Smadel. Later the Surgeon General organized this group into several small Technical Advisory Committees. The first Technical Advisory Committee was composed of David Bodian, John Enders, Howard Shaughnessy, Jonas Salk, and Joseph Smadel. Richard E.. Shope of the Rockefeller Institute and Carl Larson of the National Institutes of Health were later added to some of the ‘Technical Advisory

Committees. It is dificult to pinpoint the meeting that Dr. Rivers refers to, since he did not serve on any of these committees. It is possible, however, that he was asked to join a meeting for purposes of discussion. It is equally possible that the meeting that Rivers refers to was held under the auspices of a special committee to investigate the Salk Vaccine, which was headed by Dr. Chester A. Keefer, a special assistant to the Secretary for Health and Medical Affairs. I have found no documentary evidence of the meeting, as the papers of the National Institutes of Health on the Salk Vaccine are as yet unavailable for purposes of research. * At the time of the Salk vaccine trials, Dr. J. Orskov was director of the Statens Serum Institute in Copenhagen; it wasn’t until some years later that Prebend von Magnus became director. Dr. Prebend von Magnus, however, did play a role in the polio vaccination studies in Denmark. For information on this program, see H. von Magnus, P. von Magnus, I. Petersen, A. Godtfredsen, and M. Rgnkjaer, “Polio vaccination in Denmark: The production of formalinized polio vaccine and preliminary results,” Danish Med. Bull., vol. 2:226 (1955); S. Tulinius and E. J. Henningsen, “Polio vaccination in Denmark April-June 1955. II. Organization and procedure for the school vaccination,”

Danish Med. Bull., vol. 2:233 (1955); P. von Magnus, K.B. Petersen, V. Bech, I. Petersen, and H. von Magnus, ““Tissue cultures of trypsinized kidney cells from different monkey species,” Danish Med. Bull., vol. 2:236 (1955).

554 Chapter 14 later had at that meeting with Dr. Alex Langmuir of the U.S. Public Health Service. I remember that we were talking about the implications of the cases that had occurred in California and Idaho, when Alex went on record as saying that he was convinced that these cases were going to trigger a horrible epidemic of paralytic polio in the

United States. Everybody sat up—Alex is no dumbbell—and I thought I had better say something. “Alex,” I said—although not in these words “‘you are just a damn fool. Nothing like that is going to happen. I don’t care if ten kids have polio or a hundred kids have polio. There has never been a man-made epidemic among humans, and I don’t think there is going to be one this time.” Well, we argued the

point and I suppose that we finally generated more heat than light. You know how it is when two bulls lock horns—each bull thinks that he has won. My guess is that Alex to this day still believes that such an epidemic was a distinct possibility. He is one of those fellows you

have a hell of a time convincing. For the record, we never had that epidemic that Alex was so afraid of.

O: Dr. Rivers, did this meeting make any particular recommendations to the Surgeon General?

Rivers: I don’t remember whether we did or not. I do know that the Surgeon General did not depend on this one meeting alone for advice. I would say that he depended more on a special committee of

experts that he called together soon after the Cutter incident occurred. I wasn’t on that committee but it was quite a committee, and I don’t know where he could have gotten better advice. John Enders, Dave Bodian, Albert Sabin, Jonas Salk, ‘Tommy Francis, Joe Smadel, Edwin Lennette and Howard Shaughnessy were all members. Most of the action that the Surgeon General took after the Cutter incident was based on the recommendations of this committee.*® Earlier you

mentioned that the Surgeon General withdrew all Cutter vaccine from the market and ordered the retesting of all existing batches of commercially produced vaccine. I would like to add that other things were done as well. For instance, the U.S. Public Health Service instituted a very careful reexamination of the manufacturing process at / *° This is the committee listed in note 14.

Salk and Sabin Vaccines—1954-1958 555 the Cutter Laboratories, and a number of important amendments were also added to the existing safety requirements for producing Salk vaccine.** ‘I’o my mind, however, the best and most important thing

that was done was the organization of a special surveillance unit at the Communicable Disease Center in Atlanta, to keep track of all cases of paralytic polio among vaccinated and nonvaccinated children in the United States. Alex Langmuir was made the boss of this unit,

and I must say that from the beginning he has done a first rate job. People have often asked me, “Did anything good come out of the Cutter incident?” My answer is always, “Yes, the Polio Surveillance Unit at the Communicable Disease Center in Atlanta.’ ** I don’t know of anyone in the past six years who works in the field of polio research who hasn’t in one way or another been indebted to them.

QO: Dr. Rivers, in addition to the meetings called by the Surgeon General, several congressional committees also held hearings with reference to the Salk vaccine. I raise this point because at one of the hearings held by the Committee on Interstate and Foreign Commerce, on June 22 and 23, 1955, you and several other scientists testi-

fied on the safety and effectiveness of the Salk vaccine. Do you remember what you said at that time? *°

Rivers: I didn’t say very much. In essence, all I said was that I believed that, when the vaccine was made according to the specifications which were laid down, and was produced by a commercial house that knew its business in making a vaccine of this kind, it was safe. I didn’t call anybody any names. I went on to say that since I was certain that the Salk vaccine, if properly made, would do a great deal for the children of the United States, I thought it would be a great pity if

the Congress or anybody else stopped the production and use of the

vaccine at that time. I felt very strongly that if the program was halted it would create a doubt in the minds of the public and that it “The early actions taken by the Surgeon General are summarized in Public Health Service, op. cit., pp. 87-93. **'The Special Poliomyelitis Surveillance Unit in the Communicable Disease Center in Atlanta, Georgia, was organized on April 28, 1955. © House of Representatives: Interstate and Foreign Commerce Committee, 84th Congress Ist Session. Hearings on Poliomyelitis Vaccine, June 22-23, 1955.

556 | Chapter 14 would take a number of years before the vaccine was produced and used again. In the meantime a lot of children would needlessly contract paralytic polio and a number would even die.”°

That was my position, but not everybody at the hearings agreed with it. Dr. Wendell Stanley, for example, said some very harsh things about the safety of the vaccine, particularly about the reliability of the process of inactivation with formaldehyde. He was joined by Dr. Sabin, who further argued that it was dangerous to proceed with a vaccine made with Mahoney poliovirus and urged that the vaccina-

tion program be postponed until a satisfactory type 1 attenuated strain could be substituted in its place. John Enders supported Sabin, as did Bill Hammon who, although not present at the hearings, sent a special memorandum to the committee asking that the vaccination program be discontinued. I would like to quote here a portion of the testimony that Dr. Enders gave at the hearings because | think that it summarizes in a succinct way most of the important reasons given by virologists for opposing use of the Salk vaccine after the Cutter incident. Dr. Enders. Since Mr. Wolverton has asked for an opinion, I will say that I agree, I think, with everything—practically—that Dr. Sabin has said.

I think the great point that he made was that we could not predict with regularity that another incident such as we have had would happen on any information that we are now in the possession of. In view of that situation, I might perhaps review the facts again that he

mentioned for the sake of clarity. | 1. ‘There has been some doubt cast on the process of inactivation of the virus. We do not know absolutely whether it works according to theory, as Dr. Shannon has pointed out. 2. The safety test may not be sensitive enough to detect the amount of

virus that is sufficient to infect a few human beings who are unusually sensitive.

3. We do know that somehow—I think it is fair to say we do know now—somehow in the Cutter case, that in spite of the processing, in spite of the safety tests, live virus did get through and was inoculated, with the production of disease. Now, new safety tests may take care of that. They have not been tried so far as I know. There are certainly additional improvements that could be made along the lines that Dr. Shannon has mentioned—in particular, the » Ibid. pp. 173-174.

Salk and Sabin Vaccines—1954-1958 557 suggestion of the use of an avirulent strain. Indeed, I don’t think that, until that is done, I would advise going ahead. I believe I so recommended at a meeting on May 7 in the National Institutes of Health. I think that within a reasonable time we will undoubtedly have a safe and effective product. In view of the facts that have been brought out here this afternoon, it seems to me the better part of wisdom to wait a little while until we have it.

QO: Dr. Rivers, would it be fair to say that the other virologists present at the hearings supported your views?

Rivers: No, it would not be fair to say that. Dr. Manfred Mayer of Johns Hopkins was another who was against using the vaccine. John Paul, who served as chairman, spent most of his time performing his duty as an impartial chairman and as far as I remember did not make any plea either for or against the vaccine. Even the boys who later

went along with the notion of continuing the vaccination program didn’t completely agree with everything I said. Actually, one of the most cogent presentations for continuing the vaccinations was made by Dr. Francis, and I think his argument was far more representative of the feelings of those who finally voted to go ahead than my own. Pll quote some of what he said here, so you can get the flavor of his thinking at that time: Dr. Francis. Mr. Priest, gentlemen, I too agree that there are advantages

to be gained in the substitution of strains which have less virulence for immunization, provided they are otherwise effective. But I think that this also introduces several other questions. ‘The first of them has been referred to by Dr. Horsfall—that not only must these strains be shown to be effective under laboratory conditions, but they must also be suitable for mass production and use, and they must be stable under those conditions. Secondly, the fact that an attenuated strain is used does not ensure that there will be no risk if there is still active virus in the vaccine. The procedures which would be employed to prevent infection by strains such as Mahoney would also have to be applied to these other strains, because, while any of the Mahoney strain that slips through may produce damage directly, active attenuated strains may also change if they are allowed to be present. So it is not simply a matter of relaxing your guard and reducing * Tbid., p. 180. The editor has taken the liberty of editing the remarks of Dr. Enders and the later remarks of Dr. Francis, because the printed versions of the hearings are garbled in places.

558 Chapter 14 the requirements for production and safety by saying that, if they are in there, they should be attenuated. It makes little difference if attenuated strains are used, because the risk is still there that they may change and

| become virulent.

Finally, I think that the safety tests and the improved safety testing that have been developed are of such a nature as to give a very high degree of confidence that active virus should not occur. As Dr. Shannon says, and I think we would all agree, there is nothing that can give you absolute guarantee under all conditions that no active virus could be present in the preparation. .. . The suggestion is made that this can all be done in six months. If one were to stop the present program, the result would be to remove a product that has been proved safe and effective, and substitute for it an unknown —an idea which, at the present time, is still experimental. You would then be substituting for a proven product something that is yet to be tested, which Dr. Sabin thinks might be better, but for which the proof is not yet available and would not be available until the tests were done. . . .

In view of all these considerations, I would certainly be opposed to stopping the present program until that other work has been done. I think the suggestions which have been made are there, for anyone to work on. There is nothing in the world to hinder anyone from developing different kinds of vaccines and different procedures, and there is no hindrance to their being accepted, when the evidence is in that they are satisfactory. Dr. Paul. Dr. Francis, would you feel that you have said all you want to say on the substitution of strains, in terms of an opinion for or against? Dr. Francis. On the substitution of strains, I would agree, provided they are satisfactory. I think one might point out, no matter what else is said, that the presence of the Mahoney strain and the fact that it was used in vaccine and produced disease was of itself a significant fact for educational

purposes at least. Had that not happened, I think a number of the deficiencies and perhaps inadequacies in the type of reporting that was done on production of material might not have been detected until some other kind of accident showed up.??

There was some surprise testimony at that hearing and the most surprising as far as I personally was concerned was the testimony given by Jim Shannon of NIH. I didn’t quite know what to expect from Jim Shannon before the hearings. As I indicated earlier, I had had a run-in

with him on the question of safety just before the Vaccine Advisory Committee finally approved the vaccine for the field trials in 1954. I * [bid., pp. 198-199.

Salk and Sabin Vaccines—1954-1958 559 want to tell you that I was pleasantly surprised when I heard him make a plea for continuing the vaccination program. I hadn’t prepared anything when I came down to testify—I spoke oft-the-cuff— but Jim came loaded with charts, statistics, and a lot of other evidence, all beautifully prepared. It has always been my feeling that Dr. Shannon’s presentation helped carry the day at these hearings because it

was so beautifully done that it made it easier for Dr. Horsfall, Dr. MacLeod, Dr. Hodes, and Dr. Francis to go along.” In the end, when the committee asked us to vote on whether to continue the vaccination program we voted 8 to 3 to go ahead.

QO: Dr. Rivers, at least five of those who voted in the affirmative can

be said to have been your boys. Dr. Horsfall, Dr. MacLeod, Dr. Francis and Dr. Smadel were all previously closely associated with you at the Rockefeller Institute, and during the war Dr. Hodes served under youin NAMRU 2.

Rivers: ll admit that I could be pretty sure how the fellows I had been associated with would react. When you work with people for several years you begin to know how they think. Joe Smadel and I probably knew more about the vaccine as vaccine than anybody else who was present because we had served together on the Vaccine Advisory Committee. After the field trials nobody had to tell Tommy Francis anything about the vaccine. I believe that Horsfall, MacLeod, and Hodes would have voted the way they finally did if they hadn’t come to Washington. ‘They didn’t hear anything in Washington that they hadn’t heard before. None of these fellows are dummies. Let me tell you, if any of them thought that I had pulled a boner, they would have turned me in as fast as a cop turns in a robber. I wouldn't admit that they were my boys if they weren’t that kind of folks. ‘The people that I like and have a high regard for are people who are honest and

would turn in their own mothers if they did something crooked or wrong. I never expect Smadel, Horsfall, MacLeod, or any of my boys ever to protect me. If they think that I am wrong, they say so and they don’t pull their punches. * Tbid., pp. 162-166.

960 Chapter 14 OQ: Dr. Rivers, you indicated that the final vote was 8 to 3 to continue with the vaccination program. Unless | am mistaken, more than three people opposed the vaccine at the hearings.

Rivers: Not everybody who spoke against the vaccine voted against it. Dr. Stanley and Dr. Mayer, who had plenty to say against the vac-

cine, refrained from voting on the grounds that they were only Ph.D.’s and not physicians. I was dumbfounded, because I had never heard such a statement before. I have known a great many Ph.D.’s in my time, and I can tell you that they just love to vote. Did you ever

: try stopping one from voting? I won't say anything about Stanley’s and Mayer's reasoning—I will say that another Ph.D. was present at

those meetings who wasn’t bothered about being a Ph.D. John Enders got up and voted loud and clear against using the vaccine at that time. ‘That was perfectly all right. I have always had the firm belief that every man has the nght to vote the way he believes. You know, even if Stanley and Mayer had voted, it wouldn’t have changed the final result: the ayes would have still won.

O: Dr. Rivers, from evidence that I have seen, it is apparent that, even after the Congressional hearings of the spring of 1955, some of the pharmaceutical firms making Salk vaccine had difficulty from time to time in inactivating poliovirus. Rivers: ‘There was such difficulty, and during the summer and fall of 1955 Henry Kumm and I visited the laboratories of all the commercial producers making Salk vaccine for the express purpose of looking into the matter. Not all of the producers at that time would admit to having such a problem. However, the Parke-Davis people were frank enough to tell me that on several occasions they had had trouble in-

activating poliovirus. A short time later, when I visited the Connaught Laboratories, I heard of similar difficulties. It has always been

my belief that whether they admitted it or not, all of the producers making Salk vaccine at that time discovered occasional batches of vaccine in which the virus was not inactivated. No one in the pharma-

ceutical firms knew why this was happening. That, of course, is nothing against them. As a matter of fact, many virologists outside

Salk and Sabin Vaccines—1954-1958 561 the commercial laboratories didn’t know either. Sometime later that fall [1955] Dr. Salk and a number of other investigators began to supply evidence that the trouble might in part lie in the storage of virus fluids.?*

During the field trials the vaccine was used so rapidly that virus fluids used in preparing the vaccine very rarely got a chance to stand or be stored. After the field trials, however, the picture changed, and pharmaceutical houses began to store their virus fluids in five and ten

gallon demijohns until they accumulated large enough batches of virus to be inactivated. In some instances such virus fluids remained untouched for months. For example, Dr. Salk later showed that, although such stored virus looked normal, when the jars in which they were kept were shaken, a precipitate or cloudy sediment would rise from the bottom of the jar. He maintained that this precipitate was in fact a conglomeration of a number of virus particles and could not be inactivated with the same concentration of formalin, temperature and pH used to inactivate single poliovirus particles. ‘Io cope with the conglomerations he suggested that the commercial houses filter their stored virus fluids before undertaking final inactivation. Such extra ** Dr. David Bodian observes here:

Dr. Rivers attributes to Dr. Salk an analysis of the problem that was actually made by Dr. Richard Shope, who visited all the manufacturers and studied their details of processing of vaccine fluids, as subcommittee chairman for the NIH Technical Committee on Poliomyelitis Vaccine. The Technical Committee studied a great deal of manufacturer's data in detail for many weeks before recommending new filtration procedures (private communication ).

Dr. Bodian’s additional information points up the problems of depending on memory in history. The special Technical Advisory Committee on Poliomyelitis Vaccine, which the Surgeon General had organized, contained, among others, James Shannon, David Bodian, Thomas Francis, Jr., Jonas E. Salk, Richard Shope, and Joseph Smadel. ‘There is no doubt that Dr. Shope, as Dr. Bodian intimates, examined the problem of processing vaccine fluids. Dr. Salk, however, was no less concerned, and carried out examinations of his own. He later discussed these at length with Dr. James Shannon in a letter dated October 5, 1955. Dr. Rivers was undoubtedly privy to this letter, because a copy was found in his correspondence files. The incident that Dr. Rivers recounted above about Dr. Salk and the demijohns of poliovirus fluid actually happened and was tecounted to Dr. Rivers by Dr. Henry Kumm who visited Dr. Salk’s laboratory on October 26, 1955. See also memorandum from Henry Kumm, October 26, 1955; and especially memorandum of November 1, 1955, in which Kumm notes that he has spoken to Dr. Rivers about his observations in Dr. Salk’s laboratory (Kumm memoranda, 1955, National Foundation Archives). Both Dr. Rivers and Dr. Bodian are here telling “the truth” as they know it.

562 Chapter 14 filtrations were later written into the requirements and specifications and went a long way toward clearing up the problem of inactivation.

Q: Dr. Rivers, earlier you mentioned the Danish experience in manufacturing and using Salk vaccine, yet not all countries at that time were equally enthusiastic about adopting and using Salk vaccine.

Rivers: When we were about to begin the vaccine field trials in 1954, any number of foreign governments wrote the Foundation and offered facilities for holding the trials in their countries. ‘he Canadians and Danes later vaccinated their populations with Salk vaccine of their own manufacture, but it is true as you suggest that this didn’t happen everywhere. Dr. Pierre Lépine at the Pasteur Institute made his own polio vaccine for the French, and the British certainly were very reluctant to begin a vaccination program with the Salk vaccine. I honestly don’t know how to explain the British attitude. It certainly has nothing to do with the quality of their virologists. You will have to go a long way before you can find people of the caliber and quality

of Sir Christopher Andrewes or Alick Isaacs. I hate to blame it on British conservatism—heck, vaccination as a procedure is a British medical innovation. The only thing I know was that it was difficult to convince them. Early in 1955, Sir Weldon Dalrymple-Champneys of the British Ministry of Health visited the Foundation for the express

purpose of learning about the Salk vaccine. I thought he was won over to the vaccine, but after the Cutter incident he gave a paper in which I thought he was unduly conservative about its prospects. I didn’t say anything to him at the time; however, early in 1956, when I

learned that the British were about to undertake a limited field trial with Salk vaccine, I wrote to him to ask about the trials and the reasons for the delay. 1 would like to quote his reply to me here, because

it expresses the British attitude very clearly and incidentally casts some light on modifications which the British later introduced in the

manufacture and safety testing of Salk vaccine. : 25th January, 1956 Dear Rivers,

Thank you for your letter of 20th January. . I am sorry that you found my optimism with regard to vaccination against poliomyelitis unduly restrained, but I believe that it is useful to err,

Salk and Sabin Vaccines—1954-1958 563 if anything, on this side when trying to make people understand the prob-

lems involved in a matter of this sort. This does not mean that I do not regard the great trial of the Salk vaccine as a very remarkable achievement, which is bound to have a profound influence on the history of poliomyelitis control, even if the vaccine eventually used may be different in type. In this regard, I am very interested to read your opinion of the probable

attitude of your people to a live virus vaccine, though I should have thought that the success of other attenuated live vaccines would give some encouragement to those trying to devise one for this disease. The news items about the use of poliomyelitis vaccine of the Salk type is quite correct and I send you herewith some papers which will show you just what we are doing. The first step is described in these papers, and it is only necessary to add that vaccination will, according to present plans, begin again in November after the poliomyelitis season, when much larger quantities of the vaccine are expected to become available. It is very difficult to tell what the acceptance rate will be, but we expect to get many more children registered for vaccination in the next few months than we can provide vaccine for.

You will also see that, though there is no intention to carry out a real “trial” like yours, we do hope to get some valuable information out of our procedure, especially with regard to children under 6 years old. As regards the vaccines which will be used, that of one manufacturer contains ‘I'ype I Enders modification of Brunhilde; Type II MEF ?; ‘Type III Saukett. ‘The vaccine of the other manufacturer will contain Type I Enders’ modification of Brunhilde (as with other manufacturer); Type II SK; ‘Type III Leon.

Regarding safety tests, we have adopted those laid down in the latest U.S. Minimum Requirements, up to and including Amendment 4 of 11th November 1955, but have introduced the following modifications:

]. In the monkey tests cortisone will be given in divided doses, with an initial dose of 125 mg 2 days before the vaccine is injected, followed by 5 doses of 25 mg given every second day.

2. ‘he vaccine to be tested is injected intra-cerebrally and intra-spinally. The intra-spinal test of vaccine given to monkeys will be 0.2 ml directly

into the lumbar enlargement and 0.3 ml into the subarachnoid space around the cauda equina. All monkeys will be observed for a period of 28 days. In the final monkey

test, intra-muscular injection has been omitted as it might cause antibody production and interfere with the results. Yours sincerely, WELDON DALRYMPLE-CHAMPNEYS 7°

© Weldon Dalrymple-Champneys to Thomas Rivers, January 25, 1956 (folder, Per-

sonal correspondence, 1956, Rivers papers). .

564 Chapter 14 Q: Dr. Rivers, what effect did the progress of the Salk vaccination program in 1955 have on the development of Dr. Sabin’s research?

Rivers: I would be inclined to say that it had little or no effect for the simple reason that Dr. Sabin didn’t work by keeping one eye cocked on what was happening with the Salk vaccine. The rate of his progress and development was determined by what he was able to do in his own laboratory. My impression is that throughout 1955 his research developed very rapidly, and unless my memory plays me false, by the end of that year he was concentrating his efforts on studying the pathogenicity of viruses recovered from the stools of human subjects whom he had vaccinated on a limited basis. If Sabin had any difficulty at that time, it was in choosing stable and effective nonpathogenic strains for his vaccine. For example, although none of the nonpathogenic strains which Sabin recovered from his vaccinated subjects proved to be as pathogenic as the original strains before they were attenuated, the truth is that some of them still retained the ability to cause paralysis in monkeys upon intracerebral inoculation. I would go so far as to say that these findings convinced Sabin to discard the early type 1 and type 2 variants he had developed and to try working instead with the nonneurotropic Mahoney strain that Dr. C. P. Li and Dr. Morris Schaeffer had developed by passage in monkey testes cultures in mice,” and a type 2 virus that he isolated from the stools of healthy children sent to him by Dr. John Fox from New Orleans.?" I believe that, if you had asked Sabin in the fall of 1955 whether it was possible to get completely nonneurotropic strains of poliovirus, he would have said that it was impossible.

I would like to take a moment to say something about the Li* C. P. Li and M. Schaeffer, “Adaptation of type I poliomyelitis virus to mice,” Proc. Soc. Exptl. Biol. Med., vol. 82:477 (1953). * The origin of this virus is recounted by Dr. Sabin in a special note to Dr. Henry Kumm on the copy of a letter sent originally to Dr. Harry Eagle at the National Institutes of Health, on August 30, 1956. Dear Henry, I appreciate your note about the origin of “P712” virus. What I received from Dr. Gelfand was not a virus but a stool specimen. This specimen actually contained two viruses, one polio and one not polio. I have designated my derivatives from this in different ways, always referring to “P712” as the source. I think it matters little what the derivative is called, but rather what it does and how it was obtained (folder, CRBS #139, University of Cincinnati, 1956, National Foundation Archives).

Salk and Sabin Vaccines—1954-1958 565 Schaeffer strain. You know, I take a great deal of pride in the development of that strain. Some people might call that pride odd—I know that Dr. Li would—because the fact is, about thirty years ago I fired

Dr. Li, who was then a young man working in my laboratory, for

carrying on a sitdown strike against a work program that I had mapped out for him. ‘Twenty years later he was able to rub my nose in

that mistake. I don’t mind telling you that Dr. Li and Dr. Schaeffer demonstrated a great deal of patience and ingenuity in adapting the Mahoney strain to go in mice. It had never been done before, and I doubt that before they did their trick anybody even suspected that it could be done. I don’t know why they tried to do this—perhaps it was to get a cheap laboratory animal for diagnostic purposes. If that was their purpose, they got that and more, because the strain they finally

developed turned out to be a mutant that was avirulent for both mice and monkeys by all routes and later proved very useful to Sabin.”8

O: Dr. Rivers, what was the cause of Dr. Sabin’s difficulties?

Rivers: Basically, I think it boiled down to the fact that the terminal dilution techniques that Dr. Sabin was then using for the selection of his strains was just not sufficient to do the job. I know that, at that time, I and several other members of the Vaccine Advisory Committee believed that the tissue-culture plaquing techniques that Dr. Dulbecco had developed would provide a far better means for selecting the genetically homogenous nonneurotropic strains that Sabin needed. I remember that when Sabin visited the Vaccine Advisory Committee in December 1955 we examined these possibilities with him. However, we reached no conclusions at that time and finally de-

cided that it might be more profitable to hold a special meeting devoted to genetics so that he might have a chance to discuss his problems further with specialists working in this area.

Earlier you asked me what the National Foundation did for Dr. Sabin, and I told you that they supported his research. I would like to 8 Dr. Sabin observes, “This mouse-adapted strain was tested by me in chimpanzees and was found to be unsatisfactory and was never used in tests on human beings’’ (private communication ).

566 Chapter 14 add here that probably one of the most important things they ever did for him was to call this conference on genetics.*® Usually when Sabin attends a meeting or conference he does the telling, and more often than not it is worth while because Sabin is a very smart hombre. However, I will go on record as saying that this was probably the only conference that Sabin ever attended where somebody else did the telling. It was set up that way. I know, because I helped set it up. The Foundation invited a lot of heavy guns to this conference for the specific purpose of getting Sabin to listen—Sir MacFarlane Burnet, Edward Tatum, Joshua Lederburg, Renato Dulbecco, Max Delbriick,

Barry Commoner, Salvador Luria, and nine or ten other people of similar caliber.

Actually, we didn’t have to twist his arm that hard; nevertheless by

the time the conference was over Sabin was ready to discard his terminal dilution techniques. As a matter of fact, a short time after the conference, Sabin and Dulbecco began to cooperate in studying the plaque characteristics of the three type strains which Dr. Sabin then believed were his optimum strains—that is, those strains which showed the lowest neurotropism for monkeys and the greatest stability after propagation in the human alimentary tract. ‘These particular studies were most important, because they showed Sabin that the strains he previously believed to be homogenous in fact represented mixed populations of virus particles. I believe that at this point he decided that the homogenous nonneurotropic strains that he wanted could only be obtained from the progeny of single virus particles derived from his optimum strains by plaquing techniques, and in the months that followed he increasingly devoted himself to such studies. My remembrance is that these studies went on for approximately six or seven months. Sometime in the fall of 1956, Sabin succeeded in developing triple purified, plaqued, attenuated strains °° of poliovirus that finally appeared to have the characteristics that he was looking for—that is, they were stable, they were not paralytogenic for monkeys on intraspinal inoculation, and, except in very large doses, they were immunogenic when fed to chimpanzees and human volunteers. 9 See Proceedings of the Round-Table Conference on Genetic Aspects of Virus-Host Relationships, with Particular Reference to Polioviruses. February 23-24, 1956, National Foundation Archives. °° Dr. Sabin observes that he never called these strains (private communication).

Salk and Sabin Vaccines—1954—1958 567 QO: Dr. Rivers, what were the minimal requirements for a live polio vaccine?

Rivers: ‘These were established very early and I must say that Dr. Sabin was always very explicit about them. First, the: polio strains which were selected for the vaccine could not be paralytogenic for the most susceptible human being: second, they had to have the capacity to multiply in the human alimentary tract so that they could produce

the infection necessary for immunity; and third, and perhaps most important, the virus strains finally selected had to be stable, that is, they had to have the ability to maintain their attenuated characteristics after propagation in vitro and multiplication in vivo. ‘The first two requirements were easy enough to prove, the third one was the rough one.

O: Dr. Rivers, when Dr. Sabin began to study the plaque characteristics of his optimum strains of poliovirus in the spring of 1956 he voluntarily suspended his experimental vaccination program at the Federal Penitentiary in Chillicothe, Ohio. Did the Vaccine Advisory Committee ever interpose any additional requirements for the resumption of these tests? **

Rivers: No. Later in the fall of 1956, after Dr. Sabin had developed his new attenuated strains, he asked the Vaccine Advisory Committee for permission to resume human testing of his vaccine on a limited experimental basis. Merck, Sharpe, and Dohme at that time had prepared about 60 liters of vaccine incorporating Sabin’s new strains, and we agreed. The only limitation we put on him, as I recall, was that he restrict his new tests to adults and not do any tests with children unless they had previously been inoculated with Salk vaccine. It was not much of a restriction. I think it’s fair to say that at that time —early in 1957—Sabin himself didn’t want to do much more than

establish the safety of his new attenuated strains and determine something of their behavior and activity in humans. * Albert Sabin, Application for a Grant to The National Foundation for Infantile Paralysis, August 4, 1956. Section on Summary of Work to Date (folder CRBS #139, University of Cincinnati, 1956, National Foundation Archives).

568 Chapter 14 I don’t want to give the impression that Dr. Sabin was a shy violet in asking to do things—he wasn’t—but I want it clearly understood that at no time did he try to go off on his own or circumvent the Vaccine Advisory Committee. For example, during the spring of 1957, a number of virologists in other countries asked Sabin for seed lots of

: his newly attenuated strains. Sabin forwarded each and every one of those requests to the Vaccine Advisory Committee, and the viruses were sent abroad only after the committee had given its permission. Pll admit that we weren't exactly enthusiastic about doing this. However, the only limitation that we finally placed on such foreign shipments was that the virus strains could only be sent to highly qualified virologists for experimental purposes, and that all experiments had to be undertaken by such investigators on their own responsibilities and in their own countries. As I remember it, shipments were later made to investigators in Russia, Holland, England, South Africa, and Mexico. I want to emphasize that these shipments were made for experimental purposes and not for field trials. ‘The field trials came later.

Q: Dr. Rivers, why were the first field trials of the Sabin vaccine held in foreign countries and not in the United States?

Rivers: I would like to correct a misconception that you seem to have. It is true that initially Dr. Sabin’s vaccine was more widely tested in foreign countries than in the United States; however, I think

that you should not overlook the fact that, beginning in 1956, the Yale polio unit under the direction of John Paul and Dorothy Horstmann started to conduct limited trials of Sabin vaccine in several small communities in the United States.*? While these trials were never done on the scale of those carried out in the Soviet Union, they * Dr. Rivers undoubtedly has reference here to tests carried out in November 1956, March 1957, and November 1957 in a children’s home, and in 1957-1958 in a village community in Southern Arizona. See, further, D. M. Horstmann, J.C. Niederman, and J. R. Paul, “Attenuated type I poliovirus vaccine: its capacity to infect and spread from ‘vaccinees’ within an institutional population,” J. Amer. Med. Assoc., vol. 170:1 (1959); D. M. Horstmann, J. C. Niederman, and J.R. Paul, “The trial use of Sabin’s attenuated tye 5) poliovirus vaccine in a village in southern Arizona,” Amer. J. Hyg., vol. 70:169 (1959).

Salk and Sabin Vaccines—1954-1958 569 were nevertheless some of the most meticulous and careful ever conducted with Sabin vaccine.

I don’t know that there is one simple answer why the first mass trials of Sabin vaccine were held in foreign countries; there is certainly more than one reason why that happened. By the fall of 1957, a year before the first large-scale field trials took place abroad, a large pro-

portion of the population in the United States had already received Salk vaccine. ‘The Salk vaccine was by then established as a safe and effective immunizing agent, and Salk immunization programs were in

progress throughout the United States. On the other hand, it is fair to say that in 1957 extensive tests were still needed to establish the safety of Sabin’s vaccine. A mass trial of Sabin vaccine in the United States at that time would most certainly have disrupted the then current Salk immunization programs, and in the circumstances it would have been a very unwise move. I can tell you that as late as 1959, the Vaccine Advisory Committee still felt that it needed more laboratory information relative to the reversion of virulence of Sabin’s attenuated strains before sanctioning a large field trial with Sabin vaccine in

the United States. I know that at that time I personally argued against using the Sabin vaccine in such a program, because I was still

cause viremias. |

not satisfied that his type 2 and type 3 attenuated strains would not Abroad the situation was quite different. In many foreign countries, in 1957 and the years immediately thereafter, it was not feasible for

economic and other reasons to undertake mass immunization programs with Salk vaccine. As a result, public health officers and virologists in such countries began to take a very lively interest in the development of live-virus vaccines, not only the Sabin vaccine but the Cox and Koprowski vaccines as well. One measure of that interest is to be

found in the fact that immediately after the Fourth International Conference on Poliomyelitis—which was held in Geneva early in the summer of 1957—a special international committee of experts met

under the auspices of the World Health Organization and recommended that field trials be held to test the value of the live-virus vaccines then being developed. ‘The action taken by this committee was very important, because it also went on to set down the first ground rules for conducting such trials. I would like to insert here the major

570 Chapter 14 portion of these rules, so you can get some notion of the criteria which later guided the field trials held in foreign countries (see Appendix E).

O: Dr. Rivers, I wonder if you can give me an example of how ' countries were chosen for field trials with Sabin vaccine.

Rivers: No one chose the country. Generally, it was the public health officials or virologists of a given country that did the choosing, and usually for reasons of their own. For example, during the summer

of 1958, Czechoslovakia through WHO asked Dr. Sabin to send them enough live-virus vaccine to inoculate approximately 200,000 children in a special field trial. What had happened was that a year or so before, all of the children under 12 in Czechoslovakia had been given three doses of Salk vaccine. However, not all of the children had developed neutralizing antibodies, and public health ofhcials decided that in such circumstances it would be fruitful to determine the effects of giving 200,000 children in one part of the country a fourth inoculation with Salk vaccine and 200,000 children in another part of the country a dose of Sabin vaccine. That, of course, was not the sole purpose of the field trial, but it certainly was one of the major purposes.*?

In the Soviet Union the situation was different. In 1957, Dr. Smorodintsev, one of the investigators who earlier had received seed lots of Sabin’s attenuated strains for experimental purposes, inoculated some 3000 children in Leningrad with Sabin’s vaccine on a limited test basis. The results of this particular test were so encouraging that the Russians, who earlier under Dr. M. P. Chumakov in Moscow had developed a program of inoculating their children with Salk vaccine, decided instead to concentrate their efforts on developing a mass immunization program with Sabin live-virus vaccine. In 1958, Dr. Smorodintsev and Dr. Chumakov asked Sabin for enough vaccine to inoculate 200,000 children in two widely separated areas in the Soviet Union. I would like to point out that the Russians later used some of 8 For a report on this trial see V. Skovranek et al., “Field trial with Sabin’s live polio virus vaccine in Czechoslovakia 1958-1959,” in Live Polio Virus Vaccines, First International Conference on Live Poliovirus Vaccines. Pan American Sanitary Bureau, Wash-

ington, D.C., 1959, pp. 530-571.

Salk and Sabin Vaccines—1954-1958 571 the lots of this vaccine to produce secondary lots of Sabin vaccine in their own laboratories. In essence this marked the beginning of probably the largest live-poliovirus immunization program ever undertaken anywhere. If memory serves, by 1960 over 70,000,000 people

had been vaccinated with Sabin vaccine in the Soviet Union and I might add by all accounts most successfully.

O: Dr. Rivers, did you ever have occasion to meet any of the Russian virologists engaged in the Sabin immunization program?

Rivers: Oh yes. In February of 1956 a delegation of Russian virologists including Dr. Smorodintsev, Dr. Chumakov, and Dr. Marina Voroshilova visited the National Institutes of Health in Washington on some official business. They had some very formal discussions and

, meetings in Washington which I did not attend. Later the Russian delegation came to New York to visit the National Foundation and I met with them on that occasion. The meeting between the Russians and ourselves was informal and friendly. We gave them a lunch and we chatted. They were very much interested at that time in obtaining

copies of papers which had been published under Foundation auspices and were equally anxious to get advice on the purchase of some

laboratory equipment. However, at no time during this visit did we ever get down to any arguable discussion of either the Salk or Sabin vaccine. My suspicion is that they probably learned a great deal more about the Sabin vaccine when Dr. Sabin addressed a microbiological

conference held in the Soviet Union in June of 1956 than they did when they visited the Foundation.**

This, by the way, was not the first time that I had met Russian virologists. During World War II I had met Dr. Smorodintsev and Dr. Solovievy in Washington when they were demonstrating a new method that the Russians had then devised for making typhus vac* Albert Sabin writes, “These Russian virologists spent three days in my laboratory during their visit to the USA and carefully went over my current work. Arrangements for collaborative studies were made then. My visit to the Soviet Union followed” (private communication). The microbiological conference referred to by Dr. Rivers was the 13th All-Union Congress of Epidemiologists, Microbiologists and Hygienists held in Leningrad, June 20—June 28, 1956. Albert Sabin to Henry Kumm, June 11, 1956 (folder CRBS #139, University of Cincinnati, 1956, National Foundation Archives).

572 Chapter 14 cine. Both of these boys spoke English surprisingly well, and I was impressed by what they had to say, but for some reason or other I took a dislike to Smorodintsev. I don’t know what it was, I just didn’t like him. When he visited the United States in 1956, he rubbed me the wrong way again. I remember that we got into a discussion of tick-

borne encephalitis, and he told me in rather glowing terms of a formalinized mouse-brain vaccine that the Russians had perfected for

such infections. Ill be frank with you. I personally have never thought much of a mouse-brain antigen for an encephalitis vaccine; yet that isn’t what really riled me. The thing that got my goat was that not once in that entire discussion did Smorodintsev ever show any concern about the possible danger of an allergic encephalitis. Dr. Chumakov and Dr. Voroshilova were completely different. Also they indicated to me very early by their actions and the things that were said that they knew what they were talking about. Chumakov had done a great deal of work on Russian spring-summer encephalitis virus, and as a matter of fact had quite a memento of that research. When I met him he had a complete flaccid paralysis of his right arm, apparently the result of a previous infection with that virus. He was also very deaf, but I don’t know whether the deafness was the result of the infection with spring-summer encephalitis virus or not. Dr. Voroshilova was equally impressive. Sometime later she trans-

lated and pirated my book on Viral and Rickettsial Infections of Man. ‘The Russians, you know, do not belong to the Universal Copy-

right Convention and they pirate any damn book they want to. In due time I received a copy of my book in Russian and a nice note from Dr. Voroshilova thanking me for the use of the book. I didn’t see any reason why she should thank me because she had used it with-

out my knowing anything about it. The letter, while a nice gesture, was on the order of closing the barn door after the horse had been stolen. What bothered me about the whole affair was the possibility that Dr. Voroshilova had misquoted me and other contributors to the volume in translation. Russians on occasion are guilty of such slips, and sometimes they put down things that they think ought to have been said. I can’t read Russian and eventually I sent my copy to Joe Smadel in Washington and asked him to have one of the Russian experts at NIH check the translation. ‘They did, and Joe later informed

Salk and Sabin Vaccines—1954—1958 573 me that Dr. Voroshilova—who by the way speaks English as well as she does Russian—had done an excellent job of translation. My fears were for naught, because the boys in Washington told me that whenever Dr. Voroshilova disagreed with the text she put in a footnote to

register that disagreement, so in the end everything turned out all right.

Now that I have told you how these people struck me, I want to reemphasize that they were all very competent virologists and certainly knew what was what about polio. Dr. Smorodintsev was chief of the Department of Virology at the Institute of Experimental Medi-

cine in Leningrad, Dr. Chumakov was director of the Institute of Poliomyelitis Research in Moscow, and Dr. Voroshilova—who by the

way was Dr. Chumakov’s wife—was a senior worker in the same institute. Dr. Dorothy Horstmann of Yale, who visited the Soviet Union in 1959, later told me that she found Dr. Smorodintsev’s and Dr. Chumakov’s staffs were also very competent and that the standards of their laboratory work were very high.*°

In the early summer of 1959, Dr. Smorodintsev, Dr. Chumakov, and Dr. Voroshilova visited the United States once again. ‘This time they came to attend the First International Conference on Live Polio Virus Vaccines, which was held in Washington. It was a very important conference and I must say that they created quite a stir. During that conference Dr. Smorodintsev and Dr. Chumakov gave a number of papers which contained both experimental and epidemiological evidence that strongly supported the contention that the Sabin vaccine, as used in the Russian mass immunization program of 1958, was both effective and safe. Although the papers that the Russians gave were impressive, they did not wipe out all of the doubts which investigators here had about Sabin’s vaccine. I think it is understandable that there were such doubts. At the time the First International Con-

ference on Live Virus Vaccines was held, only a few months had elapsed following the 1958 Russian field trials. Not all of the results of those trials were then in, and a number of important follow-up stu-

dies still remained to be undertaken. Most important, the Russian *° See also D. M. Horstmann, Report on a Visit to the USSR, Poland, and Czechoslovakia to Review Work on Live Polio Virus Vaccine, August-October 1959. This trip was undertaken under the auspices of WHO (mimeograpred copy in Rivers papers).

574 Chapter 14 field trials were not controlled, and that made it damned hard for investigators here to interpret with any precision the immunizing effectiveness of the Sabin vaccine which the Russians had used.*® In

regard to safety, as I mentioned earlier, in 1959 I and a number of other investigators were still concerned about the reversion to viru~ lence of Sabin’s attenuated strains and the ability of his type 2 and type 3 strains to cause viremias. I think that it would be a mistake to say that only the members of the Vaccine Advisory Committee of the National Foundation had such reservations. | know that members of

the special Live Polio Virus Vaccine Committee appointed by the U.S. Public Health Service had similar reservations, and I can tell you

that they gave Albert quite a time during the winter of 1959 when criteria for the commercial production of Sabin vaccine had to be set up.

QO: Dr. Rivers, I would like later to examine with you in detail the development of Dr. Sabin’s research between 1958 and the present. Now I would like to turn back to the spring of 1955 and take up a matter that in one sense develops out of both the inactivated and livevirus vaccine research programs—that is, the discovery of a new group of viruses known as “orphan” viruses.

Rivers: Unless I am mistaken, the first so-called orphan virus was discovered by John Enders and his associates in 1950, when they first

began to type polioviruses by tissue-culture methods. Later Albert Sabin, Joseph Melnick, Gilbert Dalldorf, and a number of other investigators also began to turn up other such viruses. By 1955, in a period of about five years, well over 600 strains had been isolated. All of these new agents seemed to have similar characteristics: all were cytopathogenic for cell cultures, all failed to induce disease in experi-

mental animals, and none could be neutralized by poliomyelitis antisera. I think that originally Dr. Melnick was responsible for call-

ing them orphan viruses. He called them that because he claimed that, like Pirandello’s Six Characters in Search of an Author, these new viruses seemed to be in search of a disease. As a matter of fact, Melnick was the man who initially persuaded the National Founda“See Live Polio Virus Vaccines, op. cit.

Salk and Sabin Vaccines—1954-1958 575 tion to organize a special conference among its grantees for the purpose of learning more about these viruses.*” It was a good move because, by the spring of 1955, it was becoming increasingly disconcerting for investigators to look in stools for poliovirus and to discover viral agents they knew nothing about.

QO: Dr. Rivers, did anyone ever confuse these new viruses with poliovirus?

Rivers: No, but I would like to tell you a story that I believe bears on the question that you ask. In 1950 there was a polio epidemic in Central Asia, and two Russian virologists, M.P. Chumakov and M. K. Voroshilova whom I mentioned earlier, isolated a virus from several patients that they claimed was a fourth type of polio. When that report reached the United States, it caused some furor, because

we were convinced by then that there were only three types of poliovirus. Eventually we received the virus from the Russians, and upon testing we discovered that it did kill monkeys. However, when the pathological lesions left by this virus were later examined it was found that they were quite different from those caused by poliovirus. Still later it was discovered that the virus that the Russians had sent us was in fact similar to Coxsackie A’ that Dr. Melnick had earlier isolated from a case of aseptic meningitis in Kentucky.** Basically, I don’t believe that the discovery of these new viruses confused the

polio picture. Virologists at that time knew that the new orphan viruses were different from Coxsackie viruses, and that both Coxsackie and orphans were in turn different from polioviruses. If there was any confusion, it was a confusion that arose from a duplication of work, especially with the ever increasing isolation of new strains of viruses throughout the early fifties. By 1955 most virologists were agreed that what was needed was a common nomenclature, standard pools of viruses, and standard antisera. In the fall of 1955, the National Foundation organized a small special committee made up of * Proceedings of the Conference on Orphan Viruses, New York, May 19-20, 1955 (National Foundation Archives). *° Dr. Sabin notes here that Coxsackie A‘ caused transitory paralysis but did not kill.

ton). that the identification of the virus took place in Sweden (private communica-

576 Chapter 14 John Enders, Albert Sabin, Jerry Syverton, William Hammon, Joe Melnick, Gilbert Dalldorf, Henry Kumm, and Theo Boyd to deal with the problems created by orphan viruses. Appropriately, the committee was first called the “Orphan Virus Committee” but very soon it changed its name to ECHO Virus Committee.*®

: In the beginning practically every virologist had his own name for these new agents. As I mentioned earlier, Joe Melnick called them orphans in search of a disease; Albert Sabin called them human enteric viruses because they were found in the gut. Bill Hammon, in an effort to reconcile Melnick’s and Sabin’s observations, called them CEVDU’s, which stood for cytopathogenic, enteric, virus disease unknown. Although they were descriptive, none of these names particu-

larly hit the mark, and the search for a more suitable name might have gone on for a considerable time if it hadn’t been for John Enders. At one of the early committee meetings, Enders suggested that the new viruses be called ECHO viruses, because they were enteric, cytopathogenic, human orphan viruses. It’s funny, once he spilled the name, everybody immediately knew that it was just what we were looking for, and it was unanimously adopted. Today it’s part of every virologist’s lexicon. So you see, John is not only a genius in the laboratory but in other ways as well.

QO: Dr. Rivers, with the almost continuous discovery of more and more Coxsackie and ECHO viruses during the fifties, don’t the edges of the illnesses caused by these viruses become indistinguishable from one another?

Rivers: Yes. I would go so far as to say that in some instances it even seems foolish to make any serious effort to separate them, except for diagnostic purposes. ‘This is echoed—if you will forgive the pun—

in fact that today we call all the polios, Coxsackies, and ECHOs, enteroviruses. The enteroviruses are not distinguished from one another by name but by number. For instance, enteroviruses 1, 2, and 3, correspond to polioviruses 1, 2, and 3; all enteroviruses from 4 to 30 * The Orphan Virus Typing Committee was initially organized on August 9, 1955. Its name was changed to the ECHO Virus Committee following a meeting on November 4, 1955. Minutes, Orphan Virus Typing Committee August 9, 1955; November 4, 1955 (National Foundation Archives).

Salk and Sabin Vaccines—1954-1958 577 are Coxsackies, and those above 30 and up to 60 are ECHOs. I be-

eve that to date [1961] virologists have typed approximately 30 ECHO viruses. ‘The order that that typing represents is one of the fruits of the work of the ECHO Virus Committee. In one sense it can even be said that the work of this committee was similar to the work undertaken during the late forties by the Poliovirus Typing Committee. Its problems certainly were.

I say this because Coxsackie and ECHO viruses, like the polioviruses, cannot be identified by type under the electron microscope or

by clinical means. However, since they all differ immunologically, they can be differentiated from one another by type specific antisera. If each of the laboratories working with Coxsackie and ECHO viruses had been forced to prepare its own antisera, a great deal of confusion

would undoubtedly have arisen through variation of potency and other qualities. To avoid such problems, the ECHO Virus Committee sponsored a special program to prepare standard pools of antisera. | don’t mind telling you that as more and more new Coxsackies and ECHOs came to light, the problem of preparing antisera to match them became more and more complicated and expensive. I

don’t know if this program would have had the success it finally achieved if the committee didn’t also have the good sense to choose Herb Wenner to carry the ball. Previously Dr. Wenner had prepared all of the antisera against the polioviruses. He had a number of re-

search projects going when the committee asked him to produce antisera in monkeys against Coxsackies and ECHOs, and I think it was plain good luck that he agreed to take on this job as well. Pll tell you plainly, it was a hell of a job, and if it had been put up to me I wouldn’t have done it, but Wenner did and what’s more carried it out beautifully. ‘Today the National Foundation is the only agency in the world that has standardly prepared antisera for all the enteroviruses.

If a qualified virologist anywhere in the world needs any—and this. goes for the government as well—all he has to do is to write to the Foundation and he gets it without charge. ‘The only restriction is that requests can only be made for research purposes. The reason for this is that there is such a great demand for these antisera for diagnostic purposes that our stock would be depleted in no time at all if such a restriction didn’t exist.

578 Chapter 14 The Foundation has every right to be proud of the work of the ECHO Virus Committee. As a matter of fact, the National Institutes of Health thought so highly of the committee’s work that about a year ago they asked the Foundation if they could take it over, lock,

stock, and barrel. ‘he Foundation agreed, and today the National Cancer Institute supports Dr. Wenner’s production of antisera. | didn’t mind the government taking over; about the only thing that miffed me was that when the National Institutes of Health announced their support of Dr. Wenner’s work, nobody in Washington had the courtesy to say that the program they were so happy about was something that the National Foundation had originally helped to develop.

CHAPTER l 5

Early Days of Retirement Remembrance—all the joy that is left to us now; a poor joy, but our own. Sean O’Casey, Under a Greenwood Tree He Died

Q: Dr. Rivers, did your service on the Virus Research Committee, the Immunization Committee, the Vaccine Advisory Committee, and the various other committees of the National Foundation ever interfere with your work at the Rockefeller Institute?

Rivers: It did not; there was never any reason for it to interfere. To be sure, I served on all of these committees, but I want you to keep clearly in mind that they were always part of my extracurricular activity. My full-time job was as director of the Rockefeller Hospital and a member of the Rockefeller Institute. I continued in those capacities

- until my retirement in November 1955. | Q: Dr. Rivers, your retirement and Dr. Gasser’s retirement marked the end of a second generation of administrators at the Institute.

Rivers: It marked more than that. It marked the beginning of a complete change in the development of the Institute. Actually, Dr. Gasser retired two years before I did—at the end of June 1953. According to the rules of the Institute, he could have stayed on an extra year as director if he had so chosen, because his sixty-fifth birthday occurred after the end of the fiscal year in June; however, Dr. Gasser at

the time was not as strong as he would have liked to be and was in-

clined to shed his administrative duties just as soon as he could, and , the Board of ‘Trustees permitted him to retire. 579

580 Chapter 15 QO: Dr. Rivers, you mention a change in the development of the Institute. Did you or Dr. Gasser have many administrative problems during the latter part of your tenure?

Rivers: I know that I didn’t, and I don’t think that Dr. Gasser had any—that is, with one exception—the closing out of the Division of Animal and Plant Pathology at Princeton.

Q: Dr. Rivers, why was that done? From the little that I know of the history of the Institute, that division had a wonderful élan of research stemming from Theobald Smith, it had magnificent investiga-

tors such as Dick Shope, Louis O. Kunkel, Carl tenBroeck, and Norman Stoll, and, more to the point, it had an extraordinary record of production and accomplishment.

Rivers: I don’t know that I have all the answers to that question. I think that to understand that move you have to know something of the financial thinking at the Institute, and to do that you have to take into account the depression of the 1930’s. ‘Today a lot of people seem to have forgotten that depression, but there was a depression and it

had a profound effect on the administration of the Institute. Throughout its early days, the Institute had a great deal of money. However, Dr. Simon Flexner in his great wisdom didn’t spend everything he received and succeeded in saving a substantial amount of money, separate from the capital which had been put in as an endowment. When the depression began, I understand—and this is not from Dr, Flexner or Mr. Rockefeller but from other people—that Dr. Flexner wrote John D. Rockefeller Jr., and assured him that the Institute would not come to him for any extra funds during the next several years because enough money had been saved to ride out the financial emergency.

Dr. Flexner was true to his word, and throughout the depression both he-and Dr. Cole saw to it that the Institute lived well within its means. Salaries were kept tight, people who retired were not replaced, and expansion was limited. When Dr. Gasser took over he continued

} that policy, and I went along with him. We were frugal, and in the end we too succeeded in saving a tidy sum. This, however, does not

Retirement 581 mean that we stinted. For instance, the renovations and additions that I made to the Rockefeller Hospital after the war, and which cost upwards of two million dollars, were carried out with funds that Dr. Gasser and I had saved. In spite of that expenditure, Dr. Gasser and I were still able to leave the Institute with several million dollars in a

reserve fund when we retired. It was always understood between Gasser and myself that we would not start anything new at the Institute after 1950. We knew that we would both be close to retirement after that date, and that anything we might start would in all probability not be going full tilt by the time we retired. It would mean that the people who followed us would be in the position of paying bills for something we had started before they could undertake anything on their own. [ think that our decision was a wise one, although I realize that the heads of most universities today work on the principle, when you have the money spend it; you may never get another chance. I have lived through my theory of operation, and I would do it again if I had to. I believe that Dr. Gasser would too.

I think I should make clear that although Dr. Gasser and I were able to save money, it does not mean that the Institute had an unlimited or lavish income. It didn’t. As a matter of fact, as long as I can remember, there were always a number of members of the Board of Trustees who looked around for ways to economize on Institute expenditures, and from the beginning one of their favorite targets was the laboratories of the Division of Animal and Plant Pathology that

the Institute maintained in Princeton, New Jersey. ‘These board members argued that the Princeton laboratories merely duplicated the Institute’s facilities in New York, and that it would be a considerable economic advantage to consolidate all the laboratories in New York. Dr. Gasser held out for a considerable time against this pressure but in 1951 his resolve was worn down and he finally agreed to a reconsolidation. It’s no secret that that move caused a great deal of resentment and bitterness within the Institute. It has always been my feeling that a good deal of that resentment could have been avoided if Dr. Gasser, or for that matter the trustees, had acted more diplomatically or judiciously. In part, the problem was one of personality. Dr. Gasser and Dr. Carl tenBroeck, who was the chief of the Division of Animal and Plant Pathology, heartily disliked one another, and for

582 Chapter 15 some years prior to the closing of the laboratories had not been on speaking terms. When the decision to close the laboratories was reached, Gasser unfortunately did not bother to consult with or talk to tenBroeck about the impending move. In fact, nobody told the boys in Princeton anything, and they learned about the closing by reading about it in the morning paper. Although most of the investigators at Princeton were offered posts in the Institute in New York, it didn’t relieve the anger and resentment that they felt. Dr. tenBroeck was especially bitter and resigned and I doubt whether to this day he has forgiven the Institute or Dr. Gasser. Dr. Shope was another who strongly resented the closing of the laboratories at Princeton. I knew indirectly what Dick Shope felt. Dick was loyal to the memory of Theobald Smith, who was the first director of the Division of Animal Pathology, and he was loyal to his boss, Carl tenBroeck. I want to tell you that if anyone that Dick Shope is loyal to is upset, Dick is upset. Upset is a mild word. Dick was so sore that he wrote a scathing letter to John D. Rockefeller, Jr., giving Gasser and the Board of ‘Trustees

bloody hell. Mr. Rockefeller later sent the letter to Dr. Gasser for a reply. I have never had my hands on that letter, but when Gasser received it he called me over and read parts of it to me. It shook him. Gasser always had an extremely high regard for Dick Shope, and when the laboratories in Princeton were closed down I know that he pretty well offered Shope the world with a fence around it if he would come to New York. I never saw the reply that Gasser finally drafted for Mr. Rockefeller, but I do know that it didn’t succeed in mollifying Shope. Soon after the labs in Princeton were closed down, Shope

resigned from the Institute to take a post with Merck, Sharpe and Dohme. He remained angry for a long time and it took several years before he could be persuaded to come back to the Institute.

Q: Dr. Rivers, was there ever any planning of Institute policy? Rivers: I don’t believe that there was ever any planning in a formal sense. In my day both Dr. Flexner and Dr. Gasser wrote historical reviews of the work of the Institute for the Board of Trustees and made predictions in those reviews of the future lines of development in

Retirement 583 medicine and science.* However, a year and a half prior to Dr. Gasser’s retirement, the Board of ‘Trustees appointed a special committee composed of members of the Board of Scientific Directors and the Board of ‘Trustees to review the fundamental policies of the Institute and to choose a successor for Dr. Gasser. Donald David, Barklie Henry, Lindsley Kimball of the Board of ‘Trustees, and Dr. Detlev Bronk, Dr. A. R. Dochez, and Dr. George Whipple of the Board of Scientific Directors all served on this committee.

The committee had no easy task. For a period of approximately fifty years the Institute had been preeminent in the field of medical research. The Rockefeller Hospital had set a pattern of integrating laboratory and clinical research that was widely copied by medical schools and hospitals throughout the United States. Many of the investigators who had been trained at the Institute were also to be found in important posts in leading medical schools and universities. However, in 1950 the Institute was no longer unique. Many medical schools encouraged their professors to combine laboratory and clinical research. Equally important was the fact that by 1950 universities had funds at their disposal to do fundamental research in the medical as well as basic sciences.

The committee had two alternatives. It could enlarge the Institute and have it go on doing what it had successfully been doing for a half a century on a larger scale, or it could strike out on a new path. It chose to do the latter. Almost the first recommendation that it made was that the Institute preserve its high scientific standards and improve conditions to attract good people. I tell you about this recommendation because it illustrates one of the important changes that had taken place in the world of medical science. In 1920 the offer of a membership in the Institute was a sufficient magnet to attract topnotch people. By 1950 many excellent investigators passed up oppor-

tunities of joining the Institute to take posts at first-rate universities . like Harvard, Chicago, and the University of California. ‘The second

and key recommendation that the committee made was that the *Simon Flexner, Report to the Members of the Corporation of the Rockefeller Institute Covering a Review of the First Twenty-Five Years of the Rockefeller Institute for Medical Research, October 31, 1930; Herbert S. Gasser, Report to the Members of the Corporation of the Rockefeller Institute, October 26, 1951.

584 Chapter 15 Institute offer advanced training to young scientists on the predoc-

toral and postdoctoral level. In effect, it recommended that the Institute be converted to a graduate university of science. To carry

out this new program, the committee nominated one of its own members, Dr. Detlev Bronk, a distinguished neurophysiologist, to succeed Dr. Gasser. When Dr. Gasser retired in June 1953, Dr. Bronk was appointed director of the Institute.

Q: Dr. Rivers, what immediate problems did Dr. Bronk have when he took over?

Rivers: He didn’t have any. At the time that Dr. Bronk was appointed director, he was the president of Johns Hopkins University,

and, because he still had a number of obligations to fulfill, the Trustees decided that he be allowed to take up the duties of his new post gradually. In the interim I was asked to run the Institute. Q: Did you have any administrative problems?

Rivers: No. My job was a holding operation, and I never thought that it was part of my duties to effect the changes that had been recommended by the committee. ‘The only problem that I really had was the budget, and here I continued to function as I had when I ran the Rockefeller Hospital. ‘That is, toward the end of each fiscal year I spoke to the heads of the various laboratories in the Institute about their budgets, and when I completed my survey I decided who should

be cut, who should remain the same, and who should receive increases. All of this planning was done within range of the Institute’s

yearly income. I do not believe that John D. Rockefeller, Jr., had . many phobias, but he had very firm convictions, and one of these related to the amount of money that was spent each year by the Institute. Mr. Rockefeller always insisted that the expenditures that the Institute made be kept within the level that the endowment fund of the Institute itself could provide. He never allowed the Institute to accept funds from outside agencies. When Dr. Bronk took over in 1955, that policy was discarded. Today much of the research that goes

Retirement 585 on at the Institute is supported by funds from private philanthropic organizations and the government.

QO: Dr. Rivers, could you tell me what role Dr. Bronk played at the Institute during the interim period in which you served as temporary director?

Rivers: In the beginning, Dr. Bronk’s job was essentially to learn about the operations of the Institute, and I suppose you might say that during this period I served as his teacher. We had adjoining offices on the first floor of the Rockefeller Hospital and shared the services of Mrs. Mabel Bright, who was then my secretary. Initially, Bronk didn’t

spend much time at the Institute, but gradually that changed. At the end of two years, he was not only full time at the Institute, he also had appropriated unto himself Mrs. Bright. Mabel Bright is a wonderful person; she has brains and she is a first-rate secretary. I think that Bronk made a wise move when he took Mabel Bright. ‘Today she is Dr. Bronk’s chief administrative assistant. People at the Institute like her and they don’t balk at her. I think that’s important, because in a sense Mrs. Bright has made it possible for Dr. Bronk to hold the many jobs and advisory posts that he holds. God knows where he gets the energy to do what he does. He does enough work to occupy ten men. You can say anything that you want about Dr. Bronk, but you can’t say that he is lazy and you can’t say that he is dumb.

QO: Dr. Rivers, did Dr. Bronk have any trouble reorganizing the Institute according to the mandate given to him by the special committee?

Rivers: Hell, no. He cut the umbilical cord to the past swiftly and proficiently. Now, what I am about to say is not the way I felt six or seven years ago. Ihe truth is that you can’t run an Institute the same way for fifty years and still keep up with the times. God bless Bronk,

because he had the guts to cut the ties with the past. He wasn’t a young man when he became director of the Institute, and it took some courage to do what he did at that time because he had not a little opposition. I know because I was part of it. I didn’t like the idea of converting the Institute to a graduate institution, and I was fearful

586 , Chapter 15 that in the new order of things the hospital would no longer play an important part in the affairs of the Institute. In the spring of 1955, a short time after Dr. Bronk pushed through an administrative change which abolished the lines between the old department of the laboratories and the department of the hospital, I got into one hell of a fight with him. I won’t go into the details—it’s relatively unimportant— but I will say that it was as hot a fight as I have ever been in and one of the few I ever lost. I hated to lose this particular fight, because it

left me no option but to retire. It is true that I was past retirement __ age in 1955, but I was as sharp and mean as I ever was, and I didn’t want to go out to pasture. I remember that at one point I went to see Mr. O’Connor to get some legal advice about my retirement, and he looked at me and said, ““T'om, if you are going to retire from the Institute, why don’t you come and work at the Foundation?” It was one of

the nicest things that anyone ever said to me. I left-the Institute on the 26th of November 1955 and took up my new job at the Foundation on December 1. I wasn’t idle for more than four days.

Q: Dr. Rivers, did Mr. O'Connor tell you what your job would be?

Rivers: He told me that I would be a consultant, but he didn’t tell - me what my duties would be. I didn’t even know where I was going to sit. However, when I reported to the Foundation I found that a place had been made for me next to Hart Van Riper who was then the medical director. I knew everybody, but there was very little for me to do. The truth is, I would have had a pretty sorry time that first year if it hadn’t been for Dr. Henry Kumm. Henry, bless his soul, invited me to make inspection trips with him of the grantees who were

then being supported by the Foundation. It was the custom at that time, and still is for that matter, for the director of research at the Foundation, or one of his associates, to visit grantees at least once a year. It is a good idea, because sometimes you can be fooled by written reports, and it’s worth while to supplement impressions gleaned from reports by taking a look-see and asking a few questions.

Q: Dr. Rivers, what was the nature of the virus research you saw in progress? Had virus research changed much from the time you were actively engaged in the laboratory?

Retirement 587 Rivers: It had changed markedly. It had changed even before I stopped working actively in my own laboratory, not only in terms of equipment, but in terms of technique as well. Heck, in 1955 you pretty near had to be an expert in biochemistry, physics, and genetics to work fruitfully in virus research.

Q: Dr. Rivers, instead of speaking of these changes in a general way, perhaps it might be more fruitful if we discussed instead the work you Saw in progress during your visits to grantees. For instance, one of the

first laboratories that you visited with Dr. Kumm was that of Dr. Theodore Puck at the University of Colorado Medical School. Had you met Dr. Puck before this visit?

Rivers: Oh, yes, I knew Dr. Puck long before he ever became a grantee of the Foundation. As a matter of fact, I first met him in 1941

or 1942 when he was working with Oswald Robertson at the University of Chicago Medical School. Dr. Robertson was and is quite a guy and an original as an investigator. During World War I he was at the Rockefeller Institute and, together with Dr. Peyton Rous, developed a method for preserving red blood cells. Today a lot of people have forgotten that Dr. Robertson and Dr. Rous did that work, but anyone who received a blood transfusion during World War II has cause to remember, because essentially it was the Rous-Robertson method of preserving red blood cells which made it possible to ship large amounts of blood from the United States to far-off battle fields in Europe, North Africa, and the South Pacific in safety. After leaving the Rockefeller Institute in 1919, Dr. Robertson began to work on experimental pneumonia, and by the late 1930’s that interest had led him to study the problems of airborne infections. When I met Puck, he was—as a member of Robertson’s laboratory—trying to learn why

aerosols, when sprayed in the air, killed bacteria. Although Puck didn’t have very great success at that time, I could not help but be impréssed with the quality of his mind and the way he worked.

After the war Dr. Puck joined the faculty of the University of Colorado Medical School and began to study bacteriophage, and in particular the mechanisms of attachment of animal viruses to their

host cells. I remember that at the time that Henry Kumm and |

588 Chapter 15 visited his laboratory in 1956, Puck, as part of his work on host-virus relationships, was growing clones of HeLa cells in both porcine and human serum. A short time earlier he had discovered that the HeLa cells which he grew in porcine serum differed markedly in appearance from those grown in human serum. Interestingly enough, in human serum they grew in a loose, extended network, while in porcine serum they grew dense and compact. ‘These findings in essence permitted Puck to screen large populations of cells to isolate mutant strains and to begin new studies of the invasive patterns of animal viruses on host cells. He soon discovered that when HeLa cells were exposed to x-rays for a certain amount of time, they lost their power to reproduce and

instead kept on growing until they reached a giant size. Although HeLa cells in their original state were resistant to invasion by such viruses as Newcastle disease virus, in their giant state they became very susceptible to invasion by the same virus. | remember thinking at the time that if irradiated HeLa cells showed a like susceptibility to poliovirus, Dr. Puck’s techniques might be adapted for testing minute amounts of live virus in inactivated polio vaccine. Incidentally, Puck

at that time was quite interested in using x-ray irradiation as an adjunct to chemical methods of poliovirus inactivation.*

If you were to ask me why Dr. Puck did the things he did, I don’t know that I could give you a satisfactory answer, save to say that he

has always had an insatiable cunosity. The techniques that he brought to bear on his problems were not the traditional techniques used by virologists when I worked in the laboratory; they were the techniques of biophysics and biochemistry, and in this respect I think that Puck was much closer to people like Max Delbriick and Wendell Stanley than to me. I would like to add one more thing about the way Puck ran his laboratory. He did not like technicians, and at the time I visited him he didn’t have any technicians. He did have graduate students, but these fellows had to do their own work. Dr. Puck always maintained that if you hired a technician you couldn't learn anything. At that time he did his own work, and I would suspect that he still does, although I can’t say for sure because I haven’t visited his laboratory recently. °S.J. Cieciura, P. I. Marcus, and T.T. Puck, “The use of x-irradiated HeLa cell giants to detect latent virus in mammalian cells,” Virology, vol. 3:426 (1957).

Retirement 589 QO: Dr. Rivers, one of the other laboratories that you visited in 1956

was that of Dr. Wendell Stanley. Had Dr. Stanley changed much from the time when you knew him at the Rockefeller Institute?

Rivers: I wouldn’t say that he had changed. He had perhaps become a little more expansive than he was at the Institute, but the California atmosphere tends to make people who are naturally expansive a little more so than they would otherwise be. But expansive or

not, the fact remains that Dr. Stanley is the person responsible for developing the virus laboratory at the University of California at Berkeley. ‘To give you an idea of his achievement, let me say that I don’t know of any virus laboratory in the United States that is better than Stanley’s laboratory. It is extraordinarily successful, and part of

that success rests in the fact.that from the beginning Stanley succeeded in attracting topnotch people. At the time I visited him in

1956, such investigators as Heinz Fraenkel-Conrat, Carleton Schwerdt, Robley Williams and Frederick Schaffer all worked in his laboratory. I have always had a very high personal regard for Dr. Stanley, although it is true that on more than one occasion I have had knockdown dragout fights with him. He is the only guy who ever got me |. out of my seat twice. The first time was in 1935 when he crystallized tobacco mosaic virus, the second time came twenty years later when

he and his associates, Dr. Carleton Schwerdt and Dr. Frederick Schaffer, crystallized all three types of poliovirus. When Stanley went out to California in 1948, he needed a great deal of money to build up

his laboratories and I backed him with the National Foundation. | honestly didn’t know what he would deliver; the only thing I was cer-

tain of was that he would deliver something. By 1954 the National

Foundation had spent well over a million dollars in support of his laboratory, but to that time nothing much had come out of it. A number of people on the Virus Research Committee began to ask me

why I was so keen on Stanley, and did I think it was wise for the Foundation to continue giving him support? They ragged me good and proper, but I held the fort because it was obvious to me that these had been years of preparation for Stanley. It took some persuading, but in the end I got the boys on the committee to go along with me.

590 Chapter 15 In 1954 Dr. Stanley and his associates began a program of research

designed to improve the purification process of all three types of poliovirus, and to see if the biochemical and biophysical properties of

such pure preparations could be determined. Much of the surplus poliovirus fluids that the Connaught Laboratories had prepared for the production of Salk vaccine was sent by the Foundation to Stanley’s laboratory so that he and his associates could carry on this new work. I don’t remember now how many hundreds of liters of virus fluid the Foundation eventually shipped to Stanley, but I am willing to bet that at one point that Stanley had more poliovirus in his pos-

session than any other laboratory in the world. From time to time Stanley had told me, “Rivers, some day we are going to crystallize an animal virus.’ You know me, I took that kind of a prediction with a grain of salt. I wouldn’t say that it couldn’t be done, because by that time I had reached the stage where you just don’t say that things can’t be done. I was skeptical and I don’t mind admitting that some people

on the Virus Research Committee were just about ready to ask Dr. Stanley, “What the hell are you doing with all the poliovirus we have been sending you?” Luckily, before they asked that impertinent ques-

tion, Carleton Schwerdt presented irrefutable evidence that he and _ Frederick Schaffer had crystallized a purified MEF" type 2 poliovirus. Although several plant viruses had been crystallized before, this was the first time that an animal virus had been crystallized. I can’t overemphasize the importance of this achievement. Let me just say that from that time forward it became possible to study with precision the relationships between chemical structure and biological activity in animal viruses.°

I can’t talk about Dr. Stanley’s laboratory without at least saying a

word or two about Dr. Fraenkel-Conrat. Fraenkel-Conrat is not a virologist; he is a protein chemist. A short time before Dr. Schwerdt and Dr. Schaffer crystallized type 2 poliovirus, Fraenkel-Conrat made the equally important discovery that naked protein-free nucleic acid of tobacco mosaic virus could infect a cell. When I visited Stanley’s laboratory in 1956 Fraenkel-Conrat had just demonstrated that when protein from tobacco mosaic virus was combined with nucleic acid °C. E. Schwerdt and F. L. Schaffer, “Some physical and chemical properties of purified poliomyelitis virus preparations.” Ann. N.Y. Acad. Sci., vol. 61:740 (1955).

Retirement 591 from rib grass mosaic virus, a variant strain of rib grass mosaic virus

would emerge. He also showed that a recombination with protein from rib grass mosaic virus and nucleic acid from tobacco mosaic virus

was also possible and would result in a variant strain of tobacco mosaic virus. This work convinced both Fraenkel-Conrat and Stanley

that the nucleic acid and not the protein was the specificity determinant. For the record, I think it is fair to point out that Dr. Gerhard Schramm of Tubingen was probably the first to show that nucleic acid alone is infectious. Although Schramm and Fraenkel-Conrat knew each other and were in constant communication with one another, I believe that they did their work independently of each other. Investigators, you know, even if they are great friends, don’t usually. discuss their findings until they are published or fairly close to publication, and rightly so. You know, even your best friend will some-

times steal from you. A short time later, Dr. Barry Commoner at Washington University in St. Louis also came out with a similar observation. All three of these investigators did their work independ-

ently and almost simultaneously; yet it is the first man who publishes who generally gets the credit and kudos. I have always felt that

the poor fellow who publishes second or third—if he has worked independently—also deserves some credit.* Science isn’t a footrace.

Suffice it to say that, with the crystallization of poliovirus and the nucleic acid work of Dr. Fraenkel-Conrat, the Foundation got back every cent and more that it had invested in Dr. Stanley. You can never tell how you are going to get your money back when you support research, or whether you will in fact get it back. ‘The rule is you must not expect to get your money back.

Q: Dr. Rivers, I think you will agree with me when I say that much of the virus research that the Foundation was supporting at the Callfornia Institute of ‘Technology during this period also exhibited many | of the same tendencies which you have been describing. I have spe* A. Gierer and G. Schramm, “Die Infectiositat der nuclein Sdure aus ‘Tobak-mosaikvirus.” Z. Natursforsch, vol. 11:138 (1956); H. Fraenkel-Conrat, “The role of nucleic acid in the reconstitution of tobacco mosaic virus,” J. Amer. Chem. Soc., vol. 78:882 (1956); B. Commoner and E. Basler, Jr., “Variations in the nucleic acid composition of tobacco mosaic virus,” Virology, vol. 2:477 (1956).

592 Chapter 15 cific reference here to the work of Dr. Renato Dulbecco and Dr. Max Delbriick.

Rivers: I would like to speak of Max Delbriick first, because in a way he is a prime example of the new workers who have entered virus

research since World War II and who now dominate the field. Dr. Delbriick was originally trained as a physicist and received his Ph.D. in physics from.the University of Gottingen, which you may remember was one of the preeminent institutions training physicists in Germany before Hitler. Many of our own distinguished physicists, people

like Isador Rabi and Robert Oppenheimer received some of their training at this institution. Delbriick worked in physics until he left Germany, and at one time I understand, he even did some work with

Dr. Lise Meitner. When Delbriick came to the United States, he continued to work in physics but interestingly enough he also began to turn his attention to biological problems. For instance, just before ‘World War IT he published a most interesting paper on the growth of

bacteriophage with Dr. Emory L. Ellis. During the war he did an equally nice piece of work on bacterial mutation in collaboration with Salvador Luria.® I don’t know what aroused Delbriick’s interest in biological problems, I only know that he had such interests. I personally have always found it extraordinary, because most physicists that I know look down their noses at biologists and doctors. After the war, Delbriick decided to devote himself to the study of biology and went to the California Institute of ‘Technology as a professor of biology. From that day to this, he has practically spent all of his time studying

the properties and growth mechanisms of bacteriophage. In detail, this work has included the induction of mutation in phage by ultraviolet radiation, the production of new phage types by genetic recombination, chemical studies of nucleic acid, and lysogeny, which is the study of the capacity of bacteria to transmit to their descendants the potentiality to produce phage. Delbriick, like Stanley, also succeeded in attracting excellent associates, many of whom had particular skills

in physics and genetics—among them people like Jean Weigle, Giuseppe Bertani, and, for a time, Renato Dulbecco. It’s hard for me °E. L. Ellis and M. Delbriick, “The growth of bacteriophage,” J. Gen. Physiol., vol. 22:365 (1939); S.E. Luria and M. Delbriick, “Mutations of bacteria from virus sensitivity to virus resistance,” Genetics, vol. 28:491 (1943).

Retirement 593 to keep in mind the stage of development of Delbriick’s work at the time that I visited his laboratory; the only thing I remember is that

when I visited him he was studying the mechanism by which phycomyces, a species of fungus, measured light intensity. I am sorry that I.can’t tell you more.

O: Dr. Rivers, why don’t you go on and tell me about Dr. Dulbecco’s laboratory?

Rivers: In one sense, the research that I found going on in Dr. : Dulbecco’s laboratory was an extension of Dr. Delbriick’s work. That’s understandable. For a number of years Dulbecco had worked in Delbriick’s laboratory studying bacteriophage; however, about 1954 he was made an associate professor of biology and given the opportunity to take command of his own laboratory. Almost immediately he

and his associate, Dr. Margaret Vogt—a lady who, by the way, was expert in her own right on the genetics of Drosophila—began to apply the plaquing techniques they had previously developed for studying bacteriophage to the study of animal viruses and, in particular, poliovirus. They very quickly discovered that one infectious particle of poliovirus was sufficient to infect a single cell and, with that as a key, began genetic investigations of the progeny of such infectious particles. When I visited Dr. Dulbecco’s laboratory in 1956, he and Dr. Vogt told me they thought it might be possible to discover several loci in the genetic material of each poliovirus particle that were related to lack of pathogenicity. ‘Their hope at the time was that by obtaining a recombination with such loci they might eventually secure a stable variant of poliovirus with characteristics of reduced pathogenicity. Later Dulbecco and Vogt made several attempts at such recombination but had no success in obtaining a true recombinant.® That’s not surprising: a number of workers have tried that trick and failed. George Hirst tried it with influenza virus and failed. Hattie Alexander and Katherine Sprunt tried it with poliovirus and failed.’ °*M. Vogt, R. Dulbecco, and H. A. Wenner, “Mutants of poliomyelitis virus with reduced efficiency of plating in acid medium and reduced neuropathogenicity,” Virology,

vol. 4:141 (1957). , “G.K. Hirst and T. Gotlieb, “The experimental production of combination forms of virus. I. Occurrence of combination forms after simultaneous inoculation of the allantoic

594 Chapter 15 Perhaps it was just too much to expect. Let me just add here, that the Virus Research Committee had such high regard for the work being done at the California Institute of Technology that it later broke one of its cardinal rules and made a special grant to Dr. George Beadle,

who was then chairman of the Department of Biology, so that he could complete building new laboratories that Dr. Delbriick and Dr. Dulbecco were to use.

Q: Dr. Rivers, what were your over-all impressions of the trip of inspection that you took with Dr. Kumm?

Rivers: It reemphasized for me that the polio work which the National Foundation had supported had only scratched the surface in virus research, and that a hell of a lot remained to be done. It also reinforced a conviction that I had had for years, namely, you can’t do research unless you have brains, and that no one begins doing brilliant research right off the barrel. You grow into your work. I wasn’t a good

researcher when I began, and I don’t mind admitting that I was dumb a little bit and slow in getting started. Have you ever thought about what the word research means? Research—and it’s pronounced research not research—comes from the French word rechercher which means an inquiry or a diligent investigation with the primary aims of discovery. It does not come from the hyphenated word re-search. Concern for a mispronunciation may seem trivial to you; yet for me it’s an illumination of a misconception that some people have about the nature of research. Recently I attended the first Inter-American Conference on Congenital Malformations in Los Angeles, and I listened to a speech given by President Arthur Fleming of the University of Oregon. I don’t now remember the substance of that speech, but for 45 minutes he kept talking about research. Rusty McIntosh and I sat next to each other and we kind of got fed up with research. When the talk was over I did a very sassy thing. I went up to President Fleming and said, “President Fleming you gave a very nice talk, A study of serial passage in the allantoic sac of agents that combine the antigens of two distinct influenza A strains,” ibid., vol. 98:53 (1953); K. Sprunt, I. M. Morgan, W.M. Redman, and H.E. Alexander, “Production of poliomyelitis virus with combined antigenic characteristics of type I and type II,” Virology, vol 1:236 (1955).

Retirement 595 except for the fact that you kept mispronouncing the word research. You said research, and research is a disgrace—it means looking for

something over and over again, and who in the hell ever made progress that way? Research is a completely different matter.” He

looked at me as if I were out of my mind. “Dr. Rivers,” he said, , “there is a difference of opinion on how you pronounce this word. It can be pronounced either way.” I shut up because it was obvious that he had missed the point. Dr. Stanley, Dr. Puck, Dr. Dulbecco, and Dr. Delbriick are researchers. Researchers, of whom there are unfortunately many, are people who should be out plowing in the cotton.

BLANK PAGE

APPENDIX A

Remarks on a Paper Presented by Arthur Kendall, M_D.,

before a Meeting of the | Association of American Physicians

m 1932 Thomas Rivers, M.D.

Dr. Kendall’s ideas and the results of his work are interesting. The notion, however, that filterable forms occur in the life cycles of bacteria is old. Furthermore, that such filterable forms represent the active agents known as |

viruses is also not a recent conception, because it has been expressed, . from time to time during the past 8 to 10 years, by Nicolle, Kraus, Maudaroy, and others. Although most of Dr. Kendall’s ideas are not new, he has, nevertheless used a new medium in attacking problems in this field. ‘This medium is of particular interest to me because Dr. Kendall has suggested that it is suitable for the cultivation of viruses. We have two problems with which‘to deal. Firstly, do bacteria have life cycles with filterable forms and has the use of K. medium added infor-

mation regarding the question? Secondly, do the presumptive filterable forms of ordinary bacteria represent the etiological agents of poliomyelitis, vaccinia, yellow fever, etc., has the K. medium shed light upon the problem, and is this medium suitable for the cultivation of the viruses?

Concerning the first problem I shall say very little. The K. medium appears to be a starvation diet for nonproteolytic bacteria, and Dr. Dubos working in Dr. Avery’s laboratory has shown that starvation diets regularly cause certain nonfilterable saprophytic bacteria to become granular, pleo-

morphic, and filterable. When these bacteria are returned to adequate diets, normal appearances and nonfilterability are resumed by them. It seems unnecessary to assume the existence of life cycles to account for such phenomena. 597

598 Appendix A Concerning the second problem, namely, the relation of the presumptive filterable forms of bacteria to the viruses, I can speak with more assurance. No one has brought convincing evidence that any of the viruses are capable of growth in the absence of living tissue. In view of Dr. Kendall’s suggestion that the K. medium is suitable for the growth of viruses, we proceed to test the importance of the suggestion in regard to the viruses of vaccinia and infectious myxomatosis of rabbits, two agents that we have for several years been successfully cultivating in vitro in the presence of surviving tssue suspended in Tyrode’s solution or kept in a mixture of Tyrode’s solution and serum. Similar amounts of the adequate medium just described, K. medium, Tyrode’s solution, and meat infusion broth were inoculated with the viruses. All cultures were made in duplicate, one set of which was

incubated at 30°C., and the other at 37°C. At intervals of 5 days, serial transfers of the cultures were made to fresh media and the titer of the viruses in each culture was established by animal experimentation. The experiments were repeated several times and the results are interesting. Multiplication of both viruses occurred in the medium containing bits of living tissue, while no evidence of multiplication was found in any of the other media. In fact, the active agents were not demonstrable in ‘Tyrode's solution or in K. medium after the second transfers. We were particularly

interested to find that the virus of vaccinia survived longer, 4 transfers at 30°C., in the meat infusion-peptone medium than it did in K. medium.

| Dr. Kendall has also suggested that while viruses are invisible in the K. medium, they become visible when transferred to ordinary broth or to agar mixed with K. medium. We tested this point. ‘The viruses of vaccinia and infectious myxomatosis are in the so-called invisible state when grown in the modified tissue cultures. We attempted to make them become visible by seeding, on K. medium agar, highly active material known to be free from bacterial contaminants. Sets of cultures were incubated at 30° and 37°C, respectively, for two or more weeks and then examined under the microscope for the presence, of minute colonies of bacteria. Stained preparations from the surface of the agar were also examined. No evidence of organisms was found. From the results of our work as well as from the analysis of Dr. Kendall’s findings, there is no reason to suppose that the K. medium is capable of supporting the multiplication of the viruses or that its use will throw new light upon the nature of these peculiar agents.

APPENDIX B

Discussion of Papers on Poliomyelitis

by William H. Park, M.D., and Maurice Brodie, M.D., and by John A. Kolmer, M.D. October 1935 Thomas M. Rivers, M.D.

Attempts to protect monkeys against poliomyelitis by means of inactivated virus did not arise with Dr. Brodie. Many investigators before his time made such attempts, and the results were so discouraging that the matter was dropped without pursuing it in man. The favorable results reported by Dr. Brodie to have been obtained in monkeys admittedly depend upon his ability to titrate accurately and regularly 1 minimum completely paralyzing dose of virus. If this cannot be done, then all of his reported findings are invalid. Insofar as I know, no one has been able to obtain similar titration results, and this is not due to a lack of honest attempts on the part of other workers to do so. At the beginning of this particular phase of his work, Dr. Brodie used in monkeys | or 2 doses of virus treated with 0.1 percent formalin for 12 to 16 hours at 37°C., and, according to him, favorable results were obtained. It is interesting to note that he said that just as good results were obtained with one dose of 5.0 cc. as with 2 doses of 5.0 cc. each. This does

not sound reasonable unless both methods of application were without value. Indeed, that may be the case, because Dr. Schultz of California and Dr. Olitsky of New York have been able to show little, if, any, protection in monkeys vaccinated according to Dr. Brodie’s method. | Recently, Dr. Brodie has been inclined to agree with others who hold that the complete inactivation of poliomyelitis virus spoils its antigenic qualities, and has been dispensing as vaccines, virus treated for 8 hours and 3 to 5 hours, respectively. He contends that the virus treated for this short 599

600 Appendix B period of time is safe. However, he should be very careful not to decrease

the time of inactivation further. If he does, he may run into an element of danger that one should attempt to avoid. Incidentally, Dr. Brodie now says that 2 doses are superior to one. In vaccinating children, Dr. Brodie has wisely chosen a group of unvaccinated individuals as controls. After talking over the matter with him recently, I came to the conclusion that no case of poliomyelitis can as yet be ascribed to the use of his vaccine. Nor could I find any evidence for or against the efficacy of his vaccine. If you ask me for a prophecy, all I can say is: Provided Dr. Brodie does not make the time of inactivation of the

. virus too short, and provided he continues to administer the vaccine in the manner now employed, it will be reasonably safe but ineffective, particularly if one expects an appreciable degree of protection to persist for any great length of time. It has been gratifying to see that Dr. Brodie and Dr. Park in approaching this problem have used the avenue of safety, although I do not believe that the vaccine will prove to be of any value as now used. I hope that Dr. Brodie and Dr. Park will continue their work until at least 100,000 children are safely vaccinated and that the results of all this work will be care-

fully brought together, so that we can get, once and for all, an absolute answer as to whether vaccine made in this manner and given in this manner is effective. If it is not, I hope that they progress still along the avenue of safety and arrive some day at an effective vaccine. Attempts to protect monkeys against poliomyelitis by means of subcutaneous or intracutaneous inoculations of vaccines containing active virus did not originate with Dr. Kolmer. Many workers have made similar attempts and have found that, if sufficient amounts of such vaccines were given, protection could be produced in monkeys. On the other hand, these same workers also noticed that sooner or later an occasional monkey developed poliomyelitis as the result of the vaccination, and, for this reason, they considered it inadvisable to use such materials for the vaccination of human beings. Dr. Kolmer has repeatedly stated that he has in his ricinoleated poliomyelitis virus a safe, eficient vaccine. On what grounds does he make such statements?

First, let us consider the matter of safety. In the issue of the Journal of the American Medical Association that appeared October 5, 1935, he says:

“The safety of the vaccine is largely due to the fact that it is prepared from remote monkey passage virus that has apparently lost infectivity for human beings, just as the smallpox virus is changed by passage through the lower animals.” He also states: “Attenuation of the virus with sodium ricinoleate may be an additional factor of safety, but the degree of attenuation is slight and of minor importance.” In other words, Dr. Kolmer is

Rivers on Park and Brodie and on Kolmer 601 basing his claims for safety upon the fact that remote monkey passage virus is being used in the vaccine. A statement that monkey passage poliomyelitis virus is attenuated for man is nothing more than an assumption without experimental evidence to substantiate it. Investigators who are familiar with work in the virus field would not put too much dependence on such an assumption. For instance, yellow fever virus adapted to monkeys has caused the death of several workers. Furthermore, a number of virus diseases of lower animals are highly infectious for man, for example, psittacosis, Rift Valley fever, and louping-ill. In this connection, Dr. Flexner has permitted me to say that poliomyelitis virus contained in the cord of human beings, when injected into the skin of monkeys, will paralyze an occasional animal. ‘That is, a humanized virus without a single passage in animals can paralyze monkeys when given in the skin. Therefore, without definite proof to the contrary, one is not permitted to assume that a strain of poliomyelitis virus adapted to monkeys will not cause paralysis in human beings. Dr. Kolmer admits that at least 10 cases of paralysis have occurred after I or 2 doses of his vaccine. He assumes that they were not caused by his vaccine but by a natural infection acquired through exposure. Pertinent information, however, regarding the time of onset of paralysis, the location of the first signs of paralysis and the mortality rate of such cases makes it essential that Dr. Kolmer definitely show that his vaccine is safe. Now as to whether Dr. Kolmer’s vaccine will actually protect human beings against poliomyelitis. In monkeys, he uses a certain amount of vi-

rus, administered in 5 doses, for each kilogram of body weight. Dr. Schultz and Dr. Olitsky have repeated Dr. Kolmer’s work and failed to find as much immunity in their monkeys as was reported for Dr. Kolmer’s. In children, Dr. Kolmer employs less virus per kilogram of body weight than was used for monkeys and it is administered in 3 instead of 5 doses. Such a procedure leaves us absolutely flat when we seek to make comparisons. Furthermore, Dr. Kolmer, as far as I can tell, unfortunately, has no com-

parable number of unvaccinated children, chosen in regard to age and location, to act as controls for the efficacy of the vaccine in the children receiving it. ‘Thus it seems that we are to be left with a lack of definite knowledge regarding the value of Dr. Kolmer’s vaccine as well as with a sense of uneasiness regarding its safety.

APPENDIX C

Conclusions and Recommendations

of Nomenclature and Classification of Poliovirus,

First International Poliomyelitis

Conference, | New York, July 14, 1948 I. Poliomyelitis Virus. ‘UVhis term should be used to designate the agent

originally described as the cause of poliomyelitis. It is identified most readily by the character and distribution of its histological lesions in the spinal cord and by the characteristic pattern of the distribution of lesions in the brain. A. Substrains and Subgroups of Poliomyelitis Virus have been identified by immunological methods. They are as yet poorly defined, with the exception of the Lansing-like group. Strains in this group have special properties of infecting cotton rats and mice (as well as primates). Normal human sera contain antibodies to this strain, and this and other reasons favor its inclusion as an example of true poliomyelitis virus. II. Certain encephalomyelitis viruses which occur spontaneously in the mouse, such as Theiler’s TO, FA, and GD VII, have been termed “mouse poliomyelitis” by some. It is proposed that this term be eliminated and Theiler’s original designation of spontaneous mouse encephalomyelitis be used to describe these viruses. III. It is proposed that the term ‘“‘poliomyelitis-like” be eliminated from virological nomenclature.

602

APPENDIX D

Confidential Information on Infantile Paralysis Presented to the Board of Managers, Children’s Hospital, Philadelphia,

April 24, 1952 Joseph Stokes, Jr., M.D.

Publicity in newspapers throughout the country with reference to the Children’s Hospital’s part in work on the prevention of poliomyelitis in conjunction with the University of Pittsburgh and the National Foundation for Infantile Paralysis has already been appearing and may increase during the coming summer and fall. It had seemed worthwhile to the officers of the Board of Managers for the Board to be furnished a brief summary of the Hospital’s share in the recent hopeful attack against this clisease.

Actually, an attack of slowly gathering force and effectiveness by members of the Children’s ‘Hospital Staff has been occurring over a period of many years as follows:—

I. A group of the Hospital Staff headed by Drs. Rapoport and the writer used parents’ blood for injection into the muscles of many hundreds

of children during the Philadelphia epidemic of 1932 to determine whether antibodies (protective bodies) in such blood from previous exposure of the parents to the disease might be present in sufficient quantities to protect their children. Some degree of protection apparently was obtained, although the study was not sufficiently large to be statistically valid. Actually many thousands would have had to be injected—whereas

only about 2500 children: were injected. However, the results were encouraging.

2. In 1941, when gamma globulin—which concentrates by about 25 times the antibodies (protective bodies) from pooled human blood—be603

604 Appendix D came available by a method developed at the Harvard Medical School,

our laboratories (Dr. Werner Henle and the writer) were the first to determine its protective effect in mice against one type of polio virus—the Lansing type. We showed that if a dose of gamma globulin were injected into mice before or at the time of injecting the polio virus (Lansing type)

into the brain, the mice who received no gamma globulin would die of polio. ‘These results were confirmed by Dr. Kramer of Michigan, who also

demonstrated that he could protect cotton rats and monkeys in the same way.

Shortly after we obtained these findings, Dr. Kramer and the writer approached the National Foundation for Infantile Paralysis to obtain their

approval and financial support for a large scale study of the protective effect of such globulin in a sharp outbreak of polio. At this time the Foundation’s approval was not obtained because their Committee on Research was fearful that the protection afforded would be only temporary and thus not justify the cost and effort. Also, they were afraid the supplies of globulin might not be sufficient for later use on a large scale. 3. Because we could not obtain financial support for a widescale study, Dr. ‘T. F. McNair Scott and the writer decided to study the possible protection of the globulin against polio in summer camps for boys and girls, since it has been well recognized that sharp outbreaks of the disease occur in such camps. Such studies appeared opportune because we were already testing the possible protection of the globulin against the usual respiratory diseases that plague summer camps. A number of camps in Pennsylvania

were thus studied during 2 summers in which we usually injected with globulin one-third of the children chosen at random in each camp. Fortunately for the children but unfortunately for the studies, only one camp had the disease. In this camp a case occurred in the uninjected group and none in the children injected with globulin. Although of no significance, at least the result was not unfavorable. 4. A new result in another disease then helped to change the general attitude towards the use of gamma globulin. In 1944 to 1950 the writer with Dr. Neefe, Dr. Gellis and others demon-

strated that gamma globulin from the large Red Cross pools of plasma (which represented a pooling of 2000 to 3000 bloods) was highly protective against epidemic jaundice both in the Mediterranean Theater (1944) and in epidemics among civilians in the United States. An added finding, of the greatest importance to polio prevention, was the fact that this globulin not only gave a temporary immunity during epidemics of jaundice, but that if a person continued to be exposed to the virus after he had been injected with the globulin, the temporary immunity furnished by the globulin apparently could be extended into a more lasting immunity or even possibly a permanent immunity. This possibility of

Stokes on Infantile Paralysis 605 a lasting immunity encouraged us to press the Foundation for the next step.

5. Dr. William Hammon—formerly of the University of California and recently moved to the Graduate School of Public Health, Pittsburgh—and the writer agreed jointly to place considerable pressure on the National

Foundation to support the plan previously broached together with Dr. Kramer (mentioned above). After long discussions and presentation of our findings on epidemic jaundice at several meetings of their Committee

on Immunization, which we attended, agreement was reached that full financial support would be given by the Foundation to an extended effort for solution of this problem. It was agreed that the work should be supported until an answer to the question of possible protection by gamma globulin was obtained. 6. In the summer of 1951, Dr. Hammon (who became general administrator of the Study), Dr. Lewis Coriell of our Staff (who became Execu-

tive Director of the Study), Dr. Henry Kumm (formerly International Health Division, Rockefeller Foundation), and the writer organized, with the support of the Foundation, and directed a preliminary study in Utah County, Utah, in which about 5800 children were injected at the time of a severe polio epidemic—half with gamma globulin and half with gelatin.

Only Dr. Kumm and a physician from Squibb and Company, where the , vials of globulin and gelatin were filled, knew the key as to which child was being injected with globulin and which with gelatin. The results were extremely encouraging in that only one child injected with globulin developed paralysis whereas there were a number of paralyzed children in the gelatin group and in the uninjected group of the same ages. However, the numbers were not large enough to be entirely conclusive. 7. In the present year, 1952, a larger team of workers is available to test the protective value of the globulin in at least 3 severe epidemics of polio. The National Foundation has set aside $1,000,000 for the project. From April 28th on, 177 county areas will be followed continuously as to any increasing number of cases so that advance teams can enter these areas in order to determine whether the starting epidemic appears sufficiently severe | to send in the larger team for injections of globulin and gelatin. The advance team consists of one of the heads of the study and a man trained in the study of epidemics (epidemiologist). ‘The team for injecting consists of about 10 physicians and 20 nurses recruited from outside of the area, and over 150 volunteer women, recruited mostly from within the area to be studied. Five of the nine physicians in general charge of the work are from the Children’s Hospital group—Coriell, MacAllister, Barondess, Bierly, and Stokes. ‘The writer will be in charge of one of the Advance ‘Teams, which will require short periods away from the Hospital.

The work of Bodian and Horstmann in monkeys and chimpanzees re-

606 Appendix D ported in the newspapers and in Time (out Apr. 24) and in Life (out Apr. 25) supports the above findings. What they have done essentially lends point to and is in confirmation of the work above outlined. Recent work by Dr. Hammon in determining more accurately the quantity of globulin necessary to protect mice against polio has been of great importance.

If gamma globulin proves to be as highly protective against polio in humans as it is in animals, including the higher apes (chimpanzees )—and

as the preliminary work in humans now suggests it is—it may not be a final answer to permanent protection. However, it would be a real part of the answer—a part at least as important as it plays in epidemic hepatitis. Thus it would be possible to control epidemics of polio just as we now can control completely epidemics of jaundice. However, a final answer would be the immunization and permanent protection of children from infancy. In this also, gamma globulin, if successful this summer, may still play a very important part.

APPENDIX E , Criteria for Live-Virus Vaccine Trials. World Health Organization Expert Committee on Poliomyelitis. Second Report. WHO Technical Report Series 145. Geneva, 1958 It has appeared to the Committee that studies on the use of attenuated strains of poliovirus as immunizing agents against poliomyelitis have reached a stage in which trials in man on a larger scale than has been attempted hereto are now indicated. ‘This decision is based on the fact that preliminary tests on attenuated polioviruses in the hands of several investigators have failed to reveal signs of illness or other harmful effects in the vaccinees or their associates. It is the carefully considered opinion of the Committee, therefore, that the information which is now badly needed can only be obtained from field trials carried out on a larger scale than has been possible in the past. ‘The Committee strongly recommends that such trials be carried out in the near future within certain specified population

groups and areas and under the most careful supervision. In making this recommendation it is not the intention of the Committee that the use of attenuated strains should displace the use of an inactivated-virus vaccine in

any of the areas where the latter is currently being used or will be used shortly, but rather that it should supplement it or substitute for it in areas where the use of the inactivated-virus vaccine is not feasible.

The special situations which the Committee believes will lend themselves best for this type of trial are: (1) in the face of an impending epidemic or at the periphery of an already existing epidemic; (2) where polio-

myelitis of the infantile type is endemic and in particular within those areas where signs are indicative of an imminent shift to the epidemic form of the disease (see section 2.3.1, page 12); (3) to reinforce the immunity previously produced by an inactivated-virus vaccine. The value here would

be that of the enhancement of the humoral antibodies as well as induction of resistance within the alimentary tract. 607

608 Appendix E In temperate zones the trials mentioned under (2) and (3) should be carried out during seasons of the year when there is minimal spontaneous dissemination of naturally occurring poliovirus. — Criteria which should be fulfilled in the design of carefully controlled field trials which the committee has in mind are as follows:

(1) Such trials should be under the supervision of an individual who is experienced in investigations involving polidviruses, who has adequate

laboratory facilities, to whom the assistance and facilities of consulting ~ virologists may be available and who can devote an appreciable amount of time and direction to the project. (2) The strains which are recommended for use in these trials should be selected with great care; this should be a most important part of the © programme. At the present, those strains should be used which have been purified by the plaque method and which have already been fed to various

small groups of adults and children and whose behaviour under these circumstances is well documented and appears to be satisfactory. A more detailed list of criteria is as follows: (a) Progeny of triply purified plaques. (b) Complete lack of paralytogenic activity on intracerebral inoculation of maximal doses (in excess of 107 T?CDs59) in rhesus or cynomolgous monkeys and only minimal residual neurotropism by spinal inoculation in monkeys—i.e., only rare development of localized, nonprogressive paralysis in monkeys receiving doses of 10° T’CDs0 or more, and no “zone phenomenon” in which monkeys inoculated with

smaller doses of virus develop paralysis more frequently than those inoculated with larger doses. (c) Adequate and regular multiplication in the alimentary tract of nonimmune human beings should have been demonstrated with doses in the range of 10° T’‘CDso or less and these infections should be accom-

panied by an antibody response. Viremia should be either absent or rare and if virus is present it should be in minimal concentration.

(d) The strains used should have been tested extensively for any increase in the neurotropism of the virus excreted in the stools of human beings after varying periods of multiplication in the alimentary tract. The virus excreted in the stools and that derived from it in the first tissue culture passage should still exhibit distinct evidence of attenuation as determined by intracerebral inoculation of monkeys. (ec) The lots of virus to be used should be large enough to permit test feedings of at least one million individuals and these lots should have been produced under conditions comparable to those that might ultimately be used in the manufacture of still larger quantities. Each lot

WHO Report on Criteria for Live-Virus Vaccine Trials 609 should not only fulfill the requirements for neurotropic activity men-

tioned above (tested in at least 25 monkeys) but should also have been shown to be free of other viruses and bacteria as indicated by tests in tissue cultures, animals and bacterial culture media. (f) Absence of harmful reactions in small groups of human beings should be demonstrated before a lot is used in increasingly larger numbers.

(3) It is suggested that the properties of these attenuated strains, which can be tested in the laboratory, be measured in a number of different laboratories so that there can be more than one opinion as to their pathogenicity or the lack of it.

(4) It is recommended that in all such trials the administration of the agents be done on a voluntary basis. It is also essential that such trials have the approval of local health authorities.

In conclusion it should be again stressed that the object of these trials and the need for carrying them out are based upon the belief that they may further reduce the prevalence of poliomyelitis. Should these live-attenuated-poliovirus trials be successful, not only do they carry with them the hope that a more solid immunity against poliomyelitis might be achieved, but the possibility of eliminating or reducing the movement of virulent polioviruses within a given community might be realized—a result which the inactivated virus vaccine does not achieve.

APPENDIX F

Glossary of Terms . adenoviruses