Life in the Age of Insulin: A Brief History (Copernicus Books) 303147189X, 9783031471896

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LIFE IN THE AGE OF INSULIN A Brief History

Edwin Gale

Copernicus Books Sparking Curiosity and Explaining the World

Drawing inspiration from their Renaissance namesake, Copernicus books revolve around scientific curiosity and discovery. Authored by experts from around the world, our books strive to break down barriers and make scientific knowledge more accessible to the public, tackling modern concepts and technologies in a nontechnical and engaging way. Copernicus books are always written with the lay reader in mind, offering introductory forays into different fields to show how the world of science is transforming our daily lives. From astronomy to medicine, business to biology, you will find herein an enriching collection of literature that answers your questions and inspires you to ask even more.

Edwin Gale

Life in the Age of Insulin A Brief History

Edwin Gale Diabetes and Metabolism Emeritus Professor, University of Bristol Bristol, UK

ISSN 2731-8982     ISSN 2731-8990 (electronic) Copernicus Books ISBN 978-3-031-47189-6    ISBN 978-3-031-47190-2 (eBook) https://doi.org/10.1007/978-3-031-47190-2 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Paper in this product is recyclable

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In Grateful Memory Robert Booth Tattersall (1943–2020) Mentor and Friend For at first Wisdom will walk with him by crooked ways and bring fear and dread upon him and torment him with her discipline, until she may trust his soul and try him by her laws: then will she show the straight way unto him and comfort him and show him her secrets. Ecclesiasticus History is a nightmare from which I am trying to awake. James Joyce

Note to the Reader

Around 1% of people in the world injected insulin today. Nearly half a billion are known to have diabetes. Your lifetime chance of joining them is around one in three, although you may not know that you have it. Diabetes means that your body can no longer manufacture all the insulin it needs, and it has become so common because most of us are living longer and eating more than in the past. Insulin was first isolated a century ago, but its ‘discovery’ is a work in progress. Life in the Age of Insulin is about how we gained insight into our own bodies, of the people who need insulin, and of those who make a living by selling it. It tells of the creative power that emerges when many people work towards a common goal, and of collective strength founded upon the limitations of individuals. It is a story of astonishing success within a wider context of failure. We are story-telling animals, and this book will attempt a straightforward and jargon-free narrative account of how insulin was discovered, what it does, why people still struggle to obtain it, and what the future might hold. A century-long quest involving so many working lifetimes, so many brilliant people and so many Nobel prizes will inevitably stray into challenging areas. Science is the backbone of my narrative, for apparently unrelated insights have a habit of working their way through to the doctor’s office. I make no apology for trying to follow where the science leads, but I have done my best to make the underlying principles accessible to the general reader. Last but not least: every story needs its characters. It is impossible to name all those who deserve to be mentioned, but I hope to show that the personal factor has played a large part in the story of insulin. ix

Prologue

Thirty years ago, a seven-year-old boy developed the symptoms of diabetes in a remote country village in southern India. His mother had been abandoned by her husband and was destitute. His condition was diagnosed by the local healer, and the mother asked the boy’s grandfather round. Together, they reached a momentous decision. Next day, the grandfather beckoned to the boy and took him on a journey. They walked from the village to a dirt road and caught a bus to the rail station in the local town. A lengthy journey took them to the city of Chennai, and was followed by a long walk through a bewildering kaleidoscope of city streets. Eventually they reached some iron railings in front of a big white building. The grandfather told the boy to wait and melted into the crowd. He waited. Night fell and the boy waited. He collapsed on the following day and was taken into the white building, which proved to be a children’s hospital that offered free treatment for diabetes. The ketones on his breath allowed an immediate diagnosis to be made, and he was admitted for insulin and intravenous fluids. Despite the care he was given, he maintained a stubborn silence until he was able to resume his vigil by the iron railing. He collapsed again after another interminable wait and was taken inside. Only then did the reason for his silence become apparent—he could not speak the local language. A helper from the same region soon discovered that the boy did not know his address. The helper had a rough idea as to where he came from, however, and decided to take a chance on retracing the journey. Mercifully, the boy recognised the station where he boarded and could point to the road home. They took a bus to the spot where he had waited with his grandfather, retraced the path to his village and he was reunited with his mother. The hospital staff and well-wishers clubbed together to provide him with syringes and insulin, and subsidised subsequent follow-up visits to the hospital. He did the trip on xi

xii Prologue

Fig. 1  Child’s drawing (Courtesy of Dr. Tim Dornan) compared to ‘The Scream’ represents utter desolation by Edward Munch

his own when I met him there at the age of 14, and was hoping to become a hospital technician. I have worked with insulin for the best part of 40 years, and it still has the power to stir my emotions. Imagine a roomful of teenagers, each life owed to insulin. Fifty years from now, some will be teaching their grandchildren how to fish. They would not see it this way, for life at the other end of the needle can be an undiluted curse. Diabetes, to adopt Susan Sonntag’s phrase, is the passport to another country, and the price of admission is a lifetime of self-­ denial, sore legs and fingers, and a sense of difference verging on stigma. Some 70–80 million people, possibly more, injected insulin this morning. Without it, many would sicken and die. Others again—a rapidly increasing number— treat diabetes as a risk factor, and use insulin to prolong their healthy lifespan. The picture of the rabbit was drawn by a child who saw life on insulin as a trap. I still find it inexpressibly moving, and the face of the rabbit was strangely familiar (Fig. 1). Years passed before I finally realised why. And so we begin with twin stories: insulin as a lifesaver and insulin as a life sentence. This is the framework for what follows, outlined in brief summary below and in more detail later.

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A Brief History of Insulin Before the Dawn (1889–1921) Two remarkable things happened in 1889. A distinguished professor told a medical meeting in Paris that he had rejuvenated himself by injecting extracts from animal testicles. He was sadly deluded, but his claim renewed interest in what were known as the ‘ductless glands’. These had puzzled anatomists for centuries, for they looked like glands but had no visible outlet. Nor did they appear to serve any useful purpose. Wishful thinking apart, mashed-up testicles failed to enhance your virility, but messenger chemicals with profound effects upon the rest of the body—soon to be known as hormones—were identified in the thyroid and adrenals, and the science of endocrinology was born. Two young doctors, only slightly acquainted, bumped into each other in a departmental library in Strasbourg. They argued as to whether a dog could live without a pancreas, and Oskar Minkowski, a surgical wizard, took one out that same afternoon. The dog survived, but developed fatal diabetes. Further experiments confirmed this unexpected finding, and an important clue came when Minkowski found that implanting a fragment of pancreas under the skin could prevent diabetes, presumably by releasing something into the blood stream. If so, where in the pancreas did the anti-diabetic substance come from? Mysterious clumps of cells are scattered through its substance like grains of pepper, and the medical student who spotted them (Claude Bernard had failed to do so in his Memoir of the Pancreas, published in 1856) could never have dreamed that the islets of Langerhans would one day bear his name. They seemed a likely source for the internal secretion, and a Belgian physiologist proposed the name insuline (the ‘island hormone’) in 1909, 13 years before its successful isolation. Closer inspection revealed that the islets contain at least four different cell types, named alpha through delta. Prominent among these were the alpha cells, later shown to make glucagon, and the beta cells which make insulin. Hundreds of attempts were made to treat diabetes with pancreatic extracts. Some failed because the extract was given by mouth and destroyed in the stomach, but attempts to develop an injectable version came tantalisingly close to success. Even so, 32 years were to pass between Minkowski’s serendipitous discovery and the first successful human injection of insulin in January 1922. Why did it take so long?

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From Discovery to the Doldrums (1922 to About 1960) An ill-assorted group of individuals in Toronto succeeded where so many had failed, and promptly fell out over the credit. The personality of Frederick Banting, the lead investigator, was largely responsible for both outcomes. Childhood diabetes was once a death sentence. A starvation diet could delay the inevitable lapse into acidotic coma and death, but it also prolonged the misery. In contrast, moribund children could now be snatched back from the jaws of death. In the words of historian Michael Bliss, insulin was the closest thing to a ‘secular miracle’ ever witnessed. Toronto was besieged by desperate parents, but the local extraction method was too inefficient to meet the demand. Scientists at Eli Lilly devised a much improved procedure, but the insulin that came off their production line was dilute and horrendously impure, allergic reactions were common, and injections could be almost unbearably painful. The unending quest to make life on insulin more tolerable began. A committee in Toronto decided to offer insulin as a gift to the world. Manufacturers around the world were persuaded to pool their patents, and a standard preparation developed under the auspices of the League of Nations allowed them to produce insulin of equivalent strength and quality. Life on insulin was far from easy, but it beat the alternative. Meanwhile a new variant of the species—insulin-dependent humans—had emerged. What would become of it? No one yet knew what insulin was, let alone how it worked. Some hoped it would cure diabetes, others feared that its effects might wear off. As the years rolled by, however, insulin seemed to promise a normal lifespan. All went well for the first decade or so, but visual loss, kidney failure and arterial disease began to take their toll, and only one in two of the children saved by insulin would celebrate their 50th birthday. It was not yet known that prolonged exposure to high levels of glucose is poisonous to small blood vessels, and that the resulting microvascular disease can lead to visual impairment and/or kidney failure. High glucose levels also accelerate arterial (macrovascular) disease, increasing the risk of heart disease, strokes and circulatory problems in the legs. The leading question for the second half of the century would be this: can the vascular complications of diabetes be avoided by improved glucose control? The diabetes world was divided. Some insisted upon the need for good control; others maintained that vascular disease was a genetic feature of diabetes and therefore inevitable. If so, why impose tedious restrictions upon those who were going to suffer anyway? Behind this lurked yet another question: could good glucose control actually be achieved? The technology for achieving better control—or showing that you had done so—was primitive by

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current standards. No wonder that Robert Tattersall called this ‘the dark age of once-daily insulins, free diets and a sense of doom’. World War 2 brought a bitter reminder of the realities of life on insulin, for thousands of people in war-torn parts of Europe and Asia lost access to it. We will never know how many died. Anecdotes apart, their story is lost to history although the US Strategic Bombing Survey of 1947 gives some indication of what happened in Germany itself. Despite the harvest of sorrow, some early users of insulin enjoyed good health for more than 70  years; the man who injected himself for 50  years before learning that he did not actually have diabetes was an isolated exception. These were the doldrum years of diabetes, and they slowly gave way to mounting hope.

Two Types of Diabetes (~1930–1980) Diabetes was considered rare in the nineteenth century: the young died, the middle-aged could often get by on diet, and the elderly might not be aware that they had it. This spectrum would later be explained by varying degrees of insulin deficiency. The more lethal form came to be known as juvenile onset, insulin-dependent, and subsequently as type 1 diabetes. The first hint of a fundamental difference came when a Viennese physician called Wilhelm Falta suggested in 1931 that there were insulin-sensitive and insulin-resistant varieties of diabetes. Harry Himsworth in London confirmed this with a simple test of insulin sensitivity, which showed that some people with diabetes were as sensitive to its action as non-diabetics, whereas others needed far more insulin to achieve the same effect. The now obsolete discipline of constitutional medicine was founded upon the ancient belief that your physique reflects your personality and susceptibility to disease, and its legacy was anthropometry—analysis of the body based on detailed measurement. A physician in New York asked an anthropometrist to measure people attending his diabetic clinic, only to be informed that there were two body types rather than one. John Lister, a mentor of mine, combined Himsworth’s insulin sensitivity test with standard photographs for measuring physique. These required his patients (80% of whom happened to be female) to strip naked and pose before a camera, an invitation that must have required considerable powers of persuasion; no wonder that ‘the only factor in their selection (was) their willingness to cooperate’. The test confirmed that the young and lean were more sensitive to insulin than the plump

xvi Prologue

and middle-­aged. When subdivided by appearance, 38 were considered to have the first type, 37 to have the second, and 25 could not be classified. Lister proposed in 1951 that insulin-sensitive individuals had ‘type 1’ diabetes, whereas the insensitive had ‘type 2’. This was a classic orphan observation—an idea before its time—and his terminology vanished without trace, only to win immediate acceptance when revived by a visitor to his department 27 years later. A technique which required people to pose in the nude was never likely to catch on, and Lister’s classification was founded upon an obsolete concept. Nor was it a reliable means of distinguishing the two ‘types’ of diabetes. Its eventual revival was based on new sources of evidence and a new way of telling the two types of diabetes apart. The origins of the concepts that transformed our idea of diabetes can be traced back to work on the genetics of cancer in mice undertaken 60 years earlier. A winding trail leads from there to an understanding of the genetic basis of immunity, to the discovery of autoimmunity, and to the eventual realisation that type 1 diabetes has many features of an autoimmune disorder.

The Hard Yards (1960–1990) The term ‘molecular biology’ was coined by Warren Weaver of the Rockefeller Foundation in 1937, and insulin was at the forefront of the revolution that ensued. It was the first protein to have its amino acid sequence determined, and the first to have its three-dimensional structure unravelled. But if the molecule was a key, where was the lock? The insulin receptor proved to be a mammoth protein which straddles the cell membrane: insulin activates enzyme systems inside the cell when it docks on the outside. These amplify the insulin signal so effectively that one molecule of insulin is estimated to stimulate the uptake of up to a billion extra molecules of glucose per minute in tissues such as the liver, muscle and fat. This gave rise to another puzzle, for insulin receptors are present on many other cells. What are they doing there? Epidemiology, the study of disease in populations, was another beneficiary of the war against disease. A population survey conducted in Massachusetts in 1947 found one unknown case of diabetes for each that was known, which implied that some 2–2.5 million Americans were affected. This estimate of the frequency of minimally symptomatic diabetes was amply confirmed when glucose was added to automated health screens in the 1950s.

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But what exactly was diabetes? ‘No widely accepted definition exists’, said Kelly West, doyen of diabetes epidemiologists, in 1978. He would shortly join an expert committee of the WHO which rectified the situation. Diabetes meant too much glucose in the blood. But how much is too much? Prospective study of the inhabitants of the small town of Framingham in Massachusetts revealed that clinically silent elevations in glucose, cholesterol or blood pressure increase your chances of heart disease. The term ‘risk factor’ entered the clinical lexicon, and risk management now became the guiding principle of diabetes care. But what were the risks? A risk factor is defined by the risk it confers. High blood pressure increases the risk of stroke, and high cholesterol increases your risk of a coronary. When a risk has been quantified, you can measure the effect of changing it. Once this is known, agreement can be reached as to a threshold at which intervention is justified. Diabetes confers multiple risks. The risk of arterial disease rises in parallel with blood glucose and is incremental; any increase above normal (or even within the non-diabetic range) increases your hazard. Conversely, the risk of microvascular complications only becomes apparent above a certain threshold level of glucose. Microvascular disease causes characteristic changes in the retina, which can be spotted by a trained observer. The glucose threshold for retinal problems thus became the international criterion for diabetes. The important difference between the small vessel disease of diabetes and its arterial complications is that microvascular complications are specific (i.e. seen only in diabetes), whereas arterial disease is common in the population as a whole, and high glucose is only one cause among many. The new global definition drew a clear line between those with unequivocally high blood glucose and the rest, and it was also a useful guide to intervention. So far, so good, but it left many people unaccounted for—more than the number with diabetes itself. Inhabitants of the borderland between ‘diabetes’ and ‘normality’ did not require specific glucose-lowering therapy, but might well benefit from increased attention to arterial risk factors such as hypertension, cholesterol or smoking. Meanwhile, the debate concerning the need for aggressive glucose control in diabetes stalled on a practical issue: how could you measure it? Urine tests only register when your blood glucose is already too high. It was rather like driving a car by looking in the rear-view mirror. In or around 1970, however, a pregnant woman refused to come into hospital. Women were then routinely admitted at 26 weeks of pregnancy in order for a nurse to check their blood glucose four times a day with a glucose meter. Mrs. Smith (she has steadfastly refused to be named) mastered the meter within minutes and insisted on

xviii Prologue

taking it home. Her insulin was adjusted by telephone for the remainder of her pregnancy. So simple, so obvious: The technology had been around for nearly a decade, but health professionals had not imagined that people with diabetes might have the motivation or competence to use it. Self-monitoring allowed short-term glucose control to be measured, but a long-range test was badly needed. Improbably enough, a quest for inherited variants of the haemoglobin molecule in Iran showed that the haemoglobin of people with diabetes behaved differently in an electrical field. This was our introduction to glycated haemoglobin, the standard measure of glucose control today. Long-awaited clinical trials now became feasible, and a landmark trial showed that microvascular complications could be delayed or even prevented by careful control of glucose levels. Home blood glucose measurement revealed drastic fluctuations in everyday glucose control, which could be ironed out by increasing the frequency of injections. The pain of giving insulin through a blunt needle has to be experienced, but silicone-tipped needles eased the misery. When these were attached to handy insulin pens, people with diabetes soon showed that they were prepared to trade the discomfort of multiple daily injections for the added safety and well-being of better control. Technical developments such as sharper needles, home blood glucose testing, HbA1c and insulin pens eased the burden of life with diabetes, and allowed those affected much greater control of their own destiny. Highly purified insulins became available around the same time (we have now reached the 1970s), and bio-engineered human insulin soon followed. These were the ‘hard yards’ of diabetes, and I was there to see them.

Insulin Wars Insulin was offered as a free gift to the world, and the first Canadian patents were transferred to the University of Toronto for $1 apiece. Its manufacture was freely licensed in other countries, subject only to quality assurance and a commitment to share technical advances. Major exporters included the USA, Britain, Denmark and Germany, but national producers sprang up around the world, all making much the same product in much the same way. There was relatively little competition, and insulin was seen as a gentleman’s market. So it remained until Denmark launched ‘clean’ pork insulin in the 1970s. The Danes could now lay claim to a better insulin, and insulin salesmen appeared on the scene. This, unperceived at the time, was the first shot in the insulin wars. Lilly already had its eye on something more

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fundamental—biosynthetic human insulin—and would be selling it by 1982. The reek of the abattoir was banished from insulin production, but the switch to genetic engineering was expensive. Lilly apart, only the newly merged Novo-Nordisk in Denmark and Hoechst in Germany (soon to be absorbed by the French company Sanofi) were prepared to make the necessary investment. Human insulin did not outperform the highly purified pork equivalent, but rapidly became the new standard. Smaller national outfits were taken over or closed down, and the Big Three soon controlled 96% of the market by volume and 99% by value. Insulin had been globalised. Human insulin has one major commercial disadvantage: it cannot be patented. Worse still, smaller companies would soon be able to make it. The solution, from a marketing perspective, was to modify the insulin molecule in ways that could be patented. The hoped-for benefits of ‘designer insulins’ proved to be less than expected, but they were a huge commercial success. Highly effective ‘switch campaigns’ converted prescribers from animal to human insulin, and they were soon persuaded to abandon human insulin for the more expensive analogues. Profits rose sharply. A 1000-unit vial of human insulin could be produced and sold for ~$5 (US), even allowing for a profit margin of ~30%. Insulin analogues currently retail at 50–100 times the cost of manufacture in the USA, the only advanced economy that has so far failed to cap drug prices. The consequence is that one in four insulin users in the richest country in the world currently find it hard to afford, or feel obliged to cut back on its use for reasons of cost. The companies also benefitted from the trend to treat those with what was then called non-insulin-dependent diabetes (NIDDM) with insulin. Insulin was once viewed as a last resort by those with this label, and was greatly dreaded. All this changed when type 2 diabetes came to be treated as a risk factor, and data from the UK show that 2.4 per thousand of the adult population used insulin in 1991, of whom 0.7/1000 were considered to have type 2 diabetes. By 2010 the number of insulin users had increased to 6.7/1000, of whom 4.3/1000 were deemed to have type 2 diabetes—a sixfold increase. The ratio of risk to benefit is hard to compute in older patients, however, and population-based algorithms (useful guides but bad masters) were used to decide who needed insulin. Physicians who make use of common sense, compassion or experience to over-ride the witless authority of computers can expect short shrift in the law courts—which might help to explain why 22.4% of people with known diabetes in North America are currently treated with insulin, as against 13.0% in Europe (or 9.5% in Africa). The Big Three, whose combined sales of insulin rose to around $20 billion in 2020, profited by this clinical trend.

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Americans make up 4% of the global population, yet pay around 40% of the world’s legal or illicit drug bill. American health care is the best in the world for those who can afford it, and the best has got steadily better. No surprise, therefore, that the market is orientated towards wealthier people and countries. The resulting suction effect has limited access for the global poor. Not coincidentally, I was able to claim in 2008 that, on a worldwide basis, lack of access to insulin was the commonest cause of death in a child with diabetes. Charitable initiatives have done much to ease the situation since then, but the limits of charity were clearly defined when UN Secretary-­General António Guterres pointed out in February 2021 that 10 countries had acquired 75% of all COVID-19 vaccines, whereas ‘more than 130 countries had not received a single dose’ [1, pp. 318, 342]. We all benefit from commercial enterprise, but the best can be the enemy of the good, and the prospect of a world in which the rich travel first class while the global poor cling to the outside of the train is unacceptable. Access to affordable insulin is a basic human right.

Where Next? In or around 1985 I met a 16-year-old boy who was in a state of shock. He had just developed diabetes and now learned that this was a life sentence. ‘Look’ I said, ‘it won’t always be like this. Science will find a way. You won’t be on insulin for the rest of your life.’ His father took me aside, as we left the consulting room, and told me that he appreciated what I had said to his boy. ‘That’s what they told me when I was diagnosed in 1963’. I felt better when I learned that my hero Elliott Joslin said much the same to his patients in 1944. Proffering hope has always been part of the job of looking after diabetes. So what would I say now? The first century of insulin taught us that diabetes is a glucose disorder that can be reversed. Current strategies depend on injecting insulin, promoting its release from our own beta cells or making the body more sensitive to its action. Subcutaneous insulin has given millions of people a new lease of life, but is far from ideal as a mode of delivery, and the insulin analogues are improved delivery systems rather than ‘new insulins’. High-end devices optimise subcutaneous insulin by ‘closing the loop’ between smart electronic delivery systems and automated glucose monitoring, but they entail attachment to a machine and are unaffordable for most users. The ultimate dream

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would be to restore the body’s ability to make its own insulin. Little did I dream that such a solution was getting closer as I finished writing. Whole pancreas transplants offer an approximate 50:50 chance of insulin independence after 5 years, but disadvantages include the need for major surgery and long-term immunosuppression to prevent rejection. Since only about 1% of pancreatic cells actually make insulin, it is logical to transplant the islets alone. This makes major surgery unnecessary, for islet cells can be injected into the vein feeding the liver and will re-implant there. Both procedures are however limited by a shortage of suitable donors. The ideal solution would be to train stem cells—the precursors of every cell type we possess—to develop into functioning beta cells. Beta cells evolved within a community of islet cells, and a procedure developed at Harvard has made it possible to grow several stem cell lines at once. The cells adopt an islet-like shape when grown in this way, and stem cell ‘islets’ can be injected in the same way as islets extracted from a pancreas. The first recipient in a clinical trial which started in 2021 was a 64-year-old man with a 40-year history in insulin treatment complicated by disabling bouts of hypoglycaemia. He received a half-dose of islets as a precautionary measure, but can now manage without insulin for most of the time. The current limitation is that powerful immunosuppressive treatment is still needed. Could this last obstacle be overcome? It is too early to say, but we are getting closer.

Reference 1. Kahl C. Wright T. Aftershocks. Pandemic politics and the end of the old international order. St Martin’s Press; 2021.

Acknowledgments

No-one could witness the clinical effects of insulin without a sense of awe, and this hairpin-shaped molecule has helped to direct the course of human evolution. Any attempt to write a narrative which embraces a topic so vast will inevitably fall far short of its aspirations, and I hope that many others will try, for this story is far from finished. Michael Bliss revolutionized the early history of insulin, and hoped that someone would one day update the story. There are many possible stories to tell and I write as a clinician who became immersed in research. My ambition has been to tell the story of the ongoing scientific discovery of insulin, of the way we learned to use it in the treatment of diabetes, and of insulin as a commodity. I came across Kersten Hall’s Insulin—the Crooked Timber. A history from thick brown muck to Wall Street Gold (2022) when the draft of this book was already going the rounds of the publishers. Kersten is particularly strong on the basic science of insulin from its characterisation as a protein to growing it in bacteria, and I think the books are complementary. My own approach has been more clinical. Elliott Joslin was my trusted guide to the first 50 years of the century of insulin, and Robert Tattersall, my mentor and friend, guided me for much of the past fifty. I also owe an immense debt of gratitude to the 20000 or so people who talked to me of their own experience with diabetes. Special thanks to those who showed their personal faith in this enterprise, notably my friend Peter Butler. Many other friends have read and commented on other sections, and Pierre de Meyts read and commented on the whole draft. Others, too numerous to mention by name, have commented or given me ideas over the years. The faults that remain are entirely my own. xxiii

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My father once said to me that one of the more difficult things in life is to achieve something important and to get the credit for doing so. Anyone engaged in research will know that this is a team sport, and that the person who lifts the trophy often got his or her inspiration from a casual comment in the coffee room. The story cannot be told without its ‘big names’, but even giants must stand on someone’s shoulders. The tired old image of a midget perched on the shoulders of giants certainly applies in my own case, and I have enjoyed this point of vantage over a working lifetime. My thanks are due to those, far too numerous to mention here, who have inspired me on this journey, including some of those mentioned in the text. I hope they will know who they are. Above all, I must express my undying gratitude to those with the ability to instil creative envy, so different from jealousy. Jealousy devours its victims, but envy arises from the desire to emulate. First among the generators of creative envy was Robert Tattersall, who set me on my way, but many others influenced my journey; among them Torsten Deckert, Deborah Doniach, John Lister and Jørn Nerup. These apart, the ability to disagree with someone in the same line of work without forfeiting friendship and respect is something to treasure, especially when they have proved you wrong. Others again shared in the heat and burden of a sometimes turbulent career, not least Franco Bottazzo and my colleague Polly Bingley. I have also been blessed with outstandingly loyal and creative team members who have held together over the years. I know that some colleagues and users will disagree violently as to my views on the value of the newer insulins. I would not dispute for a moment that some people benefit (the pharmacokinetics are different) but the evidence that systematic use of an insulin analogue rather than human insulin is of overall benefit is limited at best. I had it was my privilege to chair a committee of the WHO on essential medicines for diabetes in 2017, and the evidence that expensive insulins had a systematic advantage over the more affordable variety was conspicuous by its absence. The stance taken by WHO has changed (analogues are now on the essential medicines list), but I am not aware that this reflects a change in the evidence. I have also had the privilege of chairing a committee for EMA, the European Medicines Agency. My admiration for the regulators is boundless but their powers are limited, and it was chilling to watch the confidential information we saw go through to publication (for which the regulators have no responsibility). It has also been my pleasure to know many people in industry, whose ethical standards are often stricter than those of the clinicians they hire, and I would like to express my undying respect for Lise Heding (1936–2008) who advised Novo for many

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years. She was an outstanding scientist in her own right, and was offered one of the more prestigious lectures at the European Association (EASD) in the 1990s. She politely declined on the grounds that she had ‘nothing new to say’, a criterion guaranteed to decimate the ranks of our distinguished speakers.

Contents

Part I Before the Dawn 1 B  eginnings  3 1.1 The Wager   5 1.2 A Riddle Wrapped in a Mystery Inside an Enigma   8 1.3 A Taste of Honey  10 1.4 The Ghastly Kitchen  11 References 14 2 B  efore the Dawn 17 2.1 Diabetes in the Nineteenth Century  20 2.2 Death on the Instalment Plan  22 2.3 The Allen Era  25 References 28 3 Firing  Blanks in the Dark 31 3.1 Why Did It Take So Long?  32 References 36

Part II From Discovery to the Doldrums 4 The  Coming of Insulin 41 4.1 The Bicycle Rider  52 xxvii

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4.1.1 Ugly Fish  60 4.1.2 Afterlives  62 4.1.3 Minkowski’s Choice  67 References 68

5 Explorers  of Unknown Seas 71 5.1 Diabetic Utopia  77 5.2 Charybdis  80 References 84 6 L  iving with Insulin 85 6.1 Danish Insulin  88 6.2 The Quest for Purity  94 References 95 7 N  emesis 97 7.1 In the Destructive Element Immerse  99 7.2 The Invisible Worm 101 References105 8 When  the Insulin Ran Out107 References112

Part III Two Types of Diabetes 9 The  Sensitive and the Insensitive115 9.1 The Swan Song of Constitutional Medicine 118 References121 10 The  Discovery of Type 1 Diabetes123 10.1 The Dancing Mouse 124 10.2 The Uses of Incest 127 10.3 Local Gardener Wins Nobel Prize 132 10.4 Biological Individuality 135 10.5 What Makes Us Unique? 140 10.6 We Have Found the Enemy, and He Is Us 142

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10.7 The Walls Come Tumbling Down 144 10.8 The Heel of Achilles 146 References147

Part IV The Shape of Things to Come 11 Th  e Endless Frontier151 11.1 The War Against Disease 153 11.2 The Pigs and the Pork Barrel 156 11.3 An Anthropologist in the Laboratory 158 References160 12 A  Short Walk Through Time161 12.1 The Wheel of Life 161 12.2 Fred Sanger’s Journey 163 12.3 The Shape of Insulin 166 12.4 The Sound of One Hand Clapping 176 12.5 Measuring Insulin 179 12.6 The Evolution of Insulin 184 12.7 Insulin Resistance 185 References188 13 Out  of the Doldrums191 13.1 Disease or Risk Factor? 192 References196 14 Th  e Hard Yards197 References201 15 I nsulin Wars203 15.1 A Needle in a Genestack 205 15.2 Business as Usual 214 15.3 The Role of the Regulator 216 15.4 All the Insulin in the World 220 15.5 Globalisation 221 References222

xxx Contents

Part V Modern Times (~1990 On) 16 Th  e Silent Majority227 16.1 What Is Diabetes? 227 16.2 Who Needs Insulin? 230 References236 17 The  Market in Insulin237 17.1 ‘That’s Where the Money Is’ 243 17.2 What Future for Biosimilar Insulin? 244 17.3 How the Other Half Dies 246 References248 18 P  ossible Futures251 18.1 The Human Factor 252 18.2 Access to Insulin 255 18.3 Preventing Diabetes 256 18.4 Replacing Insulin 258 18.5 Biological Alternatives 260 18.6 The Second Century of Insulin 263 18.7 Unfinished Business 266 References269

Part I Before the Dawn

1 Beginnings

The ‘ductless glands’ puzzled anatomists for centuries, but a major clue as to their function came when a famous Professor announced that he had rejuvenated himself with injections of animal testicles. His claims were bogus, but they started a fashion for injecting extracts from other glands and the science of endocrinology was born. It had previously been assumed that all bodily functions were directly controlled by the nervous system, but it was now appreciated that near-infinitesimal quantities of chemical substances (soon to be known as ‘hormones’) had drastic effects upon our growth and function. Purely by chance, two German investigators discovered in the same year that removing a dog’s pancreas caused diabetes. Many people guessed that tiny cell clusters in the pancreas—known as the islets of Langerhans—released an active principle into the blood stream, and physiological studies gave the first hint as to what its properties might be. On June 1st 1889, a 72-year-old physician of enormous distinction electrified the Society of Biology in Paris. Charles-Edouard Brown-Séquard held to the age-old belief that ‘seminal losses from any cause produce a mental and physical debility which is proportional to their frequency’, whereas ‘men, especially from 25 to 35 years of age, who remain absolutely free from sexual intercourse or any other cause of expenditure of seminal fluid, are in a state of excitement, giving them a great though abnormal physical and mental activity’. The belief that the testes contain some vital principle of life goes back to the ancient Greeks, and Aretaeus of Cappadocia claimed in the second century AD that if ‘any man be continent in the emission of semen, he is bold, daring and strong as wild beasts’ [1]. Some twentieth century sports coaches © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 E. Gale, Life in the Age of Insulin, Copernicus Books, https://doi.org/10.1007/978-3-031-47190-2_1

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subscribed to the same belief. Not satisfied with speculation, Brown-Séquard went on to discuss the ‘remarkable effects produced on myself by subcutaneous injection of a liquid obtained by maceration on a mortar of the testicle of a dog or of a guinea-pig to which one has added a little water’. His strength increased within 2 weeks of starting the course of injections, as did his stream of urine. He could run upstairs, lift heavy weights, and generally felt 30 years younger. So much so, as he was indiscreet enough to mention, that he had been able to pay renewed attention (‘rendre visite’) to his young wife [2, 3]. The response to his claims ranged from hilarity to desperate credulity. A visiting scientist said that this was conclusive evidence of the need for Professors to retire at the age of 70. Even so, few men passing their prime— most of the audience—could fail to ponder the topic to which Brown-Séquard had so delicately alluded. His ‘elixir of life’ was guaranteed a thriving future and more than 12,000 physicians are said to have tried its effects by the end of the year, quite often on their patients. Distorted echoes of this reached as far as 222B Baker Street. Professor Presbury, the famous Camford physiologist, is unaccountably attacked and bitten by his faithful wolfhound Roy. The 61-year-old Professor has exhibited odd behaviour such as knuckling his way along corridors, climbing drainpipes with remarkable agility and taunting a frantically barking Roy (now chained in the yard) by capering just beyond his reach. Sherlock Holmes soon links the Professor’s simian behaviour with his infatuation with a much younger woman and the mysterious packages which arrive from Prague. With hindsight, we can be sure that the science behind Brown-Séquard’s extract was little more than primitive folk belief with a dash of wishful thinking. The testes make testosterone, but they do not store it, and he could not possibly have given himself an effective dose. Despite the acclaim for the new treatment, it was a sad ending to a brilliant career. Brown-Séquard died in 1894, soon after the death of his wife. Ironically, his idea proved surprisingly fruitful, and injecting mashed-up glands became the order of the day. Inspired by Brown-Séquard’s report, the Scottish physician George Murray injected ground up thyroid tissue from a sheep into a 46-year-old woman with the clinical features of myxoedema (an underactive thyroid) in 1891. Her recovery was striking, and the extract proved equally effective when taken by mouth: she had consumed 870 raw glands by the time of her death at the age of 74 [4, p.  29]. Yet another revelation came when a physician called George Oliver took the train from Harrogate to London in the autumn of 1893. His hobby was physiology, and his children were a convenient source of experimental subjects. He obtained an adrenal gland from his butcher, ground it up, and injected it into his small son. It seemed to affect his pulse, and

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Oliver was bursting to test it further. He arranged to meet the celebrated physiologist Edward Schäfer at University College, but the Professor was intent on measuring the blood pressure of a dog when he arrived and had no great wish to be interrupted. Oliver failed to take the hint, produced the extract from his pocket and waited patiently for the experiment to end. The exasperated Professor finally injected the mysterious extract into his dog, only to watch open-mouthed as the mercury column recording its blood pressure shot skyward [5, 6]. When Edward Schäfer reflected on this moment, he saw it as the watershed between the old science of medicine and the new. The old science took it for granted that every bodily function was under the direct control of the brain and nervous system. The new version saw this as over-ridden by chemical entities released into the blood stream [7]. Murray’s extract contained thyroxine (the thyroid hormone), and Oliver’s contained adrenaline. Both have a relatively simple chemical structure, and both could be synthesised in a laboratory. Adrenaline was isolated by John Jacob Abel in the States (we will meet him again) and he called it epinephrine; by 1904 it was used to treat asthma. Synthetic thyroxine was available from 1927; both were effective at less than a millionth of a gram per kilo of body weight. They provided the first clear indication that our bodies are regulated by a complex network of potent chemical signals, and the first hint that insulin might be among them came to light in Brown-Séquard’s momentous year of 1889.

1.1 The Wager The pancreas, whose Greek name means ‘all flesh’, is a nondescript strip of tissue whose appearance is reflected in its German name of Bauchspeicheldrϋse (abdominal salivary gland). It is about 13 cm long, weighs 60–160 g, and lies behind a membrane which covers the back of the abdomen. Its central duct meets the bile duct from the liver, and they each drain their juices into the horseshoe bend formed by the duodenum as it exits the stomach (Fig. 1.1). Nature takes a relaxed attitude towards the design of the pancreas, and anatomical variants are relatively common. Pancreatic juice is alkaline—it neutralises the acid contents of the stomach—and it is packed full of digestive enzymes. This, so far as 19th physicians were concerned, was all that the pancreas did. In April 1889 Oskar Minkowski, assistant to Naunyn, a leading diabetes expert in Strasbourg, went hunting for journals in the library of a neighbouring department. He bumped into von Mering, a member of that department,

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Pancreatic duct

Duodenum

Fig. 1.1  Line drawing showing detail of pancreas. (From TeachMeAnatomy, TeachMe Series 2023—with permission)

and they paused to discuss a commercial food supplement that claimed to out-perform cod liver oil. Minkowski questioned von Mering’s assertion that pancreatic enzymes were required for fat breakdown in the gut, and they agreed that the best way of finding out would be to remove a pancreas. There are numerous accounts of what happened next, not least because Minkowski’s recorded comments date from 1926 and von Mering left no personal record. Minkowski’s account was written in response to the claim— probably motivated by antisemitism—that the Aryan von Mering had been denied due credit for the discovery. Minkowski’s unpublished reply was deposited in the archives, only to be removed by a Jewish colleague when Hitler came to power in 1933 and passed on to Minkowski’s wife. She, as will be related, duly handed it to Bernardo Houssay in Buenos Aires [8]. Minkowski reported that Von Mering had claimed that total pancreatectomy was ‘an impossible operation’, basing this on Claude Bernard’s experience that animals could not survive it [9]. Minkowski’s surgical skills were legendary—he once made medical history by removing a goose’s liver without killing the goose—and he jumped at the challenge. Von Mering provided a dog, and they operated in Naunyn’s laboratory that same afternoon. The dog’s anatomy proved favourable and the operation was a success. The plan had been to pass it back to von Mering for his experiments with digestion, but his father-in-law developed pneumonia and he was summoned to his bedside. The dog was therefore tied up in Minkowski’s animal facility. Next day an aggrieved technician complained that the dog, although taken outside regularly to relieve itself, had become incontinent of urine. Minkowski claimed that he grabbed a pipette and tested the urine for sugar, but another

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version of the story tells that his boss (a diabetes specialist) suggested the diagnosis when he saw flies clustering around its urine. Whatever the truth, Minkowski had the grace to admit that diabetes was a totally unexpected outcome of the experiment, and that his was a lucky accident [10]. There is a further twist to the story. Von Mering was famous as the discoverer of phlorizin, a poison that blocks the ability of the kidney to extract glucose from the urine, and his dog had been used in previous experiments. Minkowski could not be sure that the dog’s urine had been free of glucose to begin with. Von Mering was still out of town, and Minkowski operated on three more dogs. Two died of operative complications—but with glucose in their urine—and the fourth developed unquenchable thirst, copious urine, and a massive loss of glucose. Its life was short and unpleasant. The 1st May 1889 marked the anniversary of the foundation of Strasbourg University (Strasbourg, capital of Alsace, had recently been annexed by Germany), and the 350-year-old university became known as the Kaiser-­ Wilhelm-­Universität in 1872. This too was being celebrated in the auditorium. Von Mering, recently returned from Colmar, chanced to sit down in front of Minkowski. Minkowski tapped him on the shoulder. Did he know that taking out a pancreas causes diabetes? But why? The digestive juices were not responsible, for Minkowski could rule this out by blocking the duct which conveys them into the intestine. Next, he removed another pancreas but re-implanted a small segment under the skin with its blood supply intact. No diabetes. Minkowski concluded that the pancreas must release some anti-diabetic principle into the blood stream. Researchers hunt in packs, and this report precipitated the first of many gold rushes in diabetes. The operation itself remained a major obstacle. Mercifully, the dogs were now given chloroform before surgery, but the surgeon operated with bare hands, tearing the soft tissues of the pancreas away from its attachments and scraping the residue from the bowel wall with his finger nails. There was an element of Catch-22 about the outcome, since successful removal of a pancreas produced full-blown diabetes and the dog soon died of septicaemia. The French surgeon Hédon overcame this with a clever two-step procedure. In step one, he removed the head of the pancreas and swung the tail forward, complete with its blood supply, until it lay directly under the skin of the abdomen. The dog healed well and did not develop diabetes. Since it could not digest food properly in the absence of pancreatic enzymes, Hédon also gave it raw pancreas to eat. Ten days later, he removed the residue of the pancreas via a small incision in the skin. Glucose appeared in the urine within

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minutes, and full-blown diabetes resulted within 12 h [11]. Even a small residue of pancreas was enough to prevent this from happening. Joseph Forschbach was Minskowski’s chief assistant when he moved to Breslau (now Wroclaw, Poland), and published four parabiotic experiments in dogs in 1908. This technique joins the circulations of two experimental animals; arterial blood from one passes directly into the veins of the other. One dog had a pancreas and the other did not. The dog without a pancreas remained alive and well while their circulations were linked, but developed diabetes as soon as they were separated [12].

1.2 A Riddle Wrapped in a Mystery Inside an Enigma A 22-year-old medical student called Paul Langerhans (1847–88) examined the rabbit pancreas for his qualifying thesis in 1869. He apologised to his examiners for finding nothing new, but his report described little islands of densely innervated tissue which peppered the pancreas but stained differently from the rest of the gland [6, pp. 179–80]. He had no clue as to their nature. Langerhans contracted tuberculosis, retired to Madeira and died young— never guessing that his name would be known to every future student of medicine. The islets were rediscovered by a Frenchman called Laguesse in 1893. He charitably named them for Langerhans, and speculated that they might be the source of the internal secretion of the pancreas [13]. The main obstacle to this hypothesis was that diabetic islets often look normal under a standard microscope. Often, but not always. The first direct evidence that the mysterious internal secretion did indeed derive from the islets came when pathologist Eugene Opie reported hyalinisation (a ground-glass appearance) in the islets of 6 of 19 people with diabetes in 1901, although similar changes were not uncommon in healthy old people [14]. The islets became the focus of intense research interest, and pathologist Lydia DeWitt is said to have claimed in 1906 that ‘probably no organ or tissue of the body has been the subject of more thought or investigation’ (Fig. 1.2). Microscopic examination made it clear that islet cells contained granules, and that different types of cell were present. Two main types had been described by 1907. Large centrally-placed cells stained a brilliant violet with a chromium dye in alcoholic solution, and were christened the ‘A’ cells. If the same dye was diluted in water, however, the A cells faded from sight and another group of cells glowed violet. One observer found that ‘the ß type of

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Fig. 1.2  Chemical stains make this islet of Langerhans stand out clearly. There are about a million islets in a healthy pancreas, each of which makes insulin, glucagon and other hormones. (From Pancreatic islet of Langerhans’ cytoarchitecture and ultrastructure in normal glucose tolerance and in type 2 diabetes mellitus; Franco Folli, Stefano La Rosa, Giovanna Finzi, et al.; Diabetes, Obesity and Metabolism; John Wiley and Sons; Sep 19, 2018 - with permission)

cell appears, as a rule, considerably smaller and is, at the same time, vastly more numerous in the islet. Entire cords of them, uninterrupted by the presence of the A cells, appear in the picture, and almost invariably the cytoplasm of the entire cell is packed with the violet granules, which are uniformly distributed around the nucleus and which everywhere border on the capillaries’. His conclusion was that the islets ‘are structures which, in all probability, have the function of producing a twofold substance which, poured into the blood stream, has an important effect upon metabolism’ [15]. This twofold secretion was later identified as glucagon and insulin and the biological importance of their partnership was underlined when it showed up in almost every creature with a backbone. By 1910 most physiologists believed that the pancreatic islets produced something that stops diabetes from developing. In itself, this insight was of limited values for, as a student textbook pointed out in 1905, ‘we do not get any nearer to a solution of the question by saying that the pancreas has an internal secretion, since we have no conception how such a secretion might work’ [16, p. 495]. The hypothetical hormone was christened insuline (the

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‘island hormone’) by Jan de Meyer, a Belgian physiologist, in 1909. Edward Schäfer used the same term in 1916, 1 with the added suggestion that it might have an inactive precursor which he called pro-insuline. The hunt for this mysterious substance was now well under way, but we should pause to consider the condition they were hoping to treat.

1.3 A Taste of Honey Diabetes was known from Europe to China in ancient times. Aretaeus of Cappadocia, whose views on sexual abstinence were mentioned earlier, gave the following vivid description: Diabetes is … not very frequent … being a melting down of the flesh and limbs into urine …for the patient s never stop making water, but the flow is incessant, as from the opening of aqueducts … The nature of the disease is chronic and it takes a long time to form; but the patient does not live long once the disease is fully established; for the melting is rapid, the death speedy. Moreover life is disgusting and painful; thirst, unquenchable … and one cannot stop them either from drinking or making water. Or if for a time they abstain from drinking, their mouth becomes parched and their body dry; the viscera seem as if scorched up; they are affected by nausea, restlessness and a burning thirst; and before long they die

This famous description has never been bettered, although we may doubt his subsequent assertion that ‘wherefore, what from insatiable thirst, an overflow of liquids, and distension of the belly, the patients have suddenly burst’. Aretaeus drew an analogy with the bite of the thirst-adder which also (or so he claimed) induces an unquenchable thirst. Dipsas (the name means thirst, as in dipsomaniac) is the modern name of a harmless family of snakes, and there seems little hope of identifying the snake Aretaeus had in mind, even if it existed. He is often said to have coined the name diabetes, but his discussion of its etymology shows that the term was already well known. Aretaeus and the Roman physician Galen thought that diabetes was a kidney disease, but neither seems to have been aware that the urine tastes sweet. The ancient Hindus did know this, and explained its attraction for ants on the same basis. The taste of honey was also known to the Arab physician Ibn Sina (980–1037),  Schäfer, born in the UK to a German father, changed his name to Sharpey-Shafer in World War 1 to avoid its Teutonic connotations. He took the name ‘Sharpey’ from his old professor. Two of his sons were killed in the war. 1

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better known as Avicenna. The sweet taste of the urine is often said to have been rediscovered by the Oxford physician Thomas Willis in 1674, but it was already well known. In Moliere’s play Le Médecin Volant (1650), for example, a valet posing as a doctor tastes the urine and pronounces it sweet. By 1800 physicians knew that the serum of people with diabetes also tasted sweet—suggesting that it is not a kidney disease—and a fermentation test was used to demonstrate the presence of sugar in the urine. If the urine fermented, you had diabetes. The residue tasted of ‘small beer’, and carbon dioxide formed above it. The sweet taste was attributed to grape sugar (glucose) rather than cane sugar (glucose plus fructose) in 1815. A chemical test based on conversion of copper sulphate to cuprous oxide was later used to detect glucose in the urine. The method was simple, reliable and widely used, but did not work in serum, a limitation which probably delayed the discovery of insulin by several years.

1.4 The Ghastly Kitchen To express my idea of the science of life, I should say that it is a superb and dazzlingly lighted hall which may be reached only by passing through a long and ghastly kitchen—Claude Bernard

Theology had largely ceded the external universe to physics by the start of the nineteenth century, but life itself appeared to defy materialistic explanation until it was shown that our bodies, like those of the lower animals, obey the laws of thermodynamics. The realisation that energy and matter could neither be created nor destroyed validated the ancient belief of Heraclitus that life is a process of endless flux. Claude Bernard (1813–78) became the world’s leading expert on the physiology of diabetes. He started life as the son of a wine grower down on his luck. Unable to finish his schooling for lack of funds, he trained as a pharmacist, but soon decided that he did not want to spend the rest of his life folding squares of paper. Bernard aspired to be a playwright, and travelled to Paris in November 1834 to show two romantic dramas—the Rose of the Rhone and Arthur of Brittany—to Girardin, professor of literature at the Sorbonne. His opinion was expressed in the terse comment that ‘you have done some pharmacy, study medicine’. Physiology barely existed as a discipline when Bernard qualified, and animal experiments were new and unpopular. ‘As soon as an experimental physiologist was discovered’, as he commented in 1867, ‘he was denounced, became

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the abomination of the neighbours, and was handed over to the police for prosecution’. His wife’s wealth supported his research, and her opposition to vivisection contributed to the unhappiness of their marriage. Operations on animals (and humans) were performed without anaesthetic, and experimental surgery was considered unbearably cruel by many contemporaries. The English physician Thomas Chambers said of Claude Bernard: ‘First and chiefly, I am not convinced that we have a right to torture a creature subject to our rule merely to gain knowledge. The effect of the infliction of such pain may possibly not be injurious to others, but I know it would harden my heart, and therefore I will not do it’ [17]. Claude Bernard saw it another way. ‘A physiologist’ he said, ‘is not a man of fashion, he is a man of science, absorbed by the scientific idea which he pursues: he no longer hears the cry of animals, he no longer sees the blood that flows, he sees only his idea’. He told his students that ‘the scientific medicine which it is my duty to teach you does not exist’, and added that ‘the only thing to do is to lay the foundation upon which future generations may build, to create the physiology upon which this science may later be established’ [18]. A new world awaited discovery. The writers of medical textbooks trade in memorable history, which is often wrong. Nor can you rely on the memory of the protagonist. One fearful insight into the human condition is that we really do forget, replacing what really happened with self-serving reminiscence. Listen to the contrasting narratives that emerge from any unhappy love affair, and you will be forced to agree. It is equally clear that the recollections of great scientists rarely match the records they kept at the time. Another leading characteristic of medical historians is the immense condescension that derives from knowing what happened next. Retrospective marks are awarded for guessing the right answer, and those who got it wrong are dismissed with a regretful shake of the head. Yet another characteristic of the medical historian is laziness in attribution. Famous scientists—‘famous for being well known’—attract credit as a magnet attracts iron filings. The sociologist Robert K Merton referred to this as the ‘Matthew principle’ in deference to the gospel statement that ‘unto everyone that hath shall be given, and he shall have abundance: but from him that hath not shall be taken away even that which he hath’ [19]. This sound capitalist principle robs those who actually carried out the work of their modest hope of immortality. It is impossible—or at least impossibly boring—to tell the story of scientific discovery without its heroes, but Claude Bernard was just as capable of pettiness as any other great man, just as prone to error, and just as remarkable.

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His achievement was to track the flow of nutrients through the body of a living creature. It was believed in the 1840s that plants provide all the chemicals that an animal needs, and Bernard’s vision of the body as a chemical factory came as a profound revelation. Francois Magendie, his professor, had shown that glucose is present in the bloodstream of healthy animals, and Bernard found that fasting glucose levels were highest in the blood leaving the liver, implying that it produces glucose for the rest of the body. He performed each measurement of the glucose content of the liver in duplicate. One night, working late, he delayed the second test until the following morning. The second sample contained more glucose than the first, suggesting that a reserve form of glucose is stored in the liver. Plants store glucose as starch, which turns blue with iodine, but the equivalent substance in liver turns brownish-red. He called it glycogen (‘the glucose maker’). Spitting on the specimen removed the stain, and he deduced that saliva must contain an enzyme (‘ferment’ in the language of the time) capable of converting glycogen to glucose. A scientist is an amphibious creature. Like a male sea lion, he swims freely in the world of experiment and discovery, but recognition, reward, and hopes of posterity will depend upon his or her ability to mark out a territory on dry land and to defend this against all comers. The anxious attention to invisible boundaries, the exsufflication, warning barks, and final lumbering rush can be witnessed at scientific congresses by those with the eyes to see. Claude Bernard was easily rattled by those who failed to confirm his observations. On one occasion he dismissed the findings of a contemporary with withering contempt and encouraged the Academy of Sciences to set up a committee to resolve the dispute. Bernard’s experiments were repeated and confirmed; anathema was pronounced on those of this rival, which were not repeated. Bernard was wrong, but did not acknowledge his mistake for 22 years. His glycogenic theory pictured glucose as the ready cash of energy transfer, and he saw the liver as the bank in which this cash is stored and fed back into the circulation. Energy locked into the glucose molecule could then be released by combination with oxygen, otherwise known as combustion. Energy-rich glucose is present in the blood stream of healthy individuals, but not in their urine. This must mean that the kidneys are able to extract glucose and return it to the circulation. There is a limit to this ability, for glucose floods into the urine in diabetes, sucking fluid and electrolytes out of the body. The physiologists noted two other features of established diabetes. Aretaeus had observed that the onset of diabetes is slow, but that it accelerates in its later stages, and this would be amply confirmed. Another was that

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glucose, whether given by mouth or injected, promptly showed up in the urine. The body could not use glucose in diabetes, but the liver kept pumping it out. And so we leave Claude Bernard as a contemporary once saw him, ‘with his tall hat on, from beneath which escaped long locks of greying hair: around his neck was a muffler which he scarcely ever took off…his fingers were nonchalantly thrust into the open abdomen of a large dog which howled mournfully. He turned towards his visitor with a benevolent glance, asking him to wait a moment, and went on with his experiment’ [17]. But let us not forget the others, the arguments that arose because things weren’t measured properly, the smart inferences, the misguided hypotheses, and the false friends of misleading interpretation. This was the Brownian motion of scientific discovery, the clash of ignorant armies, the wasted lives, the grudging drift towards consensus.

References 1. Aretaeus of Cappadocia. The extant works of Aretaeus, the Cappadocian (trans: Adams F). London: Classics of Medicine Library; 1990. 2. Brown-Séquard CE. The effects produced on man by subcutaneous injections of a liquid obtained from the testicles of animals. Lancet. 1889;137(3438):105–7. 3. Tattersall RB. Charles-Edouard Brown-Séquard: double-hyphenated neurologist and forgotten father of endocrinology. Diabet Med. 1994b;11:728–31. 4. Rolleston HD.  The endocrine organs in health and disease with an historical review. Oxford: OUP; 1936. 5. Dale H. Accident and opportunism in medical research. BMJ. 1948;2:451–5. 6. Medvei VC. The history of clinical endocrinology. A comprehensive account of endocrinology from earlied times to the present day. Nashville, TN: Parthenon Publishing; 1993. p. 179–80. 7. Borell M. Organotherapy, British physiology, and discovery of the internal secretions. J Hist Biol. 1976;9(2):235–68. 8. Houssay BA. The discovery of pancreatic diabetes. The role of Oskar Minkowski. Diabetes. 1952;1(2):112–6. 9. Bernard C. Memoir on the pancreas (trans: Henderson J). Monographs of the Physiological Society no 42. New York: Academic Press; 1856. 10. Bliss M. The discovery of insulin. Chicago: University of Chicago Press; 1982. 11. Hédon E. Greffe sous-cutanée du pancreas: ses resultats au point de vue de la théorie du diabète pancréatique. CR Soc Biol (Paris). 1892;44:678–80. 12. Forschbach J.  Parabiose und Pankreasdiabetes. Deutsch Med Wochenschr. 1908;34:910 ff.

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13. Laguesse EG. Sur la formation des îlots de Langerhans dans la pancreas. CR Soc Biol (Paris). 1894;46:819–20. 14. Opie EL.  Disease of the pancreas. Its cause and nature. Philadelphia: JB Lippincott; 1903. 15. Lane MA.  The cytological characters of the areas of Langerhans. Am J Anat. 1907;7:409–22. 16. Starling EH. Elements of human physiology. 7th ed. London: JA Churchill; 1905. 17. Holmes FL. Claude Bernard and Animal chemistry. Cambridge, MA: Harvard University Press; 1974. 18. Bernard C. An introduction to the study of experimental medicine (trans: Greene HC). Dover, Mineola, NY; 1865, 1957. 19. Merton RK. The Matthew effect in science: the reward and communications system of science. Science. 1968;159:55–63.

2 Before the Dawn

When I compare our present knowledge of the workings of the body, and our powers of interfering with and of controlling those workings for the benefit of humanity, with the ignorance and despairing impotence of my student days, I feel that I have had the good fortune to see the sun rise on a darkened world, and that the life of my contemporaries has coincided, not with a renaissance, but with a new birth of man’s powers over his environment and his destinies unparalleled in the whole history of mankind. —Ernest Starling, 1923 [1]

The nineteenth century witnessed the discovery of the cell and the beginnings of evolutionary theory, and the great achievement of the first half of the twentieth century was to bring them together in the new science of genetics. More and more physiological processes would henceforth be understood in terms of the interaction of molecules. Diabetes was rare and rapidly fatal in the early part of the last century, especially in the young. Glucose given by mouth or by injection promptly appeared in their urine. In contrast, dogs with partial removal of the pancreas did not develop diabetes on a low carbohydrate diet but would do so if their carbohydrate intake was increased. Not surprisingly, early attempts to control diabetes centred on a low carbohydrate diet which was correspondingly high in fat and protein. The recommended diet for diabetes resembled the habitual diet of the Inuit, and this was therefore of particular interest. The Scientific Revolution of the seventeenth and eighteenth centuries suggested to some that we live in an empty universe governed by material forces, © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 E. Gale, Life in the Age of Insulin, Copernicus Books, https://doi.org/10.1007/978-3-031-47190-2_2

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although those of a religious turn of mind maintained that life itself could only be explained by supernatural intervention. This assumption was challenged when nineteenth century scientists showed that our bodies are subject to the laws of physics and chemistry, but one last redoubt resisted all attempts at a mechanistic explanation: the cell. William Harvey proposed in the seventeenth century that all complex life begins with an egg—omne vivum ex ovo. The great physiologist Rudolf Virchow (1821–1902) rephrased this by saying that every cell is descended from another cell—omnis cellula ex cellula. His great work on Cellular Pathology came out in 1858, 1 year before Darwin’s Origin. The two works were a perfect fit, for Darwin argued that natural selection acted upon variants of the same fundamental ground plan, and Virchow founded his ground plan upon the cell. Sadly, there was no meeting of minds, for Virchow was a staunch opponent of evolutionary theory. The twentieth century is often referred to as the Century of the Gene, but might equally be called the Century of the Cell. Little of this could be glimpsed in the 1890s, but astonishing progress was made before a pistol was fired in Sarajevo in 1914. New and previously unimagined sciences emerged: immunology, biochemistry (first named in 1903), genetics (1905), and endocrinology (probably 1909). All are based on the way cells operate and communicate with one another. A suggestion of particular note came when Paul Ehrlich advanced the theory that cells communicate by means of special receptors on their surface, a theory that might explain why some cells respond to drugs and chemical signals but others do not. The realization that molecules carry signals from one part of the body to another explained a longstanding mystery of anatomy. Glands convey juices to a body surface via a duct, but early anatomists were puzzled to find that similar cell clusters in the endocrine glands had no outlet at all. It was now evident that these ‘ductless glands’ secrete directly into the blood stream. Ernest Starling and William Bayliss discovered in 1902 that an extract of intestinal cells will cause juice to pour out of an isolated pancreas, and showed that a substance they called secretin was responsible. A classically-minded colleague suggested that such messengers should be called hormones (derived from a Greek word meaning to provoke or stimulate), and the term caught on. As the First World War devastated Europe, endocrinologists were coming to see these glands as part of a sophisticated self-regulating system. It had previously seemed axiomatic that the nervous system controlled every bodily function, and the idea that we should be controlled by chemicals floating around in the blood stream appeared unutterably crude—much as we might feel to learn that IBM communicated by pigeon post. The idea was distasteful

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for other reasons. Examine the eye, the joints of the hand—or almost any other bit of the body—and you will be overwhelmed by the perfect adaptation of form to function. Examine the brain, rooted in the body like a bulb in a pot, and you feel a reassuring sense of hierarchy, each lowly function subordinated to the will of the higher centres. Turn now from this reassuring vision of order to the endocrine glands, and you find a motley collection of organs, each a law unto itself. These glands share no common embryological origin, their structure varies and the chemicals they produce are often unrelated. It seemed perfectly obvious that evolution had cobbled them together from whatever materials lay to hand. As if further proof of their primitive origins were needed, an extract of ductless gland from one creature had profound effects upon almost any other. Gudermatsch found in 1911 that tadpoles could be transformed into frogs at any stage of their development by giving them thyroid, and Julian Huxley showed in 1920 that a single meal of thyroid caused the water-dwelling axolotl to sprout legs and metamorphose into a land-going salamander. Artur Biedl, a Viennese endocrinologist, anticipated a future level of understanding which would bring chemical signal and electrical impulse into harmony. ‘Formerly’, he said, ‘every correlation of organs was regarded as nervous; today, however, even nervous actions are regarded as brought about chemically’ [2]. Ernest Starling saw a breath-taking panorama of higher order in all this, and comments in wonder that such widespread effects should result from the presence or absence in the body of infinitesimal quantities of a chemical substance. Not everyone shared the optimism of the biologists. Robbed of appeal to divine authority, twentieth century thinkers from lecture theatre to soap box did not hesitate to claim biological sanction for their arguments. Their problem was that the multitudinous life forms that surround us can provide texts for any sermon, and that those who seek lessons from biology will find nothing more than a reflection of their own deepest needs. To a world shaken by the First World War, endocrinology provided further confirmation of the irrational roots of our behaviour. Sigmund Freud had shown that we are driven by forces lurking beneath the threshold of consciousness, inherited from our feral ancestors but tragically ineradicable. Endocrinology, another Viennese speciality with origins in human sexuality, provided further evidence that we dance to the beat of primaeval messages in our bloodstream. ‘We are marionettes of our glands’ claimed a future Oxford Professor of Medicine in 1923. Deep-rooted pessimism permeated the cutting-edge science of eugenics, which argued that our evolutionary progress towards humanity contained the seeds of our destruction. Karl Pearson outlined the principles of group

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selection and the evolution of altruism more than 50 years before these became topics for fashionable debate, and argued that our care for the weak and the diseased, reinforced by medical intervention, guarantees that inferior genetic material will be transmitted from one generation to the next. This, in his view, put an end to natural selection and—should substandard germ plasm accumulate—the boulder would begin to roll back down the hill towards primal chaos. The inference was obvious: those whose heredity was tainted should realise that they had a duty not to reproduce. Education would help them to recognise this duty, and the British eugenicist JA Thompson hoped that it would instil a ‘wholesome prejudice against the marriage and particularly the intermarriage of subjects in who there is a strong hereditary bias to certain diseases—such as epilepsy and diabetes’ [3]. The bottom feeders in this intellectual turmoil were the race theorists, and the reflection they saw was one of reverse evolution, pollution, and degeneracy. Consider psychoanalysis, they would say, and you enter a world of moral degenerates and sexual deviants. Turn now to the endocrine clinic, and you will find a freak show, complete with giants, dwarves, and bearded ladies. Who would wish to embrace these physical and moral degenerates, throwbacks and monsters of unclean desire? Only those whose racial heredity was tainted. Few noticed this cloud, the size of a man’s hand, that had appeared on their horizon.

2.1 Diabetes in the Nineteenth Century Diabetes was rare. William Osler’s 1892 Textbook of Medicine has ten pages on the subject, as against 65 on tuberculosis, and he reported that only 10 of 35,000 patients attending Johns Hopkins hospital had required treatment [4]. The Massachusetts General Hospital in Boston admitted 47,899 patients between 1824 and 1898. Of these, 172 (0.004%) were considered to have diabetes [5]. Diagnosis was made by tasting the urine in the early part of this period, which might help to explain why diabetes was considered so rare. The condition was undoubtedly far more common than this might suggest, especially in older people. William Pavy (1829–1911), a British specialist, reported in 1867 that he had treated 1360 cases, of whom 56% were diagnosed between 40 and 60 years of age [6]. Older people often had no symptoms, and hotel servants learned to diagnose diabetes by flecks of sugar caused by urine splashes on shoes left out for them to clean. Similar tell-tale flecks could be seen on clerical vestments that had been put aside for years, mute witness to longstanding diabetes. The people who consulted Pavy were for the

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most part middle aged, male and relatively well off—which is why they got to be diagnosed in the first place. Diabetes in childhood was truly exceptional. Charles West, writing in 1865, notes that William Prout (1785–1850) had treated 700 people with diabetes in the course of his professional life. Of these, 18 were diagnosed under the age of 20, and 3 under the age of 10. Pavy’s experience was of 65 cases under the age of 20 and 8 under 10. John Lovett Morse (1865–1940), Professor of Paediatrics at the Harvard Medical School, wrote the first paper on childhood diabetes in the English language in 1913; he himself had seen 19 cases. His search through three decades of clinical reports and mortality data from France and Germany allowed him to assemble a world total of 989, of whom 162 were under the age of 5. Their future was bleak, and he quotes Carl von Noorden (1858–1944) as saying that ‘with few exceptions diabetes in childhood knows no cure, no matter how mild it may appear in the beginning, nor how gradual its development in the first months or even years’ [7]. If diabetes was fatal in the young, it was precarious at any age. ‘Such an individual may be considered as existing on the brink of a precipice’, said William Prout in 1825, ‘and the general prognosis of diabetes must always be considered as very unfavourable’ [8]. Danger came in many forms, but the most characteristic was a lapse into terminal coma. The Boston physician Elliott Joslin reported that 86% of the children who come to his attention before insulin died in this way. We know the condition as diabetic ketoacidosis, and it develops when the body is flooded with glucose that it cannot use. This spills into the urine, causing intense dehydration, even as fat pours into the circulation in the attempt to feed cells hungry for glucose. Breakdown products of fat metabolism known as ketone bodies accumulate in the body; their presence gives their breath a distinctive smell akin to stored apples. Ketones are acidic, and the victim attempts to compensate by over-breathing, which blows off carbon dioxide. All in vain, however, for this downward spiral was invariably fatal in the absence of insulin. Joslin described it as follows: He finally collapses and is forced to bed, not to rest, but there to be tortured with a gruelling combat for breath. The food he has hitherto eaten nausea forces him to reject, the liquids he eagerly drinks he vomits. In his restlessness he throws off the clothes. Finally, beaten in his struggle for life, he falls back helpless, unconscious, with a pulse approaching 200, with a body temperature rapidly falling below normal, with so little liquid in the body that his muscles melt away before the touch, with the eyes as soft as jellyfish, with the skin parchment dry … In the brief space of hours the body has seemingly gone through months of the ravages of cancer, and death appears at hand. [9]

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Since early death was almost inevitable, the incidence of childhood diabetes can be judged from its mortality. The reported death rate in the USA was 1.3 per hundred thousand per year under the age of 15 in 1890, as against 3.1 in 1920. In Denmark the estimate rose from 2 per hundred thousand/year for 1905–9 to 4 for 1915–19, and the death rate rose from 2 to 7 between 1900 and 1920 in Norway. The incidence of childhood diabetes rose sharply later in the century, and the number of children under 10 who developed diabetes in Norway was estimated at around 20/100,000 per year in 2000 [10].

2.2 Death on the Instalment Plan Elliott Proctor Joslin (1869–1962) is my hero. Diabetes became the central focus of his life in June 1899 and remained so until the day of his death. His career spanned a series of seismic changes in the understanding and treatment of the condition, and his textbook of diabetes, first published in 1916, went through ten editions by 1959. Frequently reissued to mark each new accession of knowledge, it provides an invaluable chronicle of life before, during and after the introduction of insulin, and he will be our trusted guide across this changing landscape. Joslin’s father was a wealthy businessman who owned a shoe factory in the town of Oxford, Massachusetts. The family was Presbyterian, steeped in a stern yet loving puritan tradition. Tough love was their doctrine. The young Joslin was drawn to a career in medicine by admiration for two local doctors, not untinged by envy for the fine horses that conveyed the younger one round town. He was schooled in Latin and Greek at Yale before taking up his medical studies at Harvard in 1891. His family moved to Boston, and he remained there for the rest of his life. Like other wealthy Americans, Joslin made frequent trips to Europe, and became fluent in German, the language of science [11]. His second visit took him to Strasbourg, where he made himself known to Bernhard Naunyn (1837–1925), Minkowski’s chief of clinic. Three early patients influenced the course of his life. The first was 26-year-­ old Mary Higgins ‘a waif-like working girl of Irish ancestry’ whom he encountered on the wards as a second-year medical student in 1893, and whose case he worked up for presentation. Diabetes being incurable, he noted that ‘the practitioner loses all his enthusiasm the moment a patient with the disease presents himself ’. He did not encounter a second patient until 1895, and this happened to be Helen Joslin, his 54-year-old aunt. She died in coma 2 years later. Joslin decided to open a ledger which recorded the date, age and address of each person with diabetes he encountered, together with the year and

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month of onset and—stark reminder—the year of their death. Sentiment prompted him to record Mary Higgins as patient number 1; he wrote ‘untraced’ against her date of death. His aunt was retrospectively entered in second place, and he had reached number 8 by June 28th 1899. This was a 60-year-old woman whose weight had fallen by 11 kg from its previous level of 84 kg (BMI 32) in the 2 years preceding diagnosis. Her urine was loaded with glucose. Her name was Sarah Proctor Joslin, and she was his mother. It takes a brave doctor to treat his own mother—and a brave mother—but Sarah Joslin entrusted her care to her son unreservedly. It is against every precept of medicine for a doctor to treat his own family, but Joslin believed— with some justification—that with Naunyn’s help he was as well qualified as anyone else. He knew that every medication on offer was a waste of time— opium was a favourite remedy—and that diet was his only real option. But which diet? Mrs. Joslin, once decidedly obese, had lost weight rapidly before coming to medical attention; 16% would be an average loss in Joslin’s experience. Modern physicians make weight loss a central aim, but Joslin was more concerned with the flow of energy through his mother’s body. Since sugar given by mouth promptly appeared in the urine, it made sense to offer as little carbohydrate as possible. Physicians starved their patients until the urine was sugar-free and then added glucose back in small increments until it re-appeared in the urine. The critical amount—130 g per day in the case of Mrs. Joslin— was known as the ‘glucose tolerance’. The carbohydrate intake was then lowered and supplemented with protein until glucose reappeared in the urine. Fat was considered a glucose-free source of food energy, and was used to make up the residue of the diet (Fig. 2.1). Mrs Joslin’s Diet “Frequently I see patients who have taken large quantities of fat with obvious benefit... Case No. 8 must have taken 150 grams of fat daily for 14 years (and) outlived most of her family”

250 200 150 100 50 0

CHO

Fat Protein

Fig. 2.1  The diet Joslin prescribed for his mother (in g) is shown in red, and what he considered a typical diet in grey

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Mrs. Joslin now took 40–75 g of carbohydrate daily and consumed 150 g of fat at a time when almost everyone on the planet ate a high-carbohydrate diet. Carl von Voit (1831–1908), often considered the father of dietetics, showed that a man of 70 kg who did 8–10 h of moderately energetic work each day needed more than 3000 calories. Of these, two-thirds were obtained from carbohydrate, and the rest in equal proportion from protein and fat. This ratio was known as the ‘Voit standard’, and the meat-based high fat diet recommended for diabetes was both expensive and distasteful in comparison. And how safe was it? Nutritionists turned to the one human group with a comparable diet. ‘Eskimos live upon 52 grams of carbohydrate daily’, Joslin noted, and this ‘should greatly encourage diabetic patients’. His mother’s opinion has not been recorded. The Inuit diet was the focus of interest for August and Marie Krogh when they sailed from Copenhagen to Greenland on May 30th 1908. He was a brilliant young physiologist, already Associate Professor in the University of Copenhagen, and she would be the fourth woman in Denmark to be awarded the Degree of Doctor of Medicine. From their point of view the Inuit were the closest human equivalent to pure carnivores, and the pair wanted to know how they handled such a massive intake of protein and fat. The technique they planned was whole-body calorimetry, a method that allows a person’s total energy output to be measured and the sources of that energy to be estimated. A volunteer is locked into an air-tight capsule for several days while their heat output is measured together with their oxygen intake and output of carbon dioxide. Their food is weighed and so too are their waste products. The sources of food energy can be estimated because a person who metabolizes carbohydrate alone breathes out one molecule of carbon dioxide for every molecule of oxygen consumed. The resulting one-to-­ one ratio is expressed as a respiratory quotient (RQ) of 1.0. In contrast, a person who lives entirely on fat breathes out seven molecules of carbon dioxide for every ten molecules of oxygen consumed, and has an RQ of 0.7. The ‘missing’ oxygen combines with hydrogen to form water. Protein contains nitrogen, unlike carbohydrate and fat, and protein consumption can therefore be estimated by measuring nitrogen in the urine and faeces. Highly laborious though it is, this approach can generate a spreadsheet of the body’s energy economy. The Kroghs set out to manufacture an airtight capsule—only to be informed that no Inuit would consent to 4  days of solitude. Undeterred, they constructed a capsule for two. This was merely the beginning of their problems, for the Inuit found the idea of spending 4 days in a closed capsule in return for their urine and faeces utterly hilarious—‘you want what?!’— and feared

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ridicule for taking part. In the event, four women consented. The experiment confirmed that Inuit are capable of digesting almost incredible amounts of protein, leaving the Kroghs to conclude—somewhat ruefully—that ‘our observations go to show how little the diet matters after all’ [12]. The ‘Eskimo diet’ would later be popularised by Vilhjalmur Stefansson, a Canadian of Icelandic origins who lived among the Inuit for many years, and would be revived as the notorious Atkins diet much later in the century. Many others followed this this line of research with avid interest, and clinicians saw the ‘Eskimo diet’ as the perfect model for the very low carbohydrate diets they offered for diabetes. Ironically enough, Marie would soon discover this for herself. As for Mrs. Joslin, her weight fell to 65 kg (an overall loss of 19 kg) on the regimen prescribed by her son, and she remained well and virtually glucose-­ free for the next 9 years. She features prominently, if anonymously, as ‘Case no 8’ in Joslin’s 1917 textbook of diabetes, which describes her as ‘unusually strong and vigorous for a woman of 73 years’— until her death from a stroke in 1913. His 1923 edition opens with the statement that ‘in the early months of the century Naunyn taught me with Case No 8 that his methods enabled a diabetic of 60 years to live out the full expectation of life’. He refers to her on no fewer than 13 occasions, and we learn that her condition was complicated by gall stones, hypertension and arterial disease in the legs. Joslin was deeply impressed by her survival, which testifies to the grim outlook for other victims of diabetes. His life’s mission was now clear. Diabetes could be fought successfully. Science would show the way, but moral courage and tough love were equally essential. The fight became a crusade, and the crusade was personal. His mother’s sister had died of diabetes while he stood helplessly by, whereas his mother had outlived his expectations. With a family history such as this, he himself was clearly at risk, and he remained stick-thin for the rest of his life. In deference to his mentor he later called the period from 1898 to 1913 the ‘Naunyn Era’ of diabetes. But the Era had already died with Sarah Joslin, and a bitter campaign lay ahead.

2.3 The Allen Era By 1913, most authorities believed that something produced by the pancreatic islets enabled the body to store and use carbohydrate. This might be a hormone, or an enzyme that digested glucose in blood passing through the pancreas. Since even a tiny residue of pancreas could prevent diabetes, a

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healthy pancreas must have enormous reserves of this mysterious substance. The American physiologist Frederick Allen (1876–1964), attempted to swamp these reserves by overloading experimental animals with glucose, but all in vain. ‘Give the sugar by any route’, said Allen in 1913 ‘increase the quantity at pleasure; it is possible by sufficient dosage to kill the animal, but it is not possible to cause more than a fraction of the whole to be excreted in the urine’. A healthy pancreas can dispose of astonishing amounts of carbohydrate. So how much was needed to prevent diabetes? Allen tested this with operations that nibbled away at the pancreas of his unfortunate dogs, and found that loss of up to 80–85% had no obvious effect, although it increased their susceptibility to diabetes in later life. In the shorter term, however, the outcome depended on what they ate, for his dogs remained well on a meat diet, but rapidly progressed to diabetes on carbohydrate. He concluded that a vulnerable pancreas could be protected by reducing its workload. According to Allen’s model, childhood diabetes resembled a dog without a pancreas, whereas older people were like ‘half-way’ dogs with enough pancreatic tissue to see them through life—provided they did not overload it. High consumption and a sedentary lifestyle predisposed to the condition, and Allen concluded that it is ‘the excess of food rather than of carbohydrate which does the harm’. ‘Dogs which retain a sufficient amount of pancreatic tissue will never become diabetic, irrespective of diet’ he added; ‘but between the two groups is an intermediate group. On an Eskimo diet they may be found to live in health. On a Hindu diet they go down into fatal diabetes’ [13, p. 68 and 595]. The principle operated like a steelyard or beam balance; the greater the load (i.e., the glucose challenge), the more pancreas you needed to counterbalance it (Fig. 2.2). Frederick Allen’s approach worked well in older people, who presumably had more functioning pancreatic tissue. Conversely, the young could only survive on the bare minimum of food. The outcome was balanced on a knife edge. Too many calories, and you lost control of the diabetes: too few, and the victim would die of starvation—as did indeed happen. The approach was compared to a yachtsman sailing as close to the wind as possible, for an excess of fat could tip the patient into lethal acidosis. One risk thus balanced against another, a man weighing 60 kg and able to tolerate 100 g of carbohydrate might be prescribed 60 g of protein, 130 g of fat and 25 g of carbohydrate. His daily ration of the latter might consist of 198 g of thrice boiled cabbage, 142 g of similarly treated spinach, or two and a half bran biscuits. The bran was needed to counteract the constipation induced by the rest of the diet.

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Fig. 2.2  Beam balance. (Photo by Anna Frodesiak, under the Creative Commons CC0 1.0 Universal Public Domain Dedication License)

The treatment was so harsh as to seem penitential, and children hovered miserably between death from diabetes and death from starvation. One 12-year-old boy, already blind from diabetes, was reduced to eating a mixture of toothpaste and birdseed stolen from his pet canary. ‘These facts were obtained by confession after long and plausible denials’ remarked the pitiless Frederick Allen. The unfortunate child died of starvation. A few physicians hailed the treatment as a means of prolonging life, but the Austrian physician Carl von Noorden shuddered and turned away when Joslin showed him one of his cases. The controversy concerning the value of extra months or years purchased by so much misery was very bitter, and Frederick Allen was banned from the diabetic clinic at the Rockefeller Institute in New York in 1919 [14]. Diet is a remarkably emotive form of treatment, and war is waged to this day between those who maintain that children with diabetes can within reason eat what they like and those who agonise over every stick of celery. The pre-insulin diets worked well in type 2 diabetes and prolonged life in children. Their greatest value was seen in the period following the discovery of insulin, for the diet regimen kept many people alive until this became available. ‘The unfortunate diabetic’, as Sir Derrick Dunlop recalled, ‘had to consume great quantities of green vegetables drenched in margarine. The palms of his hands were usually yellow because he could not convert into vitamin A all the carotene he took. He then had to balance large portions of butter on small squares of oatcake or buns made of soya-bean meal ... but there is no doubt that many patients were well controlled on such diets and their insulin requirements

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were small’ [15]. We can hope that our successors will speak in such forgiving terms of the days when patients needed injections of insulin. Poor Fred Allen. His fate was to be criticized at the peak of his fame for the perceived cruelty of his treatment, to see it rendered obsolete at a stroke, and to outlive his glory by 40 years. His shark- bite model of pancreatic loss was long forgotten, only to be vindicated later by people who had never heard of him. The investigators who reported in 1988 that glucose infusion precipitates pancreatic islet failure in dogs with subtotal pancreatectomy were totally unaware that they had almost reproduced a classic experiment in diabetes 75 years later [16].

References 1. Starling EH. The wisdom of the body. Lancet. 1923;865–871. 2. Biedl A.  The internal secretory organs: their physiology and pathology (trans: Forster L). London: John Bale Sons & Danielsson; 1913. 3. Kevles D. In the name of Eugenics: Genetics and the uses of human heredity. Cambridge, MA: Harvard University Press; 1985. 4. Osler W. Principles and practice of medicine. Designed for the use of practitioners and students of medicine. New York: Appleton; 1892. 5. Fitz RH, Joslin EP. Diabetes mellitus at the Massachusetts General Hospital from 1824 to 1898. A study of the medical records. JAMA. 1898;3:165–71. 6. Pavy FW. Introductory address to the discussion on the clinical aspect of glycosuria. Lancet. 1885;5:1033–5. 7. Morse JL. Diabetes in infancy and childhood. Boston Med Surg J. 1913;168:530–5. 8. Feudtner C.  Bittersweet. Diabetes, insulin and the transformation of illness. Chapel Hill, NC: University of North Carolina Press; 2003. 9. Joslin EP. The treatment of diabetes mellitus. With observations upon the disease based upon thirteen hundred cases. 2nd ed. Philadelphia: Lea and Febiger; 1917. 10. Gale EAM. The rise of childhood type 1 diabetes in the 20th century. Diabetes. 2002;51:3353–61. 11. Barnett DM.  Elliott P Joslin MD: a centennial portrait. Boston, MA: Joslin Diabetes Center; 1998. 12. Krogh A, Krogh M. A study of the diet and metabolism of Eskimos undertaken in 1908 on an Expedition to Greenland. Reprinted Fb&c; 1913, 2017. 13. Allen FM.  Studies concerning glycosuria and diabetes. Boston: WM Leonard; 1913. 14. Bliss M. The discovery of insulin. Chicago: University of Chicago Press; 1982.

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15. Dunlop D.  Opening address. In: Duncan LJP, editor. Diabetes mellitus. Edinburgh: University Press; 1966. 16. Imamura T, et al. Severe diabetes induced in subtotally depancreatized dogs by sustained hyperglycemia. Diabetes. 1988;37(5):600–9.

3 Firing Blanks in the Dark

History provides no answers. We may speculate as to what might have happened if Franz Ferdinand’s driver had not taken a wrong turning in Sarajevo in June 1914, but we will never know if World War 1 would have happened anyway. In contrast, we can be absolutely certain that insulin would have been discovered if Frederick Banting had not encountered John Macleod on November eighth 1920. Minkowski’s discovery had triggered enormous interest, and it is hard to sample the vast literature that accumulated between 1890 and 1920 without the sense of witnessing an agonising game of blind man’s buff. Gifted as we are with retrospect, we must nonetheless wonder why, in the presence of so many clues, it took 31 years for insulin to be discovered. Furthermore, we need to ask why the impasse should have been ended by someone almost totally unfamiliar with the vast literature that had accumulated on the subject. The elegant eighteenth century façade of the original Bristol Royal Infirmary, now rising forlornly above the traffic fumes, admitted a 15-year-old boy on July 31st 1893. Three weeks previously he had been fit and well; now he was now thirsty, tired, and wasting rapidly. He weighed 36 kg. His physician, Patrick Watson-Williams, put him on a restricted diet with gluten bread, to which he added minced and liquid extracts of pancreas. Codeine proved ineffective, and he was tried on injections of pancreatic extract prepared in Paris by Brown-Séquard himself. His doctor then obtained a fresh preparation of fluid obtained from a bull’s testicles by a colleague in Bath. By October 26th no progress had been made, and the patient was started on morphine, the usual stand-by in such cases. By December 17th it was obvious he was doomed. © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 E. Gale, Life in the Age of Insulin, Copernicus Books, https://doi.org/10.1007/978-3-031-47190-2_3

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Watson-Williams did not give up without a fight. He visited the local slaughterhouse and found that sheep pancreas could be obtained by the simple expedient of hanging the animal by its hind legs and slashing open the abdomen. The entrails spilled out, leaving the pancreas exposed at the back of the abdominal cavity. On December 20th a surgical friend administered chloroform while Watson-Williams implanted three Brazil-nut sized lumps of sheep pancreas under the skin. The boy went into coma and died 3 days later [1]. This was Watson-Williams’ first and last experiment with diabetes, but he went on to achieve fame as an ear nose and throat specialist who, in the words of his 1938 obituary, ‘fully enjoyed his position as host at the scrumptious banquets which he gave on various public occasions’. He twinkles back at us from his photograph, looking well content. He got nowhere, but at least he tried.

3.1 Why Did It Take So Long? Minkowski had shown that a fragment of pancreas grafted under the skin could prevent diabetes after the removal of the organ itself; a clear demonstration that the antidiabetic factor was unrelated to the anatomical position of the gland and was not under nervous control. Cross-circulation experiments which linked dogs in tandem showed that the pancreas of the intact animal could prevent diabetes in an animal without a pancreas. Laguesse surmised in 1893 that the islets, with their distinctive appearance and rich blood supply, were the likely source of the internal secretion. Textbooks written in the pre-­ war period often concluded that an antidiabetic hormone must exist, and many attempts were made to isolate it. Why then did they fail? Macleod estimated that 400 attempts were made to treat diabetes with pancreas extracts or transplants before commercial insulin became available. Some people undoubtedly had their hands on insulin, others came agonisingly close. Close, but not close enough. Attempts to assign priority are pointless, but we will spend a few moments with the ghosts in this particular attic, each one so close to immortal fame, because their failure tells us how and why the challenge was finally overcome. When the Toronto group applied for the US patent for insulin in 1922–3, it was startled to learn that a similar patent had been filed by Georg Zülzer on May 28th 1912. 1 Georg Zülzer (1870–1949) was  Note: The US patents can be accessed on the internet. Zuelzer’s was #1,027,790; Banting, Best and Collip’s patent, #1,469,994, was granted on January 23rd 1923. 1

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German, and his dogged quest for the antidiabetic principle deserved a better outcome. He threw all his energies into the effort from 1907 onwards, and made many attempts to improve his method of extraction. In retrospect, his use of alcohol pointed to the future. His major handicap was that he had no blood test for glucose and had to rely on urine measurements. Joseph Forschbach, chief assistant to Minkowski in Breslau, tried the extract on 6 patients in 1909, and two of the recipients recovered from diabetic coma—hence the proposed commercial name of Acomatrol. Urine glucose responded in the others but fever and vomiting (probably allergic reactions to animal proteins) prohibited further use. Undeterred, Zülzer went on to partner with Camille Reuter (1886–1974), a senior chemist from the Swiss company Hoffmann la Roche whose production facility was just over the border in Germany. The collaboration looked promising, and 114 kg of horse pancreas was prepared in copper vessels. The extract produced convulsions in dogs. Hypoglycaemia was unknown before the discovery of insulin, and they had no blood test capable of detecting it at the time. The adverse reactions were attributed to a contaminant in the copper containers. By 1913, they finally had a test for blood glucose. A post-war report by Camille Reuter documented the effect of pancreatic extracts in seven non-­ diabetic dogs. Blood glucose fell in six. Four were given glucose and suffered no ill-effects, but two had convulsions and died. Blood glucose was measured at 17 mg/dL in one and 37 mg/dL in the other, suggesting they had died of hypoglycaemia [2]. Zülzer and Reuter seem to have mistaken these episodes for fatal toxic reactions. Their other misfortune was to use non-diabetic dogs, for the gap between a normal and subnormal blood glucose is so narrow in health that symptoms appear within minutes of injecting insulin. The prolonged effect of their extract would have been obvious if they had used dogs with diabetes. Not knowing this, Hoffman la Roche concluded that it was too short-acting to be of clinical value, and advised them to concentrate on producing an oral version. This objection might well have been overcome, but the date was now August 1914 and Zϋlzer was called up for military service. Baptized at birth, he only learned of his Jewish origins at the age of 14, and these may have contributed to his failure to prosper in academic life after the war. In all events, he protested the Nobel award to Banting and Macleod, emigrated to the USA in 1934 and left no personal record when he died in 1949. His son became a well-known paediatrician. Reuter, meanwhile, was drafted into research on chemical warfare. When the Nobel prize was awarded to the Canadians he remarked

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that insulin ‘was a beautiful dazzling bird, we had it in our hands and it got away from us’. 2 Ernest Lyman Scott (1877–1966) was working on the same problem in Chicago. He was a farmer’s boy from Pennsylvania and—like Fred Banting— had acquired his education the hard way. Scott reasoned, just as Banting did 10  years later, that he could destroy the digestive juices of the pancreas by ligating the duct, thus leaving the internal secretion intact. He struggled to obtain adequate degeneration of the secretory part of the pancreas, just as Banting would do, and he too resorted to fresh pancreas. His extraction method, like that of Zülzer, was based upon extraction of the active principle with alcohol, and Banting adopted the revised method—with acknowledgement—in the later stages of his work. Scott had indeed produced insulin, but an inability to test blood glucose made it impossible for him to clinch his results. All this, rather astonishingly, was accomplished singlehandedly in the course of a largely unsupervised Master’s thesis. He left the University of Chicago before the paper reporting his findings could be submitted, and the published report was overwritten by a supervisor who failed to grasp its significance [3]. Scott’s claims were largely endorsed when his original thesis was published in 1966 [4]. His wife published a book at her own expense after his death which poignantly justified his priority [5]. Another ghost in this particular attic was Israel Kleiner (1885–1966), who worked at the Rockefeller Institute from 1910 to 1919. His studies led to the conclusion that that the pancreas must release its internal secretion ‘continually in small amounts’. He therefore attempted to treat his dogs by continuous infusion rather than by single injections of pancreatic extract. Diabetic dogs were given an extract of their own pancreas, prepared simply by mincing, adding water, and storing in a refrigerator. This produced an unequivocal fall in blood glucose in 10 of 16 experiments, and there were no toxic effects, presumably because the dogs received their own tissue. Kleiner modestly concluded that his work ‘indicates a possible therapeutic application to human beings’. He was well on course for a Nobel-winning discovery, but fate decided otherwise; Kleiner’s boss Samuel Meltzer was incapacitated by (of all things) diabetes and had decided to retire. Meltzer wrote resignedly to the head of the Institute that, ‘there is not much difference in the fate of an old-fashioned and modern diabetic. Confusion and humbug reigned then and reigned still’ [6]. With this sad irony, his team was disbanded, and Kleiner took up a teaching post at the New York Homeopathic Hospital [7].  Quoted in the Roche Magazine 1978 (2).

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The Romanian Nicolae Paulescu (1869–1931) joined the procession. This abundantly gifted young man was considered a prodigy when he went to study medicine in Paris in 1888. He completed a heavyweight textbook of medicine on the death of his Parisian mentor, and another three-decker followed his return to Romania as Professor of Physiology in 1900. He pioneered a technique for removing the pituitary which won the praise of the great neurosurgeon Harvey Cushing, and he went on to produce extracts of dog pancreas in chilled water by a technique similar to that of Israel Kleiner. The extract was reinjected into the same dog, just as Kleiner had done, and with equally promising results. Romania entered World War 1 on the side of the Entente in that year, however, and the Central Powers occupied Bucharest on sixth December 1916. Paulescu resumed his work in 1920 and published his results in a leading French journal in August 1921, the month of Banting and Best’s first uncontestably successful experiment. His glucose measurements required 25 ml of blood, but glucose fell in seven of eight experiments in dogs, with a peak effect at 2 hours and a detectable effect that lasted for 12 [8]. He does not appear to have tested it in humans. Robert Tattersall believed that his animal experiments were more convincing than those of Banting. The patent for his extract was approved under the name of Pancrèine in April 1922, but the lack of commercial support proved insuperable [9, pp. 90–100]. Paulescu may have been a great scientist, but his political opinions were vile. This did not come to light until 2003, when the International Diabetes Federation planned to name an award in his honour to coincide with unveiling of a plaque at Hotel-Dieu, the hospital he worked at in Paris. The ceremony was hastily cancelled when the Simon Wiesenthal Institute alerted le Monde to the fact that Paulescu was a racist bigot. His non-medical writings disgorged rabid fantasies of Judaeo-Masonic conspiracies and included the allegation that Jews had smaller brains [10]. Einstein was his chosen example. He supported the movement that went on to become the fascist Iron Guard and loudly proclaimed his belief that the Canadians had plagiarised his discovery of insulin. Discussions about scientific priority always remind me of the African boy at my school who was puzzled to learn that Lake Victoria had been ‘discovered’ in 1858. He was under the impression that his own people had been fishing there. There were however important lessons to be learned from the insulin pioneers. Why did Banting, Best, Collip and Macleod succeed where others had failed? Access to blood glucose measurement was essential, and this was Best’s

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major contribution. Isolated individuals are unlikely to succeed without teamwork and institutional backing, and Macleod provided this. An impure extract made allergic reactions inevitable, which is where Collip came in. Industrial expertise would then be needed for large-scale production and was on hand in Toronto, although Eli Lilly improved on their method. The key ingredient was, however, Banting’s energy and persistence. The team never really existed as such—there is no group photograph—but the group achieved far more than the individuals could have done. A leading textbook of physiology summed up the situation in 1920 by saying that: ‘it is generally assumed that [the pancreas] secretes into the blood stream a hormone … but we have been unable to imitate the action of the pancreas … by injection or administration of extracts of this organ’ [11]. Ironically, the textbook was written by JJR Macleod, who shared a Nobel Prize for precisely this 3 years later. Macleod later said that ‘the real obstacle [was lack of ] convincing evidence that an antidiabetic hormone does actually exist in the pancreas’. This was the background to the scene in Toronto in 1921 when, as Collip phrased it, ‘the old problem of diabetes was again taken up for re-investigation’.

References 1. Watson-Williams P. Notes on diabetes mellitus treated with extract and by grafts of sheep’s pancreas. Lancet. 1894;1303–4. 2. Reuter C.  Le sécrétion interne du pancrėas et le traitement du diabėte sucré. Section des Sciences naturelles physiques et mathématiques. Archives (n série). 1924;8:84–100. 3. Scott EL. On the influence of intravenous injections of an extract of pancreas on experimental diabetes. Am J Physiol. 1912;29:306–10. 4. Magner LN.  Lyman Scott’s work with insulin: a reappraisal. Pharm Hist. 1977;19(3):103–8. 5. Scott AH. Great Scott. Ernest Lyman Scott’s work with insulin in 1911. Bogota, NJ: Privately published by the Scott Publishing Company; 1972. 6. Friedman JM. A tale of two hormones. Nat Med. 2010;16(10):1016–100. 7. Kleiner I. The action of intravenous injections of pancreas emulsions in experimental diabetes. J Biol Chem. 1919;40:153–70. 8. Paulescu NC. Recherche sur le rôle di pancrèas dans l’assimilation nutritive. Arch Int Physiol. 1921;17:85–109. 9. Tattersall R. The pissing evil. A comprehensive history of diabetes mellitus. Fife, Scotland: Swan & Horn; 2017.

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10. Laron Z. Nicolae C Paulescu—Scientist and politician. IMAJ. 2008;10:491–3. 11. Macleod JJR.  Physiology and biochemistry in modern medicine. 3rd ed. St Louis: CV Mosby; 1920.

Part II From Discovery to the Doldrums

4 The Coming of Insulin

The tygers of wrath are wiser than the horses of instruction —William Blake

What followed would pass into medical legend, as summed up by a plaque on a laboratory wall in Toronto: On the 30th of October, 1920, Frederick Grant Banting originated the hypothesis that the failure theretofore to isolate the internal secretion of the pancreas had been due to the destruction by the ferments liberated during the process of extraction. He devised an experimental method by which this destruction could be avoided and the internal secretion (now known as insulin) obtained. In May 1921 Banting and Charles Herbert Best, both graduates of the University of Toronto, conducted in this room the experiments which culminated in the isolation of insulin [1].

It does not detract from the magnitude of the achievement to say that only the last sentence of this clumsily-worded statement was true. Banting’s ‘Great Idea’ was based on ignorance of basic physiology, his insulin was too impure for human use, and the duo could not have succeeded if a visiting biochemist called James ‘Bert’ Collip had not purified it for human use. Professor JJR Macleod made it all possible. Collip left Toronto in 1922, and Macleod in 1928. Both maintained a lifelong silence on their role in the discovery, and Banting and Best were left in undisputed possession of the narrative.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 E. Gale, Life in the Age of Insulin, Copernicus Books, https://doi.org/10.1007/978-3-031-47190-2_4

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In the 1960s a Canadian physiologist alerted his brother to the existence of explosive documents relating to the discovery of insulin, but historian Michael Bliss felt unable to proceed while Charles Best was still alive. He has left a riveting account of his subsequent quest through the archives and of far-flung visits to aged survivors from the period. Some were sitting on treasures they were unwilling to share—Best’s former secretary was the sister of his wife, for example, and four filing cases of documents were reluctantly disclosed in the cellar of the last secretary of the Insulin Committee. A trip to Banting’s secretary in a nursing home revealed that Banting once told her that ‘if he had known there were so many Jews with diabetes, he wouldn’t have gone into it’. Bit by bit, the amazing history of insulin—much of which would otherwise have been lost—came to light. In 1982 he published a masterpiece of the historian’s art which concluded that Banting and Best got no further than the other pioneers, and could not have succeeded by their own unaided efforts [2]. Does any of this really matter? Many ground-breaking scientific discoveries have originated in a false assumption, and squabbles over academic priority are said to be so ferocious because the prizes are so small. This particular prize was not a small one, however, for it led to two of the most rapid Nobel Awards in medical history, and the associated clash of personalities left an abiding stain on the ill-assorted quartet that stumbled into the pantheon of fame. It would take the skills of a novelist to weave four such ill-matched personalities and agendas into a single narrative, but the story is compelling. Fred Banting (1891–1941) was the sixth child of hard-working, God-­ fearing parents who farmed a 100-acre spread about 40 miles from Toronto. Tall, physical, down-to-earth, he worked on the farm and went barefoot in summer. He was a dogged but uninspired student whose spelling was atrocious—he would be said to have dyslexia today—and his education was rudimentary by modern standards. His father offered each of his four sons $1500 on their 21st birthday. Three opted for a farm of their own, but Fred enrolled for a degree in the humanities at the University of Toronto. The date was 1910. He flunked his first set of exams and was obliged to retake the year. Around this time the wooden scaffolding around a building under construction collapsed as he was walking by, taking two workmen with it. He would always remember the quiet competence of the doctor who took charge of the situation while he stood helplessly by. This prompted a change to medicine, a profession then seen as suited to worthy plodders. He attempted to enlist when Britain engaged in World War 1 but was persuaded to complete the medical course, now slimmed down to a mere 4 years. His manual dexterity caught the eye of Clarence Starr, an orthopaedic professor who volunteered for war duty. Banting joined him in Britain when he qualified in 1917 and

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went to France in June 1918. He worked in dressing stations under shell-fire during the final allied offensive, amputating, stitching and triaging even as mangled bodies piled up outside. On September 27th, only 2 weeks before the end of the war, a jagged piece of shrapnel lodged between the bones of his right forearm as he made his way to the dressing station. He insisted on working until he was ordered—protesting—to the rear: his courage and competence earned him a Military Cross [3]. It has been suggested that some of the dysfunctional personality traits he exhibited in the aftermath of his great discovery were due to war trauma, but we know too little of his pre-war personality to judge whether these traits were innate or acquired (Fig. 4.1). The return to civilian life was a sad anti-climax. Too many men were looking for work in a country headed into recession, and Captain Banting was unable to secure a staff position in Toronto. The alternative was private practice, and he set up his shingle in London, Ontario, on July first 1920. He lacked the contacts and networking skills needed to attract referrals from other doctors, and ate his heart out in a deserted consulting room, day after day, week after week. Banting the surgeon has often been depicted as a failure, a satisfying literary counterpoint to his subsequent glory. This is not altogether true, for business began to pick up by the end of that year, although not nearly fast enough for Banting’s restless impatience. He had however managed to obtain a small income ($2 per hour) by lecturing, keeping a jump ahead of the medical students in time-honoured fashion as he did so. This prompted him to read a clinical report describing the autopsy of a man whose pancreatic duct had been blocked by a stone. The exocrine pancreas had withered, but the islets appeared unaffected.

Fig. 4.1  Banting and dog. (Wellcome Collection. Public Domain)

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His topic for Monday November first 1920 was the pancreas, and an idea came to him at 10 p.m. on the preceding Saturday: an effective islet extract might be obtained by tying off the pancreatic duct and allowing the rest of the pancreas to degenerate; such an extract might be a cure for diabetes (spelled ‘diabetus’ in his note). All agog with his habitual impatience, he took the idea to a local advisor and was referred on to Professor JJR Macleod in Toronto (Fig.  4.2). He encountered a small, shy, immaculately tailored man with a natty moustache in Macleod’s office on Monday 8th. Banting tended to become inarticulate in moments of excitement, and we can picture him pacing the floor and waving his big farmer’s hands as Macleod patiently tried to understand what he was trying to say. Suppose, as Banting stammered out, you tied off the pancreatic duct, waited for the gland to atrophy, and took out what remained? The antidiabetic principle should still be intact. Despite an abundance of first names, John James Rickard Macleod (1886–1935) was generally referred to by his initials. This seems to have typified a man who was small, painfully shy, reticent, impeccably turned out, and (above all) very British. The first of seven children born to a clergyman in the north of Scotland, he gained academic distinction in Aberdeen, won a

Fig. 4.2  Macleod in 1928 (public domain)

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medical research fellowship to Leipzig, and went on to become a Lecturer at the London Hospital. Although medically qualified, his natural milieu was the laboratory and the lecture theatre. In those far-off days the primary function of academic departments was to teach, lecturers lectured, and research was undertaken in the vacations. Team research with a focus upon a single problem was relatively uncommon, and juniors either adopted the interests of their professors or ploughed their own furrow. Macleod moved in this world like a fish in water. His lectures and textbooks were noted for their clarity, his students respected him, and his interests were broad. He published many research papers and reviews, for the most part solo efforts or undertaken with one or two close colleagues. His reputation grew so rapidly that he was invited to cross the Atlantic and take up a chair at Western Reserve University at the age of 27. He did so well that Robert Falconer, Toronto University’s President, offered him their Chair of Physiology in 1916, an offer that was renewed in 1917 and taken up in 1918. He published a lengthy and authoritative textbook of physiology in 1918 and steered it through seven editions over the next 17 years. He had written a book on diabetes from the perspective of an experimental physiologist in 1913, in which he anticipated Banting’s hypothesis by noting that ‘in a pancreatic extract, besides any substance which may have an action on metabolism, are also several very powerful ferments which may quickly destroy that substance’. The title of his last book, The Fuel of Life (1928) reflects his lifelong interest in energy exchanges within the body. Although medically qualified, Macleod was predisposed to see diabetes as problem of physiology rather than as a disease in urgent need of treatment. I have argued elsewhere that his main interest was in nervous control of metabolism, and that he probably thought Banting’s proposal had little prospect of success [4]. In 1920, for example, he wrote that ‘the most recent work has shown that injection of pancreatic extracts into a depancreatized animal produces no change in the respiratory quotient although extracts of the pancreas and duodenum may cause a temporary fall in the excretion of glucose in the urine on account of the alkalinity of the extract…’. 1 An outline of research undertaken in his department listed nine projects in 1920–21, with his own name on four. Two related to respiration and acid-­ base balance, which is why Collip opted to join him for a sabbatical in 1921. Another project concerned blood glucose measurement in the turtle, probably undertaken because he was working on an improved assay, and involved two students, Charles Best and Clark Noble.  Best (1952) in Best selected papers. p. 340–341.

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Thus it was that Banting was confronted in November 1920 by a 42-year-­ old professor at the height of his career, soon to be President of the American Physiological Society. Banting’s hypothesis was that previous attempts to isolate the antidiabetic principle from whole pancreas had failed because the antidiabetic principle from the islets had already been destroyed by digestive juices produced elsewhere in the gland. His ‘eureka’ moment came when he read that blockage to the pancreatic duct caused the exocrine (outward-­ secreting) portion of the gland to shrivel up but leaving the islets relatively unscathed. His proposal was to harvest the active principle once the rest of the gland had atrophied. Macleod, whose knowledge of the literature was encyclopaedic must have been aware that Banting’s suggestion was not original; Scott had contacted him after testing the same hypothesis 10 years earlier. Furthermore, Starling’s student textbook explained in 1905 that juice collected from the pancreatic duct is harmless because the protein-digesting enzyme trypsin is not activated until trypsinogen, its inert precursor, reaches the gut [5]. His own textbook repeated that pancreatic juice is inactive until it reaches the intestine in 1920, and an early critic of Banting’s work described this as ‘one of the best established facts in physiology’ [6]. Trypsinogen (the inactive precursor of the protein-­digesting hormone trypsin) will indeed be activated if a pancreas is left on a slab after removal, but this can be avoided by using fresh (or freshly chilled) pancreas. A paper from Macleod’s group—Banting was the first author—later showed that pancreatic extract is inactivated by 2 h of incubation with fresh pancreatic juice at room temperature. This appeared to confirm his original hypothesis, although the paper then went on to describe successful treatment of seven people with fresh beef pancreas. The apparent incongruity was explained by the claim that the team had ‘finally evolved’ an (unspecified) method of extraction [7]. Macleod appears not to have told Banting that fresh pancreatic juice is inactive, and he did not respond to subsequent criticism. The 1922 edition of his textbook states that Banting’s work was based on the hypothesis that previous failures had been due to ‘destruction of the hormone by the trypsin present in such [pancreatic] extracts’, but he goes on to repeat the conventional wisdom elsewhere [8, pp. 461 and 713]. The howler was almost immediately pointed out in the correspondence columns of the British Medical Journal and Henry Dale (of whom, more later) is said to have quipped that insulin could only have been discovered in a lab whose director ‘was slightly stupid’ [9, p. 278]. Macleod was certainly not stupid, so why did he keep silent for 6  months while Banting attempted to circumvent a non-existent problem? And what explains his lasting silence?

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The interview lasted an hour, and we will never know what went through Macleod’s head as he sat there and listened. My own guess is that he did not imagine that the proposal had much chance of success, and he infuriated Banting by pointing out the value of negative findings. Perhaps he reflected that the ignoramus he was talking to had well-honed surgical skills and boundless enthusiasm. Sentiment may have come into it, for Banting was a war hero. Macleod’s younger brother, Clement Rickard Macleod, had been a front-line doctor, and was awarded the Military Cross for courage under fire in 1917. He developed tuberculosis after the war, and was in a terminal state when Macleod visited him in Scotland earlier that year. Macleod met Banting on November eighth 1920, and his brother died on November 16th [10]. Clarence Starr, a fellow-Professor and Banting’s war-time mentor, had invited him to the wedding of one of his daughters in Toronto on the weekend prior to his meeting with Macleod, and might well have put in a kind word on his behalf. Suitably guided, as Macleod may have mused, Banting’s idea might be made into a useful project. Those who have tried to run a research department will spot another consideration, for experimental physiologists were in short supply after the war, and he had an unused room for animal experimentation that was thick with the filth of years. Why not make use of it? In all events, he offered it to Banting for 3 months in next summer’s vacation, but without a salary. Macleod was known for his cheerfulness, kindliness, and patience, at least according to his obituary, and was always willing to ‘discuss the problems of his juniors sympathetically and without a trace of condescension’. Banting’s account implies that he went out of his way to explain the practical difficulties involved in his proposal, and to suggest ways in which these might be overcome. He added (apparently on three occasions) that even negative results could be valuable. This well-meaning academic caution was experienced as a bucket of cold water, and Banting was far from satisfied when he left the Physiology Department. It was an early hint of the troubles that were to follow. Banting’s mind turned to other matters, and he applied unsuccessfully for a medical post on an oil exploration project before he finally decided to accept Macleod’s offer in March of the following year. He proposed to start on May 15th 1922, in the expectation that the project would be completed by the end of August. Macleod pointed out that he would need someone to measure blood glucose, and offered two of his more able students. Clark Noble and Charles Best were fresh from their project on the blood glucose of the turtle, and had graduated as joint silver medallists in physiology and biochemistry in June 1921. They planned to take 1-year MA degrees under Macleod’s supervision in the following year. Since participation meant loss of a vacation, the

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friends tossed a coin to decide who would take the first 4 weeks. At a later date, when things were not going well, Banting asked Best if he regretted winning the toss. ‘Who said I won?’ was the reply (Fig. 4.3). Charles Best was 22 years old. A seventh-generation Canadian, he was the son of a successful country physician who practised south of the border in Maine. As chance would have it, his aunt Anna had trained as a nurse on the wards of the Massachusetts General with Elliott Joslin, and became Case no. 875 when she developed diabetes in 1913. She died in coma in 1917. He was well on track for a conventionally successful career when the opportunity to work with Banting came along. Macleod offered ten dogs, an inadequate number for such a technically challenging experiment. The donor dog would have its pancreatic duct tied off, and the atrophied pancreas would be removed 6 weeks later, ground up with a pestle and mortar and injected into a dog whose pancreas had been removed. Since the diabetes that followed one-step removal of a pancreas frequently ended in fatal infection, Macleod suggested Hédon’s two-step procedure, and showed Banting how to perform it. The dog should heal well, and diabetes could be induced at any time by removing the graft. It was now the end of term. Exams had been marked, Macleod was just about to head off for vacation in Scotland, and the Physiology Department would soon be empty apart from Banting and Best and their dogs. Not quite, however, for additional space had been given to another project which seemed to have equally little prospect of success. Dr. E Fidlar was using the main laboratory of an otherwise empty department to conduct experiments on the

Fig. 4.3  Best and Noble in 1920 (public domain)

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respiration of a single frog. Fidlar’s frog was released unharmed into the pond it came from when Macleod returned, and has otherwise vanished from history. Banting had never been inside a dog, and soon discovered the frustrations of pancreatic surgery for himself. Tying off the pancreatic duct is not as straightforward as it might seem in theory, for extra pancreatic ducts are easily missed. Claude Bernard had reported in his Memoir on the Pancreas that an accessory duct connected to the main pancreatic duct is frequently present in the dog, and empties into the duodenum below the point of exit of the major pancreatic duct. When this common variant is present, pancreatic juice will simply exit through it, and no atrophy will occur. In the event, the pancreases of five of his first seven dogs failed to degenerate. Scott had encountered the same problem 10  years earlier, and a leading European textbook noted in 1913 that the procedure was frequently unsuccessful [11, p. 436]. Banting’s operating space was under the roof, the summer of 1921 was blisteringly hot, sweat from his forehead dripped into the operating field, and dog after dog got infected. He was reduced to buying additional dogs on the streets of Toronto, taking one victim back to the laboratory with his tie attached to its collar. Anti-vivisectionists later accused him of stealing stray dogs. By the first week of July the pair had operated on 19 dogs. Fourteen had died, and only two operations had worked properly. Even so, the impatient Banting now had two duct-ligated dogs and needed a dog with diabetes to test his extract. The first recipient had borderline diabetes, indicating incomplete atrophy of the pancreas. Nonetheless, they sacrificed a duct-ligated dog, ground up the chilled pancreas, filtered the residue, and injected it. It produced a 40% fall in blood glucose, but further injections were ineffective and the dog died. The next dog was already moribund when it received two injections of extract. It staggered briefly to its feet before it too collapsed and died. The two young men slaved on through the summer heat, juggling the experimental conditions according to whim, omitting key observations, jumping to unwarranted conclusions and generally breaking all the rules of research. The pair bonded well after some initial altercation and would look back on this as a golden period of meals cooked over a Bunsen burner and all-night work in the laboratory. Banting’s impetuosity served them well. Finding himself with some extract but no dog with diabetes to give it to, he abandoned the tedious two-step Hédon procedure and took the pancreas out in one go—just as Ernest Lyman Scott had done 10  years previously (Fig. 4.4).

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Fig. 4.4  The first unequivocal evidence that insulin works

Their great day came on August 7th. The dog in question was ready for testing at 5 p.m. on the 6th. The pancreatic extract (they called it isletin) was not ready until midnight, by which time the recipient’s blood glucose was in excess of 400 mg/dL. Five successive injections of extract were given into a vein during the night, and its blood glucose was back in the normal range by 8 in the morning. This was their epiphany, and the duo never doubted the epoch-making nature of their discovery thereafter. Other people must be persuaded, however, and their own preconceptions still had to be overcome—not least that duct ligation was essential in the donor. Ironically enough, they tested a fresh extract of intact pancreas on August 16–17th and concluded that it was less effective. Their own records suggest that the two extracts were in fact equally potent, but preconception outweighed observation and they concluded that the normal pancreas was ‘much weaker’. Four months would be wasted in the attempt to circumvent a non-existent problem. Dog after

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dog had its pancreatic ducts ligated, but they saw only what they expected to see. Their first publication claimed that pancreatic extracts had been administered on 75 occasions, and invariably lowered blood glucose; Best frequently repeated this claim in later life, but Michael Bliss reviewed their notebooks and found that the extract was effective on 42 occasions and ineffective or of doubtful value in the rest. Macleod returned from vacation on September 21st, and was undoubtedly impressed (and possibly surprised) that this forlorn hope should have yielded such promising results. Even so, it was obvious that Banting was fatally prone to over-interpret his findings, and he suggested some rather pedestrian controlled experiments. Banting, whose tunnel vision saw nothing but success, was outraged. September gave way to October, and the vacation was a distant memory. The pair now had evidence of an internal secretion, but their insistence on duct-ligated pancreas meant that they were years away from an effective treatment, although they had dreams of extracting insulin from herds of duct-­ ligated cattle. 2 Meanwhile, what should be done about their ad hoc partnership now that the vacation was over? A formal meeting took place in Macleod’s office towards the end of the month, and Banting went on the offensive, demanding salaries, better operating facilities, and an assistant to look after the dogs. These were reasonable requests, but they come across as belligerent demands in Banting’s retelling of the incident. He even threatened to take his research elsewhere. Best was horrified and told Banting that ‘I have never heard anyone talk to Macleod as you have’, but Macleod later agreed to everything while pointing out that, as head of department, he represented the University of Toronto. This merely added to Banting’s mounting sense of grievance about the man he now referred to as ‘that little son of a bitch’ [9, p. 83]. Macleod scheduled their research for presentation to the department on November 15th. There was little further progress to report, but rumours of a breakthrough were leaking out, and Joslin wrote to Macleod on November tenth to enquire about them. Banting presented his findings, no doubt somewhat ineptly, and his seething sense of injustice was amplified when Macleod summarised them succinctly in his introduction. It was clear that they were nowhere near an effective treatment, but one useful suggestion emerged from the discussion; why not show how long a dog could be kept alive by their treatment?  Best, selected papers, p. 317.

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Stung by this muted reception, Banting reconsidered the problem. He speculated (on November 16th, at 2 a.m.) that foetuses do not need a digestive system until they are born, and that foetal pancreas should therefore contain an internal secretion without digestive enzymes. Laguesse had reported that foetal islets are plentiful in sheep in 1893, and Banting’s idea was a good one. As a farmer’s son, he knew that cows were often pregnant when sold for slaughter, since this increased their weight. His preference for cattle served him well, for the islets of foetal ruminants contain far more insulin than those of other species [12]. He paid a visit to the abattoir, located some foetal pancreas, and found that it worked well. This transformed the situation, for they now had enough extract to use in humans; the over-riding requirement was to improve its purity. The standard procedure was to drop fresh pancreas into Ringer’s solution (water plus electrolytes) in a mortar packed in ice, and to grind it with sand until it became an unpleasant brown sludge. Since attempts to concentrate this by evaporation destroyed its potency, it was dissolved in alcohol, which evaporates at a lower temperature than water. Scott had reached the same conclusion 10 years earlier, and his method was used in the experiments that followed. Their extract became more potent, but they lacked the bench skills to purify it further. Banting’s hit or miss approach paid another dividend when he dropped a healthy pancreas from one of his dogs into the alcohol bath instead of the rubbish bin. The resulting extract worked perfectly. There was no need for duct ligation or foetal pancreas—and there could scarcely be a better demonstration of the tyranny of a false assumption. Amazingly enough, Banting never quite seemed to appreciate that his great idea of duct ligation was a complete red herring [13]. They taught me the same error in medical school 50 years later.

4.1 The Bicycle Rider If the fool would persist in his folly he would become wise—William Blake

The comic writer Jerome K Jerome claimed that the bicycle divided mankind in two: those who ride bicycles and those who repair them. In research, the ideal pairing is between a bicycle rider, focused on the outcome, and a bicycle repairer, focused on the means of getting there. Banting, the first phase man, bicycle rider par excellence, had largely outlived his usefulness

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by December 1921: he lacked the skill, experience or patience to turn his crude pancreatic extract into a safe and effective treatment for diabetes. At Banting’s request, Collip, a visiting Professor from the University of Alberta, was co-opted to help. The first human recipient was a 13-year-old boy who had been carried into the office of a Toronto physician by his father at the start of December. The feat was not difficult, for Leonard Thompson had survived 2 years of diabetes and weighed 30 kg. Banting insisted that an extract prepared by Best should be tried first, and the resulting ‘thick brown muck’, was injected on January 11th. Thompson’s urine glucose fell slightly, but with no discernible clinical benefit. Worse still, a sterile abscess developed at one injection site. It was a humiliating set-back. December 22nd 1921 was one of many lonely evenings for Collip in the old Pathology building in Toronto. Banting and Best had gone off to celebrate Christmas, but he stayed on to sacrifice an Airedale kept alive with pancreatic extract. His task was to check the liver for glycogen. A healthy liver contains 10% by weight of glycogen and the liver of a dog with diabetes contains hardly any, but this liver contained 25% by weight. It was the first major clue as to the action of insulin. He now had the task of keeping Leonard Thompson alive. Alcohol was used in the extraction process, and increasing its concentration caused contaminants to fall out of solution. Finally, and possibly on the night of January 16th 1922 (recent research suggests the 19th) he increased the concentration of alcohol to around 90% and the active principle precipitated. Collip, in the words of Michael Bliss, was the first person to see insulin. Looking back on that moment in 1949, he wrote that ‘I experienced then and there all alone in the top story of the old Pathology Building perhaps the greatest thrill which has ever been given me to realise’. The isolate was still impure—very much so—but it worked well in rabbits. This having been demonstrated, it was finally given to Leonard Thompson on the morning of Monday 23rd January 1922. And it worked (Fig. 4.5). The physical transformation was amazing, especially in children who hovered between death from diabetes and death from starvation. So too was the effect on their morale. As one doctor said, ‘the mental state of hopeless, irritable depression, almost melancholia, characteristic of the advanced emaciated diabetic gives way to a spirit of cheerfulness and optimism … With increasing strength the patient not only loses the sense of weakness and continuous state of fatigue but muscle activity becomes a joy’ [14, pp. 71 and 154].

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Collip’s Recipe for Insulin, 1922 • Add equal proportions of freshly minced pancreas and 95% ethyl alcohol. • Allow to stand for a few hours, shake occasionally. • Strain through a cheese-cloth, and add two portions by volume of 95% ethyl alcohol to the filtrate. • Wait some hours for the protein to precipitate. Then filter and distil in a vacuum at 30 °C. • Remove the lipoid substances by extraction with sulfuric ether in a separating funnel. Repeat once. • Add the watery solution that remains to the vacuum still and allow it to concentrate further until it reaches a pasty consistency. • Now add 80% ethyl alcohol and spin in the centrifuge. • You will see four distinct layers in the tube; the uppermost is clear and contains the active principle. Pipette this into 95% or 100% alcohol. The active principle will precipitate along with adherent substances. • Catch on a Buchner funnel, dissolve in distilled water and distil further until the desired concentration has been reached. • Pass through a Berkfeld filter, check for sterility and deliver to the clinic.

Fig. 4.5  Famous photographs of patient JL (otherwise lost to history) who received insulin in December 1922. We can only regret that there is no follow-up of his mother’s face. (Eli Lilly and Company Archives)

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For interest, we can compare Collip’s recipe with the system used to extract highly purified insulin from beef or pig pancreas in 1987. This went as follows [15]:

• Deep-freeze pancreases in slaughterhouse, transport to factory in cold storage. • Chop up the frozen glands and add acid ethanol/water. • Extract at pH 1–3 and a final ethanol concentration of approx. 60%. • Neutralise and remove the precipitate. • Add acid to pH 3–4, evaporate ethanol in vacuum, and remove fatty material. • Salt-out, isolate the salt-cake, and dissolve in water. • Adjust pH to 5–5.5, isolate the precipitate, and dissolve in acid. • Crystallise, isolate the crystals, wash, and dissolve in acid. • Recrystallise, isolate crystals, wash, and dry in vacuum. • Purify further by chromatography.

Collip’s original method is still recognisable, although much improved by refinements including careful control of pH and temperature, repeated crystallisation and further steps in purification. Meanwhile, things could scarcely be worse from Banting’s point of view. His own role in the discovery of insulin had ended in failure on January 11th, and his frustration reached breaking point when Collip disclosed, no doubt rather smugly, that he now had the magic recipe. Banting asked for it, and Collip is said to have replied that ‘I have decided not to tell you’. Banting gave a vivid account of what followed: ‘his face was white as a sheet. He made as if to go. I grabbed him with one hand by the overcoat where it met in front and almost lifting him I sat him down hard on the chair. I do not remember all that was said but I remember telling him it was a good job he was so much smaller…’ [9, p. 118] Collip left no record of the encounter, but no doubt steered well clear of Banting. The group now showed every sign of falling out over the spoils of the greatest medical breakthrough of the twentieth century prior to penicillin. Macleod seemed oblivious to the storm that was about to break, and proved unable to cope when it arrived. Banting and Best were painfully aware that they had no formal status in the Department of Physiology, and feared that they would be robbed of their glory. In truth, their fears were groundless. Then, as now, the head of a department assumes overall responsibility for the work that is done within it, and is expected (within loosely defined limits) to direct its course. Some heads expect their name to be added to every publication, but Macleod declined to be named on the first report, and would later add the pair to papers in which they played no part. His forbearance was not appreciated, and Best spoke many years later of ‘senior and more experienced investigators,

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who had not invested an hour’s work before the discovery but who were now more than anxious to appropriate a share of it’. At some risk of contradicting himself, he added that ‘we were not happy, I think understandably, after 6 months of productive independent work, to become members of a large team’. Macleod had indeed thrown the resources of his whole department into insulin [16]. With this in mind, six projects were listed. Improving the extract came first and the other five related to basic physiology. It was agreed that authorship of all six would be in alphabetical order, thus ensuring that Banting and Best came first regardless of their contribution. Collip’s insulin was keeping seven people alive by March 1922, and he raced to scale up the process. He was not in the habit of keeping careful records and found himself at sea when the recipe suddenly stopped working. A 4-year-old girl, summoned back from death’s door by injections, relapsed and died in coma. Picture the situation. Material obtained from the abattoir contains a potent but elusive trace of a wonder-working substance. No-one knows what it is, what it does (apart from lowering blood glucose) or what harm it might cause. News of the miracle cure is spreading and frantic parents are turning up in Toronto. Worse still, the four discoverers are at loggerheads, each pulling in a different direction. Collip is desperately tweaking the recipe in the hope of a better outcome. Connaught Laboratories, a not-for profit institute which produced antisera to diphtheria, is doing its best to help, but has never attempted anything like this before. Macleod wonders—with good reason—if fish might not be a better source of insulin. Banting, with nothing further to offer, is skulking in his room and hitting the bottle. By his own account he rarely went to bed sober in March and was reduced to drinking lab alcohol on two occasions. His relations with Macleod are toxic, and he has physically assaulted Collip on at least one occasion. Further anecdotal details concerning this phase of Banting’s life emerged 90  years later from the papers of William ‘Billy’ Ross, a Toronto physician who planned to write Banting’s biography. He wrote that Banting was in a state of ‘almost complete nervous exhaustion’ in February and March 1922 and was ‘ ..nearly mad … he wandered about by day like a lost soul, and by night stark staring insomnia gripped him. Soon he dropped into a state of grave melancholia. He was a failure with no future. He was so certain of this for a time that upon several occasions he found himself on his way “to the Bay”, meaning, in Toronto, on the way to self-destruction by drowning’ [17]. Best, meanwhile, is struggling with a task beyond his capacity. Seething with frustration, he confronted a tipsy and self-pitying Banting at the end of March, and threatened to quit the project. It did the trick. Still bursting with resentment about the credit for his great discovery, Banting emerged from

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seclusion to find that the public was looking for a hero. The home-grown farmer’s boy with a war medal would prove a perfect fit. Best was now working closely with Connaught, and did Banting a big favour by dividing Toronto’s meagre supply of insulin between him and the Children’s Hospital. Banting—quite literally—had to decide who lived and who died, but the awesome responsibility rescued him from redundancy. Meanwhile, progress was made. Their weak and impure extracts of insulin became more effective, despite considerable batch-to-batch variation, and Connaught’s makeshift production line used so much acetone as to pose an imminent threat of explosion. Toronto had done what it could, but it was not enough. There are curious parallels between the discovery of insulin and the discovery of penicillin. Penicillin was discovered when Alexander Fleming spotted the effect of mould upon the growth of bacteria on an agar plate he had— characteristically—omitted to tidy away. It did not occur to him that it might be used as an antibiotic, and nearly 20 years would pass before Florey and Chain developed his chance observation into a life-saving therapy. Fleming got the Nobel Prize and undying fame, whereas few have heard of Chain or Florey [18]. Even so, they lacked the expertise to scale penicillin up for industrial production, and the task fell to people in the USA whose names are largely forgotten. No coincidence that George Clowes (pronounced ‘clews’) was among them. Clowes, born in England, had already studied under some of the great names of European science when he took ship for America in 1900 at the age of 23. His interest was in the immunology of cancer, and he had been recruited to a newly-founded institute in Buffalo, NY.  Once there, he transplanted tumours and became an accomplished clinical chemist. The relevance of mice to human cancer became increasingly doubtful, however, and his research salary proved inadequate when he fell in love with his future wife in 1909. By pure chance, he was given the opportunity to act as a part-time scientific consultant for a Jamaican manufacturer of sugar and rum, and discovered an aptitude for applying science to production. His work in Buffalo took on new directions, and he obtained a patent for a powdered extract of serum that accelerated blood clotting. In 1920, he raised scientific eyebrows by accepting the newly-created post of Director of Scientific Research at Eli Lilly and Co. (Fig. 4.6). Colonel Eli Lilly, a Civil War veteran, founded a pharmaceutical business in Indianapolis in 1876 and passed it to his son JK Lilly in 1890. Few medical remedies were effective at the time, and little attempt was made to regulate what a company produced or how it was marketed. ‘Snake oil’ proliferated. In 1906 the muckraking novelist Upton Sinclair provided a graphic description

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Fig. 4.6  George Clowes (public domain)

of the Chicago cattle yards in a novel called The Jungle. He wanted to draw attention to the appalling working conditions of immigrants employed there, but his readers were more concerned by his description of the way in which their meat was handled. The outcry moved Congress to establish the Food and Drug Administration (FDA). The organisation struggled to stem a flood of patent medicines, but Lilly stood out as a manufacturer of ethical products. The term has fallen into disuse (the conjunction of ‘ethical’ and ‘pharmaceutical’ might seem a twenty-first century oxymoron), but it was based on the novel idea that potentially dangerous medications should be regulated, quality controlled, and available only on medical prescription. The company’s most successful product was calomel, a chloride of mercury used as a laxative. JK Lilly saw that he needed input from academic science, and Clowes was an inspired choice. Given a relatively free hand, he took the opportunity to

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conduct research at Woods Hole, a marine research station that became the Mecca of biological research. Scientists from all backgrounds mingled freely, and he met people who were using a new technique called isoelectric focusing to precipitate proteins. Clowes took a train to the American Physiological Society meeting in New Haven in late December 1921, and was in the audience when Banting presented his preliminary results. Banting not only fluffed his presentation, but was obliged to stand by speechless while Macleod, who chaired the session, fielded questions from authorities such as Allen and Kleiner with practised ease and spoke of ‘we’ when describing the work. Thus upstaged, Banting became more convinced than ever that Macleod was conspiring to rob him of his glory. Ernest Lyman Scott reintroduced himself to Macleod after the presentation and they walked back to Macleod’s hotel together. Clowes rang Macleod in his room to offer collaboration, only to be told that it was too early to think of commercial development. He tried again in March, pointing out that others would soon file a patent on insulin if Toronto failed to do so. Banting and Macleod believed that the Hippocratic Oath forbids a physician from seeking commercial profit, a notion that would horrify many doctors today. The Oath actually makes no mention of financial gain, although it does oblige a physician to share his goods with his teacher and instruct his teacher’s children free of charge. A defensive patent was clearly needed, however, and a hastily convened Insulin Committee in Toronto agreed in April that one should be taken out. Banting and Macleod were not named, on the grounds that they were medically qualified, and Best and Collip transferred the Canadian patent to the University of Toronto for the princely sum of one dollar each. Banting’s name was added to the US patent application in January 1923 to avoid possible legal challenge; this was also transferred to the University for a dollar apiece. Toronto would benefit from the patent until it expired in 1940, but its Insulin Committee set out to avoid commercial exploitation and to ensure that ‘the best insulin is supplied at the cheapest cost’ to countries around the world. Clowes was there when Macleod presented the updated results to the American Association of Physicians in May 1922, and received an unprecedented standing ovation for doing so. This was the first formal occasion on which the name ‘insulin’ was used. Neither Banting nor Best attended, ostensibly on the grounds of cost. Clowes went straight on to Toronto, a formal agreement was signed on 30th May, and Collip and Best went to Indianapolis on June second to show the company how insulin was made. Collip’s role had now ended and he returned to his former position in Alberta. Once there, he thought for one glorious moment that he had discovered a vegetable form of

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insulin, but this was not to be [19]. His subsequent career was distinguished, but he maintained a lifelong silence about the discovery of insulin. Lilly too experienced baffling setbacks before getting the process to work and the yield remained poor. Banting ‘almost fell on’ Clowes’ neck when presented with 150 ‘units’ of insulin (roughly equivalent to 450 units today) on 23rd July. The yield from beef pancreas was still insufficient to meet the clinical demand for insulin, and Macleod turned to fish as a possible alternative.

4.1.1 Ugly Fish Historians have tended to see Macleod’s interest in fish insulin as a form of academic displacement activity, but it was in fact perfectly rational. The yield from beef pancreas by the Toronto method was inadequate to meet the anticipated demand, and there was an urgent need to explore possible alternatives [20]. Pancreatic islets are scattered throughout the pancreas in mammals, but bony fish house them in a separate organ known as a Brockmann body. A Scottish physiologist called John Rennie gave monkfish islets by mouth to five people with diabetes and by injection to one in 1907, thus joining other ghosts in the insulin attic. Unfortunately, he boiled them first. Macleod found that a single Brockmann body from monkfish could send 3–4 rabbits into convulsions. The tiny organs could be harvested by unskilled workers, and fish might therefore be a viable source of commercial insulin. Macleod joined the marine research facility at St Andrews, New Brunswick over the summer of 1922 and 1923, and looked into the possibility of harvesting monkfish on a larger scale (Fig. 4.7). Clark Noble was one of two students assigned to the project [21]. They soon realised that there would never be sufficient monkfish to meet demand, and decided to try cod instead. A stormy trip on a sea-going trawler allowed them to harvest 2400 units of cod insulin at a cost of $0.0037 per unit. This was secretly substituted for beef insulin in six patients on the wards in Toronto, and judged equally effective. And all for nothing. Lilly’s first shipment to Toronto in June 1922 was 50  mL of a solution that contained 1 unit per mL.  By August, a total of 5390 units had been supplied to 12 clinicians. In September, the Lilly preparation began to show a 50% loss of potency. George Walden realised that most of the insulin was being discarded in the precipitate and introduced isoelectric focusing into the production line [22]. The isoelectric point is the pH at which the negative and positive charges within a protein molecule

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Fig. 4.7  Monkfish were generally disregarded by fishermen as not worth eating, in addition to which they have enormous heads and are extremely ugly, prompting a sensational article in a Halifax newspaper on August fifth 1923. Ugly Fish. (From The Lancet, DEPARTMENT OF MEDICAL HISTORY| VOLUME 359, ISSUE 9313, P1238–1242, APRIL 06, 2002, From ugly fish to conquer death: J J R Macleod’s fish insulin research, 1922–24, Dr. James R Wright Jr., MD – with permission) Isoelectric Focusing At ~pH 5.6 the positive and the negative ions in insulin cancel one another out ... and it falls out of solution

Fig. 4.8  Isoelectric focusing

balance out, causing it to fall out of solution. Beef insulin precipitates at a pH around 5.7, and isoelectric focusing caused an increase in the yield of insulin from a kilogram of pancreas to >900  units, as against 15–40  units by the method used in Toronto [23, p. 31] (Fig. 4.8). Their insulin, as Walden expressed it, now had ‘a stability many times as great and a purity ranging from ten to one hundred times as great as the best product hitherto available’. Clowes went so far as to say that ‘we can produce in Indianapolis a sufficient amount of Iletin to supply the entire needs of the civilised world’ [9]. Higher strengths of insulin (5 and 10  units/mL) were available by the end of the year, and Macleod noted reluctantly in May 1923 that ‘the method of the preparation of insulin is now so very greatly improved that it looks as if it might be unnecessary to seek for other sources’. Their

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effort was not entirely wasted however, for Japan made insulin from fish and whales in World War 2, and harvested it in commercial quantities from bonito and tuna until 1956.

4.1.2 Afterlives There are only two tragedies in life. One is not getting what you want, and the other is getting it.—Oscar Wilde

Insulin brought little happiness to those who discovered it. Banting could not possibly live up to his reputation, however hard he tried, and Best faced the long anti-climax of a conventionally successful academic career. Collip and Macleod were effectively written out of the official version of events [24]. History is constantly updated to meet the requirements of the present, and this is reflected in the story of insulin. Canada was very much in the shadow of the USA, but the University of Toronto was moving up the academic pecking order: it had generous bequests, had extended its facilities, and had a creative President in Robert Falconer. Macleod’s appointment was a prime example of his quest for academic talent. Even so, Toronto seemed hopelessly provincial to many outsiders. No wonder that Canadians grasped at the homespun narrative of a man who abandoned the plough, became a war hero and won a Nobel Prize by his own unaided efforts. Macleod, later described by a British author as ‘immodestly modest, unassuming, social, sensitive, a born researcher and teacher’ [25, p. 269] and by Michael Bliss as a ‘dapper member of the professariat’ was everything Banting wasn’t: successful, established, highly informed, cautious, and—above all— very British. His was a world that Banting could never enter, and there was no meeting of minds. Macleod knew that Banting’s great idea was not original, and had done his best to help a man with absolutely no research or laboratory experience. It seems likely that he had little faith in Banting’s vacation project [4]. I n private, Macleod commented wryly on Banting’s ‘peculiar character’, and he clearly did not consider him a gentleman. The rift was beyond repair, but we owe Macleod’s own account of the discovery to the university’s attempt to reconcile this clash of personalities. This account, written in September 1922 and not intended for publication, came to light when a copy was discovered among the papers left by his widow. Lloyd G Stevenson, the person who found it, encountered obstruction from the University of Toronto 50 years later, and was even threatened with legal action—an indication of how sensitive the issue had become. Macleod’s note was finally published after Best had

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died [16]. His correspondence at the time testifies to an almost abject attempt to placate Banting. In that same month of September 1922, for example, he refused an offer to publish his fish research in a top-rated British journal, and wrote that ‘Banting has also criticised my placement of papers for publication, stating that his work should appear in an English journal … I believe that it would only serve to fan the flames still more—and they are almost unbearably hot at present—if I were to publish my work in the Transactions of the Royal Society, dearly though I should love to do so … If I were to send to the Royal Society he would immediately say—‘I told you so, Macleod all along was trying to minimise the importance of my work’ …’. Macleod’s major achievement in the aftermath of the discovery took place behind the scenes in the Insulin Committee, of which he was the Secretary, and has gone largely unnoticed. The Committee was formally established in May 1922, and initially consisted of three members of the Board of Governors and the four discoverers—although we may doubt if Banting, Best and Collip played much part in its deliberations. The Committee arranged for insulin patents to be transferred to the University, but the phrasing caused much anxiety. Could you patent an unknown chemical entity? Alternatively, could you patent a method of extraction? If so, could your patent be superseded by a better method? This nearly happened. Failing this, could you patent insulin for use in the treatment of diabetes? The Insulin Committee had entered uncharted waters populated by sharks, for enormous profits would accrue to any commercial entity that could secure a monopoly on the use of insulin. Lilly saw this from the outset, but refrained from taking advantage. The agreement thrashed out in Toronto in May 1922 licensed the company to develop insulin for 1 year only, and was conditional upon an agreement to distribute it free or at cost. They began selling it in May of the following year. This was a remarkable concession for a commercial organisation that was about to invest a quarter of a million dollars, but JK Lilly himself wrote to Clowes in August 1922 that ‘I am almost overwhelmed with this tremendous situation, and experience some difficulty keeping my feet on the ground and my brain in normal operation’. The stipulations of the Insulin Committee might seem naïve today, but commercial deals between academic institutions and industry were almost unknown at the time. The prime objective of the insulin patent was to prevent others from taking commercial advantage, and there was a precedent in thyroid hormone. Edward Kendall, a biochemist at the Mayo Clinic, fell asleep in the laboratory one evening in 1914 while evaporating a thyroid extract in alcohol, and woke to find that a white crust had formed. He called it thyroxine, and shared his patent with the Mayo brothers, who passed on to the

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University of Minnesota on condition that it supervised commercial exploitation of the discovery. This was the model for the Insulin Committee. Since the chemical nature of insulin was unknown, it could only be defined in terms of its physiological properties, and Kendall advised Macleod to patent both the method and the substance isolated. There was a clear risk in doing so, for both might be superseded by subsequent patents. The gentleman’s agreement between Toronto and Lilly did wobble. The US patent for insulin (with Banting’s name) was submitted on January 12th 1923, and granted on October 9th. Curiously enough, the word insulin is not mentioned, and the application was for the method of extraction rather than for the elusive substance itself. As noted, a methodological patent is vulnerable to a better method, and a letter to Macleod from the patent office of Charles H Riches in Toronto dated April third 1923 outlined the chasm that had opened beneath his feet. George Walden was about to submit a patent for isoelectric focusing and the Canadian patent attorney was of the opinion that ‘these product claims have been drawn for the deliberate purpose of securing to the Eli Lilly Company a monopoly in the USA of the production and sale of Insulin by any method whatsoever, and conflicts (sic) with the policy of the University in doing the greatest good for the greatest number’. The application could have trumped the original patent, but Lilly were persuaded to abandon exclusivity by submitting it to a ‘patent pool’ held by Toronto [26]. Walden’s patent for ‘purified antidiabetic product and process of making it’ was not submitted until June 11th 1924, by which time the method was in widespread use. 3 The Committee was insistent that no-one should be allowed to monopolise the production of insulin, and manufacturers around the world were licensed to make it by the end of 1923. Participants were obliged to pool information and to participate in quality control and standardisation. It was a magnificent achievement, and we may suspect that it owed much to the unobtrusive presence of JJR Macleod. Despite his work to ensure that insulin would be a gift to the world, Macleod found himself isolated and exposed to the virulent hatred of the hero of the hour. He lacked the stamina and the temperament to continue, and returned thankfully to Scotland in 1928. Banting refused to attend his farewell dinner, insisted that his place should be set in order to remain conspicuously vacant. Macleod shuffled his feet on boarding the train home. Asked why, he replied ‘I’m wiping away the dirt of this city’ [9, p. 234]. He died in 1935 after patiently enduring the ravages of rheumatoid arthritis. Toronto belatedly acknowledged his role by naming a lecture theatre for him  The patent applications (US patents 1,469,994 and 1,520,673) can be accessed online.

3

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in 1990. Ted Ryder, who received his first dose of insulin on tenth July 1922, was there to celebrate the occasion. Collip quit Toronto on March 31st 1922. His achievement was not fully recognised in his lifetime, but he was least scarred by success. His next venture was based on the ill-starred speculation that insulin must be present in all forms of life that contain glycogen. He published claims in 1923 that substances extracted from clams, plants, and even yeast would lower the blood glucose of rabbits, albeit more slowly and over a longer period than insulin itself. Green onions appeared a promising source for the new hormone, which he believed ‘would be available the world over’ [19]. The dream soon faded. He went on to do pioneering work on parathyroid and steroid hormones, forever seeking the next big discovery. Banting and Best remained in possession of the battlefield, and the official story was based on their accounts. Macleod’s account was not published until Best died in 1978, and Collip maintained a stolid silence until his death in 1965. The Nobel Prize for 1923 was awarded jointly to Banting and Macleod, although Banting refused to appear on the same platform. The speeches were finally delivered (on separate occasions) in Stockholm in 1925, and are mainly remarkable for what they don’t say. Banting mentions Macleod once, and implied that he did not turn his attention to insulin until February 1922. Macleod’s only reference to Banting is revealingly cryptic: ‘Believing that the want of success to produce extracts of uniform potency was due to the destruction of the antidiabetic hormone by the digestive enzymes also present in the gland, FG Banting suggested that …’ Macleod limited his own role in the discovery for which the Prize had been awarded to the phrase ‘under my direction’. Banting shared the money from his award with Best, and Macleod shared his with Collip. Banting was woefully ill-equipped to live up to the expectations he had fostered. A colleague said in 1924 that ‘so much adulation has had a bad effect on Banting and has made him very unhappy’. Another noted that he ‘is now obsessed with the idea of doing something big by himself so that no honour will go to Macleod’. He worked manfully within the research institute gifted to him by a grateful country, setting his sights on cancer before entering the new field of adrenal steroids. Fifty-six dogs were sacrificed before he acknowledged that the task was beyond his capacity. It seems ironic that Banting, so desperate for recognition, should have hated the adulation and public responsibilities that came with being worshipped as a hero. Bliss mused that ‘Banting might soon have settled into a comfortable life. He would have been a competent small-city surgeon and part-time university lecturer in the tradition of practitioner-teachers. He

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would have been popular with his fellow medical men and probably become a leader in local medical circles. He would have found a wife, settled down, raised a family, and disappeared from history. He might have had a happier life than the one he led after his return to Toronto’. There is something almost heroically improbable about his success. He was, in his own words ‘probably the worst educated man ever to leave the University of Toronto in medicine’ [3]. His absence of any background in research only served to make his achievement more impressive. He found some solace in painting, for which he displayed some talent, and poetry, for which he had less. He married, but a very public and messy divorce followed what Ross referred to as ‘8 years of almost unbroken unhappiness’. No love was lost between Best and Banting in later life, and Banting remarked in 1940 that ‘Best is naïve in his abject selfishness’. Best was invited to fly to the UK to assist with the war effort in 1941, a trip which involved some personal risk. He refused. Banting agreed to go in his place, and commented that ‘if they ever give that chair of mine to that son of a bitch, Best, I’ll roll over in my grave’. Collip, now a good friend, drove him to the airfield and fetched sheepskin gloves for the journey. There was a hint of self-destructive behaviour in Banting’s attempt to fly the North Atlantic in winter, for the journey was known to be extremely hazardous. The official legend states that he was engaged in essential war duties, but his diary suggests that he simply felt an overwhelming need to be at the centre of things where young men were sacrificing their lives. In all events, the Hudson bomber crashed in the snowy wastes of Newfoundland and Banting died 20 h later. Best did get his chair. Collip maintained a dignified silence in public—his view was that history could safely be left to judge the issue—and Best’s frequently quoted reminiscences became the authorised version of what had taken place, despite mutterings of disquiet. Michael Bliss published his definitive version of events in 1982. Bliss never met Charles Best, and neither did I, but two people told me quite unprompted that he was one of the most unpleasant people they had encountered. Bliss shared their dislike, and published an acid postscript 11 years after his book. The last word can be left with him: I have not been able to make up my mind about the rationality of [Best’s] sustained attempts to rewrite the history of the discovery of insulin. At times Best’s distortions of the historic record seem to amount to a deliberate, unethical exercise in falsification which verges on scientific fraud … [in his later years he] appears to have been deeply insecure about and obsessed with his role in history. He appears to have had a profound psychological hunger for recognition, a serious ego-problem, many thought, which overwhelmed his good sense … [his

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fumbling attempts] to manipulate the historical record would have been pathetic and hardly worthy of comment had they not been so grossly unjust … Unlike Collip, Best could not rest content to let history take its course [27].

Charles Best invited comparison with the character from The Great Gatsby for whom fame as a college football star meant that the rest of his life could only be an anti-climax. Thirty years later the medical students in Toronto would line up for his autograph when Best gave them a lecture. Poor man. Bliss concludes his sad story by saying that there was ‘glory enough for all’. There was indeed. Banting’s daemonic energy drove the project forward, but he succeeded thanks to the support and expertise of Macleod, the loyalty of Best and the technical skills of Collip. The tunnel vision that drove him forward was, ironically enough, integral to the personality that allowed him to imagine that Macleod and Collip—two remarkably unassertive people—were trying to steal the credit for his achievement. The group outperformed its members, but no-one owns a scientific discovery.

4.1.3 Minkowski’s Choice Another ghost participated in the aftermath of the great discovery. Minkowski had a frustrating medical career despite important discoveries such as the pancreatic origins of diabetes, and was almost 50 when he got his first permanent appointment. Naunyn, his mentor, mingles high praise with a suggestion of laziness: ‘that spirit which pushes us into research and tortures us, and is only appeased by work done in its service, was not always alive in him and sometimes it was necessary to stimulate it’. Minkowski’s Jewish origins might suggest an alternative explanation. Germany, until then the world leader in science, became isolated in the post-war period. A postage stamp to Canada cost a billion marks, and journal subscriptions were unaffordable. Minkowski asked Banting and Best for some insulin in 1923, and a vial duly arrived in the post. Tall, calm and unfashionably bearded, the 62-year-old Professor stood at the podium and held the tiny vial up for the students to see. ‘It was once my hope that I should be the father of insulin’ he said. ‘That was not to be. But to my delight, the discoverers have called me the grandfather of insulin’. The students stamped their feet in approval. Next he showed them two patients with diabetes, a man with a foot ulcer and a child on the verge of diabetic coma, and asked which should get the insulin. ‘The child’ they responded in chorus, but Minkowski shook his head. Doctors must be realistic. One bottle of insulin would only prolong the

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child’s torment, whereas the man with the leg ulcer would have a chance of survival. The 29-year-old Minkowski who whipped out a dog’s pancreas one afternoon in1889—just to show that it could be done—might not have given up so easily. He soon had more insulin—Hoechst started production in Germany in November 1923—but the world was changing around him. When accused of suppressing credit due to his Aryan partner von Mering, he did not attempt to defend himself openly. Instead, he wrote a letter describing the events surrounding the discovery of pancreatic diabetes and deposited it in the archives in Breslau in 1926 in the hope that ‘at some future time a student of the history of diabetes may be interested in the true facts’. A Jewish professor rescued the letter from the archives when he was dismissed following the Nazi takeover in 1933, and passed it to Minkowski’s widow. Her life would have ended in a concentration camp had not Charles Best (much to his credit—and somewhat illegally) used money from the Insulin Fund to ransom her. She made her way to Buenos Aires, and Bernardo Houssay, a future Nobel laureate, took her under his wing. Fifty years after he made it, Minkowski’s discovery saved his wife [28].

References 1. Feasby WR. The discovery of insulin. J Hist Med. 1958;13(1):68–84. 2. Bliss M.  The discovery of insulin: the inside story. Publ Am Inst Hist Pharm. 1997;16:93–9. 3. Bliss M. Banting: a biography. Toronto, ON: University of Toronto Press; 1984. 4. Gale EAM. Macleod before Banting. Can J Health Hist. 2023;40:370. 5. Starling EH. Elements of human physiology. 7th ed. JA Churchill; 1905. 6. Roberts F. Insulin. BMJ. 1922;2:1193–4. 7. Banting FG, Best CH, Collip JB, Campbell WR, Fletcher AA. Pancreatic extracts in the treatment of diabetes mellitus. CMAJ. 1922;12:141–6. 8. Macleod JJR.  Physiology and biochemistry in modern medicine. 4th ed. St Louis: CV Mosby; 1922. 9. Bliss M. The discovery of insulin. Chicago: University of Chicago Press; 1982. 10. Williams MJ. JJR Macleod: the co-discoverer of insulin. Proc R Coll Physicians Edinb. 1995;23(2, Suppl 1):1–125. 11. Biedl A.  The internal secretory organs: their physiology and pathology (trans: Forster L). London: John Bale Sons & Danielsson; 1913. 12. Wright JR Jr. Frederick Banting’s actual great idea: the role of fetal bovine islets in the discovery of insulin; 2021.

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13. Pratt JH. A reappraisal of researches leading to the discovery of insulin. J Hist Med. 1954;9:281–9. 14. Macleod JJR, Campbell WR. Insulin and its use in diabetes. Baltimore: Williams and Wilkins; 1925. 15. Brange J. The galenics of insulin. Berlin: Springer-Verlag; 1987. 16. Macleod JJR. History of the researches leading to the discovery of insulin: with an introduction by Lloyd G Stevenson. Bull Hist Med. 1978;52(3):295–312. 17. Bliss M. Suicide and sour grapes: new light on the discovery of insulin. University College Alumni Lecture; 2016. 18. Macfarlane G. Alexander Fleming. The man and the myth. Oxford: OUP; 1985. 19. Collip JB.  Glucokinin. A new hormone present in plant tissue. Preliminary paper. J Biol Chem. 1923;56:512–43. 20. Wright JR Jr. From ugly fish to conquer death: JJR Macleod’s fish insulin research, 1922-24. Lancet. 2002a;359:1238–42. 21. Wright JR Jr. Almost famous: E Clark Noble, the common thread in the discovery of insulin and vinblastine. CMAJ. 2002b;167(12):1391–6. 22. Scheller JC, Galloway JA.  The development of the insulin unit. Am J Pharm. 1975;147(1):29–32. 23. Jensen HF.  Insulin. Its chemistry and physiology. New  York: Commonwealth Fund; 1938. 24. Wright JR, Gale EAM. Winner’s curse. Diabet Med. 2021;38(12):e14677. 25. Keith A. An autobiography. London: Watts & Co; 1950. 26. Cassier M, Sinding C. ‘Patenting for the public interest’: administration of insulin patents by the University of Toronto. History and technology. London: Taylor & Francis (Routledge); 2008. 27. Bliss M. Rewriting medical history: Charles Best and the Banting and Best myth. J Hist Med Allied Sci. 1993;48:253–74. 28. Houssay BA. The discovery of pancreatic diabetes. The role of Oskar Minkowski. Diabetes. 1952;1(2):112–6.

5 Explorers of Unknown Seas

The life-giving elixir was expensive and in short supply. Its recipients faced an unknown future. Life on insulin was particularly hard for children, and many dreamed of easing the burden. Hypoglycaemia was an ever-­ present danger, and its threats ranged from social embarrassment to life-­ threatening harm. The social stigma associated with insulin use was so common that many chose to keep their condition a closely guarded secret. Robin Lawrence was 28  years old when he developed diabetes. He was born in Aberdeen in 1892 and cleared the shelf of honours as a medical student. Complications of appendicitis delayed his qualification and possibly saved him from death on the Western Front. He was posted to India in 1916, and served in military hospitals behind the North-West Frontier. My grandfather, a medical orderly, may have encountered him in Peshawar. Surgery was Lawrence’s ambition, and he took up a post at King’s College Hospital in London. Repugnant as it might seem, his custom was to visit the mortuary at night in order to practise surgery upon the dead, and he was working his way through a mastoid procedure in November 1920 when a bony chip flew into his eye. The eye turned septic and the nurses who dressed it found that his urine was loaded with sugar. Lawrence consulted Joslin’s textbook in the library, only to learn that ‘by the Allen treatment of starving on a very low diet you might live 3 years with luck, and in the 1920 edition he said 4 years with luck, I found that was very depressing’ [1]. His symptoms were relatively mild, but he was virtually blind in his left eye and knew that his days were numbered. A career in surgery was out of the question, and he switched to the biochemistry department. The year that followed included a skiing holiday and a rest cure by the Mediterranean, but © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 E. Gale, Life in the Age of Insulin, Copernicus Books, https://doi.org/10.1007/978-3-031-47190-2_5

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enabled him to complete a postgraduate thesis on diabetes. His health went steadily downhill. His mother urged him to return to Aberdeen, but he had no wish to inflict a lingering death upon his family. Armed with the knowledge that the English-speaking community in Florence had no doctor, he set off to Italy with ‘a dictionary, a stethoscope and Gulliver’s Travels in Italian’. He loved Florence but grew progressively weaker despite the strictest of diets. He could no longer climb stairs and once fell asleep while taking a patient’s history. Ketones appeared in his urine, and coma threatened. He experienced pain, numbness, and tingling in his hands and feet—symptoms of diabetic neuritis—and found it hard to light or even to hold a cigarette. It began to seem ‘that the struggle to keep alive—it could not be called living—was no longer tolerable or worthwhile’. At this juncture he received a telegram from his former boss at King’s. ‘I’ve got some insulin’, it said, ‘come back quick it works’. A local garage owner who wanted to visit his son in England drove Lawrence’s car to London. The thousand mile journey took 10  days, and Lawrence was admitted to the Casualty Ward at King’s when they arrived on May 28th 1923. His weight had fallen to 60.5  kg (BMI 20) from its former value of 80.3  kg, he slept much of the day, and death seemed imminent. He celebrated his first injection of insulin in advance by eating a decent breakfast and tasting bread for the first time in months. The injection was administered at 10 a.m. on May 31st, and his urine was free from glucose by 3 p.m. The medical onlookers gave a cheer (‘not a very loud one’) for Banting and Best. By 4 p.m. ‘I had a terrible shaky feeling and a terrible sweat and an awful hunger pain. That was my first experience of hypoglycaemia … so I had some sugar and a biscuit or two, and soon got quite well, thank you’. The starvation regimen for diabetes was no longer necessary, but the experts were slow to abandon it. It proved its value by keeping people alive at a time when insulin was scarce and expensive. Lawrence stuck to his low-­carbohydrate high-fat diet for 6 months, and got by on 15 units of insulin daily. Unable to bear the constant feeling of weakness, he reverted to a normal food intake. His insulin requirement rose to 40 units daily and he felt enormously better. Robin Lawrence would have been dust in a Florentine cemetery had it not been for insulin, and his survival was due to the good fortune of working with a well-known biochemist. Paula Inge, the daughter of a famous theologian, was not so lucky. She was 11 years old when diabetes developed in 1921 and stuck loyally to her starvation diet. He father begged for some insulin in December 1922, but was told it was unavailable. Only 50 people in Britain had received insulin by this time, and it was reckoned that ten more were dying of diabetes each day. The Medical Research Council (MRC)

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had discussed insulin as early as March 24th 1922, and would later be given the patent, but licensing its production involved tedious discussions with potential British manufacturers. Inevitably, the caution it displayed was perceived as dragging its feet, and an aggrieved physician told the Secretary of the MRC that a hundred patients prayed daily for him to develop diabetes. Ironically, it was the Secretary’s son who did so. Charles Fletcher, himself a noted physician, administered the world’s first dose of penicillin in 1941 and diagnosed his own diabetes soon after. Insulin gave him 54 years of life, as against 45 for Lawrence. Paula Inge died of diabetic coma in March 1923. The world was crying out for insulin, but the challenge was formidable. Insulin was known to be a protein, but some suspected that it was the carrier for a non-protein hormone. Large-scale extraction of a protein that was sufficiently pure for injection had never been attempted, and unexplained problems haunted every production line. Banting now had all the recognition he could possibly want and more besides. From this time forth—with Best always half a step behind - he was the undisputed father of insulin. He set himself up in private practice as an expert in diabetes, and Best channelled two-thirds of Toronto’s insulin supply through him; the remainder went to the Children’s Hospital. His position astride the supply of insulin was less of a boon than it might appear, for it forced him into decisions that meant life or death to the supplicants. These were nonetheless good years for Banting. His inner demons were pacified at last, and the kindliness of his disposition shone through when he offered the children he treated a ride in his car. This apart, he could only stand helplessly by while others took over—just as he had done when the scaffolding collapsed in 1910. People looked to him for another miracle, but all in vain. Pitchforked into glory, he plugged doggedly forward into the anti-climax of a great discovery, a decent man doing his best. The first non-Canadian to receive insulin was Jim Havens of Rochester NY. He developed diabetes at the age of 15, and somehow managed to live on the starvation diet for 7 miserable years. By 1922 he weighed 34  kg, consumed 820 calories a day and was ‘barely able to lift his head from his pillow, crying most of the time from pain, hunger and despair’ [2, p. 136]. His physician travelled to Toronto to plead for insulin in May 1922. Pullman car attendants helped smuggle insulin into the USA—bootleggers may have been involved—but the insulin was of poor quality and the injections were almost unbearably painful. Lilly insulin reached him in August of that year, however, and Havens went on to become a noted graphic artist, fathered two children, and died of cancer in 1960 [3, p.  12]. Insulin was produced in Australia, Britain, Denmark, Germany, the Netherlands, Poland, and Switzerland by the end of 1923.

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Joslin’s first sample arrived on August sixth 1922 and he recalled in a talk given at the age of 90 that he was too excited to sleep. His first patient was a 42-year-old nurse called Miss Mudge whose weight had fallen from 71 to 33 kg over 5 years. Joslin said she was ‘just about the weight of her bones and a human soul’. Her weakness was such that she had only been able to leave her house once in 9 months. Six weeks after her first injection—Joslin was too nervous to give it himself—she was able to walk 4 miles daily [4]. By November 1923, 358 of his patients had received insulin. The effects were so dramatic that an uncle is said to have fainted from shock when he walked into the room of a previously moribund nephew 48 h after admission. Joslin found words for this in what he would call the ‘Banting Chapter’ of his Bible. “By Christmas of 1922, he wrote, “I had witnessed so many near resurrections that I realised I was seeing enacted before my very eyes Ezekiel’s vision of the valley of dry bones”. ‘And behold, there were very many in the open valley;

And lo, they were very dry. And he said to me, Son of Man, can these bones live? And lo, the sinews and flesh came upon them. And the skin covered them above: But there was no breath in them. Then said He unto me, prophesy unto the wind, Prophesy, Son of Man, and say to the wind, Thus sayeth the Lord God: “Come from the four winds, O breath, And breathe upon these slain, that they may live”. So I prophesied as he commanded me, And the breath came into them, And they lived, and stood up upon their feet, An exceeding great army’. Ezekiel XXXVII, 2–10.

The 1923 Edition of Joslin’s textbook, rushed out to cover the new treatment, went to press 15  months after his first patient received insulin. Not surprisingly, it is written in a style of breathless enthusiasm laced with caution. ‘Can the reader’, wrote Joslin, ‘imagine the feelings of a doctor with a background of 1000 fatal cases, who has lived to see what the ages have longed for come true…?’ ‘Who wants a vacation when he can watch mere ghosts of children start to grow, play and make a noise and see their mothers smile again …?’ Insulin changed the ground rules of medical management. People gave themselves injections—a novelty in itself—and could now manage their own

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diabetes. This created unexpected problems. It was, for example, illegal for anyone in Massachusetts to own a needle without written permission from their doctor—the main alternative reason for possession being narcotics. Patients soon knew far more about diabetes than their doctors, and Joslin’s clinic trained them as missionaries. This was not easy, for many doctors had a low expectation of their patients. Oliver Leyton, a British physician, advised that ‘those of low intelligence and but little education are made to obey through fear of punishment, a somewhat higher type by promise of reward, while the fully educated by the desire to do what is right’ [5, p. 30]. Insulin was expensive but, as Joslin pointed out, 30 cents a day was cheaper than a day in hospital. Some doctors felt threatened, but Joslin records that an elderly and overworked country physician travelled 200 miles to learn how to look after a 15-year-old girl in his care. People came to Joslin from far and wide, and he overcame the problem of distance by his lifelong habit of exchanging letters with his patients. In return, he expected them to assume full responsibility for their own well-being, and believed that those who paid for their own insulin did better than ‘charity cases’. Lives were transformed; school-teachers, doctors, lawyers and labourers could now resume their jobs. A working widow with four children came in one morning to be started on insulin, went home at 7 p.m. and was back at work next day. Like pain or grief, diabetes must be endured. The first and worst thing that people learn is that it cannot be cured, and that they are wedded to a needle until death. Syringes wielded by a nurse are unwelcome, but the idea of plunging a needle into your own flesh is both alien and repellent. For 50 years, the ritual remained much the same. The patient, still shocked and bewildered, was confined to a hospital bed and instructed in the rituals of hygiene. These included scrupulous cleansing of the skin with surgical spirit, lessons in sharpening your needle on a small whetstone, and injecting an orange with sterile water. Your glass syringe was boiled for sterility (and frequently shattered in the process). Finally, the great day came. With shaky hands, the novice would push a needle through the rubber bung of an insulin vial, invert it, inject air into the vial to avoid a vacuum, pull back on the syringe and flick it to remove air bubbles. The needle would then be poised above a fold of skin and tremulously rammed home. This was particularly hard for the first generation of malnourished insulin users, for their skin overlaid muscle like the skin on a dog. Insulin was very dilute at the time, and several millilitres would have to be injected. The fluid was weakly acidic and stung, and allergic wheals were common. The elixir of life came at a high price. To the initiates, the first injection is the boundary between BC and AD in their existence. It is, in Susan Sonntag’s phrase, the passport to a new country. The ritual still retains its power. Some of the new arrivals at children’s camps

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for 6–8 year olds think that they are the only child in the world to be affected, only to discover that this is a place where diabetes is normal. Most have been subjected to the twice daily horror of an injection by their parents, equally traumatic for both. Now, they could see other children giving their own injections with elaborate unconcern. By the end of the camp, they are all doing so. Something clutches at the heartstrings when you watch a small child give her first injection and see the triumph in her eyes when she smiles up at you afterwards (Fig. 5.1). People were still equipped with glass syringes and reusable steel needles when I started work in the clinic many years later. The syringes were stored in methylated spirit, which prevented destruction by boiling but filled the house with its pervasive smell. The syringe must then be cleaned, dried and fitted to a steel needle that was used until blunt. A fine wire was provided to unblock the needle in case of need. Things improved steadily from the 1970s. Plastic needles, silicone-coated to reduce drag (razor blades are similarly treated) became available. These were theoretically intended for single use, advice that was routinely ignored. Ritual cleansing of the injection site was often

Fig. 5.1  Life on the needle in 1943. Guy Rainsford drew delightful cartoons in his letters to Joslin, and this one shows him amidst the paraphernalia of diabetes. Note the hot water bottle on his leg to warm the injection site and the urine testing kit by his left foot. He is on once-daily insulin, so there is ‘nothing to do till tomorrow’ (Joslin Diabetes Center)

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abandoned, although Robin Lawrence’s habit of injecting the calf of his leg through his trousers was not encouraged. All things being well, children with diabetes could now be started on insulin in the course of a single home visit, and no-­one else would ever need to give them an injection. Another part of the ritual was the urine test. As performed in the 1920s, 1 inch of Benedict’s solution was poured into a small test tube, five drops of urine were added, and the tube was plunged into boiling water. The solution remained blue if the test was negative. Things were simpler by the 1970s: five drops of urine were placed in a test tube, ten drops of water were added, and a tablet was dropped into it. The mixture would froth and fizz, and the bottom of the tube became too hot to hold. You waited 15 s for the reaction to settle, and a flick of the wrist would then bring out the colour of the solution: blue for negative, orange-red for strongly positive, and shades of yellow or green for anything in between. Millions of people began each day with this ritual. These were the rites of initiation into the land of diabetes. Henceforth you were marked out, forever different. Some people get so accustomed to it that they cannot remember if they gave that morning injection or not. Others dread each jab, for injections hurt, and there are no holidays. Years back, a man in his 30s came to see me. ‘I’ve given myself seventeen thousand injections’, he said, ‘and I’ve had enough’. To this there was no answer, for the obvious response—‘how do you fancy the alternative?’—needed no spelling out. From the medical perspective, life on insulin seems like a gift, and those affected should give thanks for the opportunity to be alive. Those who find themselves singled out for a lifetime of denial are less appreciative of the privilege.

5.1 Diabetic Utopia A mother once took her small son to see Mahatma Gandhi. The boy had diabetes, and the mother wanted Gandhi to tell him not to eat sugar. Gandhi asked her to come back in a week’s time. When she returned, he told the boy not to eat sugar. The puzzled mother wanted to know why she had to wait. ‘Last week’ said Gandhi, ‘I too was eating sugar.’

Elliott Joslin was a lean man whose BMI never exceeded 21. His personal habits were abstemious to a degree, possibly because he was haunted by his own family history of diabetes, and he expected the same of his patients. His philosophy of life was set out in his revealingly entitled ‘Diabetic Creed’. This,

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the secular equivalent of his personal religion, made it clear that life with diabetes is not for the faint-hearted. The steep and rugged pathway leads to life, whereas those who were ‘careless’ (his code for lack of moral fibre) and chose the easier path would pay a high price. Self-discipline was the key [6, 7]. Joslin was the leading authority on diabetes in his generation, and did more than anyone else to establish the leadership of the USA in the clinical speciality. An old-school physician, his religious faith was Congregationalist, and his philosophy of life was Spartan. People with diabetes could win a near-normal lifespan by self-denial. His commitment was total; he worked all hours of the day and was the sort of person who could never retire. With this, loved and respected though he was, went a somewhat austere exterior. He was invariably known as ‘EPJ’, a handy device that allowed colleagues to avoid use of his name. He regarded the concept of a vacation with prim distaste, and insisted that the offending word was replaced by the euphemism ‘Arbeit’ (work) on the duty roster. Later in his career he was taken to task for under-rating impotence as a complication of diabetes. His alleged response—‘my patients never complain to me of impotence’—gives some measure of the man. Even so, passion and inner warmth kept breaking through. For example, he wrote in 1928 that: Diabetics and especially diabetic children are here to stay. Years ago I longed to buy them an island where they could grow up without realizing what they missed, but they would resent such a habitat today, because modern medicine has made them superior to their disease. Furthermore, we should miss them dreadfully … Diabetic Utopia, therefore, we want in our midst.

His interest in childhood diabetes was longstanding, and cases were readily passed on by other physicians who shared the ‘general feeling of the hopelessness of the disease in children’. By 1922 he could report that 366 (14%) of patients in his personal series had been diagnosed in the first two decades of life, with 149 presenting in the first decade. In that year he first noticed an early-rising young medical student, who had completed 2 h of laboratory work by 7 a.m., emerging ‘with enough energy and curiosity to take time to entertain and observe (and eventually, it has proved, capture) my diabetische Würmchen [‘little worms’] before she started for her classes at the Tufts College Medical School’. In 1927 she joined the almost legendary team that Joslin was to build around himself, and he sent her to Vienna at his own expense in 1928 to see how they managed childhood diabetes. She wrote the first textbook on the subject in English in 1932. Her name was Priscilla White.

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Like all who witnessed the great transformation, early physicians felt lasting awe for the power of a therapy that called children back from the dead and launched them into an unknown future. As Joslin said in 1922 ‘a new race of diabetics has come upon the scene’. The 53-year-old Joslin and the 22-year-­ old White were there to see this new beginning, and they shared the resolve to document and guide it. Childhood diabetes, as they noted, commonly presented around the age of 12 (47% developed diabetes around puberty), with both sexes equally affected. The children were said to ‘represent an average racial mixture’, although the sequel makes it clear that only those of white European ‘race’ were included. A family history of diabetes (any relative) was reported by at least 25% of families, and was assumed to represent some genetic weakness of the pancreas that became manifest with increasing age. Elliott Joslin and Priscilla White were fiercely proud and protective of the children who came their way. The girls on a starvation diet were too thin to menstruate, and women with diabetes were considered almost incapable of bearing live children until Priscilla White and others proved them wrong. Each child was special, each presented a different challenge, each was a warrior to be trained and equipped for the long war with diabetes—one of Joslin’s favoured analogies. Each, like John Bunyan’s pilgrim, would have to choose between the path through life that was steep and rugged, and the path that was broad and easy. A harsh, unforgiving creed, but for those who could acquire the necessary discipline and fortitude the prize was life itself, life fulfilled and abundant. Such was the gospel according to Joslin. Joslin’s clinic minted a medal which commemorates this transformation and reflects his uncertainty as to the future of children thus treated. It is entitled ‘explorers of uncharted seas’, and it depicts the 8-year-old George B and his dog in an open boat with the sun rising behind them (Fig. 5.2). Diabetes, as Joslin noted in 1917, should be thought of it as a weak pancreas that could be supported on the crutch of diet. Not a disease, therefore, but a disability—and disabilities can be handled [8, p. 82]. Joslin was a compassionate man, and only a strong religious faith coupled with a profound belief in the value of life—life at whatever price—could have enabled him to subject children to the starvation regimen. No wonder that the coming of insulin was an epiphany. Now, and for decades to come, he could watch the progress of children who would be dead if he had treated them less harshly. He never forgot those who died along the way. Picture the situation in 1922. From a medical point of view, the active principle of insulin is still unknown, and injecting material from dead animals carried an implication of the charnel house. No-one knew if the effects of insulin would last, and the victim would face an even more awful death should

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Fig. 5.2  Joslin Clinic Medal. This portrays the 8-year-old George B and his dog in 1931. They are adrift in a boat silhouetted against a rising sun, and are literally ‘explorers of unknown seas’. The obverse reads ‘prolonging life span after the onset of diabetes—a scientific and moral victory’

they wear off. Alternatively, as Joslin hoped, a period on insulin might allow the islets to regenerate, thus curing diabetes. Behind this lurked further unknowns. Diabetes was seen as a genetic disease affecting the islets of Langerhans, but it affected many other parts of the body. Could insulin prevent these effects, or would they progress independently? This debate would run for another 60 years. He was certainly not disposed to loosen the reins when insulin arrived. Joslin always spoke of life with diabetes in quasi-religious terms, and his patients were singled out as missionaries. Other physicians might be tempted to go easy on their patients, but Joslin insisted upon the need for unbending discipline. His was a harsh creed, but—like Gandhi—he practised what he preached.

5.2 Charybdis We saw earlier that Reuter and Zülzer were perplexed when their pancreatic extract sent dogs into convulsions, for hypoglycaemia was unknown before insulin. Collip and co-workers used rabbits to test the strength of their extract, and were equally at a loss when this s resulted in convulsions or coma. The mystery was resolved when someone suggested reinjecting glucose—with dramatic results. Insulin challenged both legal and medical precepts. From a medical point of view it meant placing a potentially lethal weapon in the hands of

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patients, and there have indeed been famous attempts to use it as a murder weapon [9]. More prosaically, careless or misinformed use could result in an interruption of the energy supply to the brain, with unpredictable consequences. The warning symptoms of hypoglycaemia are easy to recognise in the comfort and security of a research department. The bite of a cannula is followed by a shot of insulin into a vein after a period of rest. Almost exactly 16 min later, you feel the adrenaline rush, your heart begins to thump and your skin prickles with the onset of sweating. The light-headed sensation that follows is not unpleasant if you are relaxed and comfortable. Your body tells you to lie back and rest, and your temperature falls. You no longer shiver in the cold [10]. A sip of glucose soon reverses the situation, and you feel ravenously hungry. The insulin has worn off, and your body now conspires to push your blood glucose back where it belongs. The situation is quite different when blood glucose drops expectedly in the course of normal activities. An early clinical account reported that ‘the earliest symptom which most patients describe is a vague indefinite feeling of uneasiness, an uncomfortable feeling of impending danger. A peculiar mask-like immobility of the face with dilated pupils is often seen’ [11, p.  100]. The symptoms progressed to a feeling of tremulousness associated with sweating and a bounding pulse; untreated, they might progress to confusion, convulsions or loss of consciousness [12]. Glucose deprivation resembles oxygen deficiency in its effect upon brain cells. Nerves need energy to maintain an electrical charge across their outer membrane. The demand is so high that the brain—around 2% of our weight—consumes 25% of all the glucose produced at rest, together with 20% of the oxygen. The glucose pipeline feeding the brain is finely balanced, for we consume around 120–150 g of glucose per day, but never have more than 4 g in our circulation at any one time [13]. In health, the vital pipeline from liver to brain is maintained with astonishing fidelity, and a low blood glucose triggers emergency alarms at the base of the brain. These are powerful but non-specific fight or flight responses with maximal release of hormones such as adrenaline and cortisol which counteract the actions of insulin. Diabetes would be much easier to manage if we could sense subnormal blood glucose directly. Instead, we can only recognise it indirectly, and by its consequences. Almost everyone new to insulin can recognise hypoglycaemia, but many lose their warning symptoms in the course of time. The same phenomenon was noted in non-diabetics undergoing insulin convulsion therapy, an early precursor of electro-convulsive therapy (ECT). The external signs are still

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evident to an observer, but a glucose-deprived brain may be unable to recognise them—also a feature of oxygen deprivation. Those who live with a person on insulin soon acquire the ability to spot the warning signs, and dogs have learned to do so. My own (untested) explanation for this is that hypoglycaemic sweat smells different— this may be what people mean when they talk of the ‘smell of fear’. Only the victim is unaware. Some people enter a curious state of detachment, easily recognised by the practised observer and reversed by a chocolate biscuit or two. Others may lapse into coma after denying the existence of any problem. A vast spectrum of bizarre or automatic behaviour lies between these extremes. Rare though they might be, such episodes cause understandable consternation in the onlooker. The person affected may have little insight into the effect on others, and will resent being treated like an unexploded bomb. Popular mythology became populated with lurid myths of diabetes as a cause of temporary insanity or bloodthirsty crimes. Hypoglycaemia can be terrifying to witness. I have often reassured parents about it, but my first thought on having an unconscious 6-year-old thrust into my arms at a summer camp was that ‘this child is going to die!’ How, therefore, should one balance the terrors of hypoglycaemia against the long-­ term risk of running your glucose too high? The unknowns involved in this balance would perplex and torment users of insulin and their families for the next century. Hypoglycaemia added to the stigma of diabetes, then considered an ‘hereditary taint’ which was bracketed—equally unjustly—with epilepsy. The person most concerned might live in fear of social embarrassment— talking nonsense during a board meeting, for instance—and a sinister mystique was generated when the mythology of hypoglycaemia was added to fear of the needle. Eugenics was all the rage in the 1920s, and eugenicists proposed that ‘diabetics and epileptics’ should not be permitted to marry. Only one of Joslin’s young patients had fathered a child by 1928, but it was widely believed that insulin would lead to an explosion of diabetes. Ruggles Gates put it as follows in 1934: ‘the greater the success of medicine in alleviating or overcoming an inherited disease, such as diabetes in certain cases, the more serious is the racial condition produced, for the diabetic diathesis is inherited, and if insulin treatment not only prolongs the lives of large numbers of diabetics but so enables them to reproduce in large numbers, then the racial result will inevitably be a serious increase of diabetics in the population’. Reginald Ruggles Gates had a more lasting legacy, and one for which he would scarcely wish to be remembered. His failure to consummate

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his marriage to Marie Stopes prompted her to write Married Love, a practical guide to sex in marriage that helped to dispel misery and ignorance for millions of couples. Stopes was a keen eugenicist, and the two cervical caps she introduced for birth control were named ‘Pro-race’ and ‘Race’, respectively [14]. Joslin defended the right of his patients to marry and bear children but, living as he did in an era of racial hygiene, he was on the defensive. Cammidge, a geneticist, considered that the ‘marriage of diabetics is clearly inadvisable’, but adds the realistic comment that people will often ask you for advice but rarely take it [15]. Robin Lawrence reached the same pragmatic conclusion. ‘One doubts’ he remarked, ‘if either the geneticist or the doctor is justified in doing more than outlining the position and leaving the ultimate decision to the patient’. ‘Hereditary taint’ or not, people with diabetes were barred from many occupations and sometimes attempted to hide their condition. A patient of mine was an officer in the merchant marine until the captain entered his cabin while he was injecting and discharged him on the spot. Ironically, World War 2 opened employment opportunities for those with diabetes, just as World War 1 allowed more women into the workforce. In 1941 the US Civil Service Commission opened the door to federal employment, subject to limitations concerning driving, moving machinery or working at heights. This apart, people with diabetes often found work in small businesses which did not make health examination a condition of employment. Discrimination apart, there were subtle taboos regarding diabetes. Its association with urine conveyed a sense of pollution. Nor can you localise the condition. You can point to a bad heart or weak kidneys, but not to a weak pancreas. When added to the all-pervasive fear of needles and stories of weird and unpredictable behaviour, it is no surprise that people in public life chose to keep diabetes a close secret—although HG Wells joined forces with Robin Lawrence to found the British Diabetic Association in 1935. Those in the limelight today may choose not to acknowledge their diabetes, but it is rarely stigmatised. Theresa May was not a popular British Prime Minister, but noone ever suggested that her need for insulin made her less fit for an extraordinarily stressful period in office. Insulin-treated diabetes is a private and personal affair, a ‘second division illness’, as one victim put it, and there are times when the loneliness of long-­ distance diabetes cannot be shared. At such times a sympathetic medical ear may hear what no-one else will ever know.

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References 1. Lawrence J. In: Tattersall R, editor. Diabetes, insulin and the life of RD Lawrence. London: Royal Society of Medicine Press; 2012. 2. Bliss M. The discovery of insulin. Chicago: University of Chicago Press; 1982. 3. American Diabetic Association. The journey and the dream. A history of the American Diabetic Association. Arlington, VA: American Diabetic Association; 1990. 4. Joslin EP.  Harvard health talks. Cambridge, MA: Harvard University Press; 1931. p. 18. 5. Leyton O. Treatment of diabetes mellitus. 4th ed. London: Adlard & Son; 1927. 6. Barnett DM.  Elliott P Joslin MD: a centennial portrait. Boston, MA: Joslin Diabetes Center; 1998. 7. Holt AC. Elliott proctor Joslin. A memoir 1869–1963. Asa Bartlett Press; 1969. 8. Joslin EP. The treatment of diabetes mellitus. With observations upon the disease based upon thirteen hundred cases. 2nd ed. Philadelphia: Lea and Febiger; 1917. 9. Marks V, Richmond C.  Insulin murders. London: Royal Society of Medicine Press; 2007. 10. Gale EAM et al. Hypoglycaemia, hypothermia and shivering in man. Clinical Science 1981;61:463–69. 11. Macleod JJR, Campbell WR. Insulin and its use in diabetes. Baltimore: Williams and Wilkins; 1925. 12. Fletcher AA, Campbell WR. The blood sugar following insulin administration and the symptom complex hypoglycaemia. J Metab Res. 1923;2:637–49. 13. Wasserman DH.  Four grams of glucose. Am J Physiol Endocrinol Metab. 2009;296(1):E11–22. 14. Briant K. Passionate paradox: the life of Marie stopes. London: Hogarth; 1962. 15. Cammidge PJ. Diabetes mellitus and heredity. BMJ. 1928;2:738–41.

6 Living with Insulin

Early extraction methods were very inefficient, and large volumes of impure insulin had to be injected under the skin. The demand for insulin far outstripped the supply, and the Insulin Committee in Toronto freely licensed its manufacture around the world, subject only to pooling of data; standardisation was achieved under the auspices of the League of Nations. The yield of beef insulin increased enormously when isoelectric focusing was introduced into the Lilly production line, but multiple daily injections were frequently needed, and there was a crying need for longer-acting insulins. Protamine from fish sperm offered one solution, and manipulation of the zinc concentration offered another. New solutions may introduce new problems, however, and longer action combined with erratic absorption caused long bouts of hypoglycaemia, sometimes heralded by episodes of bizarre behaviour or sudden lapses into unconsciousness. Insulin allergy, another common problem, drove the quest for increased purity. Laboratories around the world raced to produce insulin in 1923, and standardisation became a real challenge. At Macleod’s suggestion, Collip tested its effects upon healthy rabbits and found that a 45% fall in blood glucose threw them into convulsions. The convulsive dose proved a handy means of testing a batch of insulin, and Collip lined his rabbits up for injection. If none had a fit, the dose was too low; if they all did, it was too high. A ‘unit’ of insulin could then be defined as the amount that would send 3 of 5 rabbits into a fit [1]. But how big is a rabbit? Toronto’s rabbits weighed two kilos, and Lilly’s only one.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 E. Gale, Life in the Age of Insulin, Copernicus Books, https://doi.org/10.1007/978-3-031-47190-2_6

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Early extracts varied so much that physicians started low and worked up to an effective dose. The solution was dilute, large volumes had to be pushed under the skin, and a high salt content added to the pain. One father wrote to Banting on 9th December 1922 begging for better quality extract. ‘We feel so sorry for the poor little girl that at times it seems almost impossible for us to stand it, when we have to give so large amounts in order to try and keep the sugar down’. Clinicians soon became aware of other limitations of injected insulin. One was that injections wore off too quickly. Most users needed at least two painful injections per day, and even then ketones often appeared in the urine during the night, evidence of waning insulin action. Walter Campbell looked forward in 1925 to a time when a continuous form of injection or ‘some method of delaying absorption’ might be available. He also anticipated that insulin might in time be succeeded ‘by one of its isomers or derivatives, robbed of certain of its limitations and with certain of its therapeutic properties enhanced’ [2]. The newly-formed League of Nations formed a biological standards committee to look into the question of standardisation. It met in Edinburgh in 1923 and defined the unit of insulin as the amount sufficient to induce hypoglycaemia in a 2 kg rabbit starved for 24 h [3]. This was later divided by three to make the clinical unit in use today. Mice were more convenient for large scale testing, and were ranged in glass pots along the shelves of a special cabinet. Each row received a different dilution of insulin, and the strength of the preparation was judged by the number of mice on each shelf that went into convulsions. The convulsive dose for a mouse is about 600 times lower than that for a rabbit, making the test far more sensitive, but it was essential to keep the mice at a temperature of 280 C, for they could survive higher doses of insulin if allowed to drop their body temperature [4]. This biological assay system was not superseded by physical methods of measurement until the 1980s. Standardisation posed a problem that was seemingly intractable. Impasse threatened until Henry Dale, the senior British representative on the League of Nations committee, proposed to share a standard sample of powdered insulin between all the producers. Macleod gave Dale his cue by responding that ‘I doubt whether it will ever become possible to prepare a standard for insulin in the form of a dry, stable solid’, whereupon Dale produced a sealed tube from his pocket and rolled it across the table. ‘There it is’, he said [1]. By the following year, 60 g of insulin powder had been prepared and distributed to producers in North America, Britain and Denmark. A conference in Geneva agreed in 1925 that ~8.5 units of insulin were present in 1 mg of dry material,

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and that a pooled preparation could henceforth be used as a standard [5]. Five institutions participated in the analysis; Eli Lilly tested 700 rabbits, whereas mice were used in Denmark; 160 mice would later be needed for each batch. The impurity of this early preparation was apparent when the League of Nations reported in 1935 that 1 mg of insulin contained 22 units; the estimate was upgraded to 24 units in 1958 [4]. Meanwhile, the quest to improve the purity of insulin went on. John Jacob Abel, a lean workaholic with a wispy beard which made him resemble a dyspeptic version of Colonel Saunders, is credited as the father of American pharmacology. A hands-on bench scientist, he began work on thyroid hormone in the 1890s and switched to the adrenals following the report by Oliver and Schäfer. He developed a crystallised extract of the active principle, published its formula, and christened it epinephrin. Takamine, a Japanese scientist working in the USA, marketed a variant on this formula under the trade name of ‘Adrenalin’, and the hormone is better known by this name outside the USA. In 1924 the 67-year-old Abel turned his attention to insulin. Adrenaline and thyroxine are small molecules, and it was hard to imagine that a massive protein could function with equal precision. Thyroxine has a carrier protein to which the active hormone is attached, and it seemed possible that the same might apply to insulin. Abel found that breaking sulphur-­ sulphur bonds disabled the molecule; it would later be shown that they link the two peptide chains in insulin. He was appalled by the impurity of commercial insulin, and was not far wrong when he claimed that it contained ‘from 80% upward of foreign or non-insulin constituents’. One mysterious property, for example, was to cause an immediate upward spike in blood glucose following injection into a vein [6]. The mysterious glucose agonist was later identified as the alpha cell hormone glucagon. Careful buffering and repeated precipitation did however allow Abel to obtain a solution of such purity that crystals appeared in the bottom of his test tube. In December 1925, he too saw insulin (Fig. 6.1). Frustration followed, for it was not yet known that zinc is necessary for the formation of insulin crystals [7]. Insulin was nonetheless one of the first proteins to be crystallised (the first enzyme was crystallised in 1926), and crystals were wrongly assumed to guarantee its purity. Allergic reactions to injection remained common, sometimes resulting in angry lumps half the width of an orange, and it was assumed that these were due to insulin itself. Since impurities also delayed the rate at which insulin entered the blood stream, increased purity meant a shorter duration of effect and some people needed four painful injections each day to control their diabetes. A longer-acting insulin was badly needed.

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Fig. 6.1  The first insulin crystals. (From Murnaghan, J.H., & Talalay, P. (1967). John Jacob Abel and the Crystallization of Insulin. Perspectives in Biology and Medicine 10(3), 334–38 (permission requested))

6.1 Danish Insulin We met August and Marie Krogh on their journey to the Inuit in 1908. Once back in Copenhagen, they made their home into a workplace. The family lived in the attic, the first floor was converted into a laboratory, and Marie saw her patients in an office on the ground floor. August had an astonishing facility for handling apparatus combined with a hunter’s instinct for the correct solution, and invitations poured in for a lecture tour of America when he was awarded a Nobel Prize for his work on capillary diffusion in 1920. He delayed the trip because of ill-health in the family. His 15-year-old son had chest problems, possibly TB, and Marie was tired and losing weight. With the excitement of the Nobel festivities behind them, they realised she had diabetes. And this was regarded as a death sentence [8]. 1 August Krogh looked for help to a burly and imposing man who had worked until recently as a general practitioner in the small town of Brande in central Jutland and was married to the local dentist. Hans-Christian Hagedorn’s father had been affected by diabetes, and two of his brothers would develop the condition in later life; he too would be affected. Well aware that diet treatment for diabetes involved endless self-abnegation, he set out to  She might in fact have had type 2 diabetes.

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find a food that could satisfy appetite without increasing blood glucose—a quest that required a test for blood glucose. The Swedish professor Ivar Bang published the first micro-method for glucose measurement in 1913. Hagedorn ordered Bang’s book in 1916, converted part of his house into a laboratory, and set out to try the new method. Chance, as Louis Pasteur famously said, favours the prepared mind, but he omitted to mention that it also favours the lucky bastard. By extraordinary coincidence, a remarkable man called Norman Jensen had been appointed pharmacist in Brande. He soon wearied of handing out plant extracts, opium, barbiturates, ‘bromide solutions to calm the nerves, quinine and acetylsalicylic acid against fever, caffeine for headaches, theobromine for shortness of breath and baldrian and digitalis for a bad heart’ [9, p. 75]. A shy, retiring man with a fussy manner, he was on course for a semi-monastic existence when he learned of the local doctor’s pet project. Hagedorn was not a patient man. His marriage was childless, and the house was over-run with his wife’s cherished cats. A beloved Siamese with an intestinal upset was imprudent enough to soil Hagedorn’s pillow, and he shot the animal in a fit of rage. His wife’s homecoming was not a happy one, and the cat was ceremonially interred beneath a wreath protesting that it had not been the animal’s fault. This was by no means the only occasion on which Hagedorn’s temper worked to his disadvantage. With Jensen’s support, things went better in the laboratory. Bang’s method had many drawbacks, but endless patience enabled them to tweak it until they had developed an efficient means of measuring glucose in 0.1–0.2 mL of blood. The Hagedorn-Jensen method attracted immediate notice when presented at a scientific meeting in 1918, and Hagedorn was offered an academic post at Copenhagen’s University Hospital. August Krogh, who shared his love for laboratory work, turned to Hagedorn rather than to more distinguished physicians for help with his wife’s diabetes. Marie’s condition stabilised on a starvation (‘Eskimo’) diet, sufficiently so for her to join her husband on a lecture tour of the USA. They set off for the New World in September 1922, and heard about insulin on the way. Krogh wrote to Macleod, and they stayed at his home in November. Fired with enthusiasm for what he had seen, Krogh decided to produce insulin in Scandinavia, and permission was readily granted by Toronto’s insulin committee. Krogh had no exclusive right to the product—medical patents could not be taken out in Scandinavia—but he resolved that the first insulin to reach the Nordic countries should be of the highest quality. Hagedorn was waiting for them at the dock in Copenhagen on December 12th 1922. Jensen and a medical colleague were summoned, and Hagedorn’s house was converted into a facility for making insulin. As described by the

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colleague: ‘HC [Hagedorn] had already been to the cattle market and acquired some pancreases. Now Mitte [his wife] was in the garden grinding the glands in a mincer, while the pharmacist was pouring hydrochloric acid over the freshly minced glands … HC then drove the extracts in his car to Krogh, who determined their biological activity’ [9, p. 112]. The pace was so frenetic that on 21st December, 9 days after returning to Denmark, Krogh had an extract of ox pancreas that could throw rabbits into convulsions. The pancreas, as they discovered, must be fresh or fresh frozen, and they invented a better way of removing alcohol from the preparation. Their first human trial was on March third 1923. The patient was in coma: his blood glucose fell but he died of heart failure. On March 23rd, insulin was given to a 10-year-old girl on the starvation regimen who was too weak to get out of bed. Ten days later and 5 kg heavier, she got up and walked. The starvation regimen was so awful that she had hidden orange peel and banana skin under her mattress to keep going. Her abdomen now started to swell, a common feature of recovery from near-­ starvation. When Hagedorn commented on this, she scandalised her mother by saying that he too had a big tummy, so what was the problem? This girl was alive and well in 1959, with two children and virtually no complications of diabetes. Five of the first eight recipients were alive 27 years later [10]. The Danes learned about isoelectric precipitation in April 1923, and found a commercial sponsor who agreed to distribute insulin at cost to the Scandinavian countries on condition that he could sell it for a profit elsewhere. The Nordisk insulin laboratory was established in May, and the offer to supply every hospital in Scandinavia at 60% of Lilly’s US price was made in June. Danish insulin had arrived. The Nordisk Insulin Company began in a kitchen, moved to a workshop and established itself in a purpose-built factory. Hagedorn was a thickset and impressive man, at times both brave and honest when it was politic not to be (for example, during the German occupation in World War 2), but also somewhat remote: like Joslin, he was generally referred to by his initials. He was imperious, at times uncontrollably irascible, and by no means easy company. His row with Harald Pedersen caused this key employee to leave and found a new insulin company (appropriately known as Novo) with his brother Thorvald in 1925. Denmark has more pigs than cows, and Nordisk insulin was made from pig pancreas and exported with success because of its reputation for quality. The purer the insulin, however, the shorter it lasts. There was a crying need for a long-acting preparation, and many additives had been tried before Hagedorn hit upon fish sperm. The idea is less bizarre than you might imagine, for insulin—like most proteins—is mildly acidic, and it made sense to see if it could

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form complexes with an alkaline protein. If so, this would raise its isoelectric point and cause it to precipitate at the pH under the skin. The precipitate would then dissolve more slowly than soluble insulin. Histones and protamine are alkaline proteins which package the nucleic acids in DNA. Protamine is the major protein in sperm and the extravagant sexual habits of male fish cause them to produce it in abundance. Hagedorn and Jensen added trout protamine to insulin in acid solution, tested it on themselves and tried it on a patient. It didn’t work. Undeterred, they found that the insulin-protamine complex formed a cloudy-grey suspension in neutral solution, and that its effect lasted for more than 12 h after injection. Rainbow trout proved ideal for their purpose and—since protamine is well tolerated by the immune system (women do not develop allergy to their partner’s sperm)—allergic reactions are rare (Fig. 6.2). A long-acting insulin was eagerly awaited, and Joslin named an era in diabetes management in its honour. The Naunyn Era was followed by the Allen Era and the Banting Era, and the period from 1935 became the Hagedorn Era. Frustratingly, insulin would not form a stable solution with protamine, and protamine insulin was initially supplied as a powder to which liquid containing a phosphate buffer must be added before use. David A Scott and colleagues from Connaught Laboratories overcame this by adding zinc to the solution and their protamine zinc insulin (known as PZI) became a huge success [11]. The action of PZI persisted for up to 72 h, thus answering many people’s dream of a ‘fire and forget’ insulin. Unfortunately, it also became notorious for erratic insulin delivery and the unpredictable bouts of hypoglycaemia that resulted. It took 10 years for workers at Nordisk to discover that a stable solution can be obtained by mixing soluble insulin with protamine in precisely balanced (isophane) proportions at neutral pH.  Millions would know this as NPH (neutral protamine Hagedorn) insulin. Hagedorn shared Macleod’s view that insulin was a gift to mankind, and the proceeds from Nordisk insulin were accordingly channelled into a trust whose task was to promote scientific and it falls out of solution

Shifting the isoelectric focus to the right creates an insulin that will precipitate under the skin, and has a much longer duration of action.

Fig. 6.2  Shifting the isoelectric point towards subcutaneous pH causes insulin to crystalise in situ, thus prolonging its action

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research, insulin production and patient care. A hospital was built in the 1931–2, and named for the eighteenth century Danish savant Nicolaus Steno (Niels Steensen in Danish). It nestled between the insulin factory and a research institute founded in 1957. Hagedorn moved freely within the resulting organisation. This bulky and imposing man was noted for his temper and staff never knocked on his door unless absolutely necessary. A former patient who developed diabetes as a small boy in the 1930s gave me a more human insight. Hagedorn’s ward rounds were formal: patients stood to attention beside their beds when the great man entered their room, and remained silent while the nursing sister reported their progress. Hagedorn would then issue his instructions before dropping to his knees and playing with the child’s toys. In a strange sad echo of events in Toronto, protamine insulin caused a rift between its discoverers. Hagedorn’s marriage seems to have become a formality—although the proprieties were rigorously observed—and he spent much of his time with a young pharmacist called Ingrid Wodstrup. A rift with Jensen occurred when Hagedorn unreasonably insisted that the patent on protamine insulin should be taken out in her name, and the rift proved bitter and lasting. Jensen had no formal appointment and (according to Canadian precedent) the rights to the new insulin had been given to the Institute for the equivalent of a dollar each. Jensen’s main wish seems to have been for reconciliation and recognition but, as he put it, ‘the bitter disagreement resulting from this has never been put aside’. He was packed off with a cheque—a paltry sum in terms of the profit from NPH insulin. Hagedorn never buried the hatchet on any grievance, and his war with the Pedersen brothers who founded Novo was bitter. No insulin manufacturer could hope to survive without the new insulin and Novo contested the patent vigorously. A famous anecdote concerning Hagedorn’s first presentation of protamine insulin to a Danish audience relates that two vials were passed around the room, but only one came back! [9, p. 181]. In the event, the patent for protamine insulin was offered to the Canadian insulin committee free of charge, and producers in other countries were speedily licensed to make it. Even so, the basic step in formulation belonged to Nordisk. Novo petitioned to use it and were refused; they produced it anyway, and a ferocious legal battle ensued. The outcome, as always, was messy, and the hostility between the two organisations was still palpable when I worked in the Hagedorn laboratories 40 years later. One positive outcome of the sibling rivalry between the Danish companies was that Novo looked for another means of prolonging the action of insulin and seem to have hit upon it during the Nazi occupation of Denmark. In all

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events, many years of development were still needed. Extra zinc was added to a neutral insulin solution with seeding techniques that created a family of insulin crystals. These dissolved at different rates after injection, and became known as the lente (‘slow’) insulins [12]. And there it rested. Endless further attempts were made, but protamine and/or zinc were by far the most effective way of retarding the action of insulin until genetically modified insulins became available 50 years later [13]. NPH remains a mainstay of insulin therapy, and its protamine is obtained from wild (chum) salmon from Honshu in Japan. The nuclear disaster at Fukushima disrupted the global supply of protamine, forcing the fish to be sourced from Hokkaido, and raising fears of a global shortage. 2 It is a fundamental rule of medical progress that every solution creates new problems. The long-acting insulins made it possible for diabetes to be treated with one or two daily injections, but convenience was counterbalanced by the uneven and often unpredictable rate at which insulin diffused into the blood stream. Hypoglycaemia was the main concern, for the long acting insulins could cause prolonged suppression of blood glucose levels. Some people entered a twilight world in which subnormal glucose levels produced no overt symptoms yet affected their behaviour. At such times they became distant, irritable, slow or irrational. Friends and relatives soon learned to recognise what was happening, and junior doctors working with Robin Lawrence knew that the barley sugar in his waist-coat pocket must be extracted and tactfully proffered if he showed signs of bizarre behaviour.3 Charles Fletcher, son of the Secretary of the MRC, reported that hypoglycaemia with loss of warning symptoms was his main bugbear after 39  years on insulin, and that he was frequently rescued from embarrassment or physical mishap by those around him. Mood swings were another feature. On one occasion he felt that ‘Armageddon is near ... I clutched my wife saying “the world is coming to an end, and I want to hold on to you”. “All right” she said “but have some Lucozade first”, and the world was saved’ [14]. Others on insulin might unexpectedly collapse into coma, or act unpredictably—one of my patients attempted to drive the wrong way round a roundabout in the middle of the Oxford rush hour. Alternatively, they might fall into a fighting frenzy or have a convulsion in their sleep. Those affected became understandably defensive and resentful when they realised that their  EMA Assessment report for protamine-containing medicinal products AMA/741250/ 2012 (15 Nov 2012). 3  I learned this from Helen Pond who later became a great authority on childhood diabetes. 2

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loved ones and friends were on perpetual tenterhooks, and those who shared their lives were condemned to endless anxious vigils for which they might receive little thanks. A new folk-lore accumulated around the subject of diabetes, and the public began to see those affected as odd and irrational folk to be treated with great circumspection. This, of course, sent diabetes underground. A man might not tell his wife about his diabetes before they married, 4 or conceal the knowledge from his friends until something went wrong. Marie Krogh’s diabetes was concealed from everyone outside the immediate family. Elizabeth Hughes, daughter of the US Secretary of State, was among the first children to be treated with insulin. She treated her diabetes as a private matter, and her fiancé learned about it 1 week after they became engaged. When she died 58  years and 42,000 injections later, her diabetes was still a close family secret [15]. Diabetes wrecked lives, and continues to do so. Nor were such prejudices confined to the public: psychiatrists and physicians confused the consequence with the cause, claimed to identify a ‘diabetic personality’, and attempted to class diabetes among the psychosomatic disorders. As Jonathan Swift said, ‘there is nothing so extravagant and irrational which some philosophers have not maintained for truth’.

6.2 The Quest for Purity Meanwhile, the insulin chemists quietly went on with the task of improving insulin. The estimated insulin concentration of standard preparations increased from 8 units per mg in 1925 to 22 units in 1935, confirming that early preparations were highly impure. Crystallisation improved matters, but Joslin estimated that hives at the injection site developed in around 10% of those starting insulin. The problem usually resolved, but some were plagued by angry red lumps like bee stings. Insulin was generally blamed, and a small but important landmark in its history came when Erik Jorpes, a distinguished Swedish physician, was consulted by a woman whose life had become a misery.. It so happened that he had had prepared some ultra-pure insulin by repeated crystallisation for a laboratory experiment, and had it on his desk. On impulse, he gave it to her, and she was cured. Others were soon to beat a path to his door, and he was able to show that ‘insulin allergy’ was due to  In 1990 a Maltese patient of mine agonised about telling his fiancée that he had diabetes. Encouraged by me, he nerved himself to tell her about it. She promptly broke off the engagement. Around the same time a beautiful young Asian girl in London was told that she had lost value on the marriage market because of diabetes and would have to marry someone of lower caste. 4

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impurities rather than to insulin itself. His report was published in 1949 [16], and the pursuit of increased purity would result in the first really ‘clean’ insulins 20 years later.

References 1. Murnaghan JH, Talalay P. HH Dale’s account of the standardization of insulin. Bull Hist Med. 1992;66:440–50. 2. Macleod JJR, Campbell WR. Insulin and its use in diabetes. Baltimore: Williams and Wilkins; 1925. 3. Jensen HF.  Insulin. Its chemistry and physiology. New  York: Commonwealth Fund; 1938. 4. Stewart GA.  Historical review of the analytical control of insulin. Analyst. 1974;99:913–28. 5. League of Nations Health Organisation. The biological standardisation of insulin. Geneva: League of Nations Health Organisation; 1926. 6. Collens WS, Murlin JR. Hyperglycemia following portal injection of insulin. Soc Exp Biol Med Proc. 1929;26:485–90. 7. Murnaghan JH, Talalay P.  John Jacob Abel and the crystallization of insulin. Perspect Biol Med. 1967;10(3):334–80. 8. Tattersall R. The pissing evil. A comprehensive history of diabetes mellitus. Swan & Horn; 2017. 9. Deckert T.  HC Hagedorn and Danish insulin. Herning, Denmark: Poul Kristensen Publishing; 2000. 10. Hagedorn HC.  Cases of diabetes of long duration. N Engl J Med. 1959;261(9):441–2. 11. Scott DA, Fisher AM. Studies on insulin with protamine. J Pharmacol Exp Ther. 1936;58:78–92. 12. Hallas-Møller M, et al. Crystalline and amorphous insulin-zinc compounds with prolonged action. Science. 1952;116:394–9. 13. Brange J. The galenics of insulin. Berlin: Springer-Verlag; 1987. 14. Fletcher C. One way of coping with diabetes. BMJ. 1980;1:1115–6. 15. Cooper T, Ainsburg A. Breakthrough. Elizabeth Hughes, the discovery of insulin, and the making of a medical miracle. New York, NY: St Martin’s Press; 2010. 16. Jorpes JE. Recrystallized insulin for diabetic patients with insulin allergy. Arch Intern Med. 1949;83(4):363–72.

7 Nemesis

Early hopes that insulin might cure diabetes were soon dashed, but so too were fears that its effect might wear off. Its most dramatic effect was to prevent or reverse diabetes coma [ketoacidosis]. Deaths from this, once commonplace, became rare where adequate treatment was available, and it looked for a while as if insulin could restore normal life expectancy. The first two decades of insulin looked hopeful, but runaway complications of diabetes affecting the major arteries or the small blood vessels feeding the eyes or kidneys supervened, and half of Joslin’s children were to die before reaching the age of 50. Was this an inevitable consequence of diabetes, or could it be prevented by careful management of circulating glucose? The first skirmish concerned the role of diet. Joslin’s children faced an unknown future, but the auguries looked good. Ketoacidosis (‘diabetic coma’), had once caused death in 86% of his cases, but Joslin insisted that, if properly supervised, no child need ever die of diabetes again. The outlook was less good for those without access to specialist care. Metropolitan Life Insurance Company records show that death from diabetes under the age of 20 fell from 4.1 per hundred thousand per year in 1916–20 (when death was virtually inevitable) to 1.1 per year in 1931–35, and remained at this level until 1945. Even allowing for a rising incidence of diabetes, this suggested that 10–20% of affected children failed to reach their twentieth birthday in families with health insurance. The reasons are not far to seek. A general practitioner in the UK might expect to encounter 2–3 children with undiagnosed diabetes in the course of a working lifetime. Not surprisingly, the diagnosis is often missed at the first visit. Few practitioners would have

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encountered it at all before World War 2, and fewer still would have access to blood glucose measurement or experience in the use of insulin. The Steno Memorial Hospital in Denmark saw 307 patients diagnosed under the age of 31 before 1933. Overall, 3–4% died within 15 years of diagnosis, but 20% died within 10 years in country areas [1]. Access to expert care was a major determinant of survival, and so too was social support. Joslin and White remarked in 1929 that ‘it is the uneducated, untrained, uncared for child in a family with limited resources who is lost’, a chilling comment that still applies today [2]. (Fig. 7.1). The experience of Joslin’s clinic between 1897 and 1945 showed the dramatic effect of insulin upon the projected survival of young people with diabetes [3]. The difference was relatively minor in those diagnosed over the age of 50 when corrected for rising life expectancy. In 1927 (era ‘D’ in the diagram) Joslin reported to the Department of Public Health in Massachusetts that death from diabetes under the age of 20 had almost vanished from the charts, and that death in those diagnosed between the ages of 20 and 50 was in sharp decline. As against this the condition was becoming more common—or was more commonly diagnosed—in older people, and the overall number of deaths attributed to diabetes was increasing [4]. Life Expectancy Pre-insulin era A 1897–1913 B 1914–1922

45.0 39.8

31.7

30.5 27.6 22.7 At age 30 16.8

At age 10 14.3

1.3 A

4.1

2.6 B

C D

C D E F

E

F

A

At age 50

8.0

6.3

B

C D

Insulin era 1922–1925 1926–1928 1929–1938 1939–1945

E

F

A

15.9 14.4 12.313.2 9.5

B

C D

E

F

Dublin LI, 1951

Fig. 7.1  Life expectancy of someone with diabetes before and after the discovery of insulin

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Joslin’s life had become a crusade against ignorance, whether in the community or in the medical profession. His crusade was so successful that he could record in the 1940s—not without satisfaction—that ‘those with onset in childhood have almost ceased to die of diabetes until the duration of the disease has passed 20 years’. He added that patients might now be expected to outlive their doctors, and that ‘we are forced to depend upon their calculated life expectancy.’ Tragically, he was wrong.

7.1 In the Destructive Element Immerse The projected life expectancy of Joslin’s young patients might look good, but appearances were deceptive. Retrospective analysis of his clinic showed that only 52% of girls and 46% of boys diagnosed at the age of 10 between 1923 and 1959 would see their 50th birthday, as against 93% and 91% in the unaffected population [5]. His patients were losing 25 years of life. The same dismal experience was reflected in Hagedorn’s clinic at the Steno Hospital in Copenhagen. Why? Coma apart, infection was a common cause of death in the days before insulin. Local infections spread easily in the presence of diabetes, and tuberculosis was rampant. There was as yet no effective treatment for these well-­recognised ‘complications’ of diabetes, but insulin allowed people to fight them off more effectively. It had long been known that diabetes is bad for arteries, and insulin seemed to make little difference. Feel the artery at your wrist. If you are young and healthy, its wall will be thin and elastic. It gets thicker and firmer as you grow older, and you may be able to roll it under your finger. In some, it will become kinked or feel like the stem of a clay pipe. Medical students were taught to look for these signs in the 1920s, and used them to diagnose the condition they called arteriosclerosis— hardening of the arteries. Hardening of the arteries is a feature of increasing age, and Joslin’s opinion was that diabetes accelerated it. German physicians had introduced the concept of Aufbrauchskrankenheiten—accelerated ageing—and Joslin maintained that the biological age of a person with diabetes should be taken as their chronological age plus 10 years. He had an uncanny instinct for getting things right, and a recent study confirmed that a diagnosis of diabetes was the cardiovascular risk equivalent of 15 added years [6]. He reported in 1928 that 50% of older patients had tell-tale flecks of calcium in the walls of their arteries on X-ray—evidence of arteriosclerosis—and cardiologists became aware that a high proportion of those with

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clinical features of arterial disease (34 out of 145 in one series) had known or previously undiagnosed diabetes [7]. Conversely, unsuspected coronary disease was common in people with diabetes, and the aorta of a 17 year old who died after 5 years of diabetes was covered in atheromatous plaques. Joslin worried that the high-fat diets he prescribed might be making things worse. The evidence of cardiovascular risk mounted until Priscilla White reached the gloomy conclusion in 1941 that ‘arteriosclerosis appears inevitable’ in children who have experienced more than 15 years of diabetes [8]. Arterial disease apart, diabetes predisposes to a highly specific form of damage to small blood vessels. Blood leaves the heart in arteries and returns via the veins. The two are linked by a vast network of tiny blood vessels which—if fully unwound—would extend more than two times round the world. The capillaries are the tiniest of these vessels, and their walls act as a filter between the blood stream and the cells of our bodies. Long exposure to high glucose levels makes these walls thicker and leakier, and this can have dire consequences in two highly specialised regions of the microcirculation: the retina and the filtration units of the kidneys. Damage to the microcirculation of the kidneys causes blood pressure to rise, and high blood pressure accelerates both kidney and eye disease. The distinction between large vessel and small vessel complications of diabetes slowly became clear. Arterial disease is widespread in the population as a whole, but is accelerated by diabetes. Improved blood glucose control has a limited effect on its progression. In contrast, microvascular complications are seen only in diabetes, and can be prevented by improved glucose control. The distinction was not appreciated until later in the century, and the big question was this: is damage to blood vessels a toxic effect of high glucose levels (and thus preventable), or an inherent feature of diabetes and therefore inevitable? The question would not be answered unequivocally until the 1980s, by which time improvements in the technology of insulin delivery had made near-­ normal glucose control a realistic option. In the interim, people with diabetes were travelling in the dark, with nothing other than urine tests to guide them. Absence of symptoms fostered the erroneous belief that all was well— until the disease caught up with you. Many doctors—Joslin was a notable exception—believed that the mounting toll of disability in their outpatient clinic was inevitable. Their patients, meanwhile, could count the white sticks and missing limbs in the waiting area, more eloquent by far than the bland reassurance of their physicians.

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7.2 The Invisible Worm One routine of diabetes care was to examine the retina with an ophthalmoscope. A mydriatic drop is instilled on the lower eyelid, and the circular muscles around the lens are temporarily paralysed. Looking along a reflected beam of light, you enter a glistening world of tiny arteries and veins which radiate from the head of the optic nerve in intricate leaf patterns. Diabetes is a predator in this subaqueous world, first seen as small red dots representing tiny balloons on the side of retinal capillaries. These may leak to produce blots of blood against the orange-pink background of the retina, and most people with diabetes will show some of these changes as the years roll by. In themselves they are usually harmless, but in times past they progressed in up to half of younger people. Progression is heralded by fluffy grey wisps known as cotton wool spots, mute witness that the underlying cells are starved of oxygen. The retina attempts to feed them with new blood vessels which spread bush-­ like on the floor of the retina or reach towards the observer like fronds of seaweed in the vitreous humour of the eye. Should one of these fragile tubes rupture, blood pumps into the juices of the eye. The victim, unaware of any problem until then, wakes to find that a grey haze has replaced the glory of daylight in one eye (Fig. 7.2).

Fig. 7.2  A photo of fluorescent dye passing through the retina in advanced diabetic eye disease. Note the tiny dots due to aneurysms and hazy patches due to leaky capillaries

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In 1934 a distinguished pathologist called Paul Kimmelstiel (1900–1970) crossed the Atlantic to avoid Nazi persecution. His suitcase contained post-­ mortem microscopic slides of a condition that can affect the filtration units of the kidney in people with diabetes. These units, known as glomeruli, are tiny clusters of capillaries, and their walls contain collagen fibres which act as the filter between blood and urine. The mesh they form is so finely woven as to be impermeable to larger molecules but glucose can infiltrate, making the mesh leakier. Tiny amounts of protein then begin to leak through, and the process is generally progressive. Damage to the microcirculation of the kidneys causes blood pressure to rise, and high blood pressure accelerates both kidney and eye disease. Once fully established, the proteinuria of diabetic kidney disease inevitably resulted in renal failure and death. Clinicians soon came to recognise that retinal damage, proteinuria, and hypertension went hand in hand, and that the fate of those affected was effectively sealed in terms of the treatment available. Harrowing examples forced themselves on the attention of physicians who took pride in caring for diabetes. As one physician wrote in 1944: There is nothing more disturbing than the diabetic who acquires the disease in childhood; who apparently is a picture of robust health – who looks and feels perfectly well – but whose blood vessels have been degenerating insidiously for years; who, in the early 20 s and 30 s, and probably married and with a family, is beginning to feel the effect of the degenerative changes, either because of progressive hypertension, kidney failure, disturbance of sight due to retinitis or a sudden attack of coronary thrombosis [9].

The incoming tide mounted steadily. Joslin considered that only 2% of deaths in his young patients were related to kidney disease in 1937, as against more than half of the deaths he witnessed from 1944 to 1950. The conquistadores who fought their way across the Isthmus of Panama found yet another ocean in front of them, and this was the equivalent moment in the history of diabetes. Forty more years of research would be needed to show the way forward, and the first clash between those who insisted upon the need for careful control and those who thought it a waste of time took place over diet. Eating with Insulin. The history of diabetes is marked by recurrence of certain ideas which rise, decline and disappear; only to go through a similar cycle again in an altered form and a new generation.—R. T. Woodyatt (1934)

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A low-calorie diet prolonged life in the days before insulin, but seemed unbearably cruel. Joslin expressed sympathy for the physician who said that he ‘wished he might never have another diabetic child to treat, so sad was it to see a child starve to death’. Children on the starvation diet showed all the hallmarks of famine, ranging from wasted limbs, pot bellies, and swollen ankles to flaking skin and hair loss. Inanition, apathy and intolerable food cravings added to their misery. Starving children don’t cry. Awful though it was, the starvation regimen undoubtedly helped some children to survive into the new era. The Children’s Hospital in Vienna, a world leader in paediatrics, did not use it, and only one child from the pre-insulin era survived—but she lived for 50 years. Many died from misadventure, inexperience, or lack of access to insulin. Cost was a major concern, for Toronto insulin retailed at $10 (Canadian) for 100  units in June 1922, equivalent to $1.20 per unit in 2008. The price fell rapidly as production improved, but insulin still retailed at 1 cent per unit in 1924, and a modern-sized vial would have cost $10, the average weekly wage in Canada at that time [10]. South of the border, Lilly insulin retailed at around $500 per year, unaffordable for many Americans. Its price fell rapidly, however, and its cost in the 1930s was only 3.5% of its cost in 1923 [11]. Insulin apart, the added costs of diabetes also had to be taken into account. Health (as against life) insurance was unknown until later in the century, and diabetes counted against you in the job market. Adolescents were advised to seek out a profession or to be self-employed. The great advantage of the low-carbohydrate diet was that it enabled people to get by on less insulin. One American practitioner of the time commented, ‘as an experiment I determined to give my poorer diabetic patients an amount of insulin per day commensurate with their means’. These comments are reported by the authors of a book called The Story of Insulin (1962), who stress that this ‘would not be acceptable by the social and medical standards of today’. Not in 1962, perhaps, but a more recent report found that one patient in four attending an urban diabetes centre in the USA was cutting back on insulin for reasons of cost in 2018 [12]. The low-carbohydrate diet was considered so integral to the management of diabetes that it came as a shock when a study from 1926 showed that a high carbohydrate diet actually improved glucose tolerance. William Sansum promptly increased the carbohydrate content of the diet of his Californian patients. A typical recommendation might add up to 2435 calories, including 245 g of carbohydrate (40% of energy requirements), 124 g of fat, and 100 g of protein [13]. The escape from the misery of an endless low-carbohydrate

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diet brought immense well-being, a benefit second only to insulin in the minds of its recipients. In 1930, the physician William Collen sent Fred Banting a copy of his diabetes manual. ‘The whole thing looks very complicated and difficult,’ replied Banting, ‘I would very much hate to be a diabetic and have to learn all about insulin and diets. I am perfectly certain that were I a diabetic patient, I would go to the doctor and tell him what I was going to eat and relieve myself of the worry by demanding of him a proper dose of insulin’ [14]. The paediatrician Karl Stolte proposed his unmeasured (‘free’) diet in the following year, based on the same principle. Patients responded with enthusiasm, for meals were now a joy ‘rather than a problem in arithmetic and a trial in self-­ abnegation’. Paediatricians were happy to release children from the psychological strait-jacket of the stricter regimen, and noted that Priscilla White reported stunting of growth in her patients at the Joslin Clinic, which still advised a strictly regulated diet. Adults, meanwhile, reported improved energy and well-being, and better nutrition improved resistance to acute bacterial infection or tuberculosis, dreaded complications in the pre-antibiotic era. Last but not least, free diets reduced the risk of disabling hypoglycaemia. But would there be a price to pay? Diabetes is a condition that can be managed with negligent ease by those inclined to do so, and a Swedish survey published in 1967 commented that ‘it might be said that each patient had his individual way of taking the insulin, and that each of the doctors had his (sic) own views as to how and when the insulin injections should be given’ [15]. An easy-going attitude was possible because a moderate increase in blood glucose causes little discomfort. Those who lived by the needle found that they could eat as they pleased, reduce their risk of hypoglycaemia and still feel well. This has been inelegantly compared to peeing in your boots to keep your feet warm, but there was then little or no hard evidence that controlling glucose could reduce the risk of vascular disease. The tools available were simply not up to the task. Forty years later a frustrated paediatrician would write a provocative article entitled ‘Good glucose control—a study in mass delusion’, and he was not far wrong [16]. The initial euphoria surrounding insulin shaded into the slow realisation that those who had survived a metabolic death were dying of vascular disease, and the issue of free diet became subsumed in the wider debate about control and complications. Traditionalists such as Joslin maintained with some fervour that tight control was the prerequisite to extended life, whereas opponents such as Edward Tolstoi pointed out that Joslin’s own data showed that his patients were dying in droves from vascular complications [17]. If complications are unavoidable, he argued, why waste time trying to avoid them? A

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daily injection of long-acting insulin would enable the body to assimilate the glucose it needed, and any excess would be discarded in the urine. Common sense has often shielded patients from the enthusiasm of their physicians, and a visiting British physician learned from Tolstoi’s dietitian that his female patients had discovered that irritation of the private parts, a common feature of poorly controlled diabetes, could be avoided by restricting their carbohydrate intake [18]. Was it justified to impose further restrictions upon people already condemned to the burden of diabetes? Julian D Boyd, writing in 1947, complained that ‘the management of diabetes mellitus has become too simple’. It was all too easy to let things slide. He cited an extreme example of the laissez-­ faire approach: a boy of normal size when diagnosed at the age of 3 was 50.5 in. tall at the age of 15 and weighed 28.4 kg. Normal growth and development require adequate food, sufficient insulin, and adequate regulation of glucose levels. Over-emphasis on diet could also be harmful, and Priscilla White noted in 1937 that 61 of 1126 children under her care had developed dwarfism—linked in her view to an over-strict diet—and she tested the effect of crude pituitary extracts containing growth hormone with some success. Paradoxically, poor growth could occur at either end of the ideological spectrum, whether because of over-insistence on diet or simply because of poorly controlled diabetes. Boyd reported in 1941 that 12 of 69 patients diagnosed in childhood were classified as dwarfs, and concluded that inadequate control was the greater problem [19]. Those with poor control were at greater risk of ketoacidosis, had little chance of successful pregnancy, and had shorter lives. Conversely, those who struggled to keep their urine free from glucose lived on the brink of hypoglycaemia, and those around them lived on their nerves. Those who put their faith in urine tests were groping in the dark, for urine tests are retrospective. One person likened it to driving a car with a speedometer that did not register until you had exceeded the speed limit. As a distinguished colleague muttered to me on his retirement, ‘it’s been a catalogue of failure.’

References 1. Deckert T, et  al. Prognosis of diabetics with diabetes onset before the age of thirty-one: I.  Survival, causes of death, and complications. Diabetologia. 1978;14:363–70. 2. Joslin EP, White P. Diabetic children. JAMA. 1929;92:143–6. 3. Dublin LI. The facts of life from birth to death. New York: Macmillan; 1951.

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4. Hamblen AD, Joslin EP.  Deaths from diabetes in Massachusetts, 1900–1925. JAMA. 1927;88:243–5. 5. Krolewski AS, et al. Onset, course, complications and prognosis of diabetes mellitus. In: Marble A, Krall LP, Bradley RF, Christlieb R, Soeldner JS, editors. Joslin’s diabetes mellitus. 12th ed. Philadelphia: Lea and Febiger; 1985. p. 251–77. 6. Booth GL, et  al. Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study. Lancet. 2006;368:29–36. 7. Joslin EP. The treatment of diabetes mellitus. With observations based upon three thousand cases. 3rd ed. Philadelphia: Lea and Febiger; 1923. 8. White P. Diabetes in youth. N Engl J Med. 1941;214:586–9. 9. Rabinowitch IM. Prevention of premature arteriosclerosis in diabetes mellitus. CMAJ. 1944;51:300–6. 10. Rutty CJ. ‘Couldn’t live without it’: diabetes, the costs of innovation and the price of insulin in Canada, 1922-1984. Can Bull Med Hist. 2008;25(2):407–31. 11. Socal MP, Greene JA. Socal and Greene. New Engl J Med. 2020;382(11):981–3. 12. Herkert D. Cost-related insulin underuse among patients with diabetes. JAMA Intern Med. 2019;179(1):112–4. 13. Tompkins WA. Continuing quest. Dr William Sansum’s crusade against diabetes. Santa Barbara: Sansum Medical Research Foundation; 1977. 14. Collen WS.  Regulated versus free diet in the treatment of diabetes mellitus. J Clin Nutr. 1954;2:195–203. 15. Grönberg A, Larsson T, Jung J. Diabetes in Sweden. A clinic-statistical, epidemiological and genetic study of hospital patients and death certificates. Stamford, CT: Esselte; 1967. 16. Malone JI, et  al. Good diabetic control—a study in mass delusion. J Pediatr. 1976;88(6):943–7. 17. Tolstoi E. The free diet for diabetic patients. Am J Nurs. 1950;50:632–54. 18. Sawyer L, Gale EAM. Diet, delusion and diabetes. Diabetologia. 2009;52:1–7. 19. Boyd JD.  Treatment of the child with diabetes mellitus. Med Clin N Am. 1947;31:279–88.

8 When the Insulin Ran Out

Insulin is for life. What would happen if it suddenly became unavailable? This happened in war-torn parts of Europe and Asia in World War 2, a small but largely forgotten part of a much greater tragedy. Not surprisingly, few records were kept, but some idea of the scale of the disaster can be gauged from individual stories and from the scanty records available. An estimated 40% of users worldwide lack secure access to affordable insulin today. Imagine what would happen if the supply ran out. This became a very real concern for civilians trapped in besieged Ukrainian cities in 2022–3, and it caused unknown numbers of deaths in Europe and Asia during World War 2. The difference between insulin-dependent and non-insulin-dependent diabetes is cruelly exposed in wartime, for enforced diet may actually benefit those who can manage without insulin. Apollinaire Bouchardat is said (I have not been able to find the source for this assertion) to have remarked that his patients with diabetes did well in the Siege of Paris (1870–1), and deaths from diabetes halved in Berlin in World War 1. The annual mortality from diabetes in 13 German cities fell from 23.3 per hundred thousand in 1938 to 15.5 in 1944 [1], and the benefits of wartime rationing persisted for more than a decade in Britain [2]. The situation is very different those who need insulin, and the Scandinavian countries established national registers at the outbreak of World War II to ensure a continued supply. A Finnish survey in 1953 indicated that diabetes had developed in 832 children born since 1939, and that 20% of these had died—remarkably few for a country engaged in a desperate struggle for survival. The reality of dependence upon insulin emerged when it became © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 E. Gale, Life in the Age of Insulin, Copernicus Books, https://doi.org/10.1007/978-3-031-47190-2_8

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unobtainable. Since the full scale of the tragedy will never be known, we must rely on anecdotes. One contributor to the BBC’s archive of wartime memories developed diabetes in childhood and was 12 in 1940 when the Nazis occupied Jersey, one of the British Channel Islands. Supplies of insulin dwindled rapidly and those who needed it were herded into hospital. She discharged herself and took to living off the land on a diet of ‘nettle soup, baynard, dandelions, groundsel, and one or two other weeds and herbs’. There was no insulin on the relief ship Vega when it visited the island in December 1944, but she had better luck at its next visit and was, according to her doctor, the only insulintreated person in the island to survive the war. Her narrative is backed by the memoirs of another Jersey doctor who recalls that around 30 people on insulin remained on the island (others had managed to escape in time); these were brought into a hospital ward for bed rest and strict diet. Morale fell as one by one they succumbed to coma. Insulin was supposed to arrive with the first visit of the Vega, but the packet was empty on arrival—presumably rifled by black marketeers. Everyone on the ward died before more insulin arrived with the second visit of the Vega. This account was written by a physician who was not personally involved in their care who believed the only survivor to have been male, although the accounts tally in all other respects. 1 The situation was equally bad in many other parts of Europe after the war. A representative of one of the governments-in-exile told Charles Best that ‘to have our children thrust back to before the insulin era is hard to bear’. Help was at hand: Greece, for example, received a shipment from the Canadian Red Cross soon after the period of occupation. Best recounts that Britain itself was at risk when one of its main supply depots was bombed, although the ‘situation was saved’ by an aerial shipment of insulin powder from the USA [3]. The situation was dire in Germany itself, although much less so than in its occupied territories. Hoechst (then part of IG Farben) produced 60% of German insulin before the war, estimated at one billion units—enough for around 700,000 users. Beef was in limited supply in wartime, although pork insulin could be obtained from Denmark, and Germany lost 35% of its cold storage capacity as a result of allied bombing. This limited the supply of frozen pancreas, prompting Lindner to develop a method of treating pancreas with salt which yielded a stable dry preparation. Even so, shortage threatened, and Dr. Conti chaired an insulin control commission in 1943 on behalf of the Artzekammer (Physician’s Association). Ration cards were issued to 200,000 people, each of whom was required to demonstrate that their insulin requirement had fallen by one-third on a starvation diet. The insulin was  BBC People’s War, Article ID: A4148110; Lewis J (1982) WW2 People’s War.

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doled out in 10 day batches, and priority was given to children and to those engaged in war work when supplies ran short: ‘useless mouths’ were turned away. The insulin supply fell from 433 million units in 1943 to 377 million in 1944, virtually ceasing for a time in1945 [1] (Fig. 8.1). The post-war period was chaotic, with supply lines and pharmacies in ruins, and a black market flourished for insulin, as it did for penicillin. Few people with insulin-dependent diabetes will have survived in the countries most ravaged by war, one element of a much larger tragedy that has gone almost entirely unrecorded. A comic footnote was added to this tragic history in 1953 when the American Diabetes Association published advice to its members as to the management of diabetes in the event of nuclear war. A good supply of insulin was recommended. Viktor and Eva Saxl were born in Czechoslovakia and married in 1940. Shanghai was a place of refuge for members of the European Jewish community unable to obtain visas to other countries. Viktor worked there as a textile engineer and Eva taught languages until she developed diabetes shortly before the Japanese invasion in December 1941. The Nazis conferred ‘honorary Aryan’ status upon their Japanese allies, and demanded the

Fig. 8.1  Insulin Registration Card. The patient was treated with Novo insulin from Denmark. (Courtesy of the Diabetesmuseum Munich, Germany)

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return of the Jewish refugees. This being impractical, some 20,000 were confined to an open ghetto in the poorest part of Shanghai, and Eva’s insulin had to be sought on the black market. On one occasion, Viktor exchanged a gold bar for 18 bottles of worthless insulin. In desperation, he decided to prepare insulin from water-buffalo pancreas according to the instructions in a medical textbook. His test preparation sent a rabbit into convulsions, and Eva was next in line. The improvised insulin factory he set up is said to have kept several hundred people alive until liberation came in 1945. The Saxls moved to the USA, and Eva became something of a celebrity at a time when few people in the public eye would admit to diabetes. Viktor resumed his career the textile business, but soon became involved in a campaign to supply insulin to poorer parts of the world. This took the couple to Chile in 1970, and Viktor died there of a heart attack at the age of 58. Eva, bereft, decided to stay on, and campaigned for diabetes until her death in 2003. The most astonishing survival story is that of Ernest Sterzer, son of a Jewish lawyer in Vienna. He developed diabetes in 1925 at the age of three and was 17 when his family was transported to Theresienstadt. Insulin was unavailable, needless to say, but Ernest stole a loaf of bread (punishable by death) from the bakery each day and traded it for insulin with the mistress of a Czech policeman. Conditions at Theresienstadt were relatively good because it was being prepared for inspection by the International Red Cross. A band was playing when the inspection team arrived, and the children were told to exclaim ‘more chocolate, Uncle Rahm!’ when the camp commandant handed it out. The family was transported to Auschwitz-Birkenau soon after, and his precious supply of insulin was lost on the way. Dr. Mengele stood by the gate in his habitual position, directing the stream of incomers to right or left. I knew a woman who was processed by Mengele. He asked if she were truly Jewish— she had blue eyes and blond hair—and said ‘pity’ when she affirmed it. I asked if he was wearing his notorious white gloves, and she was unutterably distressed by her failure to remember. Ernest’s diabetes was already out of control when he lined up, and his mother wondered naïvely if she should ask Mengele to send him to hospital. The people next in line told her not to be so crazy. In the event, she went to the gas chamber and he lived on. He was on the verge of coma when an inmate who happened to be a doctor recognized the smell of acetone on his breath. Other prisoners were told to take him to the gas chamber, but they took him to the hospital instead. The doctor in charge (another prisoner) happened to have some insulin, and kept Ernest on as his personal assistant.

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Mengele visited the hospital as Russian troops approached Auschwitz, and the inmates were told to strip naked for inspection. Ernest looked fitter than most, and Mengele asked why he was there. The doctor explained that his leg had swollen but was better now. His apparent health meant that Ernest was among 6000 inmates to be evacuated, although the precious package containing his insulin and syringe was snatched and thrown aside as he boarded a cattle truck for Germany. Three miserable days later, the evacuees reached a German aircraft factory and more doctor–prisoners checked them over. Ernest revealed his secret, and received life-giving shots of insulin until he was transferred to Oranienburg, a concentration camp near Berlin; once again the medical staff kept him alive. The final act of the drama came when the last survivors set off on a death march to the West in April 1945 against a drum-roll of Russian artillery. Ernest managed to reach American troops, and was cared for. He hitch-hiked to Vienna and discovered that his brother had reached it on the previous day, although their father had also died in Auschwitz. Vienna’s leading hospitals had no insulin but he scraped by, emigrated to the US, established a successful mailing service, went blind from complications of diabetes in 1956, and died in 1973. His remarkable memoir, succinct and totally lacking in self-pity, can be accessed online from the American Holocaust Memorial Museum. 2 The newly formed WHO was tasked to review the global supply of insulin in 1947. With considerable understatement, the committee noted that ‘from the beginning of the war, many countries had been experiencing difficulty in obtaining adequate supplies of insulin’, whereas numbers affected had doubled in 7 years in other parts of the world. The committee looked forward to a time when ‘synthetic’ insulin would be available, and reviewed other sources in the interim. Beef was in short supply and sheep pancreas was too fatty, but Australia had plans to ‘resort to’ pig pancreas. Whale insulin seemed a promising alternative, as did cod, and the Japanese were hoping to export insulin from bonito. The survey, published in 1949, requested data from 67 countries, excluding most of Africa and the communist countries. Replies received from 55 suggested their insulin consumption was 10.5 billion units per year. Unsurprisingly, given the widespread devastation, much of it was produced in America and the UK.  A million units will keep 700 people alive for a year if they use 40 units/day, and one billion units should therefore supply 700,000 people [4]. This being the case, it might be reasonable to conclude that the countries taking part in the survey (which included the main insulin exporters)  US Holocaust Museum.

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contained 7–7.5 million insulin users. Large swathes of the world’s population were excluded from this survey, but few will have enjoyed secure access to insulin. This being the case, the world total is unlikely to have exceeded ten million. By way of contrast, global insulin production was estimated at 516.1 billion units in 2018, an approximate 50-fold increase.

References 1. US Strategic Bombing Survey. The effect of bombing on health and medical care in Germany. 1947. https://collections.nlm.nih.gov/ext/dw/31520570R/ PDF/31520570R.pdf. 2. Trowell H. Diabetes death rates in England and Wales 1920–70 and food supplies. Lancet. 1974;2:998–1002. 3. Best CH. Diabetes 1952;1(4):257–61. 4. World Health Organization. Study of the supply of insulin. Second World Health Assembly; 1949. https://apps.who.int/ins/health/10665/9874.

Part III Two Types of Diabetes

9 The Sensitive and the Insensitive

The history of science may give the impression of inexorable progress, but there are times when collective wisdom turns a blind eye to new information, and diabetes is no exception. It was obvious from day one that some people needed insulin in order to survive whereas others did not. Even so, collective thinking resisted the idea that these might represent distinct forms of diabetes, and did so for the best part of 60 years. What follows is the story of how the immune features of type 1 diabetes came to light, and how the distinction became established. The nineteenth century observers saw diabetes as a pyramid: rare yet fatal in the young, frequent but less harmful in the middle aged, and common but relatively benign in the old. Frederick Allen’s pancreas-slicing experiments suggested that those with early onset had near-complete loss of pancreatic function, and Joslin drew the line between those who needed insulin and those who did not at around the age of 45. The first major challenge to the idea of diabetes as a single disease came from Harold Himsworth (1905–1993). Harry, as he was known, was raised in a family in the north of England with no intellectual pretensions, and was taken out of school at the age of 16 to work at a worsted mill managed by a family friend. A year of sullen protest and undiagnosable illness followed, until he was finally allowed to pursue the correspondence course that took him to University College Hospital in London in 1924. There he discovered that medical students were expected to learn everything about the preclinical sciences except why they might be interesting or relevant, a tradition that flourished at the same institution when I studied there 50 years later. He kept such a low profile as a medical student that the examiners had to send for his © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 E. Gale, Life in the Age of Insulin, Copernicus Books, https://doi.org/10.1007/978-3-031-47190-2_9

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photograph when he won the gold medal in 1929, but his star rose rapidly when he went on to conduct research in the Professorial Medical Unit [1, 2]. Like many before and since, his attempts to quantify the effect of insulin upon an individual’s glucose were frequently baffled. Wilhelm Falta (1875–1950), a Viennese physician, had proposed in 1931 that there were insulin-deficient and insulin-resistant forms of diabetes. My Austrian friends proved reticent when I enquired about him, for he had been an enthusiastic member of the Nazi Party. The number on his membership card (6,331,006) showed that he had joined the Party illegally before Austria was absorbed by Germany in 1938. Two sons died fighting with the SS, and he was stripped of his university appointment when the war was over. 1 We may picture Himsworth sitting at a table on the ward towards the end of the day in the early 1930s. He has been recording glucose loss in the urine of a woman with diabetes, and is trying to figure its relationship with insulin on a piece of paper. Insulin, as he notes, is more effective in some people than others. Why? He hooks a finger under his starched collar to ease the pinch, and begins to think. Suppose that Falta is right, and there are two distinct forms of diabetes? Suppose some people lose the ability to make insulin, whereas others become resistant to its action? If so, how might I prove it? Evening sunlight slants through the window behind him. He leans back, links his hands behind his head, and the chair gives a tired creak. Where is he now? He is sitting in a high place, the clouds have parted, and he is looking down upon the cities of the plain. Oh yes, and behind all this there lurks a fierce glee. So simple, so obvious, but no-one has noticed—no-one but me. This is where I belong. He stretches, shuffles his papers, smiles to the nurse and saunters off the ward. Nothing could be simpler than the test he devised, which consisted of an injection of insulin balanced by a drink of glucose. The drink prevented a fall in blood glucose, thus allowing insulin sensitivity to be measured in people with or without diabetes. His volunteers were medical students aged 18–22, ‘selected with particular reference to their veins and the shapes of the lobes of their ears’ (for ease of blood sampling). The paper he published in 1936 became a citation classic, more cited than read [3]. In the casual fashion of the time he omits to mention how many were tested, makes no use of statistics and relies upon two ‘representative’ graphs. These showed that the dose of insulin cancelled the effect of the glucose drink in young people on insulin and healthy controls but caused a sharp glucose  Interview with Prof. Michael Hubenstorf, Professor of Medical History, Vienna, December 1, 2000.

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rise in those he characterized as insulin-insensitive. Furthermore, the two groups were clinically distinct: The sensitive diabetics tend to be younger and thin, and to have a normal blood pressure and normal arteries, and as a rule their disease is of sudden and severe onset … the insensitive diabetics, on the other hand, tend to be older, obese, to have hypertension and frequently arteriosclerosis, and in these patients the onset of the disease is insidious. [4]

Harry Himsworth gave us a simple bedside experiment which required nothing more than glucose, insulin, and clinical deduction. His paper was ignored. In ancient Egypt they obliterated your existence from living memory by erasing your personal seal from the monuments. Today, they fail to cite you. Forty-one years were to pass before Himsworth’s types were served up in a fresh guise—only to win immediate and universal acceptance. Why the delay? Why the acceptance? What we believe determines what we see, but it is the distinction between insulin-sensitive and insulin-insensitive diabetes is by no means clear-cut. Joslin used Himsworth’s test, and agreed in his 1948 textbook that both diabetic and non-diabetic individuals could be grouped according to insulin sensitivity. On the other hand, his experience in 30 patients led to the conclusion that ‘from a practical standpoint such tests are of no great assistance.’ Joslin saw a continuum where Himsworth saw two categories. One was the false trail of pituitary diabetes. Pre-war investigators were fascinated by the apparent normality of the islets in diabetes, and were prompted to look elsewhere. The rare condition of acromegaly is caused by a pituitary tumour, and an excess of growth hormone commonly causes diabetes. The Frenchman Pierre Marie, credited with its first clear description, quotes an early nineteenth century description of a giant ‘tormented with such an intense thirst that he drank up to 18 bottles of pure water every day’. This example, when added to growing evidence that anterior pituitary extracts could produce diabetes in animals, suggested that an overactive pituitary might be responsible for most cases of diabetes. This led to some interesting science and some unnervingly awful experiments. X-rays were even used to irradiate the pituitary of people with diabetes [5]. The subsequent belief that something produced by the pituitary accelerated diabetic retinopathy led to surgical removal of thousands of pituitary glands in the 1950s and 1960s. Some appeared to succeed, but victims were often left with pituitary deficiency and a white stick. The belief in pituitary diabetes distracted attention from Himsworth’s findings.

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9.1 The Swan Song of Constitutional Medicine Constitutional medicine was a flourishing medical discipline in the first half of the twentieth century, now remembered mainly by those who haunt dusty corners of medical libraries. Its founding belief was that a person’s ‘constitution’—we would say phenotype—reflects their susceptibility to disease. The idea dates back to Hippocrates, who observed that plethoric individuals were more susceptible to stroke, and thin ones to tuberculosis (a classic instance of confusing cause with consequence). Members of the constitutional school linked body build to personality and personality to disease, and the stereotypes live on in medical thinking. The ‘dyspeptic personality’ may have sunk into deserved oblivion, but many still believe in the driving ‘type A’ person who is heading for a coronary, and medical students claim with alliterative inaccuracy that the typical victim of gall stones is fair, fat, female, fertile, and 40. The constitutional approach did, however, have some justification when phenotypes could be measured but genes could not. Despite a mass of fanciful medical description, interest in detailed analysis of the growth and development of the human body gave birth to the science of anthropometry, and the discipline gave us type 1 and type 2 diabetes. WH Sheldon (1898–1977), hugely influential in his day, was a constitutional psychologist who attempted to link personality to phenotype. His view was that the three germ cell layers of the early embryo (ectoderm, mesoderm, and endoderm) compete for resources in early development. This can result in three extremes: the ectomorph is a skinny individual with a predominance of nervous tissue, the mesomorph invests in muscle and connective tissue, and the endomorph has overdeveloped internal organs. Each type was thought to have a corresponding personality and predisposition to disease. Sheldon used standardized nude photographs taken from three directions to measure what he called the ‘somatotype’, and went on to develop a complex scoring system which allowed nearly 300 variants of the human body to be distinguished [6]. George Draper was a New  York practitioner of constitutional medicine whose textbook includes detailed descriptions of the peptic ulcer type, the gall bladder type and the pernicious anaemia type [7]. When Sheldon’s technique was published in 1940, Draper recruited a physical anthropologist called Dupertuis to document the ‘diabetes type’ in 225 people who attended his clinic. Dupertuis reported back that there were two types rather than one. Group I, as he termed it, had few distinctive features, but group II was typified by a characteristic accumulation of adipose tissue around the waist [8]. A young doctor called John Lister (1920–2013)—a one-time mentor of mine—began work at the Royal Free Hospital in London around this time.

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Una Ledingham was his boss, and she had noticed the existence of ‘a group of patients of characteristic physique who are almost uniformly insensitive in their response to insulin’. Her background in constitutional medicine is obvious from her description: The skull tends to be small and the bones are generally slender with tapering extremities. The features are also small and characteristically neat and centrally placed. Thus the palpebral fissure appears too small for the eyeball, the nose is small and straight, there is a short upper lip and the mouth is often of the “Cupid’s bow” formation. These features together tend to give the patient a doll-­ like appearance…

And so it goes, with more eyewash concerning the teeth (widely spaced), the skin (‘fine and soft and unusually resistant to normal wear and tear, so that even working-class women preserve this characteristic’), the hair and the nails (‘well shaped, long, and of good texture, usually displaying well-marked moons’). Convinced that her doll-faced patients represented a distinct form of diabetes, Ledingham encouraged Lister to combine somatotyping with Himsworth’s insulin sensitivity test. One hundred patients took part, 80 of them female—the Royal Free catered mainly to women. These were tough working-class women with a mean height of 5 ft 2 1/2 in (159 cm), predisposed to diabetes by stepwise weight gain after repeated pregnancies. The powers of persuasion required to make these formidable ladies pose in the nude must have been remarkable; no wonder that ‘the only factor in their selection (was) their willingness to cooperate’. The Himsworth test confirmed that the young and lean were more sensitive to insulin than the plump and middle-aged. No statistical tests were applied, but patients of the latter type were older, heavier, and less sensitive to insulin. Lister came upon the work of Draper while writing up his paper. In hasty acknowledgment (and possibly in error) he referred to the two ‘groups’ of Dupertuis as having type I and II diabetes [9]. (Fig. 9.1). There are, as he reported, ‘two broad groups of diabetics—the young thin, non-­ arteriosclerotic group with normal blood pressure and usually an acute onset to the disease, and the older, obese, arteriosclerotic group with hypertension and usually an insidious onset … these types we have provisionally designated type I and type II, respectively’.

On this view type 2 diabetes had a distinctive phenotype which combined central obesity with resistance to the action of insulin, and it was constitutional medicine’s parting gift to the world.

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Fig. 9.1  A woman with type 2 diabetes, as defined by an endomorphic physique and resistance to the action of insulin. (Courtesy of Dr. John Lister)

So it was that a perfectly accurate clinical description of the two major types of diabetes was published in a prominent medical journal in 1951, together with nomenclature that was universally accepted when reintroduced by a visitor to Lister’s department 27 years later. The idea fell so flat that Lister made no reference to his own terminology when writing a textbook of diabetes in 1959. Like Himsworth’s work, it was an orphan observation—an idea whose time had not yet come. The concept may have fallen into oblivion, but Lister did not forget. In or around 1975 this tall, ruddy-cheeked and distinguished-looking man, physician to many film stars at the nearby Ealing Studios, invited a clinician and geneticist called Andrew Cudworth (1939–1982) to deliver a lecture in the postgraduate centre at Windsor Hospital. Cudworth asked what the filing box of blue and white cards on Lister’s desk signified, and was told that Lister filled one for every patient, blue for what he called type 1 diabetes, white for type 2. Cudworth took the box back to London and the blue cards formed the basis of what became known the Bart’s-Windsor Family Study. The terms type 1 and type 2 diabetes won almost immediate acceptance when he reintroduced them in a 1976 review [10], although he made no mention, then or

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later, of John Lister’s role in the story. I asked John about this in later life. ‘Andrew was often forgetful about such matters’ he replied, with a sad shake of the head. In retrospect it seems hard to believe that those who needed insulin for survival were thought to have the same condition as those who could manage without. Previous clinicians certainly drew a clear distinction between juvenile and maturity-onset diabetes, or insulin-dependent and non-insulin dependent diabetes mellitus (IDDM or NIDDM) as they became known. Even so, they assumed that the difference was dimensional rather than categorical—a matter of degree rather than of kind. A commonly-cited hypothesis was that the young had two copies of a supposed diabetes gene, whereas older people had only one. The dual nature of diabetes may have remained an orphan observation for the best part of 40 years, but it was soon to find many parents.

References 1. Gale EAM.  Commentary: the hedgehog and the fox. Sir Harold Himsworth (1905-1993). Int J Epidemiol. 2013a;42(6):1602–7. 2. Gale EAM. Is type 2 diabetes a category error? Lancet. 2013b;381(9881):1956–7. 3. Himsworth HE. Diabetes mellitus. Its differentiation into insulin-sensitive and insulin insensitive forms. Lancet. 1936;1:127–30. 4. Himsworth HE. Lancet 1949;i:465–72. 5. Joslin EP.  The treatment of diabetes mellitus. 6th ed. Philadelphia: Lea and Febiger; 1937. 6. Sheldon WH.  The varieties of human physique. An introduction to constitutional psychology. New York and London: Harper and Brothers; 1940. 7. Draper G, Dupurtuis CW, Caughey JL. Human constitution in clinical medicine. New York: Harper; 1944. 8. Draper G, Dupurtuis CW, Caughey JL.  The differentiation by constitutional methods between pancreatic diabetes and diabetes of pituitary origin. Trans Am Assoc Phys. 1940;55:146–53. 9. Lister J, Nash J, Ledingham U. Constitution and insulin sensitivity in diabetes mellitus. Lancet. 1951;1:376–9. 10. Gale EAM. The discovery of type 1 diabetes. Diabetes. 2001b;50:217–26.

10 The Discovery of Type 1 Diabetes

Outsiders are often responsible for change in an academic discipline. The clinical distinction between insulin-sensitive and insensitive diabetes is not always clear-cut, and the separation between the two types of diabetes was not universally recognised until what we now call type 1 was seen to be associated with circulating antibodies directed against pancreatic islets and genes which influence the pattern of immune response. A long and winding path led to this discovery, and it came from the study of inbred mice. This chapter explains how it came about. The invisible consensus that forms around any specialist area was beautifully described by a Polish pathologist called Ludwik Fleck in 1935. His book translates from the German as Genesis and Development of a Scientific Fact. Science, as he maintains, is not based upon facts, but upon agreement as to which facts are important. ‘Facts’ exist within an intellectual ecosystem which he calls a ‘thought collective’ (Denkcollectiv), and authoritative opinion is structured around this. ‘There is’, as he noted, ‘an apprenticeship period for every trade, every religious community, every field of knowledge, during which a purely authoritarian suggestion of ideas take place’. Each thought collective has an inner (esoteric) circle of authority, surrounded by outer (exoteric) circles of belief. The circles are mutually supportive, for both subscribe to certain axioms which appear self-evident. The collective ‘governs the decision on what counts as a basic concept, what methods should be accepted, which research directions appear most promising, which scientists should be selected for important positions and which should simply be consigned to oblivion’. Intrusive modes of thought are promptly and emphatically rejected, for ‘the principles of an alien collective are, if noticed at all, felt to be © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 E. Gale, Life in the Age of Insulin, Copernicus Books, https://doi.org/10.1007/978-3-031-47190-2_10

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arbitrary … its explanations are [seen as] proving nothing or as missing the point, its problems as unimportant or meaningless trivialities’. In contrast, the ruling style of thought is considered authoritative. Parisian fashion, for example, ‘appears in the guise of a self-evident necessity and is thus not even recognised as a coercive force’. Thought collectives shape many aspects of our lives: a biochemist might belong to a professional thought collective, for instance, while belonging to others as a Catholic and a collector of antique clocks. At worst, however, a thought collective becomes an echo chamber, and social media are particularly effective at reinforcing this. Thomas Kuhn—a historian of science strongly influenced by Ludwig Fleck—famously referred to structured belief as a paradigm. Each paradigm has a tendency to progress from a revolutionary youth to a complacent middle age before retreating into defensive redundancy [1]. As Max Planck said, ‘a new scientific truth does not triumph by convincing its opponents … but rather because its opponents eventually die, and a new generation grows up that is familiar with it’. The invisible consensus preceding the work I am about to describe was that diabetes is a single disease. This thought collective was undermined by new evidence from unrelated scientific disciplines which showed that insulin-­ dependent and non-insulin dependent diabetes have quite different causes, although there is some degree of overlap between the two. The new paradigm triumphed almost effortlessly, and the twofold nature of diabetes, and of the way insulin is used in its treatment, has been taken for granted ever since. It all began with the mouse.

10.1 The Dancing Mouse In the ninth moon, a yellow mouse was found dancing with its tail in its mouth in the gateway of the palace of the kingdom of Yen. The animal danced incessantly. The king asked the queen to feed it with wine and meat but this did not interfere with the performance. The mouse died during the night—Annals of the Han Dynasty, 80 BC [2, p. 31]

Rats and rabbits were the favoured small laboratory animals at the start of the twentieth century, mainly because of their sturdy disposition and prolific habits. Guinea pigs were used to study immunity and became established in the public mind as the archetypal laboratory victims of experiment. Mice were bred mainly as pets, particularly in China and Japan, and the potential of the house mouse for genetic research only came to light when it was

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appreciated that varieties collected by mouse fanciers, including the random mutation that once made a mouse dance for a king, were inherited in Mendelian fashion. The discovery of a white mouse in the wild was recorded as an important augury in China, and some 30 were captured from 307 to 1641 AD. Since recessive traits such as whiteness or dancing have an obvious negative survival value, such varieties can only be preserved by inbreeding. Let us assume that you have captured a single white (albino) mouse, and mate this with a wild mouse. All offspring in the first (F1) generation will resemble the wild parent, but the desired trait can be recaptured by mating brothers and sisters from this generation. One in four of the next (F2) generation will have two copies of the gene conferring albinism and will therefore be white. If you breed only from these, their descendants will all be white, and the genetic trait will have been captured. Eighteenth century paintings show that mouse fanciers in Japan had learned how to breed strains with a variety of coat colours together with the famous dancers, and the mouse fancy, as it was called, had spread to Europe and the USA by the start of the twentieth century. Abbie Lathrop (1868–1918) was the daughter of two school teachers in Illinois, and followed the same profession until she developed pernicious anaemia. The condition, untreatable at the time, resulted in tiredness and extreme shortness of breath; life for Abbie Lathrop resembled the top of a high mountain. No longer able to teach, she cast around for another means of support, and hit on the idea of raising small animals for sale as pets [3]. She built up a mouse colony in her barn, starting with a pair of dancing mice (known as waltzers), and the orders began to trickle in. When more than 200 had been sold, she concluded that her business must be at an end, since the mice she had provided had the potential to breed at a rate sufficient to supply the whole of the USA.1 But this was not to be, for ‘instead of receiving requests from mouse fanciers interested in obtaining creamy buffs, red creams, ruby-­ eyed yellows (very rare) or white English sables, she had orders for mice by the hundred coming in from research laboratories as far away as St Louis and New York’. She scaled up her work and carried on. Dancing mice were early favourites with collectors and researchers alike. All were fascinated by their custom of ‘running around, describing greater or smaller circles or more frequently whirling around on the same spot with incredible rapidity. Sometimes two, or more rarely, three mice join in such a dance, which usually begins at dusk and is at intervals resumed during the  A female mouse can bear a litter every 21 days, and a breeding pair can potentially generate a population of 180,000 mice in just over a year. 1

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night’ [4]. Before long, Lathrop noticed that some of her dancing mice developed lumps under the skin, and she asked a researcher called Leo Loeb what these might be. He diagnosed breast cancer, and further breeding experiments resulted in a series of joint publications. Loeb found that 100% of tumours from dancing mice would grow in mice from the same strain, but not in others. Lathrop went on to breed mice with low and high rates of breast cancer, and observed that cancer was more likely to develop in pregnancy and less likely to develop following removal of the ovaries; an early indication that hormones influenced their growth. Her barns now housed more than 11,000 mice, together with assorted guinea pigs, rabbits, rats, ferrets and canaries; between them they consumed 150 barrels of crackers and 18 tons of oats in a year. Abbie Lathrop died in 1918 at the age of 50, but the descendants of the mice in her barn live on in laboratories around the world. The aboriginal mouse evolved in Central Asia, and the ancestors of the house mouse, Mus musculus domesticus invaded Europe some 8–10,000 years ago, hitching a ride on the neolithic revolution and following early farmers wherever food was stored. Wooden sailing ships became a natural residence— the traditional ship’s cat had to earn its keep—and almost all mice in Australia or the New World are descended from stowaway specimens of Mus domesticus. The house mouse is classed as a commensal (‘one that eats from the same table’) because it neither benefits nor harms mankind directly—although its depredations have always been deeply resented. It goes wherever we go, and can survive and breed at any temperature from minus 6 to +34 °C; mice can be found living in heating ducts, frozen food lockers, 500 m below the surface in coal mines or nearly 5000 m above sea level in the Andes. The house mouse has reverted to the wild in many parts of the world and natural selection has given rise to endless local varieties. Mice will eat almost anything, and the German counter-offensive at Stalingrad is said to have stalled when reserve Panzers, dug into pits and covered with straw for camouflage failed to start or burst into flames when needed because mice had nibbled the insulation on their electrical wiring. Wherever they live, mice pay the penalty of small size in terms of high energy output, and they are indefatigable foragers, travelling up to 2 km per day within their home ranges; in relative terms a 70 kg human would have to run 20,000 km a day to keep up. As it diverged from its common ancestor, the mouse pedigree branched into three (some say four) main species or subspecies; Mus domesticus inhabits Western Europe, the Mediterranean and parts of the Middle East, and is separated from Mus musculus musculus, native to Northern and Eastern Europe, by a corridor some 20–40 km wide which is occupied by hybrids between the two forms. You might imagine that the two subspecies would eventually

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blend, but not so—hybrid males are more likely to be sterile. Natural selection keeps the two main populations apart, and the mouse frontier has proved considerably more durable than most national boundaries in Europe. Central Asia and the Indian subcontinent are home to Mus musculus bactrianus, and South East Asia is the home of Mus musculus castaneus. Genetic analysis has shown that most strains of the laboratory mouse represent a predominant mixture of domesticus with some musculus and just a hint of castaneus (the legacy of the Japanese mouse fanciers), and largely confirms the ancestry recorded in the breeders’ notebooks.

10.2 The Uses of Incest If the fool would persist in his folly, he would become wise—William Blake

He was tall, athletic and commanding, and cast a spell on all those he met. He was ‘charming, full of charisma, enthusiastic, idealistic, innovative … unconventional and impractical but very persistent’ in the words of a co-­ worker. A medical writer later said that ‘he possessed a strong sense of self-­ confidence which was a source of irritation to some … his optimism bordered upon the unrealistic. It was largely because of his energetic idealism that others were inspired to play over their heads’ [5, p. 29]. ‘I can attest to his charming, even charismatic personality’ said another; ‘his presence was immediately felt and could light up a roomful of people’. His name was Clarence Cook Little, and his rendezvous with destiny came when he was captain of the Harvard athletics team. He called on the geneticist William Castle in 1910 to enquire about an undergraduate project. Castle skimmed a live mouse across the polished lab bench and told him to learn everything about it [6, p. 25]. Castle was an early convert to Mendelian genetics, and his opportunity came with the opening of the Bussey Institution for Applied Biology in Harvard in 1908. He preferred the guinea pig for his studies, but had obtained mice from Abbie Lathrop; it was Little who glimpsed their full potential. His early publications concerned the transmission of coat colours, but his attention soon turned to cancer, perhaps influenced by his own father’s death from leukaemia. Several laboratories had shown that susceptibility to breast tumours varied from one strain of mouse to another. This gave rise to great excitement, for they seemed to be getting close to a gene that caused cancer, a lure that tempted many into this complex and baffling area. As so often happens, the first phase people who break new ground have a gold-rush mentality: too much is attempted, too fast, with inadequate methods. Exaggerated claims are

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uttered, and disillusionment follows. Years of patient work, typically undertaken by people who receive little credit for doing so, will be needed to straighten the record out. Such was the case now, for early lines of mice were insufficiently inbred, and the mix of genes they transmitted confused all subsequent attempts to reproduce the original findings. ‘Optimism gradually faded’ said one such investigator, ‘as it was found that results from experiments varied so greatly that an investigator often could not even verify his own observations, much less expect a second researcher in another laboratory to do so’ [7]. Imagine the genes in a mouse as a pack of cards face down on a table. One card is marked on the back—this is your visible mutation. You distribute the cards to players around a table, and notice whether the hand with the marked card is more or less likely to win. You will have little chance if the cards are shuffled at random, but you might do better if the cards in each hand are identical time after time. The geneticists hoped to achieve this by inbreeding. If the game is played over and over again with the same cards, your notebook might for example show that A, who has the marked card, wins 60% of the time, B wins 30% of the time, C wins 10% and D never wins. You could then mix the cards from A and B to create a hand that has a 75% chance of winning. And so on, until the winning cards are all in the same hand, and you have captured the full set of genes that contribute to the development of cancer. The challenge, therefore, was to ensure that each handheld the same cards. In terms of breeding, this required a standard mouse line in which each member is identical to all the rest. This entails mating brother with sister for generation after generation, but—as everyone knows—inbreeding is harmful. Genealogical studies of European royalty suggest that inbreeding produces effete descendants, and the Habsburg jaw is cited in evidence with equal inevitability. Francis Galton studied the aristocratic blood lines of Britain and noted that they rapidly became extinct. For this he had an ingenious explanation: the sons of the nobility marry heiresses, and an heiress, by definition, is valuable because there are no other children to share the wealth. The aristocracy courts its own destruction by alliance with the relatively infertile. ‘I look upon the peerage as a disastrous institution’, concluded Galton [8, p. 132]. Animal evidence pointed in the same direction. William Castle wrote in 1916 that: In the grip of the debilitating ailments that surface through the pairing of recessive genes, an inbreeding species grows delicate and sickly, easy prey to disease. For stragglers able to survive these hazards, a barrier of sterility looms as the tenth generation of inbreeding is approached. Few scientists seriously believed that a viable strain of inbreds could be continued, even if briefly achieved [9]

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The main counter-argument was empirical for farmers and race-horse owners routinely inbreed their stock to generate pure bloodlines. Their success was due to their habit of breeding only from the healthy, thus purging harmful genes. ‘In inbred herds’, as one exponent remarked, ‘the males and females are so like each other that the offspring … might almost as well be raised by buds or cuttings’ [10, p. 99]. Little created his own strain of inbred mice, known as the dilute brown, and was soon publishing in leading journals. Simple Mendelian ratios failed to emerge, but he showed in 1914 that Mendelian models could be applied to the action of two or more genes working together—an observation whose value would emerge 30 years later. He served for a time in the Signals Corps when the USA entered World War One in 1917, before joining the research station at Cold Spring Harbor, ‘the total living accommodations of which’, he wrote in 1918, ‘consist of what wreckage may happen to be cast up on the beach’. His dilute brown strain went with him, and he was joined in 1919 by a young and newly-wed researcher called Leonell Strong. No sooner had Strong arrived on the scene—his honeymoon residence was a tent—than every last dilute brown died in an outbreak of paratyphoid, the scourge of mouse colonies everywhere. This might seem to confirm that inbred animals were too sickly to survive, but Strong decided to start again from scratch, stacking his mice in the warmest place available, which happened to be under the nuptial bed (the infected labs were considered too dangerous). Little then discovered that that an aged pair of dilute browns, the very last of their line, lived on in Harvard. They were shipped to Cold Spring Harbor at his request, although considered too geriatric to have any interest in reproduction. With the optimism of youth, Strong put them under his bed. The honeymoon tent worked its magic, for against all expectation the elderly female conceived and gave birth. Eager inspection showed that there was a single female in the resulting litter, the Eve of a future race. Leonell Strong never doubted the genetic element in cancer, for the experience of his own family told him otherwise. Mice rarely develop cancer in the wild, for they do not live past the age of 16 months. In captivity, however, they have a lifespan of 16–26 months, and the mouse is second only to man in the frequency and variety of spontaneous tumours that develop. Strong was fascinated by the work of TH Morgan with the fruit fly, but needed a small cancer-prone mammal such as the mouse for tumour research. The fly did, however, have an important message for its animal equivalent: quantitative methods are needed, and you must think big.2  The natural frequency of mutations in mice is around 1 in 26,000. Strong later raised 450,000 mice in his own laboratory over 35 years, and this was only one phase in his long career. 2

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The first tumour transplant between animals had been performed in 1889, and it was well known that such transplants flourished in some breeds but not in others. The observation that a voracious tumour would melt away to nothing in a resistant host was particularly beguiling. This being the research fashion of the moment (it attracted George Clowes to America), transplants were performed in all cancer laboratories and a mouse with a spontaneous tumour might change hands for $300, a fabulous sum at the time. Strong, meanwhile, concluded that transplantation would not help understanding of the genetics of cancer until standard mice could be bred. ‘To extract order from the chaos of genetic randomness’, we would need living ‘carbon copies’; new lines with identical copies of each gene at every locus, each mouse an identical twin of all the others. Strong proposed endless incest, mating brother with sister for generation after generation. But could it be done? Repeated brother–sister pairings should eventually eliminate almost all genetic variation, but is also guaranteed to unearth every single genetic defect and to threaten the line with extinction. Strong speculated that the only way to crash the supposed ten-generation barrier would be to breed in sufficient numbers and to select only from the robust. He himself was poor as a church mouse, but obsession, as he later remarked, pays small heed to the arguments of reason. Two albino mice were chosen to find the new line, which became known as the ‘A’ strain, and Strong left Cold Spring Harbor with the first-­ fruits of his breeding programme—400 mice and one young human. The human couple went to teach at an Episcopal college, and were installed in the old manse. The parishioners voiced their discontent when this began to fill with mice, and the incestuous colony was banished to an old chicken coop, illuminated with a single light bulb and heated by a villainous potbellied stove. Famous families of tumour-bearing mice were to descend from this historic location. Cancer-free lines were developed in parallel, and from these came the CBA strain, the Methuselah mouse that outlives all others in the laboratory. Meanwhile, the evil legacy of inbreeding began to accumulate, and ‘cleft palate, cranial and skeletal malformations, blindness, and such lethal defects as spina bifida began to decimate the ranks of the mice as pairing recessive genes opened the Pandora’s box of hereditary disease and disability’. By the seventh generation extinction seemed imminent, and only a handful of the surviving mice could mate successfully. At this critical juncture a student assistant mishandled the potbellied stove and 80% of the mice died of carbon monoxide. The sublines survived, but the A strain was represented by one survivor, a pregnant female. ‘By so slender a thread’, commented Strong,

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‘hung the “better mouse” ancestor of countless derived sublines used ever since in medical research throughout the world’. Nor was this the end of their tribulations, for Strong’s teaching contract was terminated in 1925. He now had no job, no money, and faced the prospect of enforced massacre of his entire mouse colony; he even thought of becoming a missionary. Begging letters produced no response apart from an offer by William Castle to house the colony in the Bussey Institute—an offer unaccompanied by a salary. Undeterred, and accompanied by his long-­ suffering wife and two infants, he set up a tent in the grounds of the Institute. The New England winter was harsh, and they sometimes sneaked inside to sleep on benches in the auditorium. As on other occasions in this story, the Rockefeller Institute came to the rescue by providing a fellowship. And so it was that the A strain, the ubiquitous pink-eyed mouse of laboratory fame, came to inherit the earth: For the first time, experiments with the mouse model system returned uniform, reliable, repeatable results with mathematical precision. As had been hoped, this blue-blooded mouse race proved the doom criers wrong by developing a new vigor once the threatening recessive genes had been bred out. They were more lustrous of coat, brighter eyed and livelier than their wild ancestors [7]

Nor was this all, for other lines came into their own, and Strong was able to provide Clarence Little with a breeding stock of dilute browns, descendants of the elderly mouse couple in the honeymoon tent and survivors of the potbellied stove holocaust, now fully inbred and purged of recessive genes. Little, meanwhile, had created inbred strains known as C57 and C58. The black C57 line was useful because of its low incidence of cancer, whereas almost 100% of the C58s developed leukaemia before 2  years of age. Man had remade the mouse. Imagine a world of clones. Your father, brother, son, and every male you meet is exactly the same as you; the females are also identical. The inbred mouse replaced variety with uniformity and could be raised in strictly controlled environmental conditions. Ironically enough, the attempt to isolate genetic influences for detailed study did more than anything else to highlight the importance of non-genetic factors. This was shown in 1933 when workers at the Jackson Laboratory identified a ‘milk factor’ involved in tumour transmission. The discovery came when tumour risk was found to be passed on by the mother but not the father. In due course this ‘milk factor’ proved to be a virus, and a major line of research for cancer and other complex disorders, type 1 diabetes included, was marked out for the future.

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The mouse researchers reversed evolution by substituting uniformity for diversity, thus marking out the territory that we have been exploring ever since. Simplification unmasked extraordinary complexity in the cancers they studied, as in many other forms of disease. And not only in disease, for the study of unwanted biological outcomes would teach undreamed-of lessons about that extraordinary condition we call health.

10.3 Local Gardener Wins Nobel Prize The road of excess leads to the palace of wisdom—William Blake

Clarence Cook Little was on course for a distinguished career in the academic empyrean, but the maverick strain in his character dictated otherwise. He left Cold Spring Harbor in 1922 to become the youngest College President in the USA at the University of Maine. The educational aspirations of the University were modest; 90% of its students were the sons and daughters of farmers, and 80% went back to their farms on graduation. The new President soon made his presence felt, as noted by an admiring reporter from the Kennebec Journal who made a pilgrimage to see him in March 1923. ‘Dr Little’, he reported, ‘doesn’t take himself or his job too seriously, his smile is infectious, and seeing him across his desk at perfect ease and in great good humor, it was easy to understand why he has won his way into the students’ hearts. A big brother, he appeared, of great understanding and sympathy’. The State Governor was less enamoured by the request for $1.3 million to replace the ramshackle wooden buildings in which the University was housed, and Little’s letter of resignation followed in July 1925. In this he comments acidly that ‘it seems entirely probable that the Legislature and the politically active elements of the State will require at least 2 more years to recover from the shock of having given additional support’ and concludes with the words ‘if my salary is continued during the summer I plan to use most, if not all, of it towards the expenses of the University of Maine Biological Station at Mt Desert Island.’ He went on to become President of the University of Michigan at Ann Arbor, where his support for causes ranging from birth control to euthanasia and equal rights for women soon gave rise to controversy. The students were more outraged by his decision to ban their cars from campus. From 1924 onward he took biology students on a summer course held in Bar Harbor, a summer resort situated on a small island joined to Maine by a causeway. My own introduction to the island was memorable: I arrived

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there late one evening, intent upon meeting up with friends and spending a weekend in the laboratory archives. Bar Harbor meant mouse laboratories so far as I was concerned, and I was quite unprepared for the breath-taking loveliness that awaited me when I stepped outside next morning. The island is now a place for nature lovers and the autumn leaf-peepers, but in the 1920s it was an expensive and fashionable resort patronised by the automobile millionaires of Pittsburgh, whose life-style was reminiscent of the Great Gatsby. Dress was formal and social occasions plentiful. Servants in handsome livery were ever present. In the harbor, large and expensive yachts were moored by the dozens. Along Bar Harbor’s streets there was a constant parade of the world’s fanciest motor cars—Packards, Rolls Royces, Pierce Arrows among them—and of course the Fords and Hudsons produced by companies headed by two of the island’s famous summer residents … The 1920s and 1930s were the last gasp of an opulent and lovely, if somewhat strait-laced, Victorian era [5, p. 3].

Behind lay the wood-covered island of Mount Desert, designated a National Park and with a marine biology laboratory based on its ocean shoreline. Little’s social position, persuasive powers and personal charm soon cut a swathe through the rich summer residents, and an extraordinary plan formed in his mind. He had evidently discussed this in advance with geneticist TH Morgan, for the latter wrote in May 1928 to say that Little’s proposal would require a ‘man with the muscles of an ox, the skin of a rhinoceros and the brains of a Bismarck.’ Life imitates literature. Sinclair Lewis, a popular novelist and fashionably acerbic commentator on the manners of his time, teamed up with Paul de Kruif to write a novel about medical research which came out in 1925 with the title of Martin Arrowsmith. Paul de Kruif was a microbiologist who had been booted out of the Rockefeller Institute because of philandering and now lived by his pen; he was justifiably outraged when Lewis denied him the co-­ authorship he had been promised. The novel told the story of a young medical man with a flair for research who, after many tribulations, ends up with a rich and beautiful wife and the offer of the Directorship of the McGurk Institute, a thinly-veiled version of the Rockefeller. The world was on offer for Martin Arrowsmith, but the world was not enough: he decides to walk out on his wife and son (de Kruif had recently done exactly this while his two young sons shouted ‘daddy, come back’ from the window), in order to join a penniless research colleague in a backwoods shanty. Arrowsmith’s wife demanded that he show more sense, only to be lectured as follows:

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It’s just that argument that’s kept almost everybody, all these centuries, from being anything but a machine for digestion and propagation and obedience. The answer is that very few ever do, under any condition, willingly leave a soft bed for a shanty bunk in order to be pure … the fact is I’ve suddenly seen I must go! I want my freedom to work, and I herewith quit whining about it and grab it. You’ve been generous to me. I’m grateful. But you’ve never been mine. Good-bye.3

Little must surely have read this. In all events, his life recapitulated fiction, for he resigned as President of the University of Michigan in January 1929, leaving his wife behind, and went off with a handful of helpers to set up an animal laboratory in a remote island wilderness. Arrowsmith’s projected backwoods laboratory would extend to ‘eight (but never more!) maverick and undomesticated researchers’, and so did Little’s. Leonell Strong was among them, together with his itinerant family and strains of mice. Money was provided by Roscoe B Jackson of the Hudson Motor Car Corporation and by Edsel Ford. The new animal facility was 30 m long and 17 wide, built of wood lined with brick, and was named for Roscoe Jackson after his sudden death in March 1929. The timing could not have been worse, for the Stock Market crashed in October 1929, taking most of their financial backing with it. Life was tough for the handful of pioneers, and fishing and vegetable gardening became essential activities; in 1933 the staff accepted a voluntary pay cut in order to feed the animals. Little, known to all as ‘Prexy’ (a shortened form of ‘president’) had the idea of buying a pig and feeding it upon fish scraps, freely available in this fishing community. To everyone’s disgust, its flesh tasted so rankly of fish that not even the hungry could eat it. In 1933 poverty prompted them to start selling mice to other laboratories instead of giving them away, and this was to prove the turning point in their financial fortunes. The JAX, as it was known from its telegraphic address, was on its way to becoming the world’s largest supplier of inbred mice. The building stank of mice, so much so that a change of clothes was necessary on leaving. Nor were these the only inhabitants, for a flick of the light switch would precipitate a stampede of cockroaches. Two cats lived there, both because of their scientific interest—they each had six claws—and because of the need to control uninvited mouse residents. It soon emerged that cat tapeworms live out part of their life cycle in mice (the parasites get into the cat when it eats a mouse), the whole colony got infested, and the  Sinclair, Arrowsmith, page 474.

3

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polydactylic cats had to go. Worse still, a returned mouse box (it cost less to ship the empty ones back) brought a cargo of bedbugs which infested every nook and cranny of the building. Their numbers could only be kept down by soaking everything in kerosene, a temporary measure that contributed to the final solution of the bed-bug problem when the buildings were incinerated in a forest fire in 1947. The small colony of humans grew, and in 1935 they were joined by a quietly spoken New Englander called George Snell. His standing among the islanders can be judged by the Bar Harbor Gazette, which reported many years later that the celebrated local gardener had been awarded a Nobel Prize.

10.4 Biological Individuality You may think that our recent history entitles us to feel pretty pleased with ourselves. Perhaps: but then we felt pretty pleased with ourselves twenty-five years ago, and in twenty-five years’ time people will look back at us and wonder at our obtuseness— Peter Medawar (1961)

The simplest and most successful form of tissue transplant is the blood transfusion, and it took its first faltering steps at the start of the twentieth century. Alexis Carrel, a French surgeon working (inevitably) at the Rockefeller Institute, pioneered techniques of stitching tiny blood vessels together. In 1908 he was called to see a 5-day-old baby who was bleeding to death because of a temporary clotting defect. At the insistence of the father, a well-known surgeon, the baby was strapped to an ironing board and Carrel joined the father’s radial artery to a vein on her leg—an operation of amazing virtuosity. The baby turned pink and then red as the father’s blood pumped into her. ‘You’d better turn it off, or she’ll burst’, cried an onlooker. The father’s hand survived, although the artery had to be tied off, and Carrel would in time attend the baby’s 21st birthday party. Bottled blood clots on exposure to air, and the discovery that this could be prevented by addition of citrate and glucose allowed American medical teams to give some of the first blood transfusions in World War 1. True to form, the medical profession condemned the new development, but Geoffrey Keynes (brother of the economist John Maynard Keynes) recruited a panel of volunteers in London who could be contacted by phone at any hour of the day or night and dispatched to where their blood was needed [11, p. 191]. It might seem paradoxical that blood can be exchanged freely between members of the same blood group, whereas kidneys and other organs are

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rejected by all but highly selected recipients. The explanation lies in the difference between your blood type and your tissue type. Human red cells are ghosts. They lack a nucleus, and do not carry the molecular recognition signals which constitute your tissue type on their surface. Instead, they display the restricted range of antigens that determine your blood group. Nucleated cells, in contrast, have surface receptors which act as recognition signals for the immune system. This is your tissue type, and it determines the likely success of a kidney transplant. In health, these receptors tell the immune system that the cell belongs to the same body and is healthy. Should the cell be invaded by a virus, however, the green light changes to red, and the affected cell is promptly destroyed. Type 1 diabetes involves inappropriate activation of this self-destruct mechanism by the beta cells of the pancreas—but there will be many twists in the road before we reach this point in our story. Despite all the work that had been done, common wisdom in 1935 did not go much beyond the observation that transplants between unrelated humans rarely work, and that mouse transplants are far more successful in related strains. Few saw this as clearly as JBS Haldane, who reviewed the genetics of cancer in 1933. Commenting on the work of Little, he remarked that rules governing tumour transplantation ‘are precisely similar to those which govern the transplantation of normal tissue’. This can only ‘be explained if the host only reacts to … foreign antigens in that tumour’. These ‘antigens’, as he speculated, are in fact immune recognition markers, and ‘on this hypothesis each gene is responsible for the manufacture of a particular antigen’ [12]. Peter Gorer, a recently qualified doctor with an interest in genetics, worked in Haldane’s laboratory from 1932–4 before going on to the Lister Institute in London, where he did much to justify Haldane’s insight. Gorer found that mice which rejected tumours in Strong’s ‘A’ strain produced an antibody that caused the red cells of mice from the same strain to clump together. Gorer’s papers are not easy to read, but this was clear evidence that the immune responses which determine the outcome of a transplant are under genetic control. Peter Gorer was an engaging character, son of a wealthy connoisseur of oriental art who went down with the Lusitania in 1915. His brother was Geoffrey Gorer, a well-known social anthropologist. Geoffrey, highly regarded in his day, was a companion of Margaret Mead who apparently refused marriage because this might involve having to apply medicine to his back. Peter gave little indication of academic prowess in early life and trained as a dentist before switching to medicine. He was a slight asthmatic man who smoked incessantly—even while giving a lecture—and was destined to die of lung

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cancer at the age of 544; he loved society at all levels and frequented the pubs and night clubs of London. His research inevitably lagged during the long years of World War Two, but he watched developments at the Jackson with interest, and he set off to Bar Harbor in 1946 to see if he could match his antibodies with George Snell’s genes. Gorer died in 1961, thus missing his chance of a Nobel nomination, and I visited the library at the Jackson labs in 2004 in order to research this chapter. My friend Ed Leiter collected me at the end of the day, and asked how I was getting on. I told him that there was a mass of material on Snell, but very little about Gorer. ‘OK’, said Ed, ‘let’s go see his wife’. The possibility that Gorer’s widow might have survived him by 43 years had never crossed my mind, let alone that she could be living down the road. Libby Gorer was Clarence Cook Little’s secretary in 1946, and Gorer took her back to the UK—she had vivid memories of travelling around post-war London in his Bentley—but she chose to retire to Bar Harbor when he died. After tea and patient replies to endless questions, she burrowed into a laundry box in the cupboard under the stairs and came up with a photograph. Gorer and Little got on famously, not least because they were both keen anglers and Gorer had been President of the British Fly Casting Association. George Snell was different: quiet and reserved, with just the occasional hint of the steel within. As a student he attended Dartmouth College, selected mainly because Latin was not an entry requirement, and soon found his vocation. ‘I just can’t imagine anything that better fitted my particular intellectual qualifications than genetics’, he remarked many years later, ‘I liked the mathematical angle of things. I am not a technician and you could work in genetics without doing lab work that would involve elaborate techniques, and it had a mathematical plan. This was exactly the right thing for me’. He was fascinated when Hermann Muller showed that the mutation rate in fruit flies could be accelerated by X-rays, and joined him in Texas to see if the same applied to the mouse. The Depression was a bad time for researchers, and Snell worked for a time with his brother, a pilot who made a living by barnstorming displays of stunt flying. Little had noticed his work, however, and Snell was invited to Bar Harbor in 1935. He made the trip in his Model A Ford Roadster, and was directed to the ‘Mouse House’ when he asked the way to the Jackson lab. He stayed for 66 years. ‘Dr Snell reminded me of Gepetto from the Walt Disney movie Pinocchio: a small slender balding man’, said one of his assistants. ‘Almost frail, with silver hair wreathing a balding dome, thin-rimmed  It was the epidemiologists who established the link between cigarettes and cancer: many geneticists, RA Fisher and Clarence Little included, did their best to oppose them. 4

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gold spectacles on a strong New England nose, China-blue eyes and lips that rested at the brink of a courteous smile’, said an interviewer many years later. He was spare, almost painfully thin, and suffered from a food allergy which made him avoid scientific meetings because of the need to prepare his own food. He was in addition meticulous, precise and regimented. He ‘gave us our protocols 1 year in advance … When he was about 3 months from retirement … I noticed that on his bookshelf there were notebooks dated for about 3 years into the future’ reported the assistant who compared him to Gepetto. His days followed much the same pattern: he would arrive early at the lab and work through to the early afternoon. He would then go home to work in his garden, take a nap and return to the lab. Winter evenings would be spent around a blazing log fire with his beloved wife Rhoda, often accompanied by overseas visitors and a glass of wine. Snell suggested in 1938 that the Jackson might produce a book about the laboratory mouse. Little was enthusiastic, and Snell became the editor. As such he came upon Little’s 25-year-old studies showing that Mendelian rules could be applied to multiple genes. He set himself the task of finding the genes involved in tumour rejection and worked out a complex strategy for doing so. The care and planning that went into this strategy was characteristic of a man who routinely designed his experiments 1 year in advance, and the enormity of his self-imposed task was breath-taking. Fifty years later the German geneticist Jan Klein imagined the reaction of a modern grant review committee to what Snell proposed to do: This is an ambitious proposal with no guarantee of success whatsoever. The investigator has not carried out any preliminary experiments to demonstrate that the proposed approach will work. He has no evidence that the H factors actually exist and if they do, that they are of any significance. He presents a bizarre scheme of crosses, intercrosses, and backcrosses, which he claims would produce, after a minimum of 5 years (sic!), the conjectured coisogenic lines. The only factor supporting the scheme is an elaborate mathematical derivation. The investigator, however, has no background in mathematics…’ [13]

Five years certainly was a lot for a 40-year-old man to gamble on a research project of uncertain relevance which relied on finding an unknown number of needles in a genetic haystack. His initial approach depended upon genetic linkage. Adjacent genes travel together like railway trucks, and ‘invisible’ genes can be tracked if they are hitched to marker genes with visible characteristics. The Jackson lab had an unrivalled collection of mice with visible genetic abnormalities, and Snell had a stroke of luck when he found that the

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genes which determine a strong rejection response at 10–14 days are linked to a gene located on Chromosome 17 which causes kinks on a mouse’s tail. Two other gene regions were involved in tumour rejection, but the response they produced was slower and less intense. One travelled with the gene for albinism on Chromosome 1, and the other was linked to a gene on Chromosome 2 responsible for a coat colour known as agouti. Snell lacked a name for these regions (loci in genetic parlance), until a colleague across the corridor suggested the term histocompatibility. The region associated with the strong rejection response thus became the major histocompatibility (MHC) locus. His next strategy was to breed closely related lines in search of varieties that differ only in their ability to reject a given tumour. This was done as follows: Strain A dies when given a given tumour, but related Strain B does not. When the two lines are mated, 50% of the genetic material in the offspring comes from Strain A, but some will survive the transplant by virtue of genes inherited from B. If you mate Strain A to these survivors, 75% of the genes in their offspring will derive from A, but some will survive transplantation because of genes inherited from B. The process is repeated again and again, providing tumour-resistant mice which are successively 87.5%, 93.75%, 96.9%, and so forth identical with strain A. After 14 generations you will have congenic mice which are virtually identical with line A but possess the gene or genes determining resistance to the tumour. Snell thus used a range of tumours to weave a living tapestry of genetic material. His analysis of the major locus soon became mired in complexity, however, for it contains a whole cluster of genes in close physical proximity to one another. Not just multiple genes, but multiple variants of each gene—most easily pictured as an extended family of relatives branching into endless sublines. Even so, Snell had managed to capture the genes of interest, and he knew where they were. He now needed to find out what they did. When Peter Gorer came up with antibodies that could distinguish between Snell’s mouse strains, it soon became apparent that his antigen II was controlled by Snell’s major histocompatibility locus, then known as ‘H’. This was accordingly renamed the H-2 locus, and the two minor loci were referred to as H-1 and H-3. Tumour resistance could now be linked to the generation of immune responses, and antibody testing could replace the tedious business of transplanting tumours. The phenomenon was nonetheless dauntingly complicated—but irresistibly fascinating to those who might otherwise have ended up deciphering a dead language or working as cryptographers. Outsiders felt totally baffled, and one remarked that ‘for those who did not belong to the

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H-2 fraternity, listening to expert discussions on H-2 tended to be like listening to people speaking a foreign language’. Cracking this particular code in mice, humans, and other species would take generations. Gorer died in 1961, but unassuming George Snell carried on the work. He maintained such a low profile that Ed Leiter heard the receptionist telling a caller she had no idea who they were talking about as he walked into the mouse house in 1980. He took the phone and found that someone in Stockholm was telling him about George’s Nobel Prize.

10.5 What Makes Us Unique? The story of histocompatibility illustrates that the history of biology is often made not by quantum leaps but by a plethora of small steps involving an army of participants—Leslie Brent (1997) [14]

Snell and Gorer found that genes on chromosome 17 play a key role in the immune response. Unrelated observations by people who knew nothing about their work came to similar conclusions, and the final convergence resulted in a quantum leap in our understanding of what—in biological terms—it means to be an individual.5 Once again, blood transfusion provided the starting point, in this case by investigation of feverish transfusion reactions in people who had received many units of blood. White cells, unlike red cells, do display your tissue type, and Jean Dausset, who shared Snell’s Nobel Prize in 1980, noted that the serum of people who had received multiple transfusions could cause the leukocytes of potential donors to clump together. He deduced that they had developed antibodies against white cells (rather than the red cells) received by transfusion. A woman in Leiden, already the mother of four, gave birth to twins on April 14th 1958. She bled heavily after delivery and went on to have a severe and unexplained reaction to blood transfusion. Her attendants said she must have received blood on previous occasions, but this was indignantly denied. Jan van Rood, the haematologist in charge, was aware that blood from the foetus can escape into the circulation of the mother, exposing her to tissue antigens which the baby had inherited from its father, and suggested that she had been ‘vaccinated’ against her partner’s white cells in  The original meaning of individual was “that which cannot be divided from the whole”. For cultural reasons we now use the word in the opposite sense, but the original meaning has more relevance for biology. 5

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the course of earlier pregnancies. This chance observation was of considerable practical significance, for the antibodies from the sera of ‘grand multips’ soon became a gold mine for investigators. Each laboratory built up its own collection, and more and more leukocyte antigens (now referred to as Human Leukocyte Antigens, or HLA for short) were reported in rapid succession. Anarchy was the result, for antigen x, as reported by laboratory A, might or might not be identical with antigen y reported by laboratory B. A small band of enthusiasts began to meet at workshops to exchange sera and compare results. The process was not easy, for the subject area is incredibly complex. Academic egos swell in small ponds and bruising encounters took place. The first attempt ended when the Italian chairman of the 1969 workshop stood at the podium and, with a grand gesture, shredded the accumulated datasheets with his hands. Order emerged slowly from this chaos, however, and the workshop format used by the HLA pioneers was imitated in other areas of medical science—and typically followed the same path of confusion, angry debate, and slow but steady resolution. In 1950, George Snell and Peter Gorer were working alone on a recondite problem in mouse genetics of no apparent practical relevance. By 1970, the human HLA system was recognised as a key element in our immune response, and allowed tissue transplants to be given. HLA proved to be a major player in the game of natural selection, for variation allows some individuals to survive when an epidemic sweeps through a population. Inevitably perhaps, variation introduces weakness as well as strength, and some common HLA types— common because they helped our ancestors to survive infectious disease—may also create loopholes in our immune defences. This vulnerability later provided an important key to the understanding of type 1 diabetes and many other medical conditions. I met Jon van Rood in his office in an oxblood-red building adjacent to the Leiden Medical Centre in 2007, and found myself talking to a man with a rugged face, enquiring blue eyes, a quiet sense of humour and exuberant enthusiasm. ‘Isn’t it fun’, he would repeat when talking about research. Van Rood went into medicine because he couldn’t choose between literature, history and mathematics, spent most of 1944 dodging German occupiers, and became a GP after the war. He followed his girl friend when she moved to New York in 1952 because he wanted to help but, as he ruefully remarked, someone else helped her more. Meanwhile he landed a job in the blood bank in a New York hospital and became interested in transfusion reactions. Back in the Netherlands, he developed a reporting system which equipped him to understand what had happened to the mother of twins in 1958. He also told me he had tested maternal serum number 12  in eight young people with

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diabetes in 1959. To his surprise, they all reacted, but he did not follow this up.6 The central task of the twentieth century biology was to take things apart and analyse their components. Genetic, biochemical and immune processes were teased out and broken down into interactions between molecules. Astonishing uniformity would emerge, clear evidence that all life is descended from a single ancestor. With it came the knowledge that the processes that drive living cells are closely related and often nearly identical. A visitor from another world would see this as the most striking feature of terrestrial life. For those who live here, however, it is the differences that matter, for the same molecular alphabet can convey an infinite variety of dialects. We are so alike, and yet so different. The variety springs from a multitude of minor differences between our constituent molecules, and from the way in which this repertoire is fine-tuned by experience. ‘Everything we’ve ever been on the way to becoming us, we still are’, as Terry Pratchett would say in a quite different context. There could be no better definition of biology.

10.6 We Have Found the Enemy, and He Is Us Immunology began as the handmaiden of microbiology, and concerned itself with the study of immune responses to infection. Immune responses can be harmful, for example, by causing excessive inflammation and scarring in response to infection. The great mystery of immunology, however, lay in the ability of the body to attack alien biological material while ignoring its own contents. Paul Ehrlich discovered antibodies (antikorper in German), and concluded that they were somehow prohibited from attacking your own tissues. This hardened into the dogma of horror autotoxicus. This embedded assumption (I call them mind parasites) would become a major obstacle to progress 50 years later. Ironically, the attempt of one of Ehrlich’s students to defend this dogma speeded its demise. Ernst Witebsky (1901–1969) trained with Paul Ehrlich, and came to the USA as a refugee from Hitler in the 1930s. Noel Rose (1927–2020) joined him in the early 1950s as a 23-year-old medical student, and I interviewed him for this book in the gardens of Keble College Oxford 50  years later. Tall, lean and earnest, he had the directness and  Serum 12 corresponded with HLA B8, which is in linkage equilibrium with HLA DR3, but this particular opportunity for fame passed him by. 6

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simplicity of someone who does research because he never considered anything else. When he took up the post, Witebsky showed him how to mark up his lab book as Ehrlich had done, and gave him a project designed to reinforce Ehrlich’s dogma. Theory dictated that healthy rabbits would be unable to make antibodies against their own thyroid, whereas rabbits whose thyroid had been surgically removed should be able to do so. In the event, both groups developed antibodies in response to thyroid extract, and lymphocytes invaded those with intact thyroids. A surgical colleague who dropped by the lab told them this resembled a human disease called Hashimoto’s thyroiditis. Hashimoto’s affects 1–2% of the population, mainly women, and causes progressive scarring of the gland, which shrinks, hardens and eventually fails to produce thyroid hormone. Those affected have high gamma-globulin levels. This is the plasma fraction which contains antibodies, and Rose submitted a paper suggesting they might be making antibodies to their own thyroid. Unluckily for him, referees brought up on horror autotoxicus mauled the paper so badly that Witebsky sat on it for a year, during which time they were overtaken by two young investigators from the UK. Deborah Doniach (1912–2004) was the daughter of a Ukrainian concert pianist and a Norwegian teacher of therapeutic dance. Tiny and disarmingly modest, she radiated electricity, had a consuming love for her subject and a penetrating cross-eyed gaze. The overall impression was that of a slightly manic pixie. ‘They used to tell me there was no such thing as autoimmunity’, she told me, ‘and I would stand at the podium and hold up a bottle of serum. “Here they are”, I would say, “here are the antibodies”’. This was the birth of a new paradigm, resisted by the upper ranks of the thought collective and pursued with evangelical vigour by its proponents. Autoantibodies were indeed confirmed in people with Hashimoto’s and other conditions, clear proof that the immune system can turn on the body that houses it. These were the organ-specific autoimmune disorders, and they turned out to be relatively common. They may take years to develop, and autoantibodies often appear long before the target organ shows signs of distress. Type1 diabetes is no exception. Invasion by lymphocytes is another hallmark. There is an old joke about the medical student who was asked by an examiner to explain the function of the spleen. ‘I’m sorry, sir’ he replied, ‘but I’m afraid I’ve forgotten’. ‘Oh dear’ sighed the examiner, ‘now nobody knows’. The same might have been said of the lymphocyte in the first half of the twentieth century. The immunologist Arnold Rich said in 1936 that ‘the complete ignorance of the function of this cell is one of the most humiliating and disgraceful gaps in all medical

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knowledge’. The lymphocyte is a small white cell, long-lived and nomadic, which appeared to do nothing at all before it was shown to play a central role in our immune memory. A sleeping beauty among cells, it awaits the kiss that will bring it back to life. Cells awakened by the kiss of a foreign antigen arm themselves for combat: their cytoplasm expands and they divide rapidly. The spleen and lymph nodes are packed with sleeping and active lymphocytes, and they account for all the cells in the lymphatic circulation and about 25% of the white cells in blood. By the 1960s it was clear that lymphocytes perform at least two distinct functions. One class, the ‘B’ lymphocytes, produces antibodies, whereas so-­ called killer ‘T’ lymphocytes grapple infected cells and destroy them. This dual role explains their importance in autoimmune disorders.

10.7 The Walls Come Tumbling Down At least three autoimmune conditions had been recognised by the early 1960s. Those affected by any one of these are at increased risk of the other two, and so are their relatives. This suggested that what is transmitted is susceptibility rather than disease, and that the conditions share a common genetic basis. Juvenile diabetes kept cropping up in their family history, a potent clue that it might have an autoimmune basis. If so, where were the autoantibodies? The technique used was to expose healthy islet cells to the serum of the person tested. Antibodies in the serum latch on to the target cell, and their presence can be detected by anti-antibody antibodies tagged with fluorescent dye: cells with antibodies attached glow under the microscope when exposed to light of the correct wavelength. Such was the theory, but many had tried the technique in juvenile diabetes, and all had failed. It happened in London. Richard Lendrum was looking for antibodies to the exocrine pancreas in patients with pancreatitis. He obtained his human pancreas from recently deceased individuals (usually victims of road traffic accidents) whose kidneys had been whipped out for transplantation. This gave him access to fresh pancreas and the blood group of the donor (not normally included in post-mortem reports) was recorded for purposes of transplantation. It emerged that the antibody test only worked well in donors from blood group O. With characteristic courtesy, Doniach offered Lendrum her help. A flamboyant young Venetian called Franco Bottazzo (1946–2017) just happened to be rounding off a thesis on Addison’s disease in her laboratory, and he was anxious to test serum from affected patients against as wide a range

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of tissues as possible. Lendrum offered him some fresh group O pancreas and Bottazzo opened the freezer door to find a priceless array of samples from people with thyroid and adrenal autoimmunity, some of whom also had diabetes. Unlike those who went before, Bottazzo had the right microscope, the right pancreas and the right samples. To this he added the right pair of eyes, eyes that gazed in silent wonder as islets lit up like green beacons under the microscope. He examined 171 patients with adrenal and thyroid autoimmunity, and found strong staining reactions in the islets of 13, 8 of whom had diabetes, Furthermore, two of the remainder developed diabetes after the sample was taken [15]. It was the first hint that antibodies could predict type 1 diabetes. When new ideas come, they come in a rush. Papers reporting the HLA associations of juvenile diabetes and reports of circulating autoantibodies appeared in the Lancet between October 12th and December 28th 1974, together with an anonymous editorial entitled ‘autoimmune diabetes mellitus’. I happened to sit in on the time-honoured selection procedure at the journal many years later. The manuscripts were delivered in wicker baskets and discussed in an oval room lined with editions dating back to 1827. I asked the editor who had written the anonymous editorial. He opened the volume in question, and told me that it was by a young Scottish researcher called Angus McCuish (1948–2018), and that he had received £5 for doing so! Scientific progress is generally portrayed as straightforward, logical, and inevitable, but enlightenment may come from unexpected directions. A paradigm shift breaks all the rules. Imagine a grant review committee manned by conscientious and well-informed senior investigators examining proposals in 1973. Why should the committee support young and untested investigators with no track record in diabetes when well-reputed groups have already shown that there is nothing to be found? So it would go. A long slow drift in opinion prepared the way for the climate in which the concept of autoimmune diabetes made immediate sense. Not all were converted, but this was an idea whose time had come. Clinicians were left wallowing. Investigators of whom they had never heard stood up and described unfamiliar techniques in an incomprehensible vocabulary. The alienation of the clinical specialist had begun, and physicians soon became resigned to the fact that advanced scientific discussion of the condition to which they had devoted their working lives would be beyond their comprehension. Baffled though they were, it made immediate sense to divide diabetes in two, for this mapped to the realities of clinical experience.

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10.8 The Heel of Achilles His mother dipped the infant Achilles into the river Styx to render him invulnerable, but held him by the heels as she did so. This left him vulnerable to the poisoned arrow that caused his death. Our immune system is plunged at birth into a world teeming with micro-organisms which evolve much faster than we do. Luckily, we can build new defences in real time, and hypervariable genes make immunity possible. The person sitting next to you in the train is likely to have the same insulin gene as you, but the likelihood that she will have the same set of immune defence genes is around a million to one. Inherited variability protects the population against epidemics, but it also creates individual loopholes—accidents waiting to happen (Fig. 10.1). Identical twin pairs helped the type1/type 2 paradigm to fall into place. Although early-onset diabetes was assumed to be ‘more genetic’, twin studies showed a one in three chance that the unaffected partner will never develop diabetes at all. Conversely, if one twin has late-onset diabetes, the other twin almost invariably turns out to be affected. Same genes, same environment, different outcome: how do you explain that? Crucially, it showed that type 1 diabetes is not a matter of genetic predestination. This being so, it should be possible to prevent it. This teasing reflection tempted many young investigators into this rapidly developing area. And behind it lay an even more fundamental question: why are so many people at risk of autoimmune disease, yet so few are affected? How, in other words, does the body stop type 1 diabetes from happening? The other conundrum is that lack of insulin is the only abnormality present at the onset of type 1 diabetes. This came home to me when a young man returned to the clinic after a successful pancreas transplant. He no longer had diabetes, and I had nothing to offer him. Unfortunately, his new pancreas was unlikely to last more than a few years, and he needed potentially harmful immunosuppressive therapy to prevent rejection. The long-term hope, therefore, is to engineer new beta cells which are invisible to the immune system of the recipient. Two themes come to mind. The science fiction writer Arthur C Clarke said that ‘when a distinguished but elderly scientist says that some something is possible, he (sic) is almost certainly right’. The other is that we routinely overestimate present possibilities. Proffering hope has always part of the business of diabetes, as when the Juvenile Diabetes Research Foundation (JDRF) designated the 1990s as the ‘decade of the cure’. The cure will come, but no-one knows when—or what the new challenges will be.

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Fig. 10.1  Twin sisters divided by diabetes. These were monozygotic (identical) twins, but the sister to the left developed type 1 diabetes at the age of seven, grew poorly, and died of diabetic kidney disease in her early 30s. Her sister was non-diabetic when lost to follow-up at the age of 56. (Courtesy of Robert Tattersall)

References 1. Kuhn T. The structure of scientific revolutions. Chicago: University of Chicago Press; 1962. 2. Keeler CE.  The laboratory mouse. Cambridge, MA: Harvard University Press; 1931.

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3. Steensma DP, et al. (2010) Abbie Lathrop, the ‘mouse woman of Granby’, rodent fancier and accidental genetics pioneer. Mayo Clin Proc. 2010;85(11):e83. 4. Yerkes RM.  The dancing mouse. A study in animal behaviour. New  York: Macmillan; 1907. 5. Holstein J. The first fifty years at the Jackson Laboratory 1929–1979. Bar Harbor, ME: Jackson Laboratory; 1979. 6. Rader K. Making mice. standardizing animals for American Biomedical Research 1900–55. Princeton, NJ: Princeton University Press; 2004. 7. Strong LC. A Baconian in cancer research. Autobiographical essay. Cancer Res. 1976;36:3545–53. 8. Galton F.  Hereditary genius. An inquiry into its laws and consequences. New York: Macmillan; 1892. 9. Castle WE.  Genetics and eugenics. Cambridge, MA: Harvard University Press; 1916. 10. Reid GA. The principles of heredity. London: Chapman & Hall; 1905. 11. Keynes G. The gates of memory. Oxford: Clarendon Press; 1981. 12. Haldane JBS. The genetics of cancer. Nature. 1933;132:265–9. 13. Klein J. Snell’s unwritten grant application. Immunogenetics. 1997;46(1):78–9. 14. Brent L.  A history of transplantation immunology. San Diego, CA: Academic Press; 1997. 15. Bottazzo GF, et  al. Islet cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet. 1974;2(7892):1279–83.

Part IV The Shape of Things to Come

11 The Endless Frontier

Even as clinical diabetes languished in the doldrums (Chap. 13), scientific understanding of its epidemiology and metabolic consequences forged ahead. The USA declared war against disease, and population studies supplemented by large clinical trials introduced the concept of risk factors, so central to modern medicine. Diabetes would henceforth come to be seen as a risk factor rather than a disease. Professional publically-funded investigators flourished in the new environment, as did the ‘food chain’ generated by their activity. The USA has a distinguished tradition of private philanthropy, and Frederick Gates was a pioneer in the profession of spending other people’s money. The man whose money he spent was John F Rockefeller, Jr., and it was with Gates’ guidance and advice that the Rockefeller Institute for Medical Research (later to be known as Rockefeller University) opened in New York in 1906. Gates had an agenda. High on this was the need to overcome the subservience of American science to that of Europe in general and of Germany in particular. As the Spanish scientist Santiago Ramón y Cajal pointed out in 1916: Germany alone produces more new data than all the other nations combined when it comes to biology … a knowledge of German is so essential that today there is probably not a single Italian, English, French, Russian or Swedish investigator who is unable to read monographs published in it [1].

Germany’s pre-eminence was the result of a national strategy to develop science as a tool for economic expansion and political assertion. America would © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 E. Gale, Life in the Age of Insulin, Copernicus Books, https://doi.org/10.1007/978-3-031-47190-2_11

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later follow suit. We might imagine that ours is the first generation to be concerned about manipulation of the human species, but it was widely believed a century ago that human beings and society could and should be engineered for the better. Gates—a Baptist minister—was fervent in his secular gospel: I am talking now of the religion not of the past, but of the future … as this medical research goes on you will … promulgate … new moral laws and new social laws, new definitions of what is right and wrong in our relations with each other … you will teach nobler conceptions of our social relations and of the God who is over us all [2, p. 24]

The Rockefeller Institute, founded with Rockefeller’s money and Gates’ guidance, was organised around departments with a charismatic head, and offered a more diverse and collegial approach than the leading European institutions. Jacques Loeb, an expatriate German, was a key figure; his fervent materialism was an extreme reaction to the idealistic German philosophy of his youth. His research, widely hailed at the time, showed that the development of sea urchin eggs was influenced by the chemical conditions to which they were exposed. Life was a chemical phenomenon. His longerterm importance lay in the search for the molecular basis of life, for he believed that the biology of the future must be built upon an understanding of the fundamental processes on which life depended. Since these processes are everywhere the same, the simpler the organism investigated, the better. Contrariwise, a frontal attack on the complexities of human disease as advocated by physicians was simply ‘twaddle’ (his preferred description). Loeb’s own beliefs concerning the chemistry of life were quaint and dated rapidly, but a man whose world-view originated in the early days of German biology voiced the dominant note of biomedical research in the twentieth century. The Rockefeller Institute listened, and its labs began to fill with chemists and physicists. The investment was large and the immediate pay-back smaller than expected. Paul de Kruif, the turbulent young bacteriologist who co-­ authored Arrowsmith, later took it to task for its lack of practical success. 1 ‘As the years wore on the hoped-for parade of cures did not come off’ he commented—not without satisfaction—but better things were to come. Behind the Rockefeller Institute lay the Rockefeller Foundation, destined to play a major role in giving twentieth century biology its direction. The  de Kruif was the unacknowledged co-author of the novel Arrowsmith by Sinclair Lewis, whose protagonist was based on Jacques Loeb. His book the Microbe Hunters, as compelling and infuriating as the man himself, was to attract a whole generation of students into medical research. 1

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emphasis was upon the basic processes of life, studied in terms of molecular interactions in the simplest organism available. Bacteria fitted this role admirably. Since the role of DNA had yet to be recognised, proteins were probably what Warren Weaver, director of the Foundation’s natural science division, had in mind when he coined the term ‘molecular biology’ in 1938. The Foundation had firm ideas as to the type of research it wanted to fund, and moulded both the individuals and the institutions concerned by doing so. It succeeded so well that 17 of the first 18 Nobel prizes awarded for work on the molecular biology of the gene went to researchers wholly or partly funded by Rockefeller money. A new environment emerged, that of project-­orientated technology-based research. The scale of investment rocketed as expensive instruments took over from the custom-built kit of the pioneers, and this investment had to be managed. Funding bodies, researchers, and research institutes became increasing enmeshed. Effective management became the sine qua non of research and gave rise to a new caste of investigator-managers who would be judged by the number of articles they published in leading journals and the research income they could generate.

11.1 The War Against Disease On November 17th, 1944, 10  days after being re-elected for an unprecedented fourth term of office, Franklin D Roosevelt dictated a letter to Vannevar Bush, Director of the US Office of Scientific Research and Development. The end of World War 2 was in sight, and the US economy had been jerked out of stagnation by its demands. A central command structure had been imposed upon a faltering economy, and ever-increasing demand had transformed every aspect of production from food to military material. The influx of government dollars had powered new ways of doing things, not least when it came to importing scientific methods into industry. Science was the theme of Roosevelt’s letter. His first question related to military preparedness, and the second looked beyond this to the war against disease. This must have been close to Roosevelt’s heart. Crippled by polio and prematurely aged, he suffered from uncontrolled hypertension and was destined to die from a haemorrhagic stroke on April 12th 1945 at the age of 63. The research programme he hoped to launch would reveal that both his polio and his stroke could have been prevented, but Bush’s reply of July 25th 1945 was addressed to a different President [3]. His reply caught the mood of the moment. Medical progress had influenced the course of the war to such an extent that death from disease in the

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army fell from 14.1 per thousand in World War 1 to 0.6 in World War 2, despite exposure to tropical diseases in the jungles of South-East Asia and the Pacific. Preventive measures, penicillin, and anti-malarials had played a large part. Bush went on to note that death in childhood (mainly due to infection) had fallen dramatically, and that the war against cancer and the degenerative disorders of later life was moving centre stage. Experience had confirmed Jacques Loeb’s belief that a frontal attack upon medical problems was generally unproductive, whereas important advances in treatment were ‘the result of fundamental discoveries in subjects unrelated to those diseases’. This being the case, the government should move the frontier of science forward by offering free rein to scientific enquiry. Insights generated by basic science could then be fed directly into the requirements of industry, promoting a vibrant and science-led economy. America’s next war would be against disease, and vastly increased government funding would make it possible. Several people had stumbled upon insulin in the decade before 1922, but institutional myopia and pharmaceutical disinterest left them crying in the wilderness. Never again. The concept of a broad-based yet structured attack on the causes of disease merely awaited the emergence of a society with the means and the motivation to undertake it. Molecular biology would be a key element in the onslaught, and insulin was a leading focus of research. Glittering prizes awaited the laboratory scientist. A lonely and painstaking 10-year quest won Frederick Sanger the first of two Nobel Prizes for working out the linear sequence of amino acids in the insulin molecule, and a 35-year quest culminated in Dorothy Hodgkin’s elucidation of its three-dimensional structure. She already had a Nobel Prize for the structure of Vitamin B12. Yet another Nobel Prize was won by Rosalind Yalow for discovering that radioimmunoassay could measure infinitesimal quantities of insulin in the circulation; the untimely death of her colleague Sol Berson prevented him from sharing the award. Outside the lab, two major developments directed the future course of clinical research. It was no longer enough for clinicians to study disease at the bedside; it must also be tracked through whole populations. The only previous attempt to extract systematic health information had been made by the life insurance companies, and they made money by relating your biological age (as judged by life expectancy) to your chronological age. Their estimate of biological age was based on your social situation, your personal habits, and measures such as weight, blood pressure, glucose, and cholesterol. When actuaries talk of risk they mean financial risk, not yours. The academic epidemiologists were interested in risk because they wanted to change it, and the landmark Framingham Heart Study, established in 1948, showed the way. As

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its name implies, the study was prompted by the post-war epidemic of coronary heart disease, and observation of people in a small town in America showed that risk of a coronary was closely related to pre-existing physiological variables such as blood pressure, cholesterol, and glucose. The term ‘risk factor’ entered our vocabulary. Kelly West’s magisterial Epidemiology of Diabetes and its Vascular Lesions (1978) reflected the changing view of diabetes. He admitted that he was not even aware that what he was doing was epidemiology until someone told him so in the 1960s. He and others showed that the body’s ability to handle glucose ranges along a spectrum between the statistical ‘normality’ of health and the abnormality we call type 2 diabetes, and he argued for a prognostic definition based on the level of blood glucose likely to result in future harm. Similar conclusions were reached by those dealing with risk factors such as blood pressure and cholesterol (Fig. 11.1). What followed was nothing less than a quiet revolution in the way we think about health and disease, so much so that probability-based medical care became a normal component of the ageing process. When Framingham identified blood pressure, cholesterol, and glucose as age-related risk factors, doctors began to define normality in terms of healthy young adults—statistically speaking, old age is a disease. Consideration of the risk conferred by diabetes was complicated by the fact that the condition has many unwanted outcomes. An increase in blood glucose predisposes to heart attacks and strokes, for example, but causes the small vessel disease seen only in diabetes. To complicate matters, the threshold of risk varies: arterial risk rises slowly and progressively High blood pressure Is defined by risk of stroke

High cholesterol Is defined by risk of heart attack

High blood glucose Is defined by risk of complications

Fig. 11.1  Risk factor definitions are defined in terms of risk, and are therefore circular

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within the normal range of blood glucose, whereas small blood vessel disease only occurs at levels associated with full-blown diabetes. The co-existence of two distinct types of vascular disease in diabetes, each with a different glucose threshold, would give rise to decades of confusion. The move from treating disease to treating risk changed the rules of the game, for strokes and heart attacks are infrequent events. How then can you demonstrate protection against them? Only by offering randomly allocated active or placebo treatment to thousands of people in the knowledge that most of them will be unaffected over the period of observation. Huge clinical trials are intrinsically wasteful, for the outcome will be judged on statistical analysis of a mere handful of events. Even so, analysis of such events could pave the way to interventions that could prolong thousands of lives. Here, once again, the USA would lead the way.

11.2 The Pigs and the Pork Barrel The US government made little investment in academic science in the pre-­ war period, although its promotion of agricultural research led to important advances in genetics. World War 2 transformed this state of affairs, and research and development costs rose from 0.3% of GNP and 0.8% of the federal budget in 1940 to 3% and 14%, respectively, by 1962–3. The abstract formulae of the academic physicists—hitherto an obscure and neglected breed—had translated into wealth and power, and the resulting arms and space races made them even more indispensable. Government investment in academic science funded the costs of basic research and created a cadre of trained scientists for industry to recruit; industry boomed and its profits swelled the federal coffers. Governments still needed to sell research to the taxpayer, however, and they were ably abetted in this by powerful interest groups. The pharmaceutical giants invest heavily in research but want something in return. And herein lies a dilemma, for basic research has—by definition—no practical outcome. Science writer Daniel S Greenberg pointed out that people ‘engage in basic research because they find it a stimulating and agreeable way of life, not because it may ultimately lead to better television sets’. Their activity, self-defined as useless, must then be sold to the taxpayer on the basis of the practical results it might generate. Academics were quick to appreciate the corollary, which is that any useless activity can potentially be justified. The rise of molecular biology in the second half of the twentieth century resulted in a quantum leap in the costs of laboratory research, transforming it

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from a cottage industry into a full-scale industrial process. Meanwhile the costs of medical care escalated, making health-related research a highly profitable area. Biomedical research flourishes in the USA precisely because its health care system is so costly and inefficient. To give some idea of scale, the US drug bill for 2000–2002 inclusive would, after adjustment for inflation, have paid for the Vietnam War. Any activity that generates money creates a food chain of its own, and the laboratory worker who lives off the public purse must shape him or herself accordingly. Government funds are defended by a labyrinthine bureaucratic process, and academic institutions created a mirror bureaucracy of their own to navigate it. Freebooting characters driven solely by curiosity, impatient of paperwork and procedures—in short, those most likely to change the rules of the game—are soon edged out of the food line, and people who know how to work the system take over. Research hardens into a ‘conspiracy against the laity’, and woe betide any interloper. Meanwhile, science has become the ultimate futures market, for it is based upon the attempt to purchase something that does not yet exist. The potential buyers have their own criteria. A charity representing people with diabetes will want maximum relevance and practical utility, a government body will be interested in building research expertise within a given area, and a pharmaceutical company seeks to attract investors. Scientific proposals are, however, judged by scientists. This makes science less accountable than you might imagine, and justifies the wry comment that ‘scientific research is the only pork barrel for which the pigs determine who gets the pork’. Attempts to circumvent this flourish upon the scientific illiteracy of the public, and Daniel Greenberg created a very recognisable character known as Grant Swinger in the 1960s. Grant was Director of the Center for the Absorption of Federal Funds, itself associated with the Breakthrough Institute, and a previous winner of the Segmentation Prize, awarded annually for the most publications from a single piece of research. Asked whether Grant Swinger was drawn from real life, Greenberg replied that he was fashioned about three quarters from one eminently successful operator he had observed, with borrowings from others to make up the rest. He concludes: Grant Swinger is a warning against naïve faith in the skills and disinterest of heavily credentialed ‘experts’, especially that thriving new breed of press-­ conference virtuosos who clamor for our attention. Above all, Grant symbolizes the need for us to dope things out for ourselves, and, when we can’t do that— which is often the case—to proceed cautiously and intelligently in assessing what the experts would have us believe [4, p. 2].

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Grant Swinger flourishes because the public wants to believe him. So it is that scientists and science administrators plus a few token good souls to represent the public interest sit around a table and decide who will fly and who will be grounded. Less obvious is the power struggle within the scientific community to become the official voice of medicine. The underlying agenda of all experts is to define any problem in such a way as to make themselves central to its solution. By the same token, a secondary aim is to discredit those who seek to analyse the same question from another point of view. The innocent outsider might cherish the belief that scientists will set aside parochial squabbles in order to devote themselves to the higher task of defeating a disease such as diabetes. If only. In truth, there is only one known means of uniting the diabetes research community, and that is to threaten its slice of the research budget. Faced with the possibility of reduced funding, the protagonists within a specialised area will abandon sibling rivalry in order to close ranks against the common threat. Not that the protagonists would for one moment accept this picture of their own behaviour. Many exhibit the sublime confidence that comes from knowing a very great deal about very little, and their self-belief is genuine. The economist John Kenneth Galbraith examined a PhD thesis related to the economics of war-time production. The product in question was leather, and the candidate made a convincing argument to the effect that armies must march if wars are to be won, that marching requires boots, and that boots require leather. Conclusion: the leather industry was central to the defeat of Nazism. This form of logic, argued with equal conviction, is the standard fare consumed by committees which review grant applications.

11.3 An Anthropologist in the Laboratory In 1976 an anthropologist ventured into the laboratory of a group of research scientists, one of whom—Roger Guillemin—was shortly to share a Nobel Prize for the discovery of somatostatin and other brain peptides. The anthropologist, who knew no science, behaved as he would in the highlands of New Guinea and simply recorded what people did. Most of them, as he noted, fed biological material into machines. The machines subjected this to a physical or chemical change which was quantified and converted into an electronic output. These outputs were then fed into computers which arranged them into graphs and numerical statements. Higher echelon people who lived in cluttered offices adjacent to the lab subjected the print-outs to eager

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discussion and debate, and verbal statements were submitted for publication. Every 10 days or so another article left the slipway on its way to a scientific or medical journal, at a cost of around $30,000 apiece (1970 values). The underlying alchemy, as the observer noted, was transmutation. Money was transmuted into machines. Biological material fed the machines, the machines generated numbers, the numbers generated statements, and the statements generated money. Money apart, the aim of the process was to feed a statement. The statement itself might be ranged into five levels of validity, rephrased here as follows: • Level 1: a conjecture without the force of evidence, e.g., ‘might imply that’—generally found towards the end of scientific papers. • Level 2: preliminary statements of possible relationships, ‘these observations suggest that..’ • Level 3: reinforcement of a postulated relationship, ‘there is growing evidence that..’ • Level 4: a statement of an accepted relationship, ‘this confirms that’—the stuff of textbooks. • Level 5: an unchallenged statement, as in ‘insulin contains 51 amino acids’. The task of research, the anthropologist considered, was to move statements up the hierarchy. Their progress could be tracked by the use of citations. These cluster like flies around levels 2 and 3, for this is where the battle for acceptance is raging. A statement made at level 4 might be supported by reference to a textbook or review, and level 5 statements need no citations at all. The task of the researcher is therefore to steer her proposition through disputed territory, and—if very lucky indeed—she might also get the credit for doing so. She is engaged in the construction of a scientific fact [5]. We may smile at cultural relativists who sit at their computers to argue that beliefs based on science are no more valid than any others. Science, as they will point out, is driven by politics, economics, career possibilities and organisational hierarchy. The scientists, by way of contrast, will generally see themselves as a privileged elite with a vision denied to others. Both views contain an element of truth, and experimental scientists can claim ownership of the only undisputed way in which people have ever managed to learn from their mistakes. This is fortunate, for scientists make an awful lot of them. Research is intrinsically wasteful and, as with any other quest for excellence, success emerges from a vast substrate of wasted endeavour and frustrated talent. The molecular biologist Benno Müller-Hill wrote a short and amusing history of a quest in molecular biology for something called the lac operon. Unusually,

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he does not ignore the false trails, but lists no fewer than 23 mistaken assumptions, methods or conclusions which found a home in journals such as Nature. Most scientific papers are destined for speedy oblivion. Inadequate, interim, derivative, misguided or partial in their conclusions, they are spawned within a crowded microenvironment where only the fittest or luckiest can survive. Müller-Hill nonetheless concludes that error is eventually eliminated, however slow and inefficient the process, and that we do move ever closer to a hard core of verifiable information [6].

References 1. Cajal SR. Advice for a young investigator. Revised and translated by Neely & Larry Swanson. Cambridge, MA: MIT Press; 1916. 2. Dubos RJ. The professor, the institute, and DNA. New York: Rockefeller University Press; 1976. 3. Bush V.  Science the endless frontier. In: A report to the president by Vannevar Bush, Director of the Office of Scientific Research and Development, July 1945, vol. 48. Washington: United States Government Printing Office; 1945. p. 231. 4. Greenberg DS. The Grant swinger papers. In collaboration with the Center for the Absorption of Federal Funds. Science and Government Reports; 1983. 5. Latour B, Woolgar S. Laboratory life. The construction of scientific facts. Princeton, NJ: Princeton University Press; 1986. 6. Mϋller-Hill B. The lac operon. The short history of a genetic paradigm. Berlin: De Gruyter; 1996.

12 A Short Walk Through Time

The scientific discovery of insulin proceeded at a dizzying pace in the post-­ war period. The way in which insulin affects the pathways by which food energy is distributed and released within the body became clearer. Insulin was known to be a protein, but it was not known that the amino acids within a protein have a well-defined sequence which determines its three-­ dimensional structure and hence its function. No-one knew how insulin exerted its influence upon the internal activity of cells, let alone that a special receptor transmits its signal across cell membranes. Nor did anyone know how to measure it accurately.

12.1 The Wheel of Life The origins of biochemistry (the word was coined in 1903) go hand in hand with the story of fermentation in yeast. The glucose molecule has a skeleton of six carbon atoms in a ring. When broken down to make energy, the major product is a 3-carbon molecule called pyruvate. In the presence of oxygen, yeast breaks pyruvate down to carbon dioxide and water by a process called respiration. In the absence of oxygen, it is converted to alcohol by the process of fermentation. An important landmark came when the Büchner brothers ground up yeast in the closing years of the nineteenth century and discovered that the juice remained active. Cell-free preparations allowed the stages of fermentation to be tracked and dissected, one of the great achievements of German biochemistry. In contrast, respiration takes place in intracellular

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 E. Gale, Life in the Age of Insulin, Copernicus Books, https://doi.org/10.1007/978-3-031-47190-2_12

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organelles known as mitochondria. These were discarded by standard methods of preparation, and their function took longer to be detected. Hans Krebs (1900–1981) trained with Otto Warburg, one of the great pioneers of biochemistry, and left to form his own laboratory in Freiburg in 1930. Once there, he identified the urea cycle in the liver, the first endless cycle in biochemistry to be described. Antisemitism forced Krebs to flee to the UK in 1933, but with him went the ambition to study the process by which pyruvate is converted to water and carbon dioxide. This, as he discovered, was another example of circular chemical flux. This chain reaction, known as the Krebs or citric acid cycle, is an endless self-feeding chemical conveyor belt which converts pyruvate into carbon dioxide and water, releasing packets of energy at each step in the process. The manuscript which reported this landmark achievement was rejected by the editor of Nature in 1935 on the grounds that he had ‘received a lot of good papers recently.’ Krebs was unable to get funding for his co-author William Johnson, who ended up as a turtle farmer in the Cayman Islands [1]. Nothing could detract from the achievement. As Krebs said in 1953: It is indeed remarkable that all foodstuffs are burnt through a common terminal pathway. About two thirds of the energy derived from food in higher organisms is set free in the course of this common pathway; about one third arises in the reactions which prepare foodstuffs for entry into the citric acid cycle. The biological significance of the common route may lie in the fact that such an arrangement represents an economy of chemical tools … in spite of a multitude of sources of energy the number of steps where energy is utilized is astonishingly small—only seven. 1

It was with feelings approaching awe that he and others came to appreciate that this pathway provides energy for all living things from microbes to man. It was a stunning demonstration of the unity of life. Furthermore, the concept of endless cycles, soon to be extended to intermediary metabolism as a whole, demonstrated in the sober language of science something previously seen only in the visions of mystics such as the Greek philosopher Heraclitus—that the apparent solidity of living forms, like that of a candle flame, is based upon endless flux. It might seem beyond belief that an insight of such transcendent beauty could be made dreary or incomprehensible to the uninitiated, but such has been the achievement of countless lecturers in biochemistry.  Krebs, Nobel Lecture. There were later seen to be eight steps.

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Thanks to the biochemists, however, the major energy pathways of the body had been mapped out by the mid-century, and began to look rather like a map of the London Underground system. The citric acid cycle is the equivalent of the Circle Line, from which the traveller can access any other part of the network. The switch from one line to another is accomplished by activating or inactivating key enzymes, a principal function of hormones like insulin. Pre-war biochemists knew that glucose somehow passed through the outer membrane of cells. Once inside, it attached to phosphate and was locked into the energy network of the cell. This depended upon enzymes controlled by insulin which—as many assumed—could also freely enter the cell. This model was simple, convincing, and wrong, for the cell membrane turned out to be a far more formidable barrier. As for insulin itself, its nature was a mystery. It was clearly a protein which interacted with enzymes, but its structure was unknown, no-one knew how it interacted with the cell or produced its effects, and nobody could measure it. Many—but by no means all—of these questions would be answered in the golden age that was about to dawn.

12.2 Fred Sanger’s Journey In 1943 a 25-year-old postgraduate student called Frederick Sanger (1918–2013) set out to crack the code for insulin, an apparently impossible task that would take 10 years, much of it spent working alone. A protein is formed of amino acids strung together like beads on a necklace, and the chain is known as a peptide. The challenge was to work out the sequence of the beads, otherwise known as the primary structure of a protein. It was known that 18 different amino acids are present in insulin, including sulphur-­ containing cysteine. An added incentive was that beef insulin was readily available for clinical use. In the event Sanger would use more than 100 grams, enough to treat 130 patients for a year. Imagine you have 51 tiles from a Scrabble game containing 18 letters of the alphabet. These tiles once formed a message, and your task is to work out the original sequence. You have two important clues. The first is that the amino acid sequence is like a sentence; it can be read in one direction only. This orientation occurs because the nitrogen group on each amino acid hooks on to a carbon group on the next. If we identify these as ‘N’ and ‘C’, a peptide chain will look as follows: (‘N’ end) —N..C—N..C—N..C—N..C— (‘C’ end)

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Every nitrogen group in the molecule except for the unattached group at the ‘N’ end is locked into a chemical combination. Sanger tagged this with a chemical called FDNP, and found that insulin has two free ends. This told him it contains two peptide chains. Abel had shown that insulin can be inactivated by splitting the bond between sulphur molecules. The amino acid cysteine contains sulphur, and it was reasonable to assume that sulphur-­sulphur bonds link the two peptide chains. Sanger separated them by cutting the sulphur bridges. The electrical charges of the two chains differ, and he could pull them apart by electrophoresis. This gave two sequences of 21 and 30 amino acids which he called the A and B chains. The Scrabble tiles line up as follows: A chain: (‘N’)—GIVQECCASVCSLYQLEDYCB—(‘C’). B chain: (‘N’)—FVDQHLCGSHLVEALYLVCGERGFFYTPKA—(‘C’). Chemists assign a letter of the alphabet to each amino acid, and this is the actual composition of beef insulin. As yet, however, Sanger had two words that looked like this: (‘N’)—GXXXXXXXXXXXXXXXXXXXX—(‘C’) (‘N’)—FXXXXXXXXXXXXXXXXXXXXXXXXXXXXX—(‘C’) The next step was to chop each chain into smaller fragments by standard chemical techniques, and to separate the fragments by electrophoresis and a technique known as partition chromatography [2]. The ‘N’ terminal of each fragment could then be tagged with DNP, and the fragments could be separated by electrophoresis. The amino acids in each fragment were then identified by chemical analysis, and the original sequence could be deduced by lining them side by side. To take a real example, these are the fragments obtained by dissolving part of the B chain in acid. The leader in each sequence has been tagged with FDNP, so its position is known with certainty. Chemical analysis has identified the other amino acids in each fragment. The order of linkage will be obvious if only two amino acids are present, but will remain uncertain if there are three or more, shown here by the use of brackets. The fragments you have obtained on this occasion are CG, VC, V(CG), L(CV), L(CGV), and you can match them as follows: CG VC VCG LVC LVCG

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LVCG is the deduced sequence, and you will be able to read the entire message if you have the patience to match it with hundreds of other overlapping fragments. Sanger completed his task in 1955 and his Nobel Prize was awarded only 3 years later, in 1958. He went on to show that the longer B chain is identical in cows, pigs, sheep, horses, and whales. When variation between species did occur, it was within amino acids 8–10 in the A chain, a sequence which corresponds to alanine, serine, and valine in beef insulin, highlighted above as ASV. As he reported, It would appear that there are only three positions in the insulin molecule in which species differences can occur, and that each of these two positions is occupied by one of two amino acids. This limits the number of possible structures to eight [3, 4].

Sanger drew two inferences. Since the insulin molecule is almost identical (‘highly conserved’) in all mammals, the exact sequence must be vital to its function. It followed that the three variable positions are not critical to the biological action of the molecule. A committed Quaker, Sanger stands out as the most private and biographer-­ proof of all the remarkable people who feature in this story. He had already turned his attention to DNA by the time he received his first Nobel Prize at the age of 40. The chemistry of DNA is quite different from that of proteins and its molecules are much longer. The intellectual challenge was much the same, however, and he returned to Stockholm 22 years later to share a second Nobel Prize. But that is another story (Fig. 12.1). Fred Sanger could only speculate as to how the A and the B chains of insulin came together. The problem was solved by Don Steiner (1930–2014), who showed in 1967 that that they had once formed part of the same peptide chain. This chain, known as proinsulin, is formed on a production line within

Fig. 12.1  Sanger celebrates his first Nobel Prize in 1958. (Dept of Biochemistry, University of Cambridge—with permission)

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C-peptide

-COOH -NH2

S

S

S

S S A-chain S

B-chain

Fig. 12.2  Two disulphide bridges (shown as S–S in the diagram) hold the A and B chains of insulin together when C-peptide is discarded; a third S–S bridge creates a characteristic kink within the A chain

the cell, folded in three dimensions and shunted towards the cell membrane. Once there, it is stacked in packages ready for release. Special enzymes snip off the section connecting the A and B chains when insulin is released into the circulation, thus allowing it to spring into its active configuration; the ‘snap-­ off’ segment is known as connecting or C-peptide. Since one molecule of this is released with each molecule of insulin, C-peptide measurement can be used to see how much insulin you are making. The test can be used in those who inject insulin because the commercial product contains no C-peptide (Fig. 12.2). Once the amino acid sequence of insulin was known, chemists began to make it in the laboratory. The feat was achieved in the USA, Germany, and China, but could never be a practical way of producing insulin. The primary structure had been solved, however, and the next challenge was to establish what Sanger’s string of beads looked like in three dimensions.

12.3 The Shape of Insulin Stand with your back to the front gate of Keble College in Oxford, look across the road and you will see the Natural History Museum to your right. This was where Thomas Huxley debated the merits of a monkey ancestor with Bishop ‘Soapy Sam’ Wilberforce in 1860, and where you can view the last fragment

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of a Dodo anywhere in the world—its claws. 2 Walk past the museum and turn left for 200 yards along South Park Road to reach the Dunn School of Pathology where penicillin was developed for clinical use during World War Two. You will pass an inconspicuous plaque at the entrance of the Chemistry Building telling you that this is where Dorothy Hodgkin and her team worked out the three-dimensional structure of penicillin, Vitamin B12, and insulin. 3 Oxford is that sort of place. Fred Sanger had deciphered the amino acid sequence of insulin, but there could be no real understanding of how the molecule worked until its three-­ dimensional shape was known. Imagine two tightly stretched strands of barbed wire, and the tangled coil that will result if you release them. Dorothy Hodgkin and her team set out to determine the shape of this coil, and their journey began with Louis Pasteur. Pasteur worked with crystals early in his career, and found that two distinct crystals could be formed from tartaric acid: one rotated a beam of polarised light to the right, and the other to the left. The two forms were indistinguishable on chemical analysis. By an astonishing feat of intuition, Pasteur guessed that the molecule exists in two versions, each the mirror image of the other. Look at your hands and you will get the idea. He christened these two versions of the molecules dextro and laevo according to their ability to deflect light to the right or to the left. He also noticed that the right-hand form of tartaric acid disappeared from solution when this became infected with mould, showing that mould could only consume right-­ handed molecules. Similar ‘handedness’ is characteristic of all living things. We, for example, can use left-handed but not right-handed glucose. Crystals form when molecules line up in a repeating pattern known as a lattice; each molecule lines up within it like a soldier on parade. A beam of polarised light can tell you if the rifles are in their right or left hands. Light cannot highlight molecular structure, however, for its wavelength is 1000 times greater than the distance between the atoms in a molecule. You need a much shorter wavelength. The solution emerged when two physicists met to discuss the optical properties of crystals in Munich on a February evening in 1912. The lattice theory was already well established, and the distance between the atoms in a crystal was estimated at 10−8 cm. It occurred to Max von Laue that the proposed wavelength for X-rays was even shorter at about 10−9, implying that its waves should be able to pass between the atoms in a crystal. Some waves would strike the atoms and be deflected, and the scatter effect might therefore be demonstrated by firing X-rays through a crystal. No sooner said  The last stuffed Dodo in the world was thrown on a bonfire in 1750, and a passer-by retrieved the claws.  She actually did the work in the basement of the Museum itself, just behind the Chemistry building.

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than done, and two colleagues sent X-rays through a crystal of copper sulphate placed in front of a photographic plate. Its X-ray ‘shadow’ showed up as a distinctive pattern of darkened blobs. This simple experiment demonstrated that X-rays are a form of electromagnetic radiation (confusingly, they also behave like particles). Two years after this conversation, and scarcely lifting an experimental finger himself, von Laue received the Nobel Prize in physics. A 22-year-old Cambridge undergraduate pondered von Laue’s discovery as he strolled by the Backs in the summer of 1912, and he hit on an idea that gained him a Nobel Prize in physics 3 years later. Translated into the vernacular, the idea was this. If you shine white light through a fine grid, a multi-­ coloured halo will appear. This is because some of the light has been deflected, splitting white light into the wavelengths we see as colours. The undergraduate guessed that the patterns observed by von Laue were the reflections of atoms lined up in the same orientation inside crystals. This being so, it should be possible to work backwards from the reflection to the configuration of the atoms that produced it. The undergraduate was William Lawrence Bragg, and he was working in a department which held some of the most brilliant physicists the world has ever seen, including his father, William Bragg. Lawrence Bragg’s moment of inspiration led to the formula known as Bragg’s Law, one of those transcendent insights of the physicist’s world as remote to the rest of us as the music of the spheres. When someone dies, an after-image remains. Some linger in the mind’s eye, luminous, and persistent. Lawrence Bragg (1890–1971) left such an after-image. In part this was because of his extreme simplicity, a common feature of scientists who spend little time thinking about themselves. He was reserved and unfailingly courteous, but shyness was at the root of his unusual diffidence. In an untypically revealing passage he once wrote: Although I was 15 when I entered Adelaide University, I think my emotional age was about 12 or less, and my fellow students were mature young men and women. Such a disparity has a cumulative effect. Anyone handicapped in this way is debarred from taking part in the normal activities of his age group, and the very fact that he cannot enter into their plans, schemes, differences of ­opinion, exercise of authority and so forth, means that he loses the earlier experience which would teach him how to take his part later in life in the world of affairs. He loses touch with what is going on around him and he thinks of the people who guide the course of events as ‘they’, not as ‘we’. He develops a defence mechanism to hide his inexperience from those he meets, and this again makes him shy of asking the questions the answers to which would keep him in touch. He is like a hermit crab with a formidable array of whiskers in front, but with a soft white tail which he has to conceal in a protecting shell.

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His passion for gardening was such that he offered his services as a gardener to an elderly lady when he found himself without a garden in London. The arrangement worked well until a visitor looked through a window and asked what Sir Lawrence Bragg was doing in her garden? X-ray crystallography requires a knack which goes far beyond obtaining a read-out and calculating a result. It involves a special form of intuition by means of which the researcher can picture a structure, predict the behaviour of X-rays passing through it, and match the prediction with the reality. Lawrence Bragg described it as follows: The path to success has lain through a series of patient investigations, starting with the simplest substances and working slowly upwards. Each structure that has been analysed has told us something about how atoms are arranged, such as the amount of space each kind of atom takes up in the structure, what neighbouring atoms it is likely to be associated with, how they are likely to be grouped around it, and so forth. Knowing this, one can make intelligent guesses when tackling a new structure, trying out various likely arrangements till the glorious moment arrives when everything fits … Structure analysis is an arduous task. Those of us who began in the early days and grew up with it acquired our skill and patience in stages. We would live with a given structure ever in our minds for perhaps a year, with tentative pictures of it before us when we were shaving in the morning and at our meals, and dreaming of it at night, till finally something clicked and the answer came. Crystal analysis is just like solving a very difficult cross-word puzzle [5, pp. 13–14].

His magic gift often perplexed contemporaries. ‘How does Bragg discover things?’ asked a German contemporary: ‘he doesn’t know anything’ [5, p. 130]. It does seem likely that he never really understood quantum theory—an embarrassing lapse in a leading physicist—and his grasp of basic chemistry let him down badly on occasion, as when he put forward an erroneous model of a protein spiral. Linus Pauling, to Bragg’s undying chagrin, got it right. His gift seemed to consist of an ability to imagine a problem in the simplest possible terms—which is where his lack of excess intellectual baggage may have served him well—coupled with sheer dogged persistence. Bragg senior had developed the X-ray spectrometer, which made X-ray analysis much easier. As J.D. Bernal put it, ‘it was as if a new microscope had been found which enabled the positions of the chemical atoms to be seen.’ For Bragg junior ‘it was like discovering an alluvial gold field with nuggets lying around waiting to be picked up’, and led on to ‘a glorious time, when we [father and son] worked far into every night with new worlds unfolding before us in the silent laboratory’. They analysed salt, and found that there is no such

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thing as a molecule of sodium chloride; the atoms of sodium and chloride assemble into a structure resembling a three-dimensional chess-board. The basic structures of our universe emerged one by one, until August 1914 brought all constructive endeavour to a sudden halt. The news of his Nobel Prize (shared with his father) reached Lawrence Bragg behind the front lines at Ypres; his talents were being used to develop a means of locating enemy artillery by means of sound waves. The village curé with whom he was billeted dug out a bottle of Lachrymae Christi, and they celebrated this small relic of a more innocent world against a background of gunfire. Years later, Bragg junior pondered the intriguing yet elusive nature of scientific discovery, and proposed four categories of researcher. First are the Thinkers who see an old problem in a new way. Bragg’s example is Niels Bohr. Before he came along ‘it had been tacitly assumed that an atom obeyed Newtonian mechanics like a very small steam engine’, and no further progress could be made until someone suggested an alternative. Next were the Discoverers, immortalised by a single observation. Fred Banting is an obvious example. Then come the Designers, people who devise a technique which opens up a previously inaccessible area of knowledge, and the Hunters, whom he describes as casting around like a dog on a country walk. It was said of Faraday—a physicist with no mathematical training—that ‘he smells the truth’, and the same combination of intuition and restless energy seems to have guided Lawrence Bragg through one of the longest and most consistently successful careers in the history of science. His modesty was legendary. In later life he approached a group of young crystallographers who were setting up a display at the British Association and asked them to explain what they were doing. One of them condescendingly asked this Colonel Blimp-like apparition if he knew anything about diffraction. ‘Just a little’ came the answer, with the merest hint of a twinkle. James Watson came to work in the 61-year-old Bragg’s Department in 1951 and ‘the thought never occurred to me that later on I would have further contact with this apparent curiosity out of the past. Despite his indisputable reputation, Bragg had worked out his Law just before the First World War, so I assumed he must be in effective retirement and would never care about genes’ [6, p. 42]. He would revise this judgement. Once back from the First World War, Lawrence Bragg moved to Manchester and carried on working his way through the fabric of the universe. He turned his attention to the silicates which make up so much of the surface of our planet. These consist of one molecule of silica flanked by four molecules of oxygen, thus forming a tetrahedron. In some combinations the tetrahedrons remain separate whereas in others they interlock, providing a simple yet

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sufficient explanation of the chemical and physical differences between one silicate and another. It was a dazzling demonstration of the ability of structural chemistry to provide answers to questions that analytical chemistry could never solve. It allowed the Earth’s crust to be described on the back of an envelope, and it did so with that combination of simplicity and beauty to which scientific enquiry always aspires. While Lawrence Bragg pursued the structure of the inorganic world, others began to point their X-rays at molecules derived from living creatures. Back in Cambridge, J.D. Bernal (1901–1971) was working on the sterols—the family of molecules to which cholesterol and the steroid hormones belong. Bernal, known as ‘the Sage’ to his friends because of his apparent omniscience, was outrageous, brilliant, pig-headed, bohemian in his private life, and communist in his politics. A devoted group formed about him. Their equipment was hand-made, Heath Robinson in appearance and near-lethal in its behaviour: exploding glassware and massive jolts of electricity were commonplace. A shy and unworldly 22-year-old female graduate from Oxford joined the group in 1932, absorbed its heady atmosphere and flourished beyond compare. ‘There’, as she would say in her Nobel lecture, ‘our scientific world ceased to know any boundaries’. Dorothy Crowfoot’s parents might have served as the originals for Indiana Jones, and she spent much of her childhood on archaeological digs in the Middle East. As an undergraduate in Oxford she was expected to put her two younger sisters though boarding school and to pay any bills that came along— as and when her parents remembered to send her a cheque. There were times when the romance wore thin. ‘Dorothy still hasn’t heard from her parents and has no idea whereabouts in Europe or Asia they are so can’t make any plans and doesn’t know if she will stay up here after term or go home or what’ wrote one of her anxious friends. She alone appears to have been totally unfazed by all this, for she had discovered X-ray crystallography and her life revolved around the laboratory to the exclusion of lesser considerations such as food and sleep. Cambridge was (for a time) her natural setting and she fitted it perfectly, providing that balance of calm and technical expertise that is so essential to a team with a charismatic leader. Proteins attracted her because of their sheer difficulty, but crystals were hard to obtain. A stroke of luck came in 1934 when a biochemist from Oxford went to visit the laboratory of Tiselius and Svedberg in Sweden. They had developed a technique for separating large molecules by spinning them at previously unheard of speeds in an ultracentrifuge, and their visitor came back with a test-tube containing pepsin, one of the digestive enzymes. He deposited the tube in a convenient fridge, went off

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on a skiing holiday, and came back to find that shiny crystals had formed at the bottom of the tube. Bernal looked at them under the microscope. Like fairy gold, the crystals lost their lustre on exposure to air and started to shrivel. Bernal realised that they must contain water, and that the changes were due to evaporation. He developed a technique for analysing wet crystals, and the X-ray film lit up with a shower of tiny dots. These allowed him to judge the overall shape of the protein and to estimate its molecular weight, but any hope of analysing its structure seemed light-years away. Crowfoot wrote the paper with him, and was reluctantly tempted back to Oxford by the creation of a special fellowship at Somerville College. Here she attracted attention because of her youth—she was 24—and her frail and ethereal beauty, with startling blue eyes and ‘fair hair that, when caught by the sun, stood around her head like the halo of a stained-glass window mediaeval saint’. Her seraphic indifference to circumstance, including the painful disease that would later wreck her joints, was one of her remarkable characteristics. Another was her unconcern for appearance. Her laboratory formed part of the converted cellar of the Museum adjacent to the Chemistry building, and her preparatory work was done in a small gallery from which she descended by a rickety ladder whilst clutching her precious samples in one hand. And there, on October 25th 1934, she first examined some crystals of insulin under the microscope. These were undeniably pretty, but too small for X-ray analysis. Three months were spent manipulating the acidity and concentration of zinc until larger crystals finally bloomed. She came down the ladder, positioned the sample for its 10-h exposure and waited. As she later described it, ‘the moment late that evening— about 10 pm—when I developed the photograph and saw the central pattern of minute reflections was probably the most exciting in my life’. Dazed and exuberant, she wandered the early morning Oxford streets until accosted by a policeman. There was an awfully long way to go, but she now had an estimate of insulin’s molecular weight, 37,200 (actually the weight of six insulin molecules packaged together) and she knew that, like the earth itself, it had the form of an oblate sphere. It marked the start of a quest that would take 35 years to complete. She married (thus acquiring the name Hodgkin) and gave birth to three children with little apparent disruption of her laboratory work. Stiffness and swelling first appeared in her hands when she was 28, harbinger of the rheumatoid arthritis that would later cripple them, and the disability was already such that a special lever was needed to let her operate the switch of the X-ray machine. Oxford University did its traditional best to ignore her existence, but the Rockefeller Foundation came to her rescue in 1938, thus adding yet

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another future Nobel laureate to its credit. Warren Weaver (the man who invented the term molecular biology) said of her laboratory that ‘like most British labs, it looks like the corner of a dusty old barn’. And war was once again on its way. She returned for a while to a much simpler problem, the core structure of the sterol molecule, which she solved (save for the fact that her version was the mirror image of the correct one), constructing her model with cork and wire. The key to her success was the addition of iodide to the molecule: the large atom provided a convenient landmark for other features of the structure, a trick that would later help solve the structure of insulin. And it was in wartime South Parks Road that she encountered Ernst Chain one morning. The future Nobel prize-winner was bouncing with excitement because the first animal experiments with penicillin had proved a success. Penicillin was more than a great medical discovery; it was also a major priority in the war effort, and she worked on it for several years until she had solved the structure. As with the sterols, penicillin marked a leap to a higher level of complexity in the analysis of large molecules, but the proteins still remained out of reach. Penicillin contains around 100 atoms, but proteins contain thousands. Whilst she pursued the structure of penicillin in Oxford, change was coming to the Physics Department in Cambridge. This was based in the Cavendish Laboratory, described by James Watson as ‘the most famous laboratory in the world’. Previous heads included JJ Thompson, who discovered the electron, and Ernest Rutherford, whose team split the atom. There was a definite sense of anti-climax when Rutherford’s place was taken in 1938 by a mere crystallographer. Lawrence Bragg inherited the team developed by Bernal to work on protein structure, a team which included Max Perutz, a refugee from Hitler’s Germany who had started work on the structure of haemoglobin. The war put a stop to this; Perutz was initially interned as an enemy alien and was kept busy with war work until he resumed his quest in 1944. Proteins were seen as the key to understanding biology at a molecular level, and there was little excitement when Francis Crick, an opinionated, irritating and endlessly talkative 33 year old who had achieved little—not even a PhD—joined the team in 1948 and expressed an interest in the structure of DNA. Crick and Watson knew little chemistry and were beginners in the art of analysing crystals, but they were in the right place at the right time. Furthermore, they had the right problem. Unlike the unpredictable and complex folds of a protein molecule, DNA has a breath-taking symmetry ideally suited to X-ray analysis. All DNA is alike, tediously so, but each protein is different. Perutz, whose interest was haemoglobin, was joined in 1946 by John Kendrew. He chose the less daunting challenge of myoglobin, which belongs to the same family of

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molecules as haemoglobin but is only a quarter the size. Muscle looks red when you cut it because its myoglobin content provides a back-up supply of oxygen. Diving mammals need this in large amounts, and Kendrew got his myoglobin from the whale. The magnitude of the task was eased by the appearance of the first primitive computers, with the result that investigators put their slide rules aside and spent endless hours punching cards instead. Analysis of complex problems became enormously faster and the love affair between molecular biology and the digital computer had begun. Kendrew worked out the structure of myoglobin in 1958, and it turned out to be anything but symmetrical, causing him to remark that ‘the arrangement seems to be almost totally lacking in the type of regularities which one instinctively anticipates, and is more complicated than has been predicted by any theory of protein structure’ [7, p. 278]. One year later Max Perutz saw the first three-­ dimensional pictures of the haemoglobin molecule emerge from the computers. ‘It was’, he said, ‘an overwhelming experience to see a vital part of ourselves that is a thousand times smaller than anything visible under a light microscope, revealed in detail for the first time, like the first glimpses of a new continent after a long and hazardous voyage’ [8, p. 112]. Insulin is stored in packs of six, arrayed like the slices of an orange around a core containing two atoms of zinc. Beef insulin contains 777 atoms. Only an extreme optimist could hope to sort out its spatial configuration but, as Francis Crick later said, ‘it is interesting to note the curious mental attitude of scientists working on ‘hopeless’ subjects. Contrary to what one might at first expect, they are all buoyed up by irrepressible optimism ... I believe there is a simple explanation for this. Anyone without such optimism simply leaves the field and takes up some other line of work. Only the optimists remain’ [9, p. 51]. Dorothy Hodgkin was an optimist among optimists. Visitors were horrified by the apparent anarchy that prevailed in her lab, where you might find cricket being played in the corridor with a rolled up piece of paper as the ball, or hear a baby giving voice. She moved serenely among her motley crew of younger workers, happily humming a hymn tune when engaged upon an interesting problem, never organising but guiding by gentle hints. They worked in a way that superseded all other aspects of life, and she carried the faith that they would not fail. Like Lawrence Bragg, she seemed able to draw upon intuition backed by a remarkable ability to picture a molecule in three dimensions. The problem of landmarks remained. Dorothy had solved the structure of sterols by adding iodide to the molecule, and haemoglobin had been solved by the insertion of mercury. In each case a distinctive atom which showed up clearly on X-ray could be placed in a known location within the molecule. When the group succeeded in replacing the zinc core of

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Fig. 12.3  The insulin hexamer: six molecules (coloured light or dark blue) arranged around a zinc core. (From De Metys, Bioessays 2004 Dec;26(12):1351–62. doi: 10.1002/ bies.20151]. – with permission)

the insulin molecule with big atoms of cadmium or lead, success became a matter of time. And so it was that in 1969, her feet so swollen that she had to take her shoes off, working right through a weekend, she and her team built the insulin molecule (Fig. 12.3). It once my privilege to watch an old lady with electric blue eyes and wild white hair sketch the insulin molecule in the air with hands crippled by rheumatoid arthritis, and it was unforgettable. Even so, it is one thing to reconstruct a molecule, and another to find out how it works. A faintly comic anecdote relates how Hodgkin and her team invited Fred Sanger and the biochemist Philip Randle to their laboratory. Somewhat breathlessly, they unveiled their model. ‘I got the sulphides right’ said Sanger after a while. The others were horrified to learn that he had ever been in doubt. Somewhat disappointed, Dorothy turned to Philip and asked him what he thought. ‘After a bit he put his hand up—he had these huge hands—and pointed towards one of the residues. I thought he was going to say “Ah, this is the active site”, but actually he said “is this a tyrosine?” He was still trying to work out what it all was’ [7, p. 328] (Fig. 12.4). By 1970, it was clear that the structure of insulin had been preserved, with only the tiniest of variation, throughout 350 million years of mammalian evolution. The sequence and shape of insulin, so painfully discovered, made it clear that the core structure of the molecule was an evolutionary constant, a biological Pole Star around which other molecules revolved. The secret of

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Fig. 12.4  Dorothy Hodgkin (1910–1994) in later life. Note the crippled hands

insulin action must lie in its shape, and the constancy of that shape suggested that it was designed to fit something else. Here was a key—but where was the lock?

12.4 The Sound of One Hand Clapping Some cells respond to drugs and hormones; others do not. In the early years of the twentieth century, immunologist Paul Ehrlich suggested that responsive cells must have special receptors for each signal on their surface. Plausible though the suggestion was, cell receptors remained a somewhat metaphysical concept until biochemists used radioimmunoassay to find them later in the century. Previous investigators had often assumed that insulin must get inside a cell in order to produce its effects, but radioisotopes showed that labelled insulin latches on to the outer surface. As Donald Rumsfeld so memorably put it, ‘there are known unknowns. That is to say, there are things that we know we don’t know. But there are also unknown unknowns. These are things we don’t know we don’t know’. Insulin’s previously unrecognised docking site was an unknown of staggering proportions, and would keep a whole tribe of investigators occupied for the best part of 50 years. Few appreciate the enormity of the task. A distinguished biochemist of my acquaintance found

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himself next to an unknown lady at a formal dinner. She asked politely what he did, and he explained that he was trying to work out how the signal conveyed by insulin reached the interior of the cell. How long have you been doing that? Fourteen years. Haven’t you found out yet?

End of conversation. Here are just some of the questions that were prompted by the realisation that insulin has a receptor. How does this transmit the insulin signal from one side of the membrane to the other? How is that message translated and passed on within the cell? Not least, how is the interaction on the cell surface amplified in such a way as to create an avalanche of effects within the cell? The system that emerged was so complex that each answer simply spawned further questions. Let me attempt a brief summary. The receptor itself was identified by tagging it with radiolabelled insulin and hooking it out of the cell membrane. It proved to be an enormous Y-shaped twin protein, 60 times bigger than insulin itself, which straddles the cell membrane. Its ‘arms’ reach out from the surface to lock on to the insulin molecule. Like all good locks, this one is highly specific, and only one key will fit. The ‘legs’ of this two-fold molecule cross the cell wall and its ‘feet’ protrude into the cell itself. This is the business end. It is activated when insulin docks on the outer surface of the cell, and it triggers a chain response inside it. How might this work? Picture the cell as a beehive. At its heart lie the molecules of DNA. These are the queen bees, helpless, vulnerable, of use only for reproduction. Proteins swarm around them like worker bees, nudging them into activity or putting them to sleep, tending and repairing, nursing offspring molecules and shepherding them to other parts of the hive. Every function of the cell from energy exchange to transport, construction, and communication is conveyed by protein molecules with one shared characteristic: they change shape (or charge) when they receive the right signal. The haemoglobin molecule, for example, seizes oxygen molecules when these are plentiful and releases them when they are in short supply. Max Perutz showed that this huge molecule flips from one shape to another as it binds and releases oxygen. Proteins are elastic because innumerable tiny electrical charges within the molecule create a force-field which is finely balanced near its point of equilibrium, like a child’s see-saw which can be tipped with a single finger. They are big because they need to be finely balanced, and evolution has fine-tuned them to flip from one

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Fig. 12.5  (a) Cartoon by Pierre de Meyts (‘Chuck’). (Courtesy of Dr. de Meyts). (b) Beyond the black box. Cartoon by Pierre de Meyts (‘Chuck’). (Courtesy of Dr. de Meyts)

configuration to another under exactly the right circumstances. The core structure which acts as the fulcrum has been rigorously conserved throughout all the twists and turns of evolutionary descent. This is why a molecule of insulin can land on the surface of a cell and trigger an avalanche on the other side. The cascade effect is such that Rachmiel Levine estimated in 1961 that one molecule of insulin stimulates the uptake of up to a billion extra molecules of glucose per minute. Glucose entry by passive diffusion is a basic property of cell membranes, but insulin stimulates active transport of glucose into ‘insulin-sensitive’ tissues. Surplus glucose can then be stored as glycogen or fat without compromising the flow of glucose to the brain. Levine concluded that insulin allowed glucose to be stored in specialised organs, but he was still a long way from our modern concept of a insulin receptor capable—among other things—of activating specialised glucose transport molecules in ‘insulin-sensitive’ tissues [10]. As to what happens next, the state of knowledge in the 1970s was summed up by ‘Chuck’ (actually Pierre De Meyts, a distinguished Belgian researcher) as shown in Fig. 12.5a. Thirty years later, the insulin receptor and its downstream molecules could be seen to function more like a switchboard, prompting Chuck to draw the second cartoon shown in Fig. 12.5b. It is clearly time for us to make our excuses and leave this particular subject! Before quitting the cell membrane, however, we should forget the textbook

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drawings which depict membrane receptors as rigid structures protruding from the cell surface like gargoyles from a gothic cathedral. In reality, the surface of a cell is elastic and in constant motion; a cross between a soap bubble and a simmering cauldron of soup. Huge molecules move around like icebergs, ingesting some things, excreting others, or passing on messages. Hardly any of this was known in the 1960s, when as Jesse Roth put it, ‘the cell surface of vertebrate cells was a largely underdeveloped, sparsely populated neighbourhood’.

12.5 Measuring Insulin That lyf so short The craft so long to lerne Th’assay so hard So sharp the conquerynge—Geoffrey Chaucer (after Hippocrates)

To understand how receptors were located and how insulin came to be measured, we must double back in time to 5.29 a.m. on July 16, 1945. The place, appropriately named, was the Jornado del Muerte in the deserts of New Mexico, and a blinding flash marked our collective entry into the nuclear era. The science behind the explosion finds a place in our story because radioactive isotopes can be used to track the progress of key molecules though living tissues, even at concentrations of a few parts per million. Insulin, readily available in copious amounts, was an obvious candidate. Harry Himsworth argued in the 1930s that there are insulin-sensitive and insulin-insensitive forms of diabetes, and he paid his last visit to the subject in a lengthy review in the Lancet in 1949. Insulin-insensitive diabetes is memorably described: The association of obesity and diabetes, especially in the elderly, is well recognised, and it is notorious that such patients often live for years, in reasonable health, without any insulin therapy ... despite the mildness of the symptoms astonishingly large amounts of insulin may be required to clear the urine of sugar. These patients give an insensitive response to the insulin-glucose test and can tolerate large excess of insulin without developing hypoglycaemic symptoms. But, most striking of all, reducing the patient’s weight by any dietary means not only removes the symptoms and signs of diabetes but also restores the sugar tolerance curve to normal.

The concept of insulin resistance constituted a huge problem which haunts us still: where is it, what is it, and how can it be measured? The simplest way

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of testing Himsworth’s hypothesis would be to measure the amount of insulin in the blood, but this seemed impossible. Insulin is potent at concentrations so low as to defy chemical analysis: you might as well throw a bucket of dye into Lake Superior and try to measure the amount in a sample taken from the other side. The only way of measuring insulin in 1950 was to test its biological activity. The manufacturers checked its potency by counting convulsions in mice, and the amount of insulin in a human pancreas could be judged by the same means. David Scott and colleagues estimated in 1938 that healthy human pancreas contains 1.7 units of insulin per gram (150–200 units per pancreas), as against only 0.4 units/gram in people with diabetes. A larger study found in 1952 that insulin was almost undetectable in the pancreases of those who developed diabetes under the age of 20—thus confirming Himsworth’s hypothesis concerning insulin-deficient diabetes—whereas pancreases from older individuals were later shown to contain 40–50% as much insulin as those of non-diabetics [11]. Biological tests were of little use when it came to detecting lower concentrations of insulin, however, and it was around this time that Arthur Mirsky, a Canadian physician working in New York, suggested that people develop diabetes because of an enzyme that destroys insulin [12]. This wrongheaded idea bore fruit, for Mirsky wanted to measure the rate at which insulin disappears from the blood stream, and two remarkable people took up the challenge: Rosalyn Yalow and Sol Berson. Rosalyn Yalow (1921–2011) took no prisoners. She once wrote that ‘perhaps the earliest memories I have are of being a stubborn, determined child’. The referees rejected her first paper on insulin antibodies, and her revenge was to quote them verbatim in her Nobel lecture 22 years later. There was little room for sentiment in her professional life, for she was born with three hits against her: she was poor, she was female, and she was Jewish. Yalow and others acted as ice-breakers, crashing a path through the obstacles of gender and religion for less formidable people to follow. She grew up on the East Side of New York in a secular Jewish family and battled her way to success through the public education system. Despite her academic prowess, a stenography course was considered necessary to her career. The War created openings for women and she went off to study physics at the University of Illinois after receiving a list of houses on campus which did not admit Jews. She was the only woman among four hundred men, and possibly the first to take the course since it started in 1917. There were only three Jewish people in her intake, one of whom (Aaron Yalow) would become her husband. Job prospects were far from promising when she returned to New York in 1945 as a post-doc in nuclear physics. Luckily, the Manhattan Project had

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generated enormous interest in potential applications of radioactivity in medicine, and funding poured into the Veteran’s Administration Hospitals, which (for a while) became standard-bearers within US medicine. She was put in charge of the isotope laboratory at the VA Hospital in the Bronx in 1947 and set up her first laboratory in a room vacated by the cleaners. In 1950 she realised that she needed to work with a physician, and the young man who came round to see her was Sol Berson (1918–1972). According to legend, he teased her with mathematical puzzles in the course of the interview, and she responded in kind. ‘After half an hour I knew he was the smartest person I had ever met’ was her comment. Sol Berson was 32 at the time and—like Francis Crick (who was 35 when he met James Watson in 1951)—he was an undeniably brilliant man who did not seem destined to achieve anything remarkable. Maths and music were his passion, and he could play multiple games of chess blindfolded. He took his first degree in 1938, only to be rejected by no fewer than 21 schools of medicine. He was teaching anatomy at a dental college when World War 2 created an urgent need for doctors. He enrolled in 1941 (Crick was working on mines for the British Admiralty around the same time), and qualified in 1945 before completing his military service. Remarkably, he had absolutely no experience in research. Yalow had moved out of the janitor’s room by now, and a medical colleague was needed because she wanted to tag complex chemicals with radioactive isotopes and track their movement through the human body. Their first choice fell on albumin, an abundant plasma protein, but in time—reputedly to test Mirsky’s hypothesis—they moved on to insulin. This was a natural focus of interest, for Rosalyn’s husband had insulin-dependent diabetes, and the commercial hormone was available for their studies. Under the right chemical conditions, iodine will bond with tyrosine, an amino acid present in insulin. Radioactive iodine could thus be attached to insulin and monitored with a Geiger counter. Easily said, not so easily done, but Berson and Yalow developed the method and went on to inject radiolabelled insulin into people with and without diabetes. Mirsky’s suggestion was soon disposed of, for the radioactive label vanished more rapidly in non-diabetics than in those on insulin. Revealingly, a man tested before and after insulin treatment converted to the slow pattern 4  months later. The same transition could be seen in non-­ diabetics who had received insulin shock therapy (the forerunner of electroconvulsive therapy) for psychiatric problems, a clear indication that the phenomenon related to insulin rather than to diabetes. Why did insulin hang around in the circulation of insulin users? The logical explanation was that insulin provoked antibodies, and that longer-lived

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antibody molecules had attached themselves to radiolabelled insulin. Berson and Yalow confirmed this by showing that tagged insulin could be detected in the antibody-containing gamma globulin fraction of people exposed to insulin. Clear though it was, this demonstration came up against the entrenched belief in Ehrlich’s horror autotoxicus—the dogma that insulin is a normal constituent of the body, ergo there could be no antibodies against it. The referees who vetted their paper may have been unaware that beef insulin differs from human in three of its amino acids, a small difference readily detected by the immune system. Nor did they know that commercial insulin generates impurities that encourage antibody formation. It was accordingly rejected by two leading scientific journals, Science and the Journal of Clinical Investigation, although the latter relented when the authors agreed to delete the offending expression ‘insulin antibody’ from their title! The existence of insulin antibodies soon became undeniable, and it led on to a more important discovery: radioimmunoassay. Standard explanations of radioimmunoassay resemble the instructions that come with flat-pack furniture: they make perfect sense when you have finally worked out how to assemble it for yourself. Luckily, the idea itself is almost ludicrously simple. Imagine that you have a large bag of black marbles, and that you want to estimate how many marbles are in the bag. A standard technique (known in other contexts as capture-recapture) is to add a known number of white marbles. Mix thoroughly and take a sample from the bag. If you add a hundred white marbles to a bag of black marbles, for example, and one in ten of the marbles you retrieve from the bag is white, there will have been about a thousand black marbles in the bag to begin with. Radioimmunoassay is based on the same principle. The antibodies are mixed in the test tube, thus mingling the unknown amount of insulin in your sample (the black marbles) with a known amount of labelled insulin (the white marbles). The antibodies are retrieved at the end of the experiment and the amount of labelled insulin is measured with a Geiger counter. The less label you recover, the greater the concentration of insulin in the sample you are testing, and you can read off the amount because you included tubes containing known amounts of insulin in the assay. This enables you to draw a graph (known as the standard curve) which shows the level of radioactivity that matches a given concentration of insulin, and the amount of insulin in your sample can now be read from the standard curve. Simple, but brilliant. The test is unreliable in insulin users who have antibodies, but analysis of insulin-naïve people with diabetes showed—in line with Himsworth’s belief in insulin-insensitive diabetes—that many actually produce more insulin at onset than non-diabetics [13].

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The new technique determined the fate of a whole generation of research fellows in endocrinology. Their PhD consisted in taking a peptide, raising antibodies against it, labelling it, developing a radioimmunoassay, and engaging in verbal fisticuffs with any interloper who purported to measure the same molecule. An impressive series of scientific papers detailing the presence of your peptide in every possible organ and circumstance was guaranteed to follow. Luckily for the researchers, peptides are not in short supply—and there are plenty of diseases to measure them in. The fellows came and went, but the technicians stayed on, patient ladies (as they mostly were) who sat at benches year after year, faultlessly transferring minute amounts of liquid from one tube to another with their pipettes. Machines have replaced them. Berson and Yalow were one of the great double acts of medical science. ‘Intensely competitive, disinclined to collaborate with others, and frequently harsh and unforgiving in their criticism’, they were ill-equipped to flourish within the buddy system of the medical world. A patent on radioimmunoassay would have brought untold wealth, but they would have despised anyone who considered the idea. Jesse Roth recalled that Berson reimbursed his travel expenses to scientific meetings from his own meagre salary. The pair did much of their own bench work and retired to a cramped office with paperstrewn desks rammed up against each other in the middle of the room. They never, ever, wrote a grant application. Yalow never left, despite many offers; Sol went after 18 years to become chairman of the Department of Medicine at Mount Sinai. This competitive yet unworldly man was much loved by those around him, so much so that the junior staff at Mount Sinai threatened to go on strike when his position was under threat, but he does not seem to have found much happiness in his new role. He died of a heart attack in a hotel room in Atlantic City at the age of 54, thus missing out on his share of a Nobel Prize. She carried on, brash and isolated. Few Nobel winners flaunt the fact, yet she wore her medal on every possible occasion. She seems to have had few friends or interests outside her family and her work. In 1995 a friend found her unconscious on the floor, the victim of a dense stroke and a bleeding stomach ulcer. She was raced to the emergency room of the nearby university hospital where she had frequently been an honoured guest. The resident took one look at this dishevelled old lady, covered in blood and presumably destitute, and turfed her to the nearest public hospital [14]. Against all odds she recovered and lingered on for many years. She appears to have shown little resentment towards the institution that treated her so disgracefully. The referees she never forgave [15, 16].

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12.6 The Evolution of Insulin One ‘unknown unknown’ to emerge over this period was that we have other insulin-like molecules in our circulation. Serum samples showed unexplained biological insulin-like effects which were not removed by insulin antibodies, and the clumsy term non-suppressible insulin-like activity (NSILA) was coined to describe the phenomenon. Two distinct variants of NSILA were later identified as the insulin-like growth factors IGF-1 and IGF-2, each of which resembles proinsulin. Liver cells produce them, and they mediate many of the effects previously attributed to Growth Hormone: IGF-2 is thought to play a greater role in foetal development, and IGF-1  in childhood and adult life. Every biological solution was developed within the workshop of a single cell. Biology thrives upon redundancy, for redundancy means diversity, and diversity is the basis of selection. Since life cannot be halted whilst engineering work takes place, the great challenge for molecular evolution was to build additional capabilities into a production line that is already up and running. The usual way of doing this is for segments of DNA to be duplicated, thus allowing the original production line to carry on with its designated task while the spare version develops a life of its own. This simple trick allowed the ancestral insulin gene to found a family. Each cell is a miniature Noah’s ark of biological possibility. Nothing useful has been discarded, and every successful trick has diversified. Some molecular pathways—the ones that power everything from the bacteria on your teeth to the daffodil in your garden or the fly on your windowpane—are sacrosanct. They were perfected in the deep past and will tolerate no deviation. Such pathways are hard-wired into us, but the software is almost infinitely variable, allowing useful tools to be endlessly modified and applied to different tasks. The ancestral insulin gene is a good example. Insulin is compact and roughly spherical. It resembles other water-soluble proteins in having an ‘oil-drop’ conformation with water-loving (hydrophilic) chemical groupings at the surface and water-hating (hydrophobic) groupings at its core. All insulin-like molecules are formed from a single chain of amino acids which incorporates a hallmark hairpin fold consisting of three helices and three conserved disulfide bridges [17]. The chain remains intact in some versions of the ancestral molecule; in others the middle part (C-peptide in the case of insulin) breaks away, thus allowing the remainder to spring into its final three-dimensional configuration. Molecules with the characteristic hairpin fold appeared early in the evolution of complex free-living life-forms, and

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they play an important role in growth, cell division, survival during food shortage and longevity in creatures as diverse as insects, shellfish and nematode worms. Insulin receptors and signalling systems are present on many cells which play no role in glucose metabolism, and insulin has long term, intermediate, and immediate effects. Its longer term effects upon growth and survival can be traced back to invertebrate life, energy exchange and storage of body fuels (fat and protein included) may be counted among its intermediate effects and its immediate metabolic effects emerged in the course of vertebrate evolution. The most obvious vertebrate specialisation was a complex central nervous system. Brains have high energy requirements, and glucose is their preferred fuel; other fuels (lactate during exercise, ketones during fasts, and either in the course of insulin-induced hypoglycaemia) may supplement it, but no other source can replace it. The requirement for glucose is directly proportional to the number of nerve cells, which is why hypertrophied brains which weigh around 2% of our bodies account for 20% of our glucosederived energy. Brain cells rely on glucose, and they do not need insulin to access it. Insulin-­independent glucose transporters known as Glut-1 and Glut-3 ferry glucose inside, and Glut-3 in brain cells can do so at glucose levels inaccessible to other tissues. The symptoms of glucose lack are comparable to those of oxygen deprivation, and insulin’s most pressing task is to ensure that the liver maintains an uninterrupted supply of glucose to the brain. Too little, and our survival is at risk. Too much, and we waste precious fuel in the urine. Insulin regulates the glucose supply upon which our brain depends, and must therefore have played a critical role in the evolution of this organ. The characteristics which make this possible are exquisite feedback control, a rapid onset of action and a short half-life (4–6 min) in the circulation.

12.7 Insulin Resistance He who first gave names, gave them according to his conception of the things which they signified, and if his conception was erroneous, shall we not be deceived by him?—Plato A view which takes abstract concepts for things, implying their actual existence and at once treating them as entities, is called ontology. This logical blunder has frequently crept into medicine and flourished there—Karl Wunderlich (1815–1877)

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‘Sailor, beware the Bight of Benin. There’s one comes out for nineteen goes in’. I would quote this traditional piece of advice to fellows tempted to study insulin resistance. This complex and challenging area is nonetheless a major frontier in our understanding of the ways in which insulin affects the human body, and of the ways in which we grow old. Harry Himsworth suggested that diabetes could be caused either by lack of insulin or by a failure of insulin action, and noted that insulin-insensitive people ‘tend to be older, obese, to have hypertension and frequently arteriosclerosis, and in these patients the onset of the disease is insidious’ [18] The association of insulin insensitivity with increasing age, obesity, hypertension and arterial disease has been amply confirmed, but how do you measure it? Himsworth’s test was crude, and Joslin concluded that ‘from a practical standpoint such tests are of no great assistance’. Himsworth’s test evolved into the glucose clamp, a technique which allows the effect of insulin on glucose disposal to be measured accurately in people with or without diabetes. The central problem was—and remains—that glucose disposal is a continuous variable, and that a line drawn across it can only be arbitrary. This has not prevented investigators from speaking of a mysterious entity called ‘insulin resistance’ in ways suggestive of the ontological fallacy described by Karl Wunderlich. Gerald Reaven (1928–2018), a Californian researcher, breathed new life into the concept in 1988. The glucose clamp technique had confirmed that almost everyone with non-insulin dependent diabetes was insensitive to the glucose-lowering effects of insulin, but had also shown that one lean non-­ diabetic in four was equally insensitive. The inference was clear: insulin resistance does not cause diabetes; it precipitates the condition in those with insufficient beta cell function. Non-insulin dependent diabetes is associated with central obesity, hypertension, arterial disease and abnormal lipid levels. Reaven proposed that insulin resistance was the missing link between cardiovascular risk in diabetes and non-diabetic people, and postulated it as the essential feature of a new syndrome, provisionally called ‘Syndrome X’. Malicious rumour suggests that he was hoping someone would rename it after himself. This was a plausible hypothesis, for obesity, hypertension, arterial disease and dyslipidaemia are all associated with insulin resistance. Nor would the list end there, for insulin resistance was later shown to be a feature of weight-related cancers and of cognitive decline in later life. ‘Syndrome X’—soon to be known as the ‘metabolic syndrome’—was envisaged as a composite of risk factors arising from the common soil of insulin insensitivity. Reaven’s original hypothesis did not wear well, however, for

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insulin resistance is an inconsistent feature of the metabolic syndrome, does not feature at all in some definitions, and a causal role is still in doubt. How could you then define a clinical entity with no well-defined cause or unifying feature? Undeterred, expert panels attempted to do so by listing its features. Unfortunately, risk factors are continuous variables, each of which must necessarily be dichotomized into ‘pass’ or ‘fail’ qualifiers. Not surprisingly, adding risk factors together increases risk, but was any extra knowledge gained by doing so? If not, why not treat its individual manifestations? Ironically, Gerald Reaven himself spearheaded the attack on the ‘metabolic syndrome’, most notably in a retrospective article entitled requiescat in pace (rest in peace) [19]. Commenting that there is a six-fold variation in insulin-­ mediated glucose disposal within an apparently healthy population, he conceded that ‘there is no objective way to classify an individual as being insulin resistant.’ One healthy person in three is sufficiently insulin resistant to be at risk of clinical disease, and he concluded that ‘diagnosis of the metabolic syndrome does not bring with it much in the way of pathophysiological understanding or clinical utility’. His frustration was almost palpable, for he saw insulin resistance as a ‘conceptual feature within which to place a substantial number of apparently unrelated biological events.’ Even so, a major surprise lay in store: surgeons who specialised in obesity discovered that type 2 diabetes can be reversed [20]. Obesity surgery reduces the efficiency of digestion by restricting access of food to the stomach. It had a troubled start in life, but technical advances and increasing experience have allowed it to develop into a safe and effective routine procedure. Miraculously, or so it seemed, the surgeons found that blood glucose levels could return to normal within a week of surgery in those with diabetes, and that beta cell function ostensibly returned to normal, even after years of diabetes. The concept that type 2 diabetes was due to irretrievable loss of beta cells had to be abandoned. Instead, as one expert put it, we might think of the beta cells as ‘stunned’ rather than permanently disabled [21]. The implications were equally stunning. Ill-defined though it is, the concept of insulin insensitivity is telling us something important. Genes set limits to our potential, but the extent to which we achieve it depends upon how we are nourished, how we grow and develop, and how we interact with the society in which we find ourselves. The outcome of this interaction is known as the phenotype, and the ‘Consumer Phenotype’ is associated with chronic overconsumption and a lifespan limited by age-associated degenerative processes arising within our own bodies [22]. Our criteria for normality are based on the range of body weight, blood pressure, lipid levels and blood glucose in young adults, and one or more of these

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‘normal ranges’ is exceeded in some 80% of people in their 70s. These conditions often associate together, and are in some way linked to increasing insensitivity to our own insulin. The ‘metabolic syndrome’ may add little to clinical diagnosis, but insulin resistance is telling us something important about the way we grow old in a consumer society. One important clue lies in the interaction of insulin with its receptor. Insulin has clearly defined metabolic effects and much less well-defined effects upon the ways in which cells develop and function. These effects are mediated by two distinct chemical chain reactions within the cell. One of these, the PI-3 kinase pathway, mediates glucose uptake. The other, known as the MAP kinase pathway, is responsible for a wide range of other effects. Traffic down the PI-3 kinase route is drastically reduced in the course of obesity and type 2 diabetes, whereas the MAP kinase route is relatively unaffected. The body increases its production of insulin in an attempt to compensate for glucose intolerance, thus increasing traffic along the MAP kinase pathway. Consequences include increased fat deposition, sodium retention by the kidneys leading to hypertension, proliferation of cells lining our arteries, and accelerated ageing of certain tissues. Conversely, sensitivity to the glucose-­ lowering effects of insulin is characteristic of successful ageing in non-­diabetics, and a low insulin requirement is a marker of prolonged survival in insulin-­ treated people. Gerald Reaven’s contention that raised levels of insulin can be toxic lives on, and may (as we will see) have implications for insulin therapy in type 2 diabetes. Behind this lies a wider ignorance: what exactly are insulin receptors and signalling systems doing in tissues which play no part in glucose metabolism?

References 1. Krebs H. Reminiscences and reflections. Oxford: OUP; 1981. 2. Hall KT. Insulin—the crooked timber. A history from thick brown muck to Wall Street Gold. Oxford: OUP; 2022. 3. Sanger F. The chemistry of insulin. Nobel Lecture; 1958. 4. Sanger F, Dowding M, editors. Selected papers of Frederick Sanger (with commentaries), London; 1996. p. 435. 5. Thomas JM, Phillips D Eds (1990). Selections and reflections: the Legacy of Sir Thomas Bragg. 6. Watson JD. The double helix. A personal account of the discovery of the structure of DNA. London: Penguin Books; 1968.

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7. Ferry G. Dorothy Hodgkin. A life. London: Granta Books; 1999. 8. Medawar J, Pyke D. Hitler’s Gift. Scientists who fled Nazi Germany. London: Blake Publishing; 2000. 9. Crick F.  What mad pursuit. A personal view of scientific discovery. London: Penguin; 1989. 10. Levine R.  Concerning the mechanisms of insulin action. Diabetes. 1961;10(6):421–31. 11. Wrenshall GA, Bogoch A, Ritchie R. Extractable insulin of pancreas. Diabetes. 1952;1:87–107. 12. Yalow RA.  Radioimmunoassay. A probe for fine function of biologic systems. Nobel Lecture; 1977. 13. Yalow RA. Immunoassay of endogenous plasma insulin in man. J Clin Invest. 1960;1960(39):1157. 14. Straus E. Rosalyn Yalow. Her life and work in medicine. Cambridge, MA: Perseus Books; 1998. 15. Rall JE.  Solomon a Berson 1918–1972. A Biographical memoir. Washington: National Academy of Sciences; 1990. 16. Friedman A. Remembrance: the Berson andYalow Saga. JCEM. 2002;87(5):1925–8. 17. De Meyts P. Insulin and its receptor: structure, function and evolution. Bioessays. 2004;26(12):1351–62. 18. Himsworth HE. Lancet 1949;i:465–72. 19. Reaven GM. Clin Chem 2005;51(6):931–8. 20. Pories WJ, et al. Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus. Ann Surg. 1995;222(3):339–50. 21. Ferrannini E. The stunned beta cell: a brief history. Cell Metab. 2010;11(5):349–52. 22. Gale E. The species that changed itself. London: Penguin Books; 2019.

13 Out of the Doldrums

Robert Tattersall called the period from 1936 to 1952 ‘the dark age of once-daily insulins, free diets and a sense of doom’ [1]. Insulin-treated diabetes was considered rare, and those affected learned not to advertise the fact. There was an unformulated yet widespread sense that a person was somehow diminished by a diagnosis of diabetes, and could no longer— however, brave the attempt—be considered a fully functioning and independent member of society. Others saw a mysterious and alarming condition akin to epilepsy and distanced themselves accordingly. Men were considered incapable of holding down a job and women of having babies. Fear of the needle was pervasive, and childhood diabetes was considered so demanding for parents that 10% of affected children in the UK were considered to need residential homes in the period following World War 2 [2]. The same proportion attended hostels in 1966 [3]. The longer-term prognosis was still awful, and social factors predominated. In Pittsburgh, 26% of young black Americans diagnosed between 1965 and 1979 died within 20 years of diagnosis, as against 11% of whites [4]. Michael Brownlee gave the Banting Award Lecture of the American Diabetes Association in 2005 and recalled that his parents consulted the Association’s textbook when he developed diabetes at the age of 8. They read that ‘the person with diabetes can be reassured that it is highly likely that he will live at least into his 30s’ but did not find this reassuring. Their refusal to believe it contributed to his survival. The voices of those who lived with childhood diabetes over this period have mostly been lost, but some fragments survive:

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We have been assured time and time again “your diabetic son can lead a perfectly normal life”. The first time we heard this statement was the day our son was admitted to hospital … From this day on our family life has undergone a tremendous change. Our family life has the outward appearance of a normal one. Inside of our home, but for the most part in our minds and hearts, we carry the burden of this treatable but yet incurable disease that permits one a supposedly normal life. One day he asked me, ‘Mom, will I die younger because I am a diabetic?’ Again, I tried to give him a reassuring answer’ [5].

Joslin saw the person with diabetes as the driver of a troika whose horses were diet, exercise and insulin. The road ahead offered long-term health and fulfilment. By the mid-century, however, many doctors saw the condition as a cul-de-sac leading to ever-increasing disability. Looking after them was considered a chore, so much so that it was customary in some British hospitals for the diabetic clinic to be allocated to the most recently-appointed physician. Inherited dogma guided management, and it was not an appealing specialty for ambitious young doctors. Few could have guessed that diabetes was about to get exciting. Some of those who attended the clinics outlived their doctors and had long and fulfilled lives. Others were not so lucky. As a junior doctor in the 1970s, I admitted a 34-year-old man called David. Childhood diabetes had resulted in kidney failure. Our newly-formed renal unit did not accept people with diabetes, and we could only put him in a side ward and watch him die. Uraemia is a condition in which in which the body is slowly poisoned by its own waste-products, and today’s medical students may never witness it. I mentioned David in a recent talk to young doctors in Africa as an example of the past from which we are trying to escape. One of them shook her head sadly and told me that this was what she did today. The history of diabetes is also its geography.

13.1 Disease or Risk Factor? Physicians diagnosed diabetes in the early part of the nineteenth century on the basis of symptoms and confirmed it by tasting the urine—a task routinely delegated to the junior doctor [6]. Urine tests took over as the staple of diagnosis, and blood glucose measurement did not become more widely available until the 1920s. Physicians were aware of the existence of ‘silent’ diabetes, especially in the elderly, but those affected were not considered to require

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treatment. The full extent of the underwater iceberg of diabetes in later life was not fully appreciated until blood tests were automated in the 1950s. An early indication of the true prevalence of diabetes came from a pioneer screening study in the small town of Oxford, Massachusetts (Joslin’s birthplace) in 1947. One undiagnosed individual was detected for every person known to have diabetes, and it was estimated that 1.4–1.7% of the population was affected, equating to some 2–2.5 million Americans [7]. The Framingham study showed that an increase in blood glucose was associated with an excess of cardiovascular death and disease, and diabetes graduated from a disease to a risk factor. If so, where did the excess risk begin? And could it be reversed? Answers to these questions required a clear definition of diabetes and, strange as it might seem, no such definition existed. A 1968 textbook pointed out that ‘as we lack a precise definition of diabetes there can be no specific test for its presence’. Kelly West, the doyen of diabetes epidemiologists, said in 1978 that ‘no widely accepted definition exists’. He confirmed this by sending the same set of glucose tolerance test results to leading experts, whose diagnoses were wildly divergent [8]. Some participants in two major clinical trials (UGDP and UKPDS) were later deemed not to have had diabetes at all. Hindsight is the prerogative of the historian, but we must avoid ‘the immense condescension of history’. No satisfactory definition of silent diabetes was possible on the basis of the information then available, and a new approach to health and disease was needed. From the medical point of view a disease is categorical: you have it or you don’t. In contrast, a risk factor is dimensional, and the point at which ‘healthy’ levels of glucose, cholesterol, blood pressure and adiposity shade into ‘too much’ is a matter of consensus. The underlying principles are worth considering, for the treatment of millions depends on them. A risk factor is judged by the risk it confers. The risk conferred by high blood pressure is gauged by the frequency of stroke and that of cholesterol by the frequency of heart attacks. High blood glucose is harder to pin down because it has numerous unwanted outcomes. How then could a line be drawn between those who are ‘prognostically abnormal’ and those who are not? In principle, there are four ways of drawing such a line: statistical, clinical, prognostic and operational [9]. The statistical approach would be to establish a normal range and to consider all outliers as potentially diseased. It is used, for example, as a guide to investigation and treatment of children with short stature. The major limitation of a statistical approach to diabetes is that glucose homeostasis varies with age and that a ‘normal’ 80 year old is not a ‘normal’ 20 year old.

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Fig. 13.1  Diagram ‘borderline cases’

Since the issue could not be resolved by statistics, the definition of diabetes was seen as a clinical question, and WHO convened an expert panel to clarify the situation in 1965. The panellists proved quite incapable of drawing a line between diabetes and non-diabetes, but nonetheless reached agreement about the lower limit of diabetes and the upper limit of health. Diabetes was agreed to be present when the 2-h value after a glucose load exceeded 130 mg/dL (7.2 mmol/L), whereas normality ended at 110 mg/dL (6.1 mmol/L). Those in between—almost the entire population of interest—were judged to be ‘borderline’! (Fig. 13.1). The clinicians now passed the question to the epidemiologists. Since a risk factor can only be judged by the risk it confers, prognostic criteria were needed, and these required long-term follow-up of people whose baseline glucose status was known. Simple in theory, complicated in practice. The blood glucose in a finger-prick differs slightly from a sample from a vein, for example, and whole blood differs from plasma. Which should you use? Having reached a decision, should you opt for a single fasting blood sample or a formal glucose tolerance test? The more formal test was preferred, but what dose of glucose should you use? The Americans gave 100  g, the Europeans gave 50, and they compromised on 75 g—a concession that invalidated all the data available. The test they agreed on was poorly reproducible, was influenced by what you ate over the previous 48 h, and gave different results in sthe morning and afternoon. Furthermore, the criteria used to interpret it varied wildly. The prevalence of diabetes in the fair city of Bedford in the UK might be as low as 7% or as high as 32%! It all depended upon the criteria you used [9].To everyone’s relief, standard criteria for performing and interpreting the glucose tolerance test and other diagnostic tests were proposed by the US National Diabetes Data Group (NDDG) in 1979 and endorsed by WHO in 1982 [10]. A diagnosis of diabetes was conferred upon millions of unsuspecting people when the American Diabetes Association

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decided to abandon the glucose tolerance test in favour of fasting blood glucose in 1997. Diagnoses are categorical, but risk factors are dimensional. Dimensional consequences of high blood glucose include susceptibility to infection, cataracts, peripheral nerve damage, and arterial disease. These are associated with diabetes, but not necessarily specific to it. In contrast, characteristic changes in the small blood vessels which supply the kidneys and retina are found only in diabetes. Furthermore, the tell-tale features of diabetic eye disease can be identified by a trained observer with an ophthalmoscope. Prognostic studies showed a strong correlation between retinopathy and a venous plasma glucose in excess of 120 mg/dL (6.7 mmol/L) fasting, or 200 mg/dL (11.1 mmol/L) 2 h after a dose of glucose. This applies equally to different ethnic populations, and susceptibility to retinopathy is the basis of our international definition of diabetes. Arterial disease, by way of contrast, is common in people without diabetes, and blood glucose is only one risk factor among many. Arterial disease is not specific to diabetes and has no clear lower limit in terms of blood glucose. No surprise that blood glucose control has a relatively limited influence on its short-term progression. Conversely, microvascular complications such as retinopathy are categorical: they occur only in diabetes, and can be prevented by careful control of blood glucose levels. ‘Scientists and natural philosophers’ as Karl Marx said ‘have hitherto endeavoured to describe the world, but the real task is to change it’. How then should one proceed? Clinical diabetes was classed as insulin-dependent or non-insulin-dependent in the 1970s. Tablet treatment for non-insulin-­ dependent diabetes was relatively untested, and diet was the staple of management. Population surveys showed a high prevalence of clinically silent diabetes in the population at large. Should such people be sought out and treated? Operational criteria were needed to tell the physician when, why and how to intervene. The criteria adopted by the WHO came as a breath of fresh air. A formal diagnosis of diabetes equated to a prognostic risk of retinopathy, and a new category–impaired glucose tolerance (IGT)—was applied to those below this threshold who were at increased risk of arterial disease; also. Those with diabetes could in theory reduce their risk of small vessel complications by lowering their blood glucose to levels seen in impaired glucose tolerance. Those with impaired glucose tolerance, meanwhile, could reduce their chances of arterial disease by attention to other cardiovascular risk factors such as diet, cholesterol, blood pressure and smoking. Impaired glucose tolerance carried the additional risk of progression to frank diabetes at a rate estimated at 1–5%

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per annum by the NDDG, and it made sense for people in this category to reduce this risk by attention to diet and exercise. Little noticed at the time, diabetes was being transformed from a disease to a risk factor. ‘Diseases are not immutable entities’, as epidemiologist Robert Hudson pointed out; they are ‘dynamic social constructions’, and silent hyperglycaemia had become a dynamic social construct [11]. Our current classification of diabetes by risk of retinopathy is far from perfect but has never been seriously challenged. Conversely, the relationship between lesser degrees of hyperglycaemia and cardiac risk has given rise to unending controversy. The quotation from Karl Wunderlich which heads an earlier chapter warns that we should not confuse abstract concepts with reality, and confusion is inevitable when the same term is used to describe a fulminating clinical catastrophe and a silent chemical deviation from the norm. A shifting man-made definition is not an objective entity.

References 1. Tattersall R.  The pissing evil. A comprehensive history of diabetes mellitus. Swan & Horn. 2. Henderson P.  Incidence of diabetes mellitus in children and need for hostels. BMJ. 1949;1:478–9. 3. Beardmore M, Reid JJA. Diabetic children. BMJ. 1966;2:1383–4. 4. Nishimura R, et al. Mortality trends in type 1 diabetes. The Allegheny County (Pennsylvania) registry 1965–1999. Diabetes Care. 2001;24:823–7. 5. Sultz HA, editor. Long term childhood illness. Pittsburgh, PA: University of Pittsburgh Press; 1972. Chapter 8. 6. Fitz RH, Joslin EP. Diabetes mellitus at the Massachusetts General Hospital from 1824 to 1898. A study of the medical records. JAMA. 1898;3:165–71. 7. Wilkerson HLC, Krall LP. Diabetes in a New England town. A study of 3,516 persons in Oxford, Mass. JAMA. 1947;135(4):209–16. 8. West KM. Epidemiology of diabetes and its vascular complications. Amsterdam: Elsevier; 1978. 9. Rose G, Barker DJP. Epidemiology for the uninitiated. 2nd ed. London: BMJ Press; 1986. 10. National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes. 1979;28(12):1039–57. 11. Hudson RP. Disease and its control. The shaping of modern thought. Westport, CT: Greenwood Press; 1983.

14 The Hard Yards

Life on insulin depends more upon the behaviour of the person affected than almost any other form of medical treatment. A newer and more positive attitude emerged in the second half of the twentieth century as people with diabetes came to see themselves as active agents rather than passive recipients of medical advice. One key step forward came when they pricked their own fingers and measured their own blood glucose. Overall control could be judged from laboratory tests and evidence in favour of tighter glucose control began to accumulate. Sharper needles made injections less painful, and many users discovered the advantages of better glucose control for themselves—even when this meant extra injections. Insulin pens and insulin pumps appeared, and a landmark controlled study showed that intensified management could reduce the progression of small vessel complications. Patient-centred management based on education and feedback aimed to place the person with diabetes in the driving seat. Elliott Joslin has been our trusted guide through the first 40 years of the Age of Insulin, and was already 53 when he witnessed its coming. Unbending to the last, he rose on the morning of Sunday January 27th 1962, now aged 92, took the subway to church on that cold winter morning, returned for lunch, dictated letters to his patients in the course of the afternoon and dined with his family. He retired to bed and closed his eyes, never to open them again. W.B Yeats said that a man must ‘choose perfection of the life or perfection of the work’. Joslin would not have seen any difference. The period from the 1930s to the 1980s has been called the golden age of modern medicine, and readers of Lewis Thomas will recall that few effective therapies existed prior to the sulphonamides in 1937. Insulin apart, he lists © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 E. Gale, Life in the Age of Insulin, Copernicus Books, https://doi.org/10.1007/978-3-031-47190-2_14

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these as liver for pernicious anaemia, thyroid extract for hypothyroidism, vitamin B for pellagra, vaccination or antitoxin for diphtheria, and not much else. In contrast, the period between 1937 and 1987, as described by Seamus O’Mahony, ‘had witnessed the arrival of penicillin, effective drug therapy for tuberculosis, kidney dialysis, organ transplantation, endoscopy, CT and MRI scanning, in vitro fertilisation, the eradication of smallpox and the discovery of the double helix of DNA’ [1]. Although there was—and is—still a long way to go, the daily lives and prospects of those with diabetes got better. I was there to witness it. Before my time, the medical ‘houseman’ was expected to be resident and continuously on call for 6 months. A colleague who preceded me by a decade or so recalled that he dared to ask his chief for permission to dine out with friends after 3 months of uninterrupted duty. His boss, the redoubtable Sir Walpole Lewin, readily agreed. Come the night, Sir Walpole appeared on the ward, sat down, crossed his arms, and told my colleague to go off and enjoy himself. Things were more relaxed in my day, but I had experienced 4 years of non-stop front-­ line medical duty by 1976. We worked ‘one in two’ rotas which meant a full day’s work plus every second night and weekend, a weekend being defined as Friday morning to Monday evening. Youth, the intensity of the experience and the camaraderie of hospital life kept us going, but we lost touch with everyday life and—in retrospect—went mildly insane. Marriages fell apart. I dreamed of growing vegetables and writing beautiful books, but had no other means of earning a living. The diabetic clinic was not inspiring. My consultant was a kindly man in the throes of depression. He would sit with his head propped wearily on his hand as people poured their hearts out and the queue outside the door grew longer. His patients loved him. He went off to Canada in the hope of a better life (it wasn’t), and his place was taken by the 33-year-old Robert Tattersall. Robert had done the unthinkable, for he was a consultant at St Bartholomew’s Hospital, and consultants only left Bart’s to engage in private practice. Robert had a limitless interest in detail. Under his tutelage, I tried injecting myself. One trial of the standard needles was enough, and we switched everyone to the silicone-coated disposable version. I learned that research could change people’s lives, and before long I was hooked. The 1950s and 1960s opened unimagined scientific vistas, but the medical speciality of diabetes was seen as suited to the kindly plodder rather than those impatient to change the world. It was nonetheless ripe for change, and change was coming from several directions at once. Attitudes were changing in ways that were slow, intangible and hard to describe. The change marked a shift in the boundaries of exclusion as more people came to accept the

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‘normality’ of diabetes. Joslin, as ever well ahead of the game, pointed out in 1917 that diabetes is not a disease; it is a disability. Disabilities can be corrected. Short sightedness is reversed by a visit to the optician, and osteoarthritis of the hip can be relieved by a hip replacement. If you could correct the insulin deficiency of type 1 diabetes, the disease would no longer exist. Slowly but surely, the speciality evolved into teams of nurses, dietitians, and educators based in full-time diabetes centres. Their function was to coach and advise, never to pass judgement. Empowerment, an over-used word, was working its way through the system. Not everywhere, alas, and at different speeds, but change was in the air. Johnny Ludvigsson in Sweden provided inspiration to a generation of paediatricians. By chance, three of his former patients came my way at different stages in my career. Competent, informed, professional in their approach, they were there to check me out. I too had witnessed the birth of a new race. Meanwhile, better tools were being forged to counter the disability of diabetes, increasingly seen in terms of avoidable risk, and hope began to replace fatalism. There were still two schools of management. The laissez-faire variety maintained that the glucose disorder of diabetes is part and parcel of a presumed genetic disorder which also causes vascular disease. Glucose abnormalities might predominate in some individuals and vascular disease in others, but nothing could be done about it. Luckily, members of this school were headed towards retirement, and the rest of us were casting around for better ways of treatment. One major problem was that blood glucose could only be measured at the occasional clinic visit. We were groping in the dark. One woman changed all this. She is a lady of decided views who has steadfastly refused to be identified, so I will settle for calling her Mrs. Smith. In 1972, pregnant women with diabetes were admitted to hospital 3  months before they were due. Their blood glucose was tested four times daily, and their insulin was adjusted accordingly. When Mrs. Smith was due for admission to St Thomas’ Hospital in London, she realised that the only reason for being incarcerated was to have her blood glucose measured four times a day. She promptly commandeered a meter and took it home. Her physician was Clara Lowy, a childhood refugee from wartime Berlin, who backed Mrs. Smith to the full and adjusted her insulin by phone [2]. The idea was not new; Oliver Leyton had argued in 1927 that insulin treatment was unsatisfactory without blood glucose estimation, and he taught some of his patients to perform a horrendously complicated laboratory analysis at home. Some proved willing and able to do so. Glucose meters for hospital use had been around since 1962, but health professionals took it for granted that insulin users would be incapable of using the instrument and

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unwilling to jab their fingers. In fairness, it should be mentioned that the meters were as bulky as transistor radios and by no means user-friendly. Furthermore, the blood lancets were savage. The Ames Corporation was the leading manufacturer of glucose meters in the early 1970s, but its management rejected our advice to invest in meters for people with diabetes, consigning itself to oblivion in the process. Robert Tattersall took the hint from Clara Lowy and began to loan glucose meters to those who consulted him. They could now see what happened when they skipped a meal or consumed a Mars bar and, thus empowered, they soon learned to adjust their own insulin and to check their blood glucose before driving to Mansfield. Papers from London and Nottingham on home blood glucose monitoring appeared side by side in the Lancet in 1978. My name was on one. The technique—so simple and so obvious—spread around the world, and it changed the culture of diabetes management. As for Mrs. Smith, I took on her care when Clara Lowy retired. This dauntless lady was virtually unscathed by 40 years of diabetes and had the latest meter in her hand-bag. When taken to task for incautious use of her first name, I came to understand why no-one attempted to stand in her way when she walked off with the ward meter. Blood glucose monitoring transformed the day-to-day tactics of life on insulin, but we lacked an overall guide to strategy. Sporadic blood tests were not enough: we needed a benchmark for overall control. This emerged from an unexpected direction—the study of haemoglobin. Proteins differ in the electrical charge they carry, and can therefore be pulled apart by electrophoresis; the technique was used to identify inherited variants of the haemoglobin molecule such as the one responsible for sickle cell anaemia. Samuel Rahbar, an Iranian researcher, learned the technique in the 1960s, and Hermann Lehmann, a leading British authority, encouraged him to investigate the Iranian population. Rahbar constructed his own equipment and screened 1200 people for haemoglobinopathy. Two samples stood out from the rest, and both came from people with diabetes. Rahbar thought he had discovered a genetic marker for the condition. Experience showed that the haemoglobin variant was not inherited. Study of identical twins discordant for diabetes showed that the abnormal haemoglobin was present only in the affected twin. Furthermore, the abnormal band returned towards normal when diabetes was brought under control. It emerged that glucose can attach itself irreversibly to one end of the haemoglobin molecule, thus changing its charge on electrophoresis. The more glucose you have, the more likely this is to happen. A human red blood cell is packed with haemoglobin molecules, and glucose hitches on to a small proportion of these

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(4–6% of the total in non-diabetics) as they journey around the body. Those with diabetes are exposed to higher glucose levels, and their glycated fraction therefore increases to 7–14% or more. Red cells are replaced every 3 months, and the level of HbA1c (as this peak is known) reflects overall exposure to glucose over several weeks, thus providing a long-term measure of glucose control. HbA1c came into clinical use in the late 1970s and combination with home blood tests made it possible to measure both short-term and long-term glucose control, and to correlate this with the frequency of complications. Better still, long-term trials which randomised participants to average or better-­than average glucose control could now be planned—and would soon make it clear that people on insulin were no longer at the mercy of their condition.

References 1. O’Mahony S. Can medicine be cured? The Corruption of a Profession. New York: Apollo; 2019. 2. Lowy C. Home glucose monitoring; who started it? Br Med J. 1998;316:1467.

15 Insulin Wars

Factories around the world processed animal insulin in much the same way at the start of the 1960s. Some countries exported it world-wide, others aimed to make enough for their own needs. From the consumer perspective, insulin was like petrol at a filling station; the brand did not greatly matter. All this changed when Danish manufacturers laid claim to a ‘cleaner’ (more highly purified) product. Allergic reactions became rare, and fewer insulin antibodies appeared to facilitate better glucose control. The ‘cleaner’ insulins were aggressively marketed. Meanwhile, investigators in the USA raced to generate the human insulin molecule by genetic engineering, and the first ‘human’ insulin was marketed by Eli Lilly in 1982. Genetically engineered variants of the insulin molecule—insulin analogues—were soon in the pipeline. The newer technology came at a high cost, not to mention the research that made it possible, but the insulin analogues could be patent-protected and sold at a higher price. Opinions differ as to their advantages, but aggressive marketing persuaded many prescribers to switch from animal to human insulin, and from human insulin to analogues. Smaller manufacturers were soon priced out of the market, and three corporations now controlled some 92–98% of insulin sold on the planet. Insulin had been globalised. I was shown round a British insulin factory in the 1980s. It was a depressing dockside building with cracked and stained concrete floors, and the pervasive salty-sweet aroma of entrails hung in the air. We watched as beef pancreas was tipped into a glorified mincer and piped through a series of stainless steel tubes before emerging as a much diminished liquid residue

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containing insulin. The purification steps that followed yielded a product with few impurities—a few parts per million. But it wasn’t pure enough. The design of this production line had changed little over 40 years, and beef pancreas was used because the slaughterhouses had plenty. Beef insulin differs from human insulin in three of its 51 amino acids, but the immune system can spot the difference. Everyone on beef insulin formed antibodies and, as Berson and Yalow had discovered, the circulating reservoir of antibody-­ bound insulin could delay and prolong the effect of injection. The Danish manufacturers had an advantage in this respect, for they had an ample supply of pigs—raised to satisfy the British passion for bacon and eggs. Pig insulin differs from ours in one amino acid only, and the immune system struggles to tell them apart. Insulin allergy was unrelated to the presence or absence of insulin antibodies, and generally took the form of angry bumps at the injection site, disfiguring hollows under the skin or (very rarely) as anaphylactic reactions. Erik Jorpes showed that insulin allergy can be treated with thrice-crystallised insulin, which implied that the phenomenon was due to impurities rather than to insulin itself. Jorgen Schlichtkrull, a skilled insulin chemist who worked for Novo, supplied Dorothy Hodgkin with pork insulin crystals and had a daughter with diabetes. His team set out to produce a purer insulin by chromatography, a technique that passes the substance to be purified though long columns filled with permeable material. The speed at which molecules travel through this medium is determined by their physical characteristics, and they emerge at the other end of the process in separate bands. Pure insulin emerges as a single well-defined peak, and impurities show up as a cluster of foothills. ‘Single peak’ or monocomponent insulin became the watchword of the manufacturers, and the Danes could lay claim to a cleaner product. Sales representatives for the insulin manufacturers appeared on the scene in the 1970s to the bewilderment of young doctors like me for whom insulin was … well, insulin. Thorstein Veblen, the American sociologist and wit, remarked that the main outcome of research was to make two questions grow where one had grown before, and the advent of cleaner insulins produced a whole crop of new questions. Allergies were now much rarer—but did the new insulins enable people to control their diabetes more effectively? If so, was it because they had fewer antibodies? And, talking of antibodies, was the difference between pig and beef insulin important? These hitherto academic questions could now be posed by pitting pig against cow, and ‘clean’ against ‘dirty’ insulin. The answers mattered, for a somnolent market was waking up to the fact that all insulins were no longer the same. This, little noticed at the time, was the first shot in the insulin wars.

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Type 1 diabetes results from insulin deficiency, and insulin therapy aims to correct it. We evolved to fire small packets of insulin into the liver as and when needed. Insulin is short-lived—its half-life in the blood stream is counted in minutes—and a third of the insulin reaching the liver is destroyed on the way through. This means that the liver ‘sees’ more insulin than the rest of the body. In contrast, injected insulin is dumped under the skin and—after inevitable delay—is absorbed from there into the general or systemic circulation. It is not subject to feedback regulation, and nature’s solution cannot be matched by dumping a pre-specified amount of ‘fire and forget’ insulin under the skin. A healthy pancreas operates in two modes: a sharp burst of insulin after meals and a steady trickle in between. The makers of insulin aim to match this by combining a fast-acting insulin before meals with a slow-acting insulin to provide constant background levels in between, otherwise known as the basal-­ bolus approach. An insulin infusion pump works on the same principle. Continuous blood glucose monitoring was a distant dream when I went into research, and I had to stay up all night and draw blood through a cannula if I wanted to find out what was happening to the people I was trying to look after. To my horror, I found that one in three of those tested dropped their blood glucose to vanishingly low levels during the night, sometimes for hours on end. Oddly enough, their blood glucose ranged from normal to high on the following morning and they reported few or intermittent symptoms. The reason, as it emerged, was that the supper-time dose of insulin was too short-­ acting. This being the case, increasing the evening dose in an attempt to bring morning glucose levels under control simply drove them too low in the middle of the night. The solution was almost laughably simple: one large dose of insulin before supper was replaced with two smaller injections before supper and bedtime. Not rocket science, but it got them through the night—and they felt better next day.

15.1 A Needle in a Genestack The advent of the highly purified Danish products coincided with the exciting prospect of producing insulin in the laboratory rather than the meat market. Man-made insulin ended theoretical concerns about a future shortage of animal pancreas, for the new supply was potentially infinite. It would also, for the first time, allow people to be treated with ‘human’ insulin. The human insulin molecule can be built by purely chemical means, but this is a slow and painstaking business. Getting bacteria to do the job was far

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more appealing. The challenge for the genetic engineers was to get their hands on the intact genetic code for insulin, given that the displacement or omission of a single nucleotide will convert the signal into gobbledygook. You also need a switch, known as the promotor region, to turn it on; for the gene will otherwise sit around and do nothing. Nor did anyone know where the insulin gene was located within the three billion or so nucleotides which make up the human genome; a true needle in a haystack. So, how might you find it? There were two main possibilities. One was to build the gene yourself, for its structure can be deduced from the amino acid sequence of the protein it makes. The synthetic gene could then be fed into bacteria and multiplied ad infinitum. The technical challenge was mind-boggling, however, and others hoped to short-circuit the task by getting hold of the intact gene and teaching bacteria to make it. The insulin gene resembles a zip fastener composed of two strands of DNA. Each side of the zip consists of a chain of nucleotides linked by a sugar-­ phosphate backbone, and the strands come together in such a way that a purine nucleotide on one side of the zip always lines up with a pyrimidine, an adenine with a thymine, and a cytosine with a guanine. The zip splays apart when the gene is activated, and the code is presented on the newly-exposed strands of DNA. Since each strand of DNA is the mirror image of the other, single-stranded RNA can ferry the code from the nucleus to structures known as ribosomes in the cytoplasm. These transcribe each codon into the corresponding amino acid. The newly-formed peptide spools off the molecular assembly line like ticker tape, springing into its three-dimensional configuration as it does so. Proinsulin, the insulin precursor, is now ready to be packaged into its storage form and shipped to the surface of the cell. The ‘central dogma’ of molecular biology used to be that the transfer of code from DNA to protein is a one-way process: ‘DNA makes RNA makes protein’. It was overturned by the realisation that retroviruses can make DNA from RNA. The virus inserts its own genes into host cells or bacteria with the help of an enzyme known as reverse transcriptase, and hijacks the machinery of the cell to manufacture its own viral proteins. Reverse transcriptase made it theoretically possible to reconstruct the insulin gene, and hijacked bacteria should then go on making insulin until it could be harvested. Messenger RNA is the essential first step in this process, and the right messenger will only be found in cells that make insulin. Here, oddly enough, the story loops back to Shields Warren (1898–1980), a Boston pathologist who worked with Elliot Joslin in the 1920s. His career took a new turn when the Atomic Energy Commission invited him to look into the after-effects of the atomic blasts in Hiroshima and Nagasaki. Ionising radiation is notorious for

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its ability to cause genetic mutation. What kills can also cure, however, and radiation has the potential to cure cancer by breaking up the DNA of tumour cells. Medical researchers were reckless with other peoples’ lives in the post-war period, and Warren was horrified to discover that Californian researchers were injecting plutonium into cancer patients with little concern for informed consent. He drew up a code of conduct to stop this from happening. The relevance to our story is that he also tested the effects of radiation upon rats, and blood glucose fell so low in one of the animals that a technical fault was suspected. It turned out that the dose of radiation had triggered an insulin-­ secreting tumour—an insulinoma—that could be transplanted freely from one animal to another. Healthy cells have feedback mechanisms to ensure that they produce no more insulin than is needed, but an insulinoma has no brakes and is wholly given over to the production of insulin. This made it a rich source of the messenger RNA that the investigators were seeking. A group of academics met in Indianapolis on May 24th 1976, and listened with eager attention to a member of Warren’s team as he described the insulinoma work. The coming race between the West and the East Coasts of America was already in evidence. From University College San Francisco came William Rutter and Howard F Goodman, and from Harvard came Wally Gilbert, one of the really big hitters in DNA, and a future winner of the Nobel Prize. Not there, but present in spirit, was another Californian: Herbert Boyer. ‘I have wandered through all the sciences at some level’ remarked Gilbert at a later date. ‘My PhD is in mathematics, and I began as a theoretical physicist at Harvard University. I then became a biologist without a license and won a Nobel Prize in Chemistry’. Along the way he helped to found a company called Biogen, and retired from science to take up a second career as a photographer of industrial detritus whose work is exhibited in leading galleries. In 1976, however, he had a lean and hungry look. His first move was to commandeer Warren’s rat tumour—much to the dismay of the Californians—and to set about extracting its RNA. Military histories are generally written in bloodless terms of manoeuvre, strategy, and outcome; the panic, chaos, and shattered corpses must be inferred. Scientific history is similar. The celebrated rat insulinoma did not give up its secrets gracefully, for it turned out to be a murderous lump of gristle that had to be mixed with sand and ground with a mortar and pestle. And, just as progress was being made, public concern about genetic engineering led to the closure of the highly specialised laboratory facilities that Gilbert needed for his gene transfer work.

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With few exceptions, scientists tended to downplay the risks of genetic engineering. They argued that the species barrier had already been breached by cell hybridisation experiments, and that people had bombarded fruit flies and rodents with X-rays for 40 years in order to produce random mutations. Directed modification of genes under controlled conditions seemed much less hazardous. One major safety concern could not be overlooked, however, for genetic engineering involves manipulation of viruses and bacteria by people with no background or training in microbiology, often in ignorance of standard precautions developed within the discipline. Worse still, they could hardly have picked on a less suitable bacterium, for E. coli is present in every human bowel, and exchanges genetic information freely with other bacterial strains. This information could cause fatal illness. Furthermore, viruses can cause cancer, and the thought that infected bacteria might spread cancer though a population was not a cheerful one [1]. The resulting debate was passionate. The public mistrusted the scientists, and no-one knew what the real risks were. The scientists were invited to consider what they were doing, a suggestion that might with equal usefulness be presented to competitors lining up for the 100-m dash at the Olympic Games. The scientists painted a glorious future of bioengineered health, human insulin included. The extremes ranged from Frankenstein in one corner to Biotopia in the other. Messy arguments lead to messy compromise, and grudging consent was given for the revolution in genetic engineering to go ahead. In the interim, the debate about genetic engineering came at exactly the wrong time for the contestants in the insulin race. Everything they attempted would now be under the closest possible public scrutiny, and woe betide anyone who screwed up. Inevitably, someone did. By January 1977 a post-doc on the West Coast had overtaken Harvard in the race to produce DNA from rat RNA, and had located a band on the electrophoresis gel that might represent the insulin gene. He needed to confirm this by sequencing, which involved fitting ‘linkers’ to either end of the DNA preparatory to insertion into a bacterial plasmid—but NIH had yet to certify the plasmid he was using. What followed achieved notoriety [2]. NIH approved the vector on January 15th but this was only the first step in a two-­ step procedure: actual use of the vector was illegal until it had also been certified, which did not happen until July 7th. Did he jump the gun, or did he misunderstand the difference between approval and certification? In all events, the gene was inserted into the plasmid in January, the plasmid was transferred into bacteria, and two promising clones emerged. Painstaking analysis of the nucleotide sequence showed that

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it looked like insulin: but the law had been broken. News of this might bring the whole recombinant enterprise to a grinding halt, not to mention the prospect of NIH funding. The clones were accordingly dunked in hydrochloric acid, no doubt with extreme reluctance. We might suspect that some had been squirrelled away, for further clones were generated within 3 weeks when a similar plasmid was given the green light in April. The report appeared in Science, and many failed to notice that this was, after all, rat insulin. Harvard, meantime, was floundering in the qualifying round while others had reached the semi-finals. Worse still, another contestant had emerged. Herb Boyer, who missed the Indianapolis meeting, was also based at UCSF; his expertise lay in the development and use of plasmid vectors. In 1973 he helped to show that genes from unrelated bacterial species function perfectly well in E. coli [3]. Soon after, his group showed that DNA from a toad could make toad RNA inside a bacterial cell. Animal genes could be implanted into bacteria and would potentially function there [4]. Boyer was a born entrepreneur who had made unsuccessful overtures to a number of companies. Given the gold rush mentality that was soon to emerge, it is ironic that Robert Swanson, a young venture capitalist, was going the rounds of prominent scientists with equal lack of success. Not surprisingly, there was immediate rapport between the two when their paths intersected, and a company was founded with an initial capitalisation of $500 each. They called it Genentech. The new company was greatly resented. ‘Capitalism sticking its nose into the lab has tainted interpersonal relations’ as one senior member of faculty at UCSF would later remark—‘there are a number of people who feel rather strongly that there should be no commercialisation of human insulin’. 1 The new outfit did however have some big advantages: it was fast on its feet, fully committed, and free of academic constraints such as the need to write endless grant applications. Two early decisions had enormous implications. The first was to make DNA in the laboratory rather than by the potentially faster route of RNA in bacteria. The second was to pilot the technology with a recently discovered hormone called somatostatin, a much shorter peptide than insulin. Although fully justified by the outcome, each choice represented a big gamble. The two decisions were linked, for the company had been joined by Keiichi Itakura, a talented Japanese chemist who was confident that he could accelerate the tedious business of building DNA from scratch. It took courage for the fledgling company to put its eggs in this particular basket, for it had recently taken the Nobel laureate Gobind Khorana 9 years and more than 20  David Martin, cited in Wade 1977t.

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chemists to build a smaller gene in the laboratory. Happily, the technology was improving rapidly, and it made sense to start with a gene which is quarter the length of insulin. The tortoise had one big advantage over the hare. Cloning of recombinant DNA was stalled by administrative fiat in 1977, but the terms of the edict did not include synthetic DNA.  This being the case, there was nothing to stop them from building a gene for the smaller hormone somatostatin, which was achieved by June 1977. But would the gene express the hormone? The first demonstration was a failure—embarrassingly so because Swanson had been invited to the laboratory to witness its success—but key lessons were learned. Chief among these was the need to prevent somatostatin from destruction by smuggling it into a bigger protein. The ploy worked, and the hybrid gene made a hybrid protein which accumulated within the bacteria. The bacteria were killed, the protein was harvested, and somatostatin was liberated by a simple chemical procedure. Genentech had made a human gene and grown it in bacteria; the DNA had made RNA, and the RNA had made the right protein. The gene had been both cloned and expressed, a landmark that was rightly celebrated at a press conference to mark the appearance of their paper in Science in December 1977 [5]. It was a magnificent achievement, but it still wasn’t insulin. Meanwhile, Harvard finally got in on the act by making cDNA from the infamous rat insulinoma. This could be fitted into a plasmid containing the gene for the enzyme penicillinase, which confers antibiotic resistance by inactivating penicillin. The penicillinase gene has a leader sequence which switches on production of the hybrid or fusion protein. The experiment worked even better than anticipated, for penicillin-resistant clones showed up on the culture plates. Penicillinase was being produced and exported to the cell surface. Did this apply to insulin? If so, the team had not only taught the bacteria to clone and express insulin: they had also trained them to secrete it [6]. There were only two snags: the first was that this was still rat insulin, or (more accurately) rat proinsulin, and the second was that the amount of insulin produced was derisory. Production on an industrial scale would be needed to guarantee the continued health and well-being of a single diabetic rat. Notwithstanding, there were now three horses in the race for human insulin, and two had commercial jockeys, for Gilbert had helped to find a company called Biogen. The loophole that allowed Genentech to evade legal constraints by making their own DNA gave them a huge advantage. They could use standard sterile laboratory facilities, for example, whereas their rivals were obliged to use ultra-sterile facilities available only within germ warfare establishments. Thus it was that Wally Gilbert and his colleagues loaded themselves and their

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reagents onto a plane in September 1978 and headed across the Atlantic to the British Microbiological Research Establishment at Porton Down. They had an insulin gene derived from a human insulinoma and permission to use the facility for just 4 weeks. A frustrating if somewhat comic clash of cultures ensued, for the resident scientists, civil servants to a man, wore suits and worked a sedate 9–5 day with frequent tea breaks. This was their first encounter with molecular biologists who dressed in jeans and trainers, worked around the clock with fanatical intensity and possibly smoked illicit substances. Nor did the invaders take to wearing a gas mask in the laboratory, an unavoidable but entirely excessive precaution. Even so, the project began well before graduating from bad to worse. With gut-wrenching irony, they discovered that their human insulin gene had gone astray, and that the original rat gene had contaminated all their cultures. The trip was a disaster. To add to their misery, a press release was going the rounds: Genentech had made human insulin. The insulin in our pancreas is embedded within proinsulin. It is freed by cutting out the middle portion of the peptide chain and discarding it as C-peptide. The two ends of the protein then spring into their active configuration, locked into place by cross-linking chemical bonds. This means there are two potential ways of making insulin. Harvard and UCSF wanted to make proinsulin and remove the C-peptide; Genentech wanted to make the A and B chains separately and hook them together. This too was a gamble, for no-­ one knew if the two halves of the insulin molecule would unite correctly. Worse still, endless purification steps were needed before the chains could be persuaded to mate, whittling away at the minute amount of material they had to begin with. Collip saw insulin in his test tube in January 1921, and the equivalent date for biosynthetic insulin came on the night of August 23rd 1978 when antibody testing confirmed a correctly-folded insulin molecule. They had made insulin [7]. A contract with Eli Lilly was signed on August 25th, and the triumph was announced to the world at a press conference on September 6th. Investors were jostling for a slice of the action, and the conference netted $ten million for a 2-year-old company which had not as yet produced enough insulin to trouble a rabbit. Lilly was rightly cautious, and the contract set demanding milestones. It looked for a while as if Genentech might fail to meet them, but the problem was solved by linking the insulin gene to the bacterial gene for tryptophan. Bacteria normally obtain tryptophan from their environment, but will switch on the gene to make it in the absence of tryptophan. Plug the insulin gene into this sequence, and they will make insulin as well. The resulting protein was generated in such quantities that the E. coli bulged like pregnant sausages under the electron micrograph [8]. Major challenges remained

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before the method could be scaled up for industrial production, but that was Lilly’s problem (Fig. 15.1). The RNA route they pioneered would later become the standard route to insulin biosynthesis, but UCSF and Harvard could only stand by as Genentech scooped the commercial trophies. The company put 1.1 million shares on the market in October 1980 at $35 each, and they rocketed to $71 in the course of the day. Boyer and Swanson, whose initial outlay was $500, now held $66 million of stock in a company with no product. Lilly pushed human insulin forward with enormous energy, and had tested it in healthy volunteers by 1980 [9]—the first recombinant DNA product to be injected into humans. It proved very similar to pork insulin, and caused few allergic reactions. The company opted to pour all its resources into human insulin and committed an estimated $70–80 million to construction of facilities in Indianapolis and Liverpool. It obtained marketing approval from the US government, and by 1983—only 7  years after that first meeting in Indianapolis—human insulin was in full-scale production. Lilly was now the only company in the world with biosynthetic insulin. What followed should have been a walkover, but pig insulin differs from ours by one amino acid and Novo had devised a chemical means of replacing it. Formally speaking, this made it first on the market with human insulin, enabling it to form a partnership with Squibb pharmaceuticals and to contract with Biogen (the company Wally Gilbert helped to found) to make biosynthetic human insulin for marketing in the USA. The gloves were off, and this was nothing less than a formal declaration of intent. Genentech set a frenetic pace in the development of new biosynthetic agents, and marketed human growth hormone in 1985. Wally Gilbert consoled himself by sharing the 1980 Nobel Prize with Frederick Sanger for rapid sequencing of DNA.  William Rutter and Howard Goodman pursued

Fig. 15.1  Insulin inclusion bodies in bacteria. (Courtesy of Bioton Ltd)

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distinguished academic careers in UCSF. Even so, molecular biology would never be quite the same. The postdocs whose work and ingenuity had driven technical progress had been elbowed aside when patents were up for grabs or the latest breakthrough was announced at a press conference. Even so, a skilled bench operator now had a market value, and ambitious juniors pondered their own chances of wealth and fame. The age of innocence was over. The creation of recombinant insulin was a towering scientific achievement, but human insulin made little practical difference to the lives of people with diabetes. Those who lived through this era will recall the transformational effect of sharper needles, pen injection and insulin pumps, but pork and human insulin were virtually indistinguishable [10]. There was, furthermore, widespread public concern about the use of a genetically modified product, and many insulin users complained that their warning symptoms of hypoglycaemia had been affected. Worse still, some feared that the switch to human insulin had precipitated unexplained night-time deaths in young people with diabetes, although this fear receded with time. In the event, the main impact of engineered insulin was commercial rather than clinical. I worked for a year as a research fellow at the Steno Memorial Hospital in Copenhagen in 1980. The Steno was founded by Hagedorn: animal insulin was extracted in the Nordisk factory next to the hospital (founded 1931–2), and the profits from insulin supported patient care in the hospital. A research foundation funded basic research in the adjacent Hagedorn Research Institute, built in 1957. The Institute became the Mecca of European diabetes, and was noted for the robust independence of its chief physicians and investigators. My stay coincided with a crunch decision for Nordisk: should it—or should it not—invest in human insulin? A team researched the topic and concluded that human insulin offered little clinical advantage. This may have been factually correct, but human insulin for human beings was a no-brainer in marketing terms, never mind the evidence. Nordisk finally lost the race, 60 years after the Pedersen brothers founded Novo, and the ostensibly friendly merger between the two Danish manufacturers was widely seen as a hostile takeover. The Hagedorn Institute would later be closed. Lilly and Novo—soon to become Novo-Nordisk—were now fully committed to genetically engineered insulin. Hoechst was keen to join the club, but faced an adverse regulatory environment in Germany. It remained in the race by virtue of a $70 million partnership with Howard Goodman, now located at the Massachusetts General Hospital in affiliation with Harvard University [11], although the company was unable to market recombinant human insulin in Germany until 1998. By this time it had been absorbed into

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Aventis and then Sanofi, a parent company with little track record in diabetes. Almost incidentally, it had also acquired the rights to insulin glargine—the most successful bioengineered analogue. And then there were three.

15.2 Business as Usual A CEO is judged by share price. This is a powerful stimulus to actions that are sometimes blatantly illegal, as shown by the Volkswagen emissions scandal. Diesel cars were unpopular in the US until European carmakers set out to penetrate the lucrative US market with high performance engines which combined high mileage with low carbon emissions. European legislators rewarded them for lower emissions by reducing fuel taxes, but US standards were more stringent. Goodhart’s ‘Law’ states that a measure ceases to be useful once it becomes a target. Europe’s premier car makers came to view emission levels as a target, and were tempted into an astonishingly reckless and irresponsible attempt at fraud. Particulate emissions are tested by placing the car’s wheels on rollers while the steering wheel remains stationary. Volkswagen fitted each and every car with an electronic system designed to recognise the test situation and to activate a temporary filter in order to fake the results. The fraud worked well until a team at West Virginia University tested emissions under standard driving conditions and found them forty times higher than stated [12]. VW were named and shamed in the law-courts, but it soon emerged that all its major European rivals had fitted ‘defeat devices’ to their diesel cars in order to get away with emissions which were already six to sevenfold in excess of Europe’s relatively lax standards. VW’s former CEO was indicted for fraud and conspiracy, and would be slammed into jail if he were foolish enough to visit America. In Europe, he walks free. To this day, few Europeans know the details of this monstrous scam. Fewer still seem concerned that our leading car manufacturers knowingly caused tens of thousands of deaths from pollution. Three lessons can be drawn. The first is that big business considers itself above the law. The second is that the deaths you can’t see or count are invisible. The third harks back to the sixteenth century economist Thomas Gresham who noted that devaluation of the currency caused the valuable money to disappear from the circulation. This has come down to us as ‘the bad money drives out the good’, otherwise known as ‘Greshams’s Law’. The realisation that a prominent competitor was cheating prompted other manufacturers to do likewise.

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Is the pharmaceutical industry any different? Yes and no. It produces life-­ giving drugs, does many good things, and people are drawn to it for the best of motives. At higher management levels, however, sales come first, as shown in the recent opioid epidemic. As I write this, the coronavirus epidemic virus is estimated to have caused 573,000 American deaths. CDC believes that the opioid epidemic caused 400,000, and these lives were sacrificed to profit. Arthur M Sackler, founder of Purdue Pharma, died in 1987. The Medical Advertising Hall of Fame (sic) said that ‘no single individual did more to shape the character of medical advertising than the multi-talented Dr Arthur Sackler. His seminal contribution was bringing the full power of advertising and promotion to pharmaceutical marketing’ [13]. The ‘full power of advertising and promotion’ works by the skilled diffusion of money, influence and flattery through the medical community. The resulting network includes charities, the media, academic institutions and politicians, thus creating a ‘web of influence’ which entangles us all. The tobacco industry once defended itself by instilling doubt as to the conclusions of academic science, a strategy easily reversed by those who wish to promote unwarranted confidence in weak evidence. The opioid manufacturers used this strategy to downplay fears of addiction and to encourage use of higher doses. Furthermore, they extended the market for opioids, previously restricted to people with terminal cancer, to all types of pain. This was underpinned by clever marketing, well-remunerated ‘key opinion leaders’, grants, and lucrative contracts to academic institutions, and well-publicised acts of charity. As with the VW scandal, the most striking feature of the opioid affair is the response—or rather lack of response— it generated in the wider community. The watchdogs barked, but no-one was listening. When a corporation behaves badly, it is easy, convenient and comforting to use the ‘bad apple’ argument. VW and Purdue Pharma were named and shamed, and everything else went on as before. Unfortunately, the bad apple defence is patently untrue, for other European carmakers cheated over emissions, and other companies profited from the opioid business. Shaming the worst offenders does not condone the rest. There two faces to any pharmaceutical business. The public face is represented by doctors, scientists and sales staff whose faith in the product is genuine. This makes them ideally suited to promote it. Ask about cheating, and they will tell you other companies do it, but theirs is different. The private face of the industry, meanwhile, is represented by business people whose sole function is to market the product and to attract investors. If sales are their measure of success, sales become the target.

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The unacceptable face of the market in insulin was seen when the regulatory authorities encouraged the manufacturers to undertake post-marketing studies of new products in order to generate useful data. One manufacturer set out to ‘recruit’ 340,677 insulin users in 54 countries. The stated aim was to ‘remedy the deficit of data on the efficacy and safety of insulin analogues in routine clinical use in clinical care in less well-resourced/newly developed countries’. Since the insulin analogues did not at the time feature on the WHO list of essential medicines, ‘deficit of data’ was scarcely a burning issue. These so-called investigative studies offered clinicians a bounty for each person switched from human to analogue insulin, and the patient (or the patient’s health care system) paid the increased price. The doctor earned his or her remuneration by completing one questionnaire when switching a patient to analogue insulin and another 6 months later. The scientific value of the data can be judged from the fact that the questionnaires reported an 80-fold drop in the frequency of severe hypoglycaemia. These Mickey Mouse studies converted 340,000 people to long-term use of a more expensive product they did not need, and the profits this generated were well in excess of the cost of the whole exercise [14]. Even as one arm of the company implemented this policy, another won praise for its charitable donations to diabetes care in developing countries.

15.3 The Role of the Regulator Let me jump back to a key moment in my own journey through this treacherous area. The year was 2002 or thereabouts, and my faith in the system by which new drugs come to market had been badly shaken by what I had learned about a blockbuster called troglitazone. This was launched in the USA in 1997 and withdrawn in March 2000 after hundreds, possibly thousands, of people had died from inflammation of the liver. The intriguing aspect of the story, from my point of view, was that the drug had been launched in Europe in October 1997, only to be withdrawn 6 weeks later. Sir Richard Sykes, CEO of what was then Glaxo-Wellcome, appears to have withdrawn it on receiving information concerning 135 cases of serious liver toxicity and six deaths from its US makers. This brave decision was abundantly justified by subsequent events, and many lives were saved outside the USA and Japan. Why was the response so different on either side of the Atlantic? I was researching the story, and asked to meet an official called David Graham who had signed off on the final (and utterly damning) FDA report [15, 16].

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I expected an invitation to his office, so his instructions came as a surprise. I was to wait for him outside a Washington subway station, and should look out for a dark blue SUV driven by a man in a fawn jacket. I wondered if I had strayed into a novel by John le Carré. Graham proved to be a wiry, youthful-­ looking man, described by someone who knew him as resembling an adult cub scout. He was in the midst of uncovering the Vioxx scandal at the time, and his quiet passion for the truth was overwhelming. ‘You’re an idealist’, he said towards the end of the meal, and I took it as an accolade. Idealists are what institutions can do without, and Graham was a thorn in the side of the FDA. Officials found it particularly galling when journalists asked ‘but what does David Graham say?’ when enquiring about a new drug. The Vioxx scandal brought this to a head, and Graham testified in 2004 before a Senate hearing that rofecoxib (its generic name), had caused an estimated 89,000—113,000 deaths from stroke or heart attack following its approval by the FDA. ‘The agency has lost its way’, he said, and is ‘incapable of protecting’ the US against a repetition of the disaster. He noted that there was a built-in conflict of interest within the system, for ‘the same group that approved the drug is also responsible for taking regulatory action against it’ [17]. Prescription medicines are swallowed in the confident belief that the safest and most appropriate drug has been prescribed, but this is not necessarily the case. A new drug takes up to 10 years to reach the market, and passes through three phases of testing. Phase I is a ‘canary in the coal mine’ technique by which volunteers are exposed to the drug under carefully monitored conditions. These human guinea-pigs are numbered in tens, and their role came into sharp focus when vaccines against COVID-19 were tested. Phase II tests efficacy (does this agent really lower blood pressure?), and involves hundreds of people. Phase III trials are carried out in thousands of people under conditions approximating to clinical use, and are considered ‘pivotal’. Why pivotal? Because the future of the drug will depend upon the wording of the label agreed with the regulators, and upon the success with which these same trials are marketed to medical professionals. Post-marketing surveys, sometimes referred to as Phase IV studies, are encouraged but not mandated, and we have just seen an eye-watering example of misuse. The regulatory pathway is daunting but well-greased. The cost of taking a new drug to market is variously estimated, $800 million being a frequently-­ used example, although such estimates include accountancy mark-up for ‘opportunity costs’—the profit that might have been made by investing the same amount of money in something else. Even so, this is a very expensive business, and the cost of launching a new insulin is a major deterrent to companies that might otherwise market cheaper insulins of equivalent quality.

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The Food and Drug Administration (FDA) was founded early in the last century, and its remit was to check on and regulate the production of any ingestible substance sold to Americans. It does so in the full glare of publicity, has attracted the interest of politicians, and its investigations have sometimes resulted in criminal prosecution of senior executives. For all its faults, it remains the most effective and respected consumer protection agency in the world. Trials performed for regulatory purposes constitute most of the scientific evidence we will ever see. This should not matter if the studies are well performed and carefully monitored, but this is where we encounter a clash of cultures. Science is based upon full and open disclosure, whereas marketing is based upon selective disclosure of information available only to the company. The VW emissions scandal showed that a reputable corporation was fully prepared to release lethal poisons into the environment, even though anyone with the requisite expertise could unmask the fraud by taking a VW to bits. No such worry for a pharmaceutical company, for their database is a commercial secret, partially disclosed to regulators who have no way of knowing whether the primary data were entered and analysed correctly. Billions of dollars in potential sales are authorised on the basis of data processed and presented by individuals whose career depends upon a successful outcome. The FDA is the most influential drugs regulatory authority in the world, but its criteria for approval of a new drug have become less rigorous over the past 20  years. This is partly down to the ‘Law of Unintended Consequences’, for the FDA adopted procedures to expedite approval of orphan drugs (drugs for rare diseases), which inadvertently opened the door to ‘cases in which therapeutics are eventually used for indications much broader than those originally approved’. The upshot, as diplomatically phrased in the conclusion of one review, is ‘an increasing need for continued evaluation of therapeutic safety and efficacy after approval’ [18]. Otherwise said, caveat emptor. I was privileged to chair a medical advisory group for the European Medicines Agency (EMA)—the European equivalent of the FDA—for 6 years. It really was a privilege, for the people in the organisation are well-­ trained, highly professional, committed and strictly impartial. Unlike the FDA, which conducts its business in the full glare of publicity and is subject to all manner of political interference, EMA is a highly secretive organisation, and its powers are effectively limited to approving or rejecting new applications for medicinal products and negotiating the contents of the product insert. I doubt if a single politician in Europe has much insight into its workings—a sure sign that the money is elsewhere.

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Every professional group has its mind set, and the mind of a regulator is tidy. Necessarily so, for there is a lot of meticulous work to be done, and there are 32 countries in the European Union. The regulator’s task is clearly defined, and each drug is processed in exactly the same way, regardless of differences in biological action. Another key feature is that regulatory teams work in close partnership with the mirror bureaucracy of the company. The people engaged in this monumental task tend to think alike, and there is a shared sense of accomplishment when all the boxes are ticked. Economist Joseph Stiglitz called this ‘regulatory capture’. The mental processes of a clinician are less tidy, and practising doctors are handled with caution in EMA headquarters. Respected, of course, but not entirely trusted to be impartial. Nor were we at the table when key decisions were made. The advisory group I chaired only became involved in the latter stages of the regulatory process, and its role was to answer predefined questions. Since these were sometimes phrased in such a way as to invite a negative response, I came to suspect that we were a convenient way of conveying bad news to the companies. Over and above this, I learned some important truths about the regulatory process. One was that the published version of a study may bear little relation to the reason for doing it. The regulators might, for example, mandate a study to address a safety concern which will not even be mentioned in the subsequent publication. Instead, this might present an unrelated finding which chanced to reach statistical significance, and showcase this as the original purpose of the study. Endpoint shifting, as this tactic is called, is the most common reporting error in published trials, and was recently detected in one in four of 67 clinical trials published in five leading journals over a 6-week period [19]. Safety concerns are the most common reason for withdrawing an approved drug, but post-marketing surveillance is entrusted to companies who control their own database and have an unfortunate tendency to drive through amber lights. Furthermore, the regulators have little ability to police the system. I discovered this when an investigator contacted me concerning what she considered serious company malpractice. My calls to EMA went unanswered. When I persisted, I discovered that the guard dog had no teeth. The FDA has the unenviable task of steering a course between an enormously wealthy industry and the ‘best politicians that money can buy’. Its task became more difficult when the pharmaceutical lobby became turbocharged with income in the latter part of the twentieth century, and the Agency reached an all-time low under the Trump administration when it bowed to presidential pressure by endorsing hydroxychloroquine for the treatment of coronavirus.

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In sum, regulators fulfil a vital task in screening new drugs and devices before they reach the public, but they have limited access to a database owned by the people who stand to profit most. The outcome of all their hard work is a label which lists the acknowledged properties of a drug and the indications for which it may be used. FDA has frequently initiated litigation regarding off-label promotion of a product, but repeated safety failures have revealed its limitations in terms of post-marketing surveillance. The repercussions are world-wide, and few doctors—let alone consumers—appreciate that the fact that a drug has been approved does not mean that it is safe, especially in longer term use. Nor, as experience has shown, need it work better than existing medication. The only certainty is that it will be more expensive.

15.4 All the Insulin in the World Warsaw had changed by 2019. The former Palace of Culture with its echoes of fin-du-siècle Chicago is dwarfed by asymmetric skyscrapers, each deviating from the standard slab design. It makes you feel queasy. Warsaw is flat, and new factories stand out like Lego blocks among the decaying buildings on its outskirts. Among them you will find the shiny grey home of Bioton, the fourth company in the world to make recombinant human insulin. Bioton, with its 600 employees, is dwarfed by the Big Three, and Bogusław, the Production Manager, took me around a newly-built facility which resembles nothing so much as a state-of-the-art whisky distillery. The factory itself is utterly deserted, but an endless succession of shiny vats wrapped in convoluted stainless steel piping can be viewed through windows in the corridor. Bogusław, immensely proud of his creation, had a booming voice and a non-stop delivery that outran his rate of respiration. He showed me the vats where genetically engineered E. coli containing the gene for human proinsulin were released into nutrient medium. The exponential increase that follows is monitored by the optical density of the medium until the bacteria, now heavily pregnant with proinsulin, are shunted along a pipe to be harvested. Proinsulin is released by disrupting the bacterial wall, and numerous filtration processes follow before the insulin is precipitated by isoelectric focusing, just as in 1922. The re-suspended precipitate now passes through a series of HPLC columns until only a single proinsulin peak remains. Enzymes cut out the C-peptide and the newly-liberated A and B chains spring into their functional configuration. The resulting insulin is re-suspended in water from a spring 350 m below the surface, and stabilising and antibacterial agents (known as excipients) are added. Here, for the first time, you encounter humans: they

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run the machines that fill and label vials and cartridges for dispatch. I watched the consignment for Thailand go by, and asked Bogusław how much he could produce. He mopped his brow and told me that, given sufficient resources, he could make all the insulin in the world.

15.5 Globalisation Insulin was a major scientific discovery that doubled up as the miracle remedy for a lethal disease. As such, it has many possible histories. The standard ‘history of science’ approach offers a triumphal vista of progress, and was probably on Ernest Starling’s mind when he spoke in 1923 of ‘a new birth of man’s powers over his environment and his destinies unparalleled in the whole history of mankind’. Another version of the story tells of its application to medical knowledge, and of the way in which the medical tortoise plodded behind the hare of scientific understanding. It took 50 years for the chemists to extract pure insulin from animal pancreas, for example, and 30 more to ascertain the benefits— and limitations—of genetically modified insulin. The clinical story, meanwhile was one of initial euphoria followed by decades of despair as the vascular complications of diabetes took their toll and 50% of affected children failed to reach their 50th birthday. Incremental advances did much to dispel the gloom, and sharper needles, finger-prick blood tests and insulin pens helped to ease the burden of diabetes. Less obviously, attitudes changed. The focus of clinical care shifted from senior physicians to their teams and from there to the person with diabetes. The distinction between the small and large vessel complications of diabetes emerged from epidemiological analysis, and clinical trials eventually showed that improved glucose control can change the course of vascular complications and thus confer longer life. As seen from a global perspective, this is nonetheless a war that we are losing. Diabetes currently affects an estimated one in 11 adults on the planet and kills or disables far more people than it did a century ago. Readers of this book have a one in three lifetime risk of diabetes, and one adult in 125 on the planet currently requires insulin. Seen in this light, our best medical efforts are a skilled rear-guard action. Worse still, the health gap between the global rich and the global poor is getting wider. Yet another story is of insulin as a commodity. The world produced 516 billion units of insulin in 2016, as against 10–12 billion units in 1949—a >40-fold increase. It is likely that more than 600 billion units will be needed

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by 2030. The pioneers once offered insulin as a free gift to the world, but one American user in four currently reports skimping on its use for reasons of cost, with inevitable consequences for their long-term health [20]. Nor is the richest country in the world alone: only 40–50% of users world-wide are believed to have reliable access to affordable insulin—and insulin is only one aspect of the care they need. Ironically, genetically modified insulin, which can be produced cheaply in limitless amounts, contributed to the escalating cost of insulin. Global outreach, market dominance, patent-protected products and handy pens and devices enabled three corporations to acquire 96% of the market. This coincided with the trend to use insulin for what had previously been seen as ‘non-­ insulin-­dependent’ diabetes. It was the most fundamental change in insulin use over the past century, and the Big Three were there to take advantage of it. For all the progress that has been made, the story of insulin is far from finished. Ingenious manipulation of the insulin molecule cannot alter the fact that injection under the skin is a highly unphysiological way of putting it into the body. Elliott Joslin dreamed of restoring a normal lifespan to those affected, and to this we may add the dream of restoring fully autonomous insulin secretion. A history of insulin should ideally range from scientific ideas to real-world consequences, not forgetting the people at the sharp end of the needle and the financial and political implications of the systems that cater to their needs. This, the final section, will open with consideration of the recent trend towards wider use of insulin in people with type 2 diabetes. This leads on to the market in insulin, to the influences which act upon it, and to some possible futures. Our starting point will be a more fundamental question—who needs insulin?

References 1. Morange M. A history of molecular biology (trans: Cobb M). Cambridge, MA: Harvard University Press; 1998. 2. Wade N. Recombinant DNA:NIH rules broken in insulin gene project. Science. 1977;197:1342–5. 3. Cohen SN. Construction of biologically functional bacterial plasmids in vitro. PNAS. 1973;70:3240–4. 4. Morrow JF, et al. Replication and transcription of eukaryotic DNA in Escherischia coli. PNAS. 1974;71(5):1743–7. 5. Itakura K, et al. Expression in Escherichia coli of a chemically synthesized gene for the hormone somatostatin. Science. 1977;198(4321):1056–63.

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6. Villa-Komaroff L, et  al. A bacterial clone synthesizing proinsulin. PNAS. 1978;75:3727–31. 7. Goeddel DV, et al. Expression in Escherichia coli of chemically synthesized genes for human insulin. PNAS. 1979;76(1):106–10. 8. Williams DC, et al. Cytoplasmic inclusion bodies in Escherichia coli producing biosynthetic human insulin proteins. Science. 1982;215(4533):687–9. 9. Keen H, et al. Human insulin produced by recombinant DNA technology: safety and hypoglycaemic potency in healthy men. Lancet. 1980;2(8191):398–411. 10. Sonnenberg GE, Berger M. Human insulin: much ado about one amino acid? Diabetologia. 1983;25:457–9. 11. Culliton BJ. The MGH-Hoechst Agreement. Science. 1982;216(4551):1201. 12. Michaels D. The triumph of doubt. Dark money and thescience of deception. Oxford: OUP; 2020. 13. Marks JH. Lessons from corporate influence in the opioid epidemic: towards a norm of separation. Bioethical Enq. 2020;17:173–89. 14. Gale EAM.  Post-marketing studies of new insulins: sales or science? BMJ. 2012;344:e3974. https://doi.org/10.1136/bmj.e3974. 15. Gale EAM. Dying of diabetes. Lancet. 2006a;368:1626–8. 16. Gale EAM.  Troglitazone: the lesson that nobody learned. Diabetologia. 2006b;49:1–6. 17. Lenzer J.  FDA is incapable of protecting US ‘against anothervioxx’. BMJ. 2004;329:1253. 18. Zhang AD, et  al. Assessment of clinical trials supporting US Food and Drug Administration approval of novel therapeutic agents 1995-2017. JAMA Open. 2020;3(4):e203284. 19. Goldacre B, et al. COMPare: a prospective cohort study connecting and reporting 58 misreported trials in real time. Trials. 2019;20:118. 20. Herkert D. Cost-related insulin underuse among patients with diabetes. JAMA Intern Med. 2019;179(1):112–4.

Part V Modern Times (~1990 On)

16 The Silent Majority

The great majority of people who inject insulin would once have been said to have non-insulin dependent diabetes. Type 2 diabetes, as it is now known, is a catch-all diagnosis defined by the absence of other known causes of diabetes, notably the evidence of immune activation characteristic of type 1. Type 2 is a complex disorder with multiple precipitating factors, age, and overweight included. Clinicians see it as a constellation of risk factors rather than as a single disease. Arterial risk can also be reduced by treating high blood pressure or cholesterol, for example, or by cutting out cigarettes. Glucose-specific risks such as retinopathy or kidney disease are treated by careful control of blood glucose, which is where insulin comes in.

16.1 What Is Diabetes? Those who lecture on the diabetes circuit dread this title, and for two good reasons. The first is the implication that you have reached your sell-by date and have nothing new to contribute. The second is that there is no very satisfactory answer. We have seen that there are four possible ways of drawing a line between health and disease—statistical, clinical, prognostic, and operational. Statistical deviation is of limited application to a condition that affects one old person in three. We must, therefore, rely on a prognostic classification based on estimates of future risk. Nor is this all, for an operational decision is then required

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as to the level of risk that justifies intervention. This is decided by expert committees and passed on to front-line doctors in the form of clinical guidelines. Take hypertension. Most strokes occur in people who do not have a high blood pressure, although the risk increases at higher levels. Since there is no clear transition between high-risk and low-risk blood pressure, we use an operational cut-off. As with the all-important pass mark in an exam, this converts dimensionally distributed data into two categories that are separated by a single millimetre of mercury. This approach can be applied to any clinical situation, the main limitation being that it is tailored to the herd rather than the individual. Herd management of hyperglycaemia is complicated by the fact that we have three markers of glucose exposure—the glucose tolerance test, fasting glucose, and glycated haemoglobin—and these are not well correlated. The benefits of treating people at borderline risk can be estimated in terms of QALYs (quality of life years) gained, as against the disadvantages of treatment. Blood pressure rises with age, but older people are at greater risk of side effects such as dizziness and falls. Even so, CDC estimated in 2002 that treating blood pressure is cost-effective at any age. In contrast, the relative costs of ‘intensive’ glucose control soon spiral upward (Fig. 16.1). Cost-effectiveness ratio (cost/QALY) of intensive glucose control 85-94

Yrs

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Fig. 16.1  Intensive glucose control of a 25–34 year old with diabetes was estimated to cost $10 thousand for every QALY (quality of life year) gained in 2002. The costs rise astronomically in later life. (Drawn from data from CDC, JAMA, 2003; 287; 2542)

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It is hard to escape the conclusion that we are treating large numbers of old people for ever-diminishing clinical benefit. This is not to suggest that older people should not be treated effectively, merely to question the relevance of ‘one size fits all’ solutions. Management should surely be based on individual evaluation regardless of age, wishes should be respected, and the best available evidence (often lacking in the elderly) should be applied. Unfortunately, the guideline culture of medicine lumps everyone together, and reinforces this with the witless authority of computers. Diabetes did not trouble our remote ancestors, for they were lean and active, and rarely survived into later life. In modern times, people such as the Pima of Arizona were catapulted from life at the subsistence level to a combination of inactivity and increased food intake which has now made diabetes more common than non-diabetes in their adult population (Fig. 16.2). Conversely, food shortages in times of war or recession are associated with dramatic reductions in the prevalence of type 2 diabetes [1]. We are all overweight by comparison with the past, and type 2 diabetes is so prevalent because we live longer and eat more. The dramatic benefits of intensive diet or weight loss surgery—which include apparently complete recovery from type

Fig. 16.2  From Bulletin 34 of the Bureaus of American Ethnology by Ales Hrdlička, entitled Physiological and Medical Observations among the Indians of Southwestern America and Northern Mexico. 1908. (Reproduced under the Creative Commons license)

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2 diabetes—provide further confirmation of the close association between food intake and risk of diabetes. Increased consumption largely accounts for the rise of type 2 diabetes in the twentieth century, but does not explain why some individuals and ethnic groups appear more susceptible than others. The ultimate responsibility rests with our genes, but (with the exception of rare single-gene disorders) these are neither necessary nor sufficient for the development of diabetes. The interaction of genes with environment is what matters, and obesity outperforms genome scans as a marker of risk. With this in mind, we are now ready to consider why some people with type 2 diabetes need insulin.

16.2 Who Needs Insulin? Insulin and/or diet were the only treatment options in 1950. The true frequency of undiagnosed diabetes in older people was not as yet appreciated, and this realisation coincided with the discovery of other clinically silent risk factors such as blood pressure or cholesterol. The medical world began treating risk. Drugs designed to prevent future illness such as thiazide diuretics for hypertension and clofibrate for cholesterol were available by the 1960s, and large clinical trials were undertaken to test their benefits. Anti-hypertensives worked so well in preventing stroke that the trial had to be stopped. Clofibrate was less convincing in preventing heart attacks, and the true value of cholesterol reduction did not become fully apparent until the statins arrived later in the century. Tolbutamide, the first effective tablet for diabetes, was introduced in 1958, and was soon followed by phenformin from a different drug class. The University Group Diabetes Program (UGDP) study, launched in 1961, set out to compare insulin, tolbutamide or phenformin with diet alone, and it was a disaster. There were so many deaths on tolbutamide that this arm of the study was brought to a premature close in 1969. Phenformin precipitated a rare but fatal condition called lactic acidosis and would soon be taken off the market. Worse still, outcomes on insulin were no better than on diet alone. Consternation at these findings was followed by ferocious in-fighting, prompting the investigators to protest that ‘the main difficulty with the UGDP is not its design, execution or analysis, but rather that it reached an unpopular conclusion’ [2, 3]. We should recall that the notion that diabetic complications could be prevented by glucose-lowering therapy was still a contested hypothesis, and that the distinction between microvascular complications—which are highly

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responsive to glucose-lowering therapy—and arterial complications—much less so—had yet to be appreciated. Not knowing this, the investigators lumped them together. Other limitations of the trial stand out in retrospect. International criteria for the diagnosis of diabetes had yet to be agreed, and a third of the participants did not even have diabetes by later criteria. Worse still, the groups were matched regardless of pre-existing vascular disease, which turned out to be the main determinant of survival. The one finding to stand the test of time was UGDP’s most unpopular conclusion, which was that glucose lowering has no short-term effect on cardiovascular disease. UGDP ended in 1975, and its legacy was confusion tinged with despair. Only the bravest of the brave would dare to step into this blood-stained arena, but the man to do so was at hand. Robert Turner was a diabetes specialist in Oxford. His demeanour was mild, his smile benign, and his single-­ mindedness disconcerting. This was a man who could listen to dissenting points of view with a kindly smile, only to conclude with a breezy ‘I think we’re all agreed about that’—‘that’ being his original point of view! The UK Prospective Diabetes Study (UKPDS) was planned in 1976, launched in 1977, and lurched from one funding crisis to the next over the next 20 years. He remained imperturbable throughout. Success might be defined as a receptor defect, and Robert’s defect consisted in an inability to hear the word ‘no’. Interventions are best measured by hard endpoints—outcomes which directly affect the health and well-being of the people involved. Heart attacks and strokes are hard endpoints, and death is hardest of all. The disadvantage of hard endpoint studies is that they take a long time to perform and are horrendously expensive. Funders shun them, drug companies are in too much of a hurry, and academics are disinclined to wait 10 years for a result. Hence the widespread resort to surrogate endpoints. A surrogate endpoint is a marker of risk rather than outcome and might be based, for example, upon the assumption that anything that lowers blood pressure will lower the risk of stroke. This speeds the process of drug approval, but can also be misleading. Drugs that meet the surrogate endpoint may turn out to have unacceptable side effects, for instance, while other drugs do better than predicted. Statins do more than lower cholesterol, for instance, and metformin has benefits over and beyond its ability to lower blood glucose. Surrogate endpoint studies must derive their credibility from hard endpoint studies, which is why almost every recent treatment for type 2 diabetes has taken Robert’s study as its point of reference. Robert himself compared it to We Didn’t Mean to Go To Sea, a children’s story by Arthur Ransome. The voyage began—20 years before it ended—with a simple question: does glucose control improve the health and life expectancy of what was then called ‘maturity-onset’ diabetes? [4] A secondary aim was to

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compare the risks and benefits of different treatments in the light of the discouraging results from UGDP. The trial aimed to recruit people aged 25–65 with newly diagnosed diabetes and no immediate need for insulin. This criterion not only predated the type1/type 2 classification: it predated international criteria for diabetes. Robert considered anyone with a fasting blood glucose above 6 mmol/L (108 mg/dL) to have diabetes, whereas WHO set the fasting threshold at 7.8 mmol/L (140 mg/dL) 5 years later. It is hard to remember how little we knew about non-insulin-dependent diabetes in 1977. HbA1c and self-monitoring of blood glucose were novel, the relationship between glucose exposure and vascular complications was uncertain, and the progressive nature of late-onset diabetes had yet to be appreciated. Failure to appreciate this progression played havoc with the original plan, which was to compare the fate of participants randomised to diet, tablets or insulin. Diet was seen as ‘conventional’ treatment, and tablets or insulin as ‘intensive’. Those on ‘intensive’ treatment aimed for a fasting test in the non-diabetic range, whereas those on diet had looser targets. The design leaked badly, and only 38% of those allocated to diet were still able to achieve acceptable control 10 years later [5]. Diet failures were randomised to ‘intensive’ treatment, and those who failed on tablets went on to insulin because there was nowhere else to go. All this confounded the original intent-to-­ treat design. The old joke says that ‘if you want to get there, you shouldn’t start from here’, and Robert would undoubtedly have designed a different study if he had fully appreciated the magnitude of the task or had access to secure long-­ term funding. By way of comparison, the US Diabetes Complications and Control Trial (DCCT) was a nationally-organised and adequately-funded affair. It ran from 1983 to 1993, and randomised 1441 young adults with type 1 diabetes to standard injection treatment as compared with intensified therapy with multiple injections or insulin pumps. There was no movement between treatment arms, the difference in HbA1c was impressive at 1.8%, and the study provided unequivocal evidence that treatment could delay or prevent microvascular disease. Robert, meanwhile, was tethered to a flawed study design. His life became an incessant battle, and the need for commercial support resulted in a proliferation of add-ons and sub-studies which distracted from the main purpose. By the end there were three sulfonylurea subgroups, two subgroups on other tablets (metformin and acarbose) and other combinations of tablets and insulin. A quite separate study of anti-hypertensive treatment was also—and far more usefully—embedded within the design. By 1990, Robert had submitted more than his own weight in funding applications, and supporters had raised

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£800,000 in private donations. It was a magnificent example of persistence in the face of almost insuperable odds but, as an observer said of the charge of the Light Brigade, it was no way to fight a war. The study added immeasurably to our understanding of type 2 diabetes, and is rightly celebrated as a triumph—but was almost impossibly hard to interpret. DCCT had clear-cut results which could be summarised in a few key papers, but UKPDS has (to date) given rise to 86 published analyses, sub-­ analyses and study extensions—testimony to the sheer volume and complexity of the data generated. Since you cannot rescue an over-complicated design by sophisticated statistical analysis, its limitations haunt us still. The UGDP investigators complained that their study was criticised because its findings were unpopular, whereas UKPS gained instant acceptance because it said what everyone wanted to hear. Everyone expected to hear that improved glucose control leads to better outcomes in type 2 diabetes. UKPDS did show this, but not as clearly as many have assumed. The devil lay in the detail. The most widely cited outcome, known as the epidemiological analysis, showed that every 1% decrement in HbA1c was associated with 15% fewer deaths from diabetes, 14% fewer coronaries, and 37% fewer microvascular complications. Impressive but what it showed was that those in better control did better regardless of treatment. The actual treatment effect, complicated as it was by movement between groups, was less impressive. Even so, the epidemiological outcome is still routinely cited as if intervention were responsible. So, what did the treatment comparison show? More to the point, what didn’t it? It did not show that people on intensive treatment live longer or experience a better quality of life. They had fewer heart attacks, but this did not reach statistical significance. Since cardiovascular disease is the major cause of excess mortality in late-onset diabetes, this borderline result prompted three more intervention trials in the USA. Combined analysis of 27,000 participants showed a reduced frequency of non-fatal myocardial infarction (730 vs. 745) but more strokes (378 vs. 370) and more episodes of heart failure (459 vs. 446). The analysis concluded that intensified glucose control would be able to prevent one non-fatal heart attack in 119 people. In contrast, treatment of non-glucose risk factors was more effective. Tighter blood pressure control was associated with a 15% reduction in diabetes-related deaths in UKPDS, for example, with an 11% reduction in myocardial infarction and a 13% reduction in microvascular complications. The value of combined treatment of all risk factors was shown by a Danish study which randomised 160 people to intensified versus standard treatment of all leading risk factors, including those which predisposed to arterial disease. The study began in 1993 and ran for 7.8  years, by which time the

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benefits of the combined treatment were so obvious that this was offered to every participant. By 2014, vascular complications of diabetes were twice as common in those originally assigned to conventional risk reduction therapy, and 55 of 80 had died, as against 38 in the intensified group. The authors later estimated that all-round treatment had conferred 7.9 years of extra life [6]. These are findings to make you sit up and take notice, and they testify to the value of treating overall risk rather than blood glucose alone in people with type 2 diabetes. Microvascular changes develop slowly, and measurable endpoints are relatively uncommon within the short period of a study. This being so, statisticians lump them together for the purpose of analysis. Evaluation of the packaged results for UKPDS after an average of 10.7 years showed an impressive 25% risk reduction in microvascular endpoints, for example, but this was heavily influenced by a surrogate endpoint: laser treatment for diabetic retinopathy. The study found that 8% of intensively treated patients needed laser treatment, as against 11.2% of those on conventional therapy. A 28% reduction in risk sounds impressive, but the bottom line is that 10 years of intensive treatment enabled one person in 31 to avoid laser therapy. In sum, UKPDS provided impressive confirmation of the relationship between adverse outcomes and exposure to glucose, but did not show that intensified glucose control improved shorter term survival or quality of life. Nor did it show that insulin performed better than other glucose-lowering therapies, although it remains the treatment of last resort. Furthermore, the cardiovascular benefits of improved glucose control were marginal in comparison with the treatment of non-glucose risk factors such as blood pressure, cholesterol or smoking. Worse still, an alarming finding from the US trials was that mortality tended to rise in those who were most successful in lowering their glucose. Analysis in the UK suggested much the same, particularly in users of insulin (Fig. 16.3). UKPDS was nonetheless largely responsible for the rapid increase in insulin use in the UK. Estimates show that 2.4 people per 1000 of the adult population used insulin in 1991, and that 0.7/1000 of these were considered to have type 2 diabetes. By 2010 the number of insulin users had increased to 6.7/1000 and 4.3/1000 were deemed to have type 2 diabetes—a six-fold increase. This dramatic shift was based on the widespread impression that UKPDS had confirmed a specific benefit for insulin treatment—which it hadn’t. It had confirmed the need for better glucose control in type 2 diabetes, but it had not shown that insulin was necessarily the best way of achieving it.

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Fig. 16.3  The U-shaped response. Mortality rates increase at higher levels of HBA1c, but rise again at lower levels—less so in tablet-treated patients (left panel) than in those on insulin (right panel). The higher mortality on insulin might be related to hypoglycaemia. (From The Lancet, Volume 375, Issue 9713, 6–12 February 2010, Pages 481–489—with permission)

The makers of insulin were not responsible for this situation, but they made the most of it. At my own centre, for instance, the trickle of people with type 2 diabetes referred for insulin swelled to a flood, and we were grateful when one of the companies offered to fund a diabetes nurse specialist to help us. We failed to appreciate that the insulin she prescribed (we used it in appreciation of her help) repaid her salary ten times over. In sum, insulin is very useful in type 2 diabetes, but has not been shown to have any unique advantage as a first-line treatment. There is no magic dividing line between those who are deemed to have type 2 diabetes and those who are not, and the benefits of aggressive treatment of blood glucose diminish with age. Even so, medical wisdom continues to treat an abstract concept as a concrete entity. Nor is type 2 diabetes a single disease, let alone one capable of scientific definition [7]. We can only hope that future generations will treat older people according to evidence and individual evaluation rather than algorithms.

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References 1. Gale E. The species that changed itself. London: Penguin Books; 2019. 2. Kilo C, et al. The crux of the UGDP. Spurious results and biologically inappropriate data analysis. Diabetologia. 1980;18:179–85. 3. Schwartz TB, Meinert CL. The UGDP controversy. Thirty-four years of contentious ambiguity laid to rest. Perspect Biol Med. 2004;47:564–74. 4. Turner R, et al. UKPDS: what was the question? Lancet. 1999;354:600. 5. UKPDS Study Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS33). Lancet. 1998;354(9131):837–53. 6. Gaede P, et al. Years of life gained by multifactorial intervention in patients with type 2 diabetes. Diabetologia. 2016;59(11):2298–307. 7. Gale EAM. Is type 2 diabetes a category error? Lancet. 2013b;381(9881):1956–7.

17 The Market in Insulin

In 1947, details supplied to the WHO by 55 countries (including the major exporters) showed that annual production of insulin ran at about 10.5 billion units per year. Estimates from 2018 showed that insulin production ran at about 516 billion units with the potential to increase to 634 billion by 2030 [1].1 Nearly half a billion people are thought to have diabetes, and 96.5% of affected adults are thought to have type 2. Around 60 million of these are treated with insulin, as against an estimated ten million or so considered to have type 1. Affluence and socio-economic position apart, there are surprising differences in the frequency of insulin treatment. A recent estimate is that 22% of those with a diagnosis of diabetes in North America are on insulin, as against 17–18% in Asia, 13% in Europe and 9.5% in Africa [2]. Why might this be? Elective insulin use (i.e., treatment not mandated by symptoms) is largely driven by algorithms. Clinical algorithms tend to assume that the excess health burden associated with each increment in HbA1c could be entirely reversed by glucose-lowering, although risk factors such as obesity, cigarettes, and high blood pressure may require attention. The financial implications of algorithm-driven prescription are staggering. To take one example, the effect of increasing the target level of HbA1c from 7% to a more achievable 8% would reduce the theoretical global requirement for insulin in type 2 diabetes by 45%. Algorithms are based on the assumption of net benefit, but the intermediate assumptions may not always be true. They assume, for instance, that all 1

 Health Action International, www.haiweb.org.

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those transferred to insulin will achieve their target level of glucose control. In UKPDS only 47% of insulin-treated patients achieved a target HbA1c below 7% at 3 years, as against 37% at 6 years and 28% at 9 years [3]. Algorithms serve another purpose in a litigious society, for the practitioner who follows them is absolved from legal blame for the outcome. It has often been shown that patients and practitioners tend to overestimate the benefits of preventive medication, and some older people might well decline the latest refinements of therapy if the margin of risk and personal benefit was spelled out more accurately [4]. This is not to dismiss the life-enhancing potential of preventive therapy, merely to emphasize the need to provide accurate information and to respect the wishes and experience of those who take medication. Whatever the cost, the benefits of insulin depend upon the skill with which it is used. One feature of global insulin use is the widening rift between the options available to the rich (or the richer countries) and the rest. The wealthy have access to glucose sensors and smart pumps, but there is less money to be made from selling insulin to the poor. What follows will examine the asymmetrical market that dominates the world’s supply of insulin. In 2003 global pharmaceutical sales (all products) amounted to $492 billion, of which $229.5 billion (47%) was spent in the USA. The world spent an estimated $322 billion on illegal drugs in the same year, and 44% of the sales were in North America. 2 In both instances, 4% of the world’s population generated nearly half the revenue. Both markets are characterized by a high margin between the cost of production and the price paid by the user, and it is not hard to understand why a drug baron might wish to market crack cocaine in Brooklyn rather than Rwanda. The active pharmaceutical ingredients of a 10 mL vial containing 1000 units of genetically—engineered ‘human’ insulin—enough to keep the average user alive and well for a month—could recently be purchased in bulk on the open market at a price equivalent to $4–5 per vial. A vial of the identical Lilly insulin cost $21 in 1999 and $332 in 2019. On the face of it, these uncorrected figures suggest a 1000% increase in cost and a profit margin well in excess [5]. 3 No wonder some Americans struggle to pay for it. Another striking fact is that roughly half the world’s population survives on an income below $10 a day, insufficient to buy insulin in the USA. In 2002 or thereabouts I was contacted by a market analyst called Alexandra Hauber, who suggested we might meet up. She was interested in an article I had written about the marketing of drugs known as the glitazones, and told  IMS data, World Drug Report 2005, Vol 1, Chapter 2. Estimating the value of illicit drug markets.  ‘Seems like a scam’: Americans with diabetes criticize Biden’s insulin proposal. Guardian, 4th Jan 2022.

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me that she had often wondered when doctors would get wise to the ways in which they were being manipulated. Alex was much younger than I had imagined, and we collaborated on an article called ‘The Market in Diabetes’ which showed that the market in insulin had risen from $2 billion in 1995 (uncorrected figures) to a projected value of $11.8 billion in 2010 [6]. By any measure, a sixfold increase in income over 15 years is impressive, but the Big Three were grossing more than $20 billion in insulin sales by 2020. An indication of the esteem in which the pharmaceutical industry is held came when Alex Azar, President of the US division of Eli Lilly from 2012 to 2017, became Secretary of Health and Human Services under Donald Trump in January 2018. On February 15th 2019, Brian Martinotti, US District Judge for New Jersey, gave the green light for a national class-action lawsuit against the Big Three. The action was filed under the Racketeer Influenced and Corrupt Organizations Act (18 U.S.C 1962), which had been invoked against the tobacco manufacturers some years earlier. It alleged that the three companies had raised the benchmark prices of their products in ‘an astounding and inexplicable manner’, and went on to say that ‘drugs that used to cost $25 per prescription now cost between $300 and $450 … in the last 5 years alone, Sanofi, Novo Nordisk, and Eli Lilly have raised their benchmark prices by over 150%. Some patients pay almost $900 per month just to obtain the insulin drugs they need to survive’. The Atlantic is wider than you think. We speak the same language but we take different things for granted. European clinicians assume that the state will provide for those who cannot provide for themselves. Money is never seen to change hands in Britain’s NHS and is rarely a consideration when treatment is discussed. I once decided to try my hand in private practice, and a wealthy West African businessman was among my clients. He asked how much he owed at the end of the consultation, and I said I would send him a bill. Not satisfied, he insisted on paying me there and then, and I muttered shamefacedly that 50 pounds would do. He extracted a fat roll of £50 notes, thumbed one off and plonked it on the desk. I decided private practice was not for me. Three aspects of American life baffle the outsider: its political system, its legal system, and its health care system. Americans have the right to own assault rifles, but no clear right to universal healthcare. In the absence of a joined-up federal health strategy, the Medicare and Medicaid systems (established in 1965) were described as ‘a compromise between those who wanted national health insurance for everyone, and those who wanted the private sector to continue to be the source of insurance coverage’ [7]. The outcome was an unequal tug of war between a healthcare sector hungry for profit and

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a public sector struggling to contain costs. The USA offers the best specialist healthcare in the world to those who can afford it, but health costs per person are twice as high as those of any other OECD country. Nor does the USA do well on international comparisons. A measure called the Healthcare Access and Quality (HAQ) Index ranked it at position 29  in 2017, just ahead of Croatia [8]. Outrage at the cost of insulin in the USA should also be seen in the context of a steep rise in other healthcare costs. In the last quarter of 2017, health employed more Americans—roughly one in eight—than any other sector of the economy. Most of the new jobs were for lower-echelon clerical staff or health care assistants, but the upper reaches of the sector are lucrative in the extreme. The tax-payer pours hundreds of billions of dollars into government-­ funded health care, and indirect support comes from tax breaks for employers who provide insurance. Public support ‘makes health care employment practically invincible, even during the worst downturns’. 4 Americans, according to the Washington Post (September 2021) spend twice as much per capita on prescription drugs than residents of other wealthy nations, mainly because US law prevents the government from negotiating a lower price. As a result, one in seven health care dollars is absorbed by pharmaceuticals. The high price of insulin prompted Congress to hold an enquiry in 2019. This had its revealing moments. The hearing seemed to assume that the manufacturers were entirely to blame for escalating prices, and opinion polls suggest that 80% of the public share this belief. Doug Langa, US President for Novo-Nordisk, went largely unheeded when he asserted that the producers were locked into a pricing system beyond their control, and that they were unable to reduce prices because pharmacy benefit managers (PBMs) would remove their products from the formulary if they did so. He claimed that 68 cents of every dollar made on the sale of insulin went on rebates, discounts and so forth, and added that human insulin was inexpensive, safe, effective, and used by 775,000 Americans. He did not explain why nearly seven million other Americans paid ten times more for analogue insulin (human insulin could then be bought in Walmart for $25 per vial), although the insurance process itself appears to mandate the more expensive option. ‘The challenge’, as Langa concluded, ‘is that the current system is broken’. Not everyone in Congress was listening. Jan Schakowsky (Republican, Illinois) told the manufacturers that she ‘didn’t know how you people sleep at night’. If Congress wanted a scapegoat it only lacked a mirror, for health care  Health care just became the US’s largest employer. The Atlantic, Jan 9, 2018.

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is a political issue. No citizen of the UK is obliged to worry about health cover, and this assumption is as natural to us as the air we breathe. For all its failings, the National Health Service is the UK’s most popular and trusted institution, and remains a standing reproach to politicians who trust in the primacy of the profit motive. Paradoxically, universal health cover can be less expensive than privately-funded health care. National heath expenditure was $3.6 trillion in the USA in 2018, accounting for 17.7% of GDP. This was equivalent to $11,172 per person, as against $4316 in the UK in 2017. 5 Medical insurance forms part of the standard US employment package, but with wide variation as to what is on offer. Since the scheme does not extend to the indigent or unemployed, the 2007 Census found that 45 million people had no form of health insurance at all, a situation that President Obama sought to remedy. Retired people do however qualify for taxpayer-funded insurance under the Medicare and Medicaid schemes. These benefits extend to listed chronic disabilities, a list that was subsequently extended to renal dialysis (which now costs more than the space program) and (don’t ask me why) Lou Gehrig’s disease. Medical insurance is expensive, but costs can be reduced by limiting cover, by requiring the insured to pay the first part of their medical bills, or by capping liability. This is where medication comes in, for insurance companies will only refund costs for a list of approved indications known as the formulary. Maintaining an up-to-date formulary in a changing market is a major challenge, and the task is outsourced to specialist companies known as pharmacy benefit managers or PBMs. Three companies dominate this business in the USA, and they gross an estimated $200 billion yearly for doing so. This gives them immense bargaining power. In theory, PBMs are in the business of keeping costs down, for example, by replacing branded drugs with cheaper generics. In reality, they profit from high prices. The official ‘benchmark’ price for branded insulin set by the manufacturers is purely notional; the manufacturers sell insulin to the PBMs at a secretly-­ negotiated and much lower price, and the PBMs pass this ‘rebate’ on to the insurers. The gap between the benchmark and actual price is known as the ‘spread’, and the PBMs pocket a proportion of the difference—a proportion which furnishes a large part of their income. The wider the spread, the more they make. This perverse incentive prompts manufacturers to raise their prices and PBMs to maximize their kickback. Since competition might wreck this cosy arrangement, the companies have raised their prices in perfect harmony.  CMS.gov Fact Sheet, ONS 29 Aug 2019, Lancet paper.

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All this was clearly set out in a report from a US Senate Finance Committee in 2021. The Committee examined the interplay between the manufacturers and the PBMs and pointed out that the manufacturers are responsible for setting the list price, known as the Wholesale Acquisition Cost (WAC). Other manufacturers ‘shadow’ each price hike within days or even hours, thus maintaining perfect lockstep. Revealingly, the PBMs regard insulins as interchangeable, which allows them to deny a place on the formulary to uncooperative manufacturers. This might help to explain why expensive branded insulin analogues are almost exclusively used outside the charity sector in the USA. The Senate Committee concluded that ‘insulin manufacturers compete fiercely, using rebates as bargaining chips to receive preferred formulary placement for their products and to block competition’. I happen to know that one company hired a computer system used by the military for war games to guide its deliberations on price. The Senate Finance Committee concluded that ‘PBMs use their size and aggressive negotiating tactics, such as the threat of excluding drugs from the formularies, to extract more generous rebates, discounts and fees from insulin manufacturers. To be clear, PBMs have an incentive for manufacturers to keep list prices high, since the rebates, discounts and fees PBMs negotiate are based on a percentage of a drug’s list price—and PBMs retain at least a portion of what they negotiate’. The benchmark price may be a convenient fiction but it is an unavoidable fact for the patient, whether insured or uninsured. The uninsured patient has a choice between an unaffordable bottle of insulin or a downhill trajectory towards death. Those who are insured pay the full costs, but the insurers pay much less. The Class-Action lawsuit gives an example: A woman attends her pharmacy to buy a box of disposable insulin pens, each prefilled with insulin. If she has not as yet reached her ‘deductible’ (the threshold for reimbursement), she pays the full price of $405. If she has reached the deductible, she might pay 30% of the cost of the pens (in this example $135). ‘If she assumes that her insurer is paying the remaining $315’, says the documentation, ‘she is wrong’, for the insurers will pay a much lower price negotiated by the PBM.

This system works to the benefit of the makers of insulin, the insurance companies and the PBMs. The costs—whether in money or health—are met by those who need insulin. A 2015 poll found that rising healthcare costs was the public’s most pressing issue, and stories about insulin are endless. Sports hopeful Jordan Williams bought insulin intended for dogs at $25 per vial in Walmart. Luckily, dogs get human insulin. Karyn Wofford flew from Georgia

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to Seattle, drove to Vancouver, and bought a year’s supply of insulin for $700. It would have cost $2500 at home, so the trip paid for itself. 6 Therefore, where in all this are the bad guys? The Class Action pointed out that ‘In 2014, patients paid for 24% of their out-of-pocket prescription drug expenses through deductibles, compared to just 4% in 2004. Similarly, patients paid for 20% of their out-of-pocket drug expenses through coinsurance in 2014, compared to just 3% in 2004’. Otherwise said, the rising price of insulin is symptomatic of a much wider trend, and healthcare costs are cited in 62% of US bankruptcies. Litigation is a possible way out of this particular blind alley, but the need to resort to litigation is a clear sign that the system is failing. When a whole system malfunctions it becomes very hard to point the finger, and even harder to allocate blame. The participants may wish to avert their gaze from the consequences of their actions, but there is no place at the table for those who do not accept the rules of the game. Since the rules of this particular game do not allow for a referee, a runaway escalation in drug prices is almost inevitable.

17.1 ‘That’s Where the Money Is’ Willy Sutton is alleged to have said this when asked why he preferred to rob banks, and America’s drug bill might be explained on the same basis. As we have seen, the price of insulin has risen sharply in recent years, despite public outrage and legal or political challenges. It did however fall steeply in 2023, when Lilly and Novo-Nordisk lowered the cost of analogue insulin by around $70 per vial. This has been presented as an act of altruism, but might be seen as a response to a rapidly changing market situation. Several manufacturers are developing or actively marketing therapies for diabetes based on injection of analogues of a gut hormone known as glucagon-like-peptide 1 (GLP-1). These drugs can be useful in the management of type 2 diabetes, mainly by promoting weight loss by reducing appetite (delayed gastric emptying is one of the mechanisms). The Novo-Nordisk product for diabetes known as semaglutide sold out recently because non-diabetics were buying it for weight loss, and higher dose injections of the same product have been developed for obesity. The ostensible reason for using these agents is that weight loss is good for your health, an assumption based on a surrogate endpoint. The benefits of  Guardian, 1 Aug 2019 (Jordan), https://www.t1intenational.com/blog/2019/05/03/travelling-canada-­ cheaper-insulin/ (Wofford). 6

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weight loss achieved by diet or appropriate weight loss surgery are long-lasting and well established, but the long-term benefit and disadvantages of high-­ dose injection therapy are currently unknown, especially given that long-term treatment will be needed to prevent rebound weight gain. It has been said that you cannot produce a baby in 1 month by making nine women pregnant, and we are currently in the early stages of pregnancy when it comes to the longer term health benefits of new treatments for obesity. In marketing terms, this represents another no-brainer. The market for the new therapies for obesity has been estimated at around $54 billion world-­ wide ($28 billion in the USA alone), and the potential profit is enormous. Novo-Nordisk had a net worth of $93.6 billion in 2013,as against an estimated $308.5 billion in 2023. The big manufacturers are well positioned to undercut cheaper insulin manufactured elsewhere, and could at a pinch afford to give it away. The politicians are now heavily involved in the question of insulin pricing in the USA, which has been changing almost weekly. An overview of the complexity of the issues involved is provided by a recent piece of news and analysis [9]. What we do not know is the knock-on effect on insulin prices elsewhere.

17.2 What Future for Biosimilar Insulin? The license to produce a new medicinal agent runs for 20 years, and the clock starts running when the application is filed with the regulatory authorities. It takes 8–10 years for the product to gain regulatory approval, after which the manufacturers have an effective monopoly on its use until the licence expires. This period of exclusivity is when most of the profit is made, and companies will often go to great lengths to prolong it by tactics known as ‘evergreening’. When the licence expires, other companies can market the identical therapeutic entity, although they are required to show differences in the means of production. These versions of the same product are known as generics. Perversely, the escalating price of branded pharmaceuticals was the major incentive to the market in generics. An important milestone came when AIDS was ravaging Africa. The condition could be controlled by a combination of three drugs made by different companies known as HAART (highly active antiretroviral therapy), but at a cost per patient of around $12,000 per year. In 1997 Nelson Mandela made it possible for lower cost antiretrovirals to be imported in South Africa, although this fell foul of an international trade arrangement known as TRIPS (trade-related aspects of international property rights), designed to protect intellectual property. The immediate response to

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this perceived threat came when 39 drug manufacturers threatened to sue South Africa. Stalemate prevailed until an Indian manufacturer of generics offered to sell a generic version of HAART to Médecins sans Frontieres for $1 a day (30–45 times less than the official price). This brought hope to 34 million people and proved a public relations disaster for Big Pharma, whose main defence lay in the allegation that Indian companies could not be relied on to produce safe and effective generics. FDA promised to send its inspectors to overseas factories whose products might be sold in the USA. What ensued did much to confirm what people feared. On one occasion in 2013 two FDA inspectors were walking along a corridor in an Indian factory when they unexpectedly came upon a company employee carrying a plastic garbage bag. The man turned and fled, and the pair followed in hotfoot pursuit, retrieving the bag when the man threw it into a trash bin. It proved to contain torn records of insulin manufactured at the plant (owned by Wockhardt, who market their insulin world-wide) which showed that the company sold vials containing black particles due to an electrical meltdown to clients in India and Africa [10]. Katherine Eban, upon whose book this part of the account is based, has shown that the prevailing Indian attitude to drug regulation was far more relaxed than in the West. Countries such as India and China are well capable of manufacturing high quality pharmaceuticals, but proved to have little hesitation in cutting corners, especially when marketing to the world’s poorest countries. Market logic is to reduce production costs while maximizing profit, and this has meant that many branded products now contain cheaper Asian ingredients. FDA is officially tasked with regulating and inspecting the production of goods intended for the American consumer, but the boom in generics has made the task almost impossibly big, and there is a well-established trend for the worst medicines to be exported to the least-regulated markets. The producers of generics have clearly demonstrated that expensive branded products can be brought within easier reach of the consumer—one reason being that had no need to invest in research and development. The conflict between cost and quality is most acute when death is the only option for those who cannot afford a drug. Type 1 diabetes is an obvious example. Strictly speaking, there is no such thing as a generic insulin. The molecule itself may be identical and the amount in the bottle exactly the same, but the formulation must be slightly different. An exact copy is not permitted, and the insulin is therefore marketed as a ‘biosimilar’; i.e., a product with a closely similar biological action. The exclusive licences for branded insulin have now expired but the people who make it are understandably keen to make as much money as they can in the process. Gresham’s Law (bad practice drives out the

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good) and Goodhart’s Law (a measure that becomes a target ceases to be a useful measure) still apply. The difference between a generic and biosimilar label is important because the FDA expects a new insulin to pass through the same barriers of registration, clinical trials, and approval as any other. This is not a challenge to the Big Three, protected as they are by brand recognition, and near-complete control of the market, but it is a formidable challenge to any newcomer. Not to the big corporations, however, for Lilly has been able to produce and market biosimilar insulin glargine to the profitable US market at around 85% of the price of its branded rival. The large manufacturers might well protest that throwing the door open to others risks flooding the market with poor quality insulin, but quality control could easily be implemented and enforced by testing random samples at internationally validated laboratories. The world needs affordable insulin, but someone will have to police the system.

17.3 How the Other Half Dies Childhood diabetes can be a financial catastrophe for poorer families in some parts of the world, and there are credible rumours that Indian children—girls in particular—may once have been sacrificed in order for the rest of the family to survive. India is more prosperous now, and insulin can be purchased for as little as $3 per vial. We may hope that life or death decisions such as these no longer have to be made, but I was able to claim in 2008 that lack of access to insulin was the leading cause of death in a child with diabetes [11]. What then are the constraints? The acquisition cost of insulin may not be the central problem: this could lie in the mark-up in the price of insulin as it moves from the warehouse to the pharmacy counter. Novo-Nordisk have a longstanding commitment to offer insulin at a ceiling price of $3 per vial to 76 of the world’s poorest countries, but it has yet to be seen how this translates into availability. The current model of care in one East African country, according to private information, is that insulin can be purchased in bulk at less than $5 per vial. About two thirds is bought by the government and the remainder by private pharmacies who sell it over the counter for about six times the purchase price. The system is driven by what is on the shelf, and it is a gamble whether insulin users will pay the lower or higher price when they present a prescription (Fig. 17.1).

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Fig. 17.1  Lancet cover 1908 and picture of untreated diabetes

About 10 years ago, Health Action International arranged for volunteers to purchase the indentical vials of insulin at pharmacies in 48 different countries, and the 20-fold difference in price is shown in Fig. 17.2. As this might confirm, the main problem lies in the mark-up between factory and pharmacy. In theory, 20 countries currently export insulin, whether produced on licence for the Big Three or by smaller manufacturers. In practice, however, the situation is confused by the fact that some countries import more insulin than they need, whether in bulk or in packaged form, and re-­ export it elsewhere [2]. The need for insulin might be pictured as a pyramid. The tip is represented by those with type 1 diabetes—ten million at least—who would perish without it. Next we come to people with type 2 diabetes who are unable to control their symptoms with tablets. The base—by far the greater potential part of the market—is made up of people with few symptoms and suboptimal glucose control, as defined by algorithms based on their level of HbA1c. By the standards of the wealthier nations, many people with diabetes are undertreated with insulin in poorer parts of the world, implying an enormous unmet need. Cheaper insulin would undoubtedly help, but much more is needed to ensure

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USA Namibia Indonesia Argentina Fiji South Africa Georgia New Zealand Palestine Cameroon Philippines Australia Bahamas Israel Suriname Brazil Guyana Netherlands Syria Spain Nigeria Ghana Malawi Canada Ukraine Dominican Republic Tanzania UK UAE Ireland Ecuador Turkey Cambodia Peru Viet Nam Grenada Lao PDR Yemen Sudan Ethiopia Mali Zimbabwe Zambia Uganda Egypt Pakistan India Senegal

0

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US$ 40

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Fig. 17.2  Pharmacy costs for the identical vial of insulin [Health Action International]

that it is used effectively. Healthcare is a political issue, and only politics can resolve it. In the interim, I have dreamed of a ‘Rough Guide to Diabetes’, freely available on the internet, that would point users—and voters—in every country to the most cost-effective and evidence-based use of the resources at their disposal.

References 1. Basu S, et al. Estimation of global insulin utilisation for type 2 diabetes mellitus, 2018 to 2030: a microsimulation analysis. Lancet Diabetes Endocrinol. 2019;7(1):25–33. 2. Sharma A, Kaplan WA.  Insulin imports fail to meet many countries’ needs. Science. 2021;373(6554):494–7, see also Supplementary tables.

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3. Lebovitz HE.  Insulin: potential negative consequences of early routine use in patients with type 2 diabetes. Diabetes Care. 2011;34(Suppl 2):S225–30. 4. Trewby PN, et al. Are preventive drugs preventive enough? A study of patients’ expectation of benefit from preventive drugs. Clin Med. 2002;2(6):527–33. 5. Gotham D, et al. Production costs and potential prices for biosimilars of human insulin and insulin analogues. BMJ Glob Health. 2018;3:e000850. 6. Hauber A, Gale EAM.  The market in diabetes. Diabetologia. 2006;2006(49):247–52. 7. De Lew N, et al. A layman’s guide to the US health care system. Health Care Financ Rev. 1992;14(1):151–16. 8. Global Burden of Disease. Lancet. 2018;391:2236–71. 9. Suran M. All 3 major insulin manufacturers are cutting their prices—here’s what the news means for patients with diabetes. JAMA. 2023, published online 29th March, 2023. 10. Eban K. A bottle of lies. New York: Harper; 2019. 11. Gale EAM. Dying of diabetes. Lancet. 2006;368:1626–8.

18 Possible Futures

Diabetes affects about 4% of the global population. Readers of this book have an approximate 30% lifetime chance of developing it—the author did, at the age of 77—although the proportion affected varies considerably from one society or ethnic group to another. Only about one in fifty of those affected will need insulin to begin with, but there is an approximate one in three chance that someone developing diabetes will be offered it at a later stage. I have argued that evolution has already optimised the section of the molecule that docks with its receptor, which means that there are in fact no ‘new insulins’; merely modified delivery systems which vary in their speed of onset or duration of action. Individual patients may benefit from altered time-action characteristics, but independent evaluation has failed to identify any systematic advantage over human insulin, especially in type 2 diabetes. We may well be approaching the limits of possibility when it comes to engineering the insulin molecule for subcutaneous use, and one member of the Big Three announced in 2019 that it was pulling out of the race. Potential alternatives such as islet or whole pancreas transplants can offer holidays from injections, but currently require powerful immunosuppressive therapy. A new and promising development is to culture synthetic ‘islets’ from pancreatic stem cells which could be injected into the liver, although they would still need protection against the immune defences of the body. The great advantage of synthetic islets is that their supply does

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 E. Gale, Life in the Age of Insulin, Copernicus Books, https://doi.org/10.1007/978-3-031-47190-2_18

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not rely on human donors. Prevention is better than palliation or cure, however, and war-time experience has shown that the incidence of type 2 diabetes and its complications could be reduced by putting the whole population on a diet. Prevention of type 1 diabetes is currently beyond our reach, although it is now possible to predict and delay its onset. In commercial terms, the global market for insulin is still dominated by three big providers. Its mark-up value (i.e the difference between the cost of manufacture and the cost to the customer) currently varies between 50 and 5000% in different contexts or parts of the world. Not surprisingly, the global market is heavily skewed towards its more profitable sectors. The USA is an anomaly among the richer nations in that its government lacks the ability to bargain over drug prices, and this bellwether market accounts for >40% of global insulin sales by cost. Recent changes in insulin pricing in the USA suggests that consumer outrage can translate into political action, but one may suspect that the big producers of insulin are seeking to make their profits elsewhere. In global terms, it is time to acknowledge that insulin (human or its much touted analogues which are no longer patent-protected) is cheap to produce, so much so that enough quality insulin to satisfy the needs of an average user could be sold at a profit for around $60 per year. All this would need is free market competition. Access to affordable insulin is a basic human right, but so too is access to other necessary equipment, such as syringes and diagnostic strips, together with a clinical support system and informed advice as to how to manage your diabetes. Another factor which cannot be ignored is the widening gap between rich and poor countries and individuals. The rich can afford high-­ tech interventions such as continuous glucose monitoring and automated insulin delivery, but only a small fraction of health systems or wealthy recipients have access to this level of care. Most users still adjust their insulin dose by hand in response to estimates of glucose control and personal experience of hypoglycaemia, just as they did a century ago. Low-tech solutions which make better use of what is already known are quite feasible, however, and would make a far greater difference to the global health of people with diabetes.

18.1 The Human Factor Diabetes specialists fall into two categories: those who treat diabetes and those who treat people with diabetes. Those in the first category see no difference between the statements. Don’t get me wrong: we need both. I

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recently came back from retirement to teach on a paediatric diabetes course, and sat in on a practical management session about insulin pumps and computer algorithms. The technicalities were quite beyond me, but I took comfort from a remark attributed to my hero Nye Bevan at the birth of the NHS. Was it better, he asked, to survive in a cold and impersonal modern hospital, or to die surrounded by love and empathy in an old-fashioned one? There are times when cold and impersonal will do just fine. Every individual is an experiment in living with diabetes. The game is no longer played in a fog, thanks to modern technology, but it is played alone. It can help to know that someone who understands the rules is watching from the side-lines. I call this ‘witnessing’, and it is an under-rated yet essential part of the medical consultation. Every specialist in chronic disease does it differently, and (as I learned when substituting for absent specialists as a junior) they each attract a different type of patient. What works for some does not work for others, as I discovered for myself after failing to persuade one young man to take better care of himself. He saw another doctor while I was away, and came back a reformed character. I felt somewhat peeved, for I had done my best, and Dr. X was not known for his empathy. ‘What did he tell you?’ I asked. ‘He said I would die if I didn’t do as he said’ Ah well.

People change their behaviour when someone is watching, a phenomenon first recognised on the factory floor of the Hawthorne works in Chicago in the 1920s. According to legend–the experiment is not well documented— the investigators found that an increase in ambient lighting boosted the productivity of workers on the shop floor. All well and good, until someone else found that productivity was boosted further when the lights were dimmed below baseline [1]. The Hawthorne effect is alive and well in diabetes, as I demonstrated with the help of friends from Eli Lilly. We analysed six clinical trials which had compared human insulin with lispro (a quickacting analogue) in more than a thousand people. Clinical data were collected at a screening visit, but treatment was not changed until a second visit 2–6 weeks later. Even so, HbA1c fell by an average of 0.24% within 28 days of the screening visit, and recruiting people to a trial had a greater effect than changing their insulin, just as the Hawthorne investigators might have predicted [2]. Of interest, the improvement was inversely proportional to the original level of control; the poorly controlled showed most

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improvement, whereas the well-controlled did no better. This is just what you might expect if you invited people at random to enlist in an exercise programme: the couch potatoes would improve and the marathon runners would not. Diabetes is where personality meets physiology, and this is what makes it so fascinating. It is all too easy for doctors and patients to exchange signals across a void in understanding. A psychology student carried out an anonymous survey of younger women attending my clinic. She found that that each and every one considered herself too fat, including those whose BMI was subnormal. Poor glucose control sucks calories out of the body, and one in three had at some point reduced her dose of insulin in the attempt to lose weight: three were doing so at the time of the survey. We were transmitting on one wavelength and they were tuned to another. The only effective way of guarding against the human factor is the double blind trial. Many users reported a change in their warning symptoms of hypoglycaemia when human insulin reached the market. You cannot—and never should—question the reality of someone else’s subjective experience, but blinded crossover comparisons showed that volunteers who reported problems could not distinguish reliably between animal and human insulin [3]. Curiously enough, the company that insisted on the need for blinded comparisons in support of human insulin showed less enthusiasm when the time came to compare human and analogues. This was wise, for participants in a blinded comparison between quick-acting human and analogue insulins sponsored by another manufacturer could not tell them apart [4]. Openlabel comparisons between a heavily promoted new product and a more familiar old one tend to favour the former, and entire development programmes were founded upon this simple psychological principle. And it works. Everyone on insulin feels isolated, but no-one is ever quite alone. We are part of a much bigger story, a tradition that—like any other—contains hard truths and tempting fallacies wrapped around a core of collective experience. Behind all this looms the lore of diabetes, the tips, tricks, and insights that only people with diabetes know, and which they pass on to those who advise them. This invisible tradition was beautifully expressed by Richard Horton, Editor of the Lancet, when he wrote: ‘The most valuable lesson that knowledge can teach us is that its creation depends upon a continuous line of human relationships and traditions that go far back into the past. That continuity is an unbroken thread. It links cultures and peoples; it brings tolerance and understanding; it delivers hope and compassion’ [5].

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18.2 Access to Insulin People die unnecessary deaths for many reasons, lack of food or clean water among them, and access to insulin is only one aspect of the dysfunctional way in which we manage this planet. Even so, you have to start somewhere, and this is a remediable problem. Insulin has been around for a century, and could be sold at a profit in the USA for around a dollar a day and for about a dollar a week in poorer parts of the world—an affordable price for the difference between life and death. Access to insulin is only part of the battle, however. And here, inevitably, we come back to politics—and politics, equally inevitably, comes back to money. The price of every pharmaceutical is geared to what the market will bear rather than to the cost of production. Consumer outrage can lead to political action, and President Biden has pegged the price of insulin at $35 per vial. The insulin may be cheaper, but much of the profit is made on patent-­ protected delivery devices such as insulin pens. Open competition could make insulin more affordable, and Civica is a new entrant on the US insulin market (supported by the State of California) whose mission is to ‘make quality generic medicines accessible and affordable to everyone’, and it plans to introduce biosimilar versions of the three insulin analogues that account for 80% of insulin prescriptions. A pack of biosimilar glargine could for instance retail at $55, as against $425 for branded Lantus [6]. Formidable opposition from those who profit from the existing system seems likely, and the insulin manufacturers can afford to lower their prices, not least because other segments of a rapidly changing market in diabetes and obesity now look more inviting. This apart, there is currently little political or financial incentive for change. John Kenneth Galbraith pointed out 70  years ago that the countervailing power vested in monopoly purchasers is an effective way of countering the power of monopoly providers. This already goes on behind the scenes, where many national governments or healthcare providers currently negotiate prices of their own, and there is no reason why they should not club together to bring prices down. Universal health care is actually cheaper, which is why health costs account for around 18% of US GDP, as against 12–13% in western European countries. The future of diabetes was once projected against a background of unlimited economic progress, an assumption that can no longer be considered secure. Worse still, we seem to be heading for a world in which high-tech health care is reserved for the wealthy and the global poor must shift for

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themselves. Even so, hi-tech research may point the way to low-cost solutions, so let us consider some of the possibilities.

18.3 Preventing Diabetes Type 2 diabetes has become so common because we eat so much and live longer. It should not be equated with obesity—many victims are not overweight, and most obese individuals do not have diabetes—but overconsumption is characteristic of our society. The ‘consumer phenotype’ that results is associated with central fat deposition, diabetes, raised lipid levels, high blood pressure, arterial disease, and weight-related cancers—all of which contribute to the degenerative disorders of later life [7]. Conversely, enforced food shortage in times of war or economic hardship causes the incidence of diabetes and related conditions to plummet. A change in lifestyle would reverse much of the health risk associated with our consumer culture, but poverty and deprivation go hand in hand with obesity in wealthy societies, and there is no easy solution for this particular challenge. The other side of the coin is an ageing population. ‘Abnormalities’ of glucose metabolism are more or less ‘normal’ in the oldest old, and have less prognostic significance than in a younger person. Once again, let me emphasise that I am not advocating neglect, merely an approach which takes account of the evidence, the circumstances, and the wishes of the person concerned. Fortunately, we have access to experienced and highly trained people who are ideally positioned to offer personal advice. They are called doctors. The incidence of type 1 diabetes has risen for different reasons. European children are four times as likely to be affected as they were at the start of my working life, and the rise in the youngest age group is particularly striking [8]. The gene cluster on chromosome 17 which makes up the HLA region (see page 121) is largely responsible for genetic susceptibility: some genes increase overall risk, others are protective, and an overall risk score can be derived from their combination. This having been said, most people with genetic susceptibility to type 1 diabetes will never get it. A rising incidence within a relatively stable population suggests that something in our environment has changed. This effect can actually be measured in reverse, for the HLA risk score was higher in children who were diagnosed 50 years ago than in matched children diagnosed to day. Today’s children are more susceptible than in the past [9]. Why? The reflex is to seek out a single cause such as diet, vaccination or viruses. Despite intensive search over 60 years, no such agent has been incriminated beyond reasonable doubt. Here once again, identical twins may give an

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important clue. They have identical genes and share the same environment, yet only one in three will develop type 1 diabetes within 20 years of the first. The likely explanation is that the twins may be identical, but their immune systems are not. Each and every immune system embarks on a random walk in its journey through life, and the difference between the identical twins may lie in their response to the environment they encounter. Otherwise said, their genes may be identical, but their immune phenotype is different [10]. My own view is that a changing immune phenotype may be responsible for the post-war rise in type 1 diabetes and other autoimmune conditions such as multiple sclerosis. On this hypothesis, we should also consider the possibility that something that has always previously been there might have disappeared. Some years back, I became interested in an experiment of nature. The quest for inbred mouse strains, described earlier, led to the development of the non-­ obese diabetic (NOD) mouse, which develops a condition closely similar to human type 1 diabetes—but only if reared in germ-free conditions. Infection is the bane of animal laboratories, and mice infested with pinworm are almost invulnerable to diabetes. Pinworms are members of a class of intestinal parasites known as helminths, intestinal worms that are notorious for their ability to manipulate the immune system of their host. A paper from 1947 estimated that 31% of Americans and 36% of Europeans were infested, and that 40–60% of children currently had pinworms. Pinworms have co-existed with us throughout evolutionary time but have largely vanished from more affluent populations over the past few generations. Coincidentally, type 1 diabetes shot up first in western populations, and is now a world-wide phenomenon [11]. We all fall in love with our own hypotheses, so let me hasten to add that I am not claiming that loss of pinworms is directly responsible for the rise of type 1 diabetes. This is just one of several possible examples of the way in which our immune systems have changed, and it suggests to me that we should be looking at the development of the immune system in general rather than for specific precipitants [7]. Since immune systems can be manipulated—we routinely do so with vaccination—better understanding of their development might help us to eradicate autoimmune disease. Primary prevention of type 1 diabetes might potentially be achieved by a change in our child-rearing habits. The alternative approach is secondary prevention. In 1976 Andrew Cudworth, my predecessor at Bart’s Hospital in London and the man who re-introduced the distinction between type 1 and type 2 diabetes established a population-based study of families with early-­ onset diabetes. His hypothesis was that genetic susceptibility would be increased in the siblings of a child with diabetes, and could be measured in

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terms of HLA-associated risk. Childhood diabetes was considered a disease of sudden onset at the time, and Cudworth was looking for its precipitating cause. Since viral infection seemed the most likely cause, he aimed to catch it red-handed by repeated screening of susceptible children. If such a virus could be isolated, genetically susceptible children could be vaccinated against diabetes. His expectations were confounded when the family study showed that people with newly diagnosed diabetes have no consistent viral footprint. What they do have is antibodies against their own islets, antibodies that appear years in advance of the clinical condition and can predict its onset. A condition that can be predicted lends itself to prevention. The first large-scale trials got under way in the1990s, but were uniformly unsuccessful until the advent of teplizumab, a monoclonal antibody which disables one element of the immune response and has to date succeeded in deferring the onset of diabetes. The treatment is not without risk of immune injury, and the jury is still out when it comes to its longer-term benefits. We do at least know that type 1 diabetes can potentially be delayed, and that secondary prevention is becoming a viable option. Even so, diverting an activated immune system from its prey is a risky business, and safety must be the prime consideration. One unexplained feature of type 1 diabetes is why it develops so slowly. One participant in our family study had a ‘full house’ of genetic susceptibility and islet autoantibodies at the age of 12. We lost touch, but she contacted me 20 years later to say she had just developed diabetes. How had her body managed to resist it for so many years? It is now clear that apparently functional beta cells linger on in many people with typical type 1 diabetes, and that they are still there decades after diagnosis. If we could understand why some islets are spared while others are not, we might potentially be able to insert a spoke into progression to diabetes. Type 2 diabetes is generally seen as an interaction between insulin deficiency and loss of sensitivity to its action: a loss which can often be reversed within a few days of weight-loss surgery or—less dramatically—by stringent diet. Type 2 diabetes is eminently preventable but you would have to change the lifestyle of whole populations in order to make this happen, and commercial incentives to make us consume more are light-years in advance of public health initiatives designed to make us eat less.

18.4 Replacing Insulin Insulin therapy is complicated by the fact that our brains need an uninterrupted supply of glucose. Insulin plays a key role in distributing fuel energy around the body, but its effect on glucose threatens our minute-to-minute

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survival. This immediacy distinguishes the treatment of diabetes from other disorders of metabolism, and the brain’s dependence on glucose comes at a high price. By the same token, glucose is a handy guide to metabolic regulation: if glucose is well controlled you can be reasonably sure that other aspects of metabolism are functioning well. The pancreatic islets command the gateway to the liver, and feed insulin into it. Small pulses act mainly upon the liver, whereas larger and more frequent pulses after meals spill over into the general circulation and direct surplus fuel towards muscle and fat. The liver removes (‘clears’) up to half the insulin reaching it from the pancreas, so the liver normally ‘sees’ far more insulin than the rest of the circulation. Each pulse of insulin is coordinated by a neural network which links the million or so islets in a pancreas, and glucagon from the alpha cells acts to complement many of the actions of insulin. This dual control system operates across a spectrum ranging from starvation to repletion, and insulin’s role is to store fuel when available and to let it go according to need. When you consider that the body’s sensitivity to insulin (the amount needed to achieve a given effect on glucose) varies six-fold within a population and twofold or more in the course of normal daily activities, it is easy to see that nature has given us a control system of exquisite beauty and complexity. Our attempts to imitate this model of precision by dumping insulin under the skin might seem laughably crude by comparison. Injected insulin is not subject to control and releases insulin—after inevitable delay—into the wrong side of the circulation. The remarkable thing about injected insulin is that it works as well as it does, testifying to the versatility of the bodies we are gifted with. Biosynthetic human insulin freed the world of diabetes from reliance on the abattoir, and made it possible to adapt the insulin molecule for subcutaneous use by speeding or slowing the rate at which it is absorbed. Faster absorption was achieved by redesigning the molecule to dissociate more rapidly following injection, and slower absorption by delaying uptake, thus converting the body into an insulin ‘sponge’ that leaks it into the circulation at a slow yet relatively steady rate from multiple injection sites. Despite the ingenuity of the molecular engineers, possible ways of speeding or slowing the absorption of subcutaneous insulin are limited, and face a future of diminishing returns. Alternative strategies are under active consideration. One might be an insulin which acts preferentially upon the liver, but progress on this appears to have stalled. A glucose-sensitive ‘smart’ insulin would be an enticing alternative. This would operate within a glucose-sensitive matrix designed to promote insulin release when glucose levels are high and to prevent it when hypoglycaemia threatens. Progress is currently limited by the need for a matrix

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capable of fulfilling both functions. Initiatives such as these hold out hope for the future, but many obstacles have yet to be overcome. An alternative is to combine physiology with electronics. One approach, for example, is to deliver insulin into the cavity lining the gut, from whence it passes directly into the liver. The risk of infection can be reduced by surgical implantation of the pump under the skin of the abdomen. The implanted pump has a reservoir which can be topped up by injecting insulin through the skin. One problem is that fibrils form within standard insulin and threaten to block the pump, which is where insulin engineering comes in. The dream of taking insulin by mouth has been with us for more than a century, but faces formidable obstacles, the most obvious being that insulin is destroyed by stomach acid. Once past the acid bath, however, insulin is absorbed through the lining of the small intestine and passes directly into blood feeding the liver. Oral insulin has always had a fatal attraction for investors, and endless attempts have been made to sneak insulin past the stomach. Intestinal absorption is both inefficient and erratic, however, which makes precise dosing impossible. In sum, we must live with the limitations of injected insulin for some time to come. Lack of feedback control is first among them, and a hi-tech solution is offered by renewable glucose sensors linked electronically to a subcutaneous insulin pump. This ‘closed-loop’ system delivers insulin according to a sophisticated algorithm, and is the latest incarnation of the artificial pancreas. The artificial intelligence incorporated in such systems is improving steadily but cost is a major constraint. Some people dislike the thought of being wired to a machine, but others greatly appreciate the security that comes with the knowledge that your blood glucose is going to look after itself during the night.

18.5 Biological Alternatives If taking out a pancreas causes diabetes, replacing it makes obvious sense, and the first human pancreas transplant was performed in 1966. More than 50,000 whole pancreas transplants have been carried out since then, and around 85% of recipients currently manage without insulin for at least a year. Whole pancreas transplantation is most often used in people who already need immunosuppression for a kidney graft; 6–8 years is the average period of freedom from insulin, and some grafts function well after 20 years. Successful combined kidney and pancreas grafts confer freedom from both dialysis and injections, and the delight of the recipients can scarcely be imagined. Obvious constraints include the scarcity of fresh human pancreas, usually obtained

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from kidney transplant programs, and the need for lifelong immunosuppression to protect the graft from rejection. Another limitation is that only around 1% of pancreatic tissue makes insulin. The other 99% generates up to 1.5 L of digestive juice each day, and this must be disposed of, usually by drainage into the small intestine or the urinary bladder. The bladder is generally preferred because the level of pancreatic enzymes in the urine can be used to monitor graft function. It is logical to transplant the islets without the rest of the pancreas, and islets can be obtained by mincing up a fresh pancreas and digesting it with the enzyme collagenase. Technical refinements make this possible, but fresh human pancreas is not easy to come by, and the isolation procedure is stressful for the cells involved. This apart, islet transplantation has many advantages. A major operation is no longer needed, since islets can be injected directly into the blood vessels feeding the liver, and topped up in case of need. They take root in the liver and begin to make insulin. Freedom from insulin is desirable but not essential, for even a subset of functioning beta cells cushions the need for external insulin and makes unstable diabetes easier to manage. Despite its current limitations, therefore, islet transplantation is the more promising biological route. The most intractable obstacle is rejection, not least because standard immunosuppression can itself harm beta cells. Breakthrough seemed to have been achieved in 2000 when James Shapiro and colleagues in Edmonton reported that insulin-independence had been achieved in seven consecutive patients by infusing islets with steroid-free immunosuppressive cover [12]. Striking though the achievement was, only 10% of recipients were insulin-­independent at 5 years. Even so, 80% were still making some of their own insulin, and the procedure is particularly useful in those with type 1 diabetes and disabling hypoglycaemia. The other big obstacle is a lack of fresh human islets. One alternative would be to obtain them from a non-human species such as the pig, whose insulin is closely similar to ours. The major problem is that our immune system launches a reflex attack known as a hyper-immune response upon tissue from another species. One way of avoiding this would be to engineer the cells in such a way as to render them invisible to the human immune system, but this raises the spectre of cancer, and is beyond our current ability. Added to this, the logistics of growing islets in another species are daunting and a recent review concluded that 10 adult and more than 90 juvenile pigs would be needed to free a single human adult from dependence on insulin [13]. A more promising route is to grow our own islets from scratch. There are more than 200 types of specialised cells in the human body, each tracing its

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Fig. 18.1  Directed differentiation of stem cells towards a beta-cell lineage produces clusters of related daughter cells. These are not true islets, but subtle modification of the medium has allowed synchronous development of several islet cell types. (From Diabetologia 2021 May 64(5):1030–36 Melton, D. The promise of stem cell-derived islet replacement therapy. Diabetologia 64, 1030–1036 (2021)—open access)

descent from the original cell formed by the fusion of egg and sperm. Every cell with a nucleus possesses the identical genetic information—how to make insulin, for instance—but only the genes it needs get switched on. Some are needed for basic housekeeping and others for functions specific to that type of cell. Attempts to grow new beta cells from progenitor stem cells brought an unexpected dividend, for attempts to grow several types of islet cells at the same time produce clumps of related cells which form spontaneous islet-like clusters (Figs. 18.1 and 18.2). Ideally, a synthetic islet such as this will take root in host tissue and function independently. Stem cell-derived islets have been injected into the first human volunteers, and (if confirmed) a potentially limitless supply of islets will be available for transplantation. The sting in the tail is that immunosuppression is still required. How might this be avoided? A possible way of evading the immune system is to package the transplanted cells within special capsules or membranes. An ultrafine mesh might in theory allow the transplanted material to obtain the nutrients it needs without coming into contact with the immune system, but early attempts have failed because the ‘tea-bag’ technique also bars access to the blood supply it needs [14]. Will future attempts succeed? Alternatively,

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Endocrine cell

Directed differentiation Opportunities: improve protocols by reducing the number of steps, time, factors and costs. Gain complete control of cell composition SC-islet

Fig. 18.2  An example of a ‘stem-cell islet derived’ produced from an embryonic stem cell by a six-step procedure. The synthetic islet contains cells which stain for insulin, glucagon, and other islet hormones. (From Diabetologia 2021 May 64(5):1030–36 Melton, D. The promise of stem cell-derived islet replacement therapy. Diabetologia 64, 1030–1036 (2021)—open access)

could transplanted islets be rendered invisible to the immune system? We have reached the end of the history of insulin and—just possibly—the beginning of its future.

18.6 The Second Century of Insulin Old age, as Anton Chekhov pointed out, is the most unexpected thing that can happen to you. I belong to a society in which 90% of people survive past 60, and 50% past 80. Old age is inevitably a time for reflection about a past that cannot be changed, opportunities lost and hearts broken. It is also, believe it or not, a time of blessings; a time when the bittersweet taste of life is sharper than ever before and each day is sufficient to itself. ‘As you make your bed, so must you lie on it’ is one of its harsher truths. Your wealth, your health, your way of life and your well-being are the legacy of a vanished life in which wisdom and folly were hopelessly entangled. One of the great comforts of my own life has been a sense of common purpose: a feeling that the possibilities of life can be extended, that science is a good way of learning from our mistakes, and that the future can be made better. Let me try to convey a flavour of what my world has been like.

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The rules for a ‘caucus race’, as witnessed by Alice during her visit to Wonderland, are as follows. Assorted weird beasts arrange themselves around a circular race-course and run when they like, stopping when they like, until the end of the race is announced. The Dodo is then asked to select the winner, and after some thought announces that everybody has won, and all must have prizes. Biomedical research is organised and funded upon much the same principle. When we observe the diabetes peer-review event, for example, we will note that there is no entry criterion other than membership of an academic or research institution. Any species of investigator from molecular geneticist to podiatrist can join, for all assert the right to be there. How can this be? Let us pick up a high-scoring grant application at random. The investigator, as we will note beneath the slick and hackneyed cut and paste of the prose, wishes us to believe a number of things that cannot easily be reconciled. First, as befits a scientist at the leading edge of her speciality, her proposal will offer real promise of scientific advance, for her primary concern is with the disinterested advance of knowledge. And yet, as with the Zen archer who hits his target without trying, she goes on to inform us that this advance is precisely what is needed to solve the practical problems of diabetes. It will, as she points out, open the door to possible new therapies (or, if inspiration falters, new ‘insights’), with useful financial consequences. Science, medicine, and the economy will all benefit. There is, as you will learn, no area of research so remote from any possible practical outcome or relevance that cannot, with the aid of human ingenuity, be brought to bear upon the problem of diabetes. Such is the caucus race. The contestants have all received prizes, for otherwise they would be in no position to compete for more. Their principal objective is to stay in the race. Each applicant needs to further his or her career and to support research staff and their families; the funding proposal is simply a means to an end—so much so that well-organised investigators have sometimes completed the work before the application is submitted, thus ensuring a near-perfect track record of achievement. Completing the work is only half the battle, however, for in Wonderland the success of a project is not judged by the knowledge gained, but by the status of the journal in which it is published. The institution within which the applicant works is equally indifferent to the content of the research—unless it can grab some favourable publicity in the process—but will be able to tell you how much income has been generated at the push of a button. And here we pass beyond satire. Research is judged on the basis of the number of publications, the name of the journals in which these appear, and the income generated. Happily there is more to it than this, for these are

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externals, things needed to ensure a successful academic career. Within each area of research there is a more elusive commodity known as esteem. Without it, you are lost. Your grants will not be funded, and your name will not be on the table when prize lectures and awards are handed out. How does one acquire esteem? The middle path is safest. Acquire the reputation of being a ‘good scientist’. Being translated, this means that you have technical expertise untainted by novel ideas. Your work will be honest, well performed, well-­ funded, and will threaten no-one. Next, be useful. Organise meetings, edit journals, serve on committees and write the policy statements. Defer to others in the field. Invite them to the podium, and cite their work. Be nice to them behind their back, for they will soon find out if you are not. Judge kindly, for you are being judged. Best of all, grow old and be tolerated. Only the young will aspire beyond this, for they suffer from the Icarus Complex and dream of flying far above base comparison with lesser mortals. They should consider the fate of their role model, for Schadenfreude is the licensed blood sport of academia, esteem can turn to envy, and lesser suns will strive to melt the wax from your wings. Is that all, the reader may ask? Of course not. Think of any other field of human endeavour, and you will expect it to have its personalities, its politics and a fair dash of futility. Academic science offers all these things, yet holds the key to something more sublime. As with the air passenger who dozes the hours away before glancing through the window at a panorama of snowy mountains, the researcher is reminded from time to time of a wider scheme of things in which it is a joy to participate. Research is pleasurable and addictive, for you have the freedom and money to satisfy your curiosity, to dream in the bath, to float new ideas and to know that each experiment will judge your skill and cunning without mercy. And so it is that you find yourself within a global village whose other inhabitants share your knowledge and passion, and you hunger for the highest accolade of all—the respect of those you respect. Mountain guides do not pause to admire the scenery, and neither do you, but you know that you are travelling through a landscape of transcendent beauty. Nor is that all, for although you wake at night with the premonition that your work will die before you do, you never doubt that you are right to try. Your enemy is a horrible disease and you have found what the rest of humanity seems to lack, the moral equivalent of war. There is, you decide, no finer task, no finer company. All this says nothing more than that the biomedical researcher is, like all other human beings, profoundly muddled, a patchwork of the mundane, the ludicrous, the self-seeking and of that elusive quality which forbids us to give up all hope for our species. Forgetful of the past yet hopeful that those to

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come will remember him, the investigator has stumbled into a system that— however, slowly and inefficiently—takes note of former errors and sets them straight. This is a system that links the living with the dead, the genius with the lucky bungler, and reveals the awesome power wielded by a multitude of fallible individuals linked by a common purpose. For science, as Abraham Maslow has said, is a means by which even the unintelligent can help to advance knowledge, a ‘technique whereby non-creative people can create’ [15, p. 62]. The research enterprise, as at present constituted, is necessary but not sufficient to tackle the questions we face. Medical techno-science is essentially pragmatic in its approach, convergent in its thinking, and mechanistic in its understanding. It is geared to the acquisition of new information, to the extent that research laboratories operate like production lines, and publish in football teams. Their findings are fed into electronic databases and listed in review articles that are as riveting as a stock market report. The data pile up so rapidly that bioinformatics and data processing become major industries; silicon dominates because the supply of paper cannot keep up. And yet, despite the blizzard of data, no knowledge is of the slightest use to anyone until it has been processed and presented by a single human brain. This is our one unique gift, and one that we neglect at our peril.

18.7 Unfinished Business And so, how should we look back on the first century of insulin? Our themes have been the ongoing scientific discovery of insulin, its use in diabetes and its development as a commodity. From the scientific point of view, the gap between where we were then and where we are now is breathtaking. It might seem that we have little more to learn about the molecule and the way it shifts glucose across cell membranes—but who knows? In a wider context, we still have much to learn about the role insulin plays in the growth and development of our own bodies, and about the way in which we age. Insulin combined a ground-breaking scientific discovery with a near-­ miraculous treatment for a lethal disease, but it remains a treatment rather than a cure. Effective treatment has converted a lethal disease into an onerous risk factor. Insulin insensitivity and glucose intolerance are common in older people, but its consequences for our health vary enormously. Risk is multi-­ layered, individual and dimensional, and the epidemic of over-prescription in the elderly should in my view be countered with a combination of common

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sense, the wishes of the person concerned, and realistic evaluation of the likely benefit. Readers who have persevered this far will know that I am an advocate of old-fashioned doctoring, in line with William Osler’s dictum that ‘the person that has the disease is more important than the disease that has the person’. Artificial intelligence will never be able to meet the needs of a human being, although it will undoubtedly suggest plenty of diagnoses. The ontological fallacy (mistaking abstractions for entities) has dominated our thinking about type 1 and type 2 diabetes. Non-insulin-dependent diabetes has many shapes and forms, and a blanket definition based on the absence of characteristic features of type 1 diabetes betrays this complexity. I look forward to the day when we have better tools to unpick the individual features of what we call type 2 diabetes; only then will we know when and how best to treat it with insulin. Last but not least, we come to the commodity. It is absolutely true that we need the resources of industry and private investment to produce and market insulin, but we should not forget that the profit motive is an incentive to make money rather than to provide a public service. Countervailing power is needed to ensure that private investment is used for the public good, and countervailing power is failing. My working lifetime has seen the rise and fall of a movement towards what was known as evidence-based medicine. As the name implies, evidence-based medicine relies on access to the evidence, and is therefore the first casualty of drug development: Why? Because the pivotal studies are designed, analysed, and presented in such a way as to favour the positive aspects of new drugs. The randomised controlled trial might seem an impartial oracle, but those who do not know how to set one up to bring in the desired result are probably not on a company payroll. When things go wrong, there is always the option of ‘losing’ a study or hiding it behind a misleading abstract that never sees full publication. The conclusion seemed clear: evidence-based medicine was falling at the first hurdle when it came to the introduction of these important new drugs, and the gap had been filled with skilled misinformation … An expert is hired for his opinion. The expert ­clinician moves too easily across the invisible divide between opinion and advocacy. His value lies in his reputation for independence and integrity, but these qualities cannot be marketed without the risk of compromising them. There is too much secrecy at the interface of industry and academic medicine, and too much money going across it; the honest work done by the many is devalued by the dishonesty of the few. It is too easy to be drawn into this world by imperceptible degrees, bolstered by special pleading and fostered by the prevailing culture of secrecy, complicity and cheerful cynicism. Wriggle as we may, there is only one

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standard of honesty. The tough question for all who move between the two cultures is this: whose doctor are you, anyway? [16]

Imagine that you have driven into the last filling station before a desert, and find two otherwise identical petrol pumps, one of which costs six times more than the other. You are told that the more expensive fuel is better. Not in terms of performance—it is essentially the same stuff—but because confidential comparisons undertaken and paid for by the makers of the expensive fuels have shown statistical benefit. Consumer watch-dogs must rely on comparisons reported by companies who stand to profit by the results. Even so, these suggest that most users will find the cheaper fuel just as effective. Noting your concern, the filling station attendant points you to another pump which offers ‘biosimilar’ petrol made to the same standard as the more expensive brand, whose patents happen to have expired. This costs only five times as much as standard gasoline. You feel bewildered, but the desert looms ahead. You fill up at the more expensive pump. A consumer study performed in 2009 showed that the price of an identical vial of insulin varied up to a 100-fold between pharmacies around the world. How did this situation arise? Those who sell insulin know that its users cannot do without their product. Why not sell it for as much as the market will bear? Since the global market for insulin is highly asymmetrical, it is logical for them to concentrate their efforts on the more lucrative sectors. Hence the apparent paradox that people in the world’s richest country sometimes struggle to pay for it, as do those in poorer parts of the world. It seems easy and obvious to blame the manufacturers, but much of the mark-up occurs between the factory and the pharmacy counter. Those who service this pathway are entitled to a slice of the cake, but it is society at large which dictates how big that slice should be. A truly free market in insulin would soon bring prices tumbling down, and a deliberate attempt to market insulin at a modest profit would have the same effect. So too would a medical profession that followed the evidence—such as it is—rather than the blandishments of industry and paid more attention to the needs of those it is supposed to serve. At the end of the day, it is pointless to assign blame for a system that has arisen spontaneously. One principle does, however, seem clear: insulin is a public good, and access to it is as much of a human right as access to clean water. In the final analysis, the price of insulin is a political issue—which means that all those entitled to vote for a government are responsible. As to what lies in store, we might feel confident that techno-science will ultimately defeat insulin-deficient diabetes, but no-one could put a date on this, and

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there is a growing risk that environmental catastrophe might supervene. In the interim, the gap between the global rich and the global poor is getting wider, and high-tech solutions designed for the wealthy exclude those who cannot afford them. Those of us who believe that access to affordable insulin—and to the means of using it effectively—is a basic human right face an uphill struggle. The battle to stem the tide of what we may loosely call type 2 diabetes is one we will continue to lose while economies flourish. Paradoxically, a rising rate of diabetes and obesity testifies to the fact that more people are getting enough to eat. Obesity and diabetes (‘diabesity’), once a problem for the wealthy in poor countries, is now a feature of social disadvantage in wealthy countries. Widespread economic recession threatens the world as I write this, and might yet provide a highly unwelcome solution to the pandemic of type 2 diabetes. Assuming that this can be averted, our options for the future will be to eat as we please and rely on pharmaceuticals to stave off the consequences, or to lead healthier lives. The best insulin is made in our own bodies. Immune-mediated diabetes could potentially be prevented—the ideal solution—or possibly reversed by replacing cells that make islet hormones. Non-immune diabetes is already largely preventable, and can often be reversed by food deprivation. We are confronted with apparently insurmountable opportunity.

References 1. Gale EAM.  The Hawthorne studies: a fable for our times? Q J Med. 2004;97:439–49. 2. Gale EAM, et  al. Recruitment to a clinical trial improves glucose control in patients with diabetes. Diabetes Care. 2007;30:2989–92. 3. Maran A, et  al. Double-blind clinical and laboratory study of hypoglycaemia with human and porcine insulin. BMJ. 1993;306(6871):167–71. 4. Gale EAM for the UK Trial Group. A randomised controlled trial comparing insulin lispro with soluble insulin in patients with type 1 diabetes on intensified insulin therapy. Diabet Med. 2000;17:209–14. 5. Horton R. How sick is modern medicine? New York Review of Books. http:// www.nybooks.com/articles/archives/2000/nov/02/how-­s ick-­i s-­m odern-­ medicine/. Accessed 2 Nov 2000. 6. Dafny LS. A radical treatment for insulin pricing. NEJM. 2022;386(23):2157–9. 7. Gale E. The species that changed itself. London: Penguin Books; 2019. 8. Gale EAM. The rise of childhood type 1 diabetes in the 20th century. Diabetes. 2002a;51:3353–61.

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9. Gillespie KM, et al. The rising incidence of childhood type 1 diabetes is associated with a reduced contribution from high-risk HLA haplotypes. Lancet. 2004;364:1699–700. 10. Eisenbarth GS. Banting Lecture 2009. An unfinished journey: molecular pathogenesis to prevention of type 1A diabetes mellitus. Diabetes. 2010;59(4):759–74. 11. Gale EAM. The discovery of type 1 diabetes. Diabetes. 2001b;50:217–26. 12. Shapiro AM, et  al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid –free immunosuppressive regimen. NEJM. 2000;343(4):230. 13. Coe TM, et al. Current status of porcine islet xenotransplantation. Curr Opin Organ Transplant. 2020;25(5):449–56. 14. Butler PC, Gale EAM. Reversing type 1 diabetes with stem cell derived islets. A step closer to the dream? J Clin Investig. 2022;132(3):e158305. 15. Maslow A. The further reaches of human nature. London: Penguin Books; 1971. 16. Gale EAM. Between two cultures: the expert clinician and the pharmaceutical industry. Clin Med. 2003;3:538–41.