Who Wrote the Book of Life?: A History of the Genetic Code 9781503617575

Citation preview

WHO WROTE THE BOOK OF LIFE?

A HISTORY OF THE GENETIC CODE

WRITING

EDITORS

SCIENCE

Timothy Lenoir and Hans Ulrich Gumbrecht

WHO WROTE THE BOOK OF LIFE?

A HISTORY OF THE GENETIC CODE

Lily E. Kay

STANFORD UNIVERSITY PRESS STANFORD, CALIFORNIA

Stanford University Press Stanford, California © 2000 by the Board of Trustees of the Leland Stanford Junior University Printed in the United States of America crP data are at the end of the book

For Kurt and Paulette Olden

ACKNOWLEDGMENTS

I could not have researched and written this project during a six-year period were it not for the enormous range of collegial, institutional, and financial resources I enjoyed. Such support represented a much appreciated vote of confidence, which countered the occasional skeptical voices. The book has many contributors, including colleagues and friends, students, archivists, and, of course, several of the scientists whose work directly or tangentially figures in the text. I owe a great debt to Manfred Eigen for his generous hospitality during my spring 1992 visit at the Max-Planck Institute fur Biophysikalische-Chemie in Gottingen. Although, chronologically, his scientific work is recounted only at the end of the book, his contributions to this project-in the form of lent publications, access to his library collection, and provocative discussionsformed the project's conceptual starting point. I am also grateful to Marshall Nirenberg for providing me with his laboratory diaries and for enduring extended interviews conducted over a three-year period. Heinrich Matthaei, too, gave freely of his time and supplied me with copies of his laboratory notebooks. I also have benefited from lively discussions with Sydney Brenner and Joshua Leder berg and from their personal archival treasures, as well as from the historical nuggets of Martynas Yeas. Communications with Heinz Fraenkel-Conrat, Morris Halle, Henry Linschitz, Wayne O'Neil, Leslie Orgel, Robert Sinsheimer, Heinz von Foerster, and members of Brookhaven National Laboratory contributed to different aspects of this historical reconstruction; and spirited conversations with Ernst Mayr have kept an evolutionary perspective on molecular biology within close range. Each of these scientists has been remarkably open-minded to my queries and challenges despite some differences in outlook. Responsibility for the final scientific and historical interpretations is mine alone. Numerous scholars read and commented on various parts of the manuscript; I have not always followed all of their suggestions, but I am very grateful to William Aspray, Mario Biagioli, James Bono, Yoonsuhn Chung, Angela Creager, Lorraine Daston, Soraya de Chadarevian, Paul Forman, Peter IX

x

Acknowledgments

Galison, Jean-Paul Gaudilliere, Herbert Gottweis, Loren Graham, Morris Halle, Donna Haraway, Victoria Harden, Ruth Harris, Thomas Hughes, Henry Krips, Joshua Lederberg, Timothy Lenoir, Michael Mahoney, Helmut Miiller-Sievers, Marshall Nirenberg, Robert Richards, Henning Schmidgen, Skuli Sigurdsson, Denis Thieffry, and Mary Winsor. I am indebted to Robert Olby, Silvan Schweber, Michael Fischer, and most of all to Hans-Jorg Rheinberger, for thoughtful readings of the manuscript, animated discussions, and the fine balance of criticism and support. The financial and institutional support for this project was extensive in scope and duration. At its embryonic planning stage it benefited from MIT's Provost Fund and an Old Dominion Fellowship; soon after it received a generous grant from NIH-ELSI branch, cosponsored by NSF (1993-9 5). These funds and leave time facilitated travel to archives, interviews, and conferences as well as the long writing periods. I especially thank archivists Madeleine Brunerie, Helen Samuels, Tom Rosenbaum, and Clifford Mead for their resourcefulness and engagement with this project. Equally important, these funds provided for several research assistants. I am grateful to MIT's undergraduate students Ashwin Balogopal, Ahlam Hashem, and Smruti Vidwans; graduate students Steven Collier, Evan Ingersoll, and most of all Eric Kupferberg for their excellent research and patient photocopying from scientific and popular sources; and to Slava Gerovitch for always raising critical questions. The remarkable intellectual community of the Max-Planck Institute for the History of Science in Berlin has nurtured this project at its final stage. I also thank Judith Stein, Phyllis Klein, and Betsy Keats, the support staff of MIT's Program in Science, Technology, and Society, for their administrative and editorial services. Debbie Meinbresse deserves particular thanks for her smiling help and expert preparation of the manuscript. Helen Tartar and Nathan MacBrien of Stanford University Press have been an author's dream, joyfully shepherding the manuscript through the editorial and production phases with refined academic and aesthetic sensibilities. Finally, I thank Charles Weiner, Alan Attie, John Eskridge, and especially Peter Kuznick for the constancy and scope of their friendship and collegiality, and my family, Kurt and Paulette Olden, for their spirited generosity. I can only hope that all this support is judged worthwhile in what one sympathetic grant reviewer called "the marketplace of ideas." L.E.K.

CONTENTS

PREFACE ABBREVIATIONS

I.

The Genetic Code: Imaginaries and Practices

XV XXI

I

2. Spaces of Specificity: The Discourse of Molecular Biology Before the Age of Information

38

3· Production of Discourse: Cybernetics, Information, Life

73

4· Scriptural Technologies: Genetic Codes in the 19 sos

!28

5· The Pasteur Connection: Cybernetique Enzymatique, Gene Informateur, and Messenger RNA

193

6. Matter of Information: Writing Genetic Codes in the r96os

2 35

7· In the Beginning Was the Wor(l)d?

294

Conclusion

326

NOTES

335 381 427

WORKS CITED INDEX

ILLUSTRATIONS

I. The genetic code 2. Erwin Schrodinger, I930s

4 6o

3· Stern's representation of "modulated" nucleic acid chains incorporating different "gene codes"

68

4· Dounce's scheme of protein synthesis via an RNA intermediate 5· Norbert Wiener, I950s

7I

6. Claude E. Shannon, I950s

93

7· Schematic diagram of a general communication system 8. John von Neumann, ca. I952 9· Henry Quastler with his wife, Gertrud, I 9 5os IO. George Gamow, ca. I9 55 II. The twenty different types of diamonds; and diamonds arranged along a schematic representation of the double helix 12. Members of the RNA Tie Club, ca. I 9 55

74 97 I03 II7 I30 137 I42

13· Drawing of the RNA Tie Club from Gamow's notebooks 14· Twenty possible triads of triangular code; and schematic diagram of triangular code

143

I5. Gamow's illustration of Teller's sequential (Russian bath) code

I46

I6. Alexander Rich, Francis Crick, Sydney Brenner, ca. I9 55 I7. Codes without commas

I 55 I6I

I8. Schematic representation of fully overlapping, partially overlapping, and nonoverlapping triplet codes

I64

I9. Heinz Fraenkel-Conrat and Wendell M. Stanley, ca. I957

I8I

20. Tobacco mosaic virus

I83

2!. Sequence of I 58 amino acid residues

I88

22. The bactogene apparatus for continuous bacterial culture; and the chemostat device for continuous bacterial culture

200

I45

23. Fran C) (U > G or C) UC (U A) UA UA(UJ-. !*jtf 14,. M...ff -fA 17nt i ~ [b JE~' 6iZ:: 1.~'' xP~~- 0 -"""- .:-'IYJ ·-1=1 :.X. ;;;;y 1;/Ui "t

.

1

ao:-,

~ -YJ I t::v ! ~ ilirfi ~r:~ }4)JJ( :#R ~~ILJtl.; Ji'.¥ f1fi ~ i-1£ i1{J: Jifttr~kt.l lftJt'3t! ~ >Ff,t1{1f{Y~I .~t S! ~! ~ I lh '"" -"~ ~ ~·~~ JiXI /ffiJJE., lfllllJo -:Lt, '1.l!J_,i;:Jiifr, l/c; i

P-11

1

tti it: Pl':fdsi~'J :31X ~r,:~iJU FIGURE

4 I.

z

~~

I

JL

.W.."·

0

I

63. Chi Chi-After completion

64. Wei Chi-Before completion

co!Ilp.Iementar~'

The final two states (63, 64) m the I Chmg code, Before Completio~" and "After ~omp~etion": thetr !Ileamngs and combmatonal potenttal.

--1

!

At o 1;6'! Iff1\ jflT ~~~ t.i J¥0 ~~~ s ·lll.:r ~ it~~ ~W:lf.f:'J' 1rl lliJEl 1S i"ii- i~l~ tfl)~ 1=t l,l~l ~ .~ .!£.o 'o-!r ./~ .~ i

= = == ==

= = I

'!.!•

~! {mj ·~~"J..U..,.//1'-'

,xPI~IJ\ ~~

°

~JJt. JY¥: !.if' tf1 i!*i ~lo ']fJ\ ~~~~ll* Jf ffr. '!Jfff ~~

~.~Io/~ aJ1h'@ ~ -tJLi EJ.fiio:X:~ o _1;p rPl £lj/ioj -tJLo! l1 1iE ~ f; . 1

1

"''

1

~j,f.~,j}f;~t 0 !~ 1 fj ,1J!.{f)i:lG 1

1l!t,!ijtJ!:tJJAt ~-

I ,0 ~~ J.t!1t( l;iit11:t* _1! B \;J;.'II ~:.; }tj\ ~J 1

t:J oJ'tl _,., 1

01 /

L..l .?f';.

:iff

ot-1'' o

1' +:if! 'i1t !J!ll.:k 1« ~~~ !ffii ir: o rt I ~ I -fr 1 JI tb : ~-;}:~til ~~/JL ~~~ ol

!l~ i)t ~T I

O·

'T

0

~it!Y. . Olit!jJJ~.\;r; [j!Lol~~!f ~

f~:*t.lf(jj t~-l~l k, 1M~ Ys1-¥

Complementary hexagrams in the I Ching. From Zhou yi benyi (The Fundamental Meaning of the I Ching) (Taipei, Taiwan: Huailan chubanshe, 1975).

In the Beginning Was the Wor(l)d?

c

u 4

0

u

G 20

6

317

A 24

12

28

u c 45

32

36

52

40

56

44

60

G A

--------------~-------------+------------+-----------~~ 17 9 25 13 1 5 29 21

u c

c

49

33

37

53

41

57

61

45

--G

--A

G

2

1!1

6

22

10

26

1-1

3-l

-so

38

54

42

58

4.6

30

--u

=-= c

=G 62

A

19

3

7

23

·11

27

15

31

u

c A

51

.35

39

55

43

59

47

=G 63

A

FIGURE

4 2.

Martin Schonberger, The I Ching and the Genetic Code, p. Reprinted by permission of the Aurora Press.

72.

If one of four DNA bases is assigned to one of the digrams (note that the assignment is arbitrary), then each of the sixty-four hexagrams comes to represent one of the codons. In this manner the "natural" order of the I Ching states can generate the full array of the genetic code (see Fig. 42). Stent felt that "the congruence between it [I Ching] and the genetic code is nothing short of amazing .... Perhaps students of the presently still mysterious origins of the genetic code might consult the extensive commentaries on the I Ching to obtain clues to the solution of their problem." 50 Martin Schonberger, the first to work out in detail these homologies, extrapolated their meanings in a manner similar to Jakobson: rather than observing contingent convergences, he extracted ontological significance from the two systems:

318

In the Beginning Was the Wor(l)d?

the Book of Changes and the Book of Life. He saw both as a manifestation of universal flow of information representing a cosmological principle. And yet we shall not be able to evade the question: Are both "books" a manifestation of a common principle? Is what is involved here perhaps one universal code which was discovered s,ooo years ago by the Chinese-and 10 years ago by Watson and Crick? In other words: Is there only one spirit whose manifestation (=information?) must of necessity find its expression in the 64 words of the genetic code on the one hand or in the 64 possible states and development of the I Ching ... on the other? 51

As with Jakobson, the answer was affirmative and pointed to a universe fundamentally different from that portrayed in Jacques Monad's Chance and Necessity. Rather than viewing DNA-based life as a product of chance, it would be chance subject to the structures and patterns of the I Ching. And rather than being a gypsy living on the edge of an alien world, as Monad decried, a human being would enjoy a deep sense of security that emerged from being planted physically and spiritually in an internal natural order. 52 True, scientists might discard such spiritual claims, but they cannot easily ignore a clear double standard of warrant: if one were unwilling to consider the validity of the striking analogy between the I Ching and the genetic code, then how could one embrace the far weaker analogy between language and DNA, and even treat it as an ontology? This tension between ontology and analogy may be neutralized through the notion of "chimera," proposed by the semiotician Franc;:oise Bastide, in her essay "Linguistique et Genetique." She analyzed critically the exchanges between Jacob and Jakobson, demonstrating (as Canguilhelm had argued) that models do not act unilaterally: the act of transporting models across disciplines simultaneously subverts their respective objects of inquiry. Thus, in assigning "intrinsic meaning" to the code Jakobson negated Saussure's theory of arbitrariness of the sign; Jacob, on the other hand, undermined the very idea of linguistic communication by admitting to a code without senders or receivers. But rather than expect fidelities and in order to cope with "our spaces of ignorance," Bastide suggests that modern biology might view its objects as chimera: a hybrid mythological creature like a centaur, an animal body with human head. The animal body is nature, subject to the laws of elemental interactions, while the head represents the indeterminate level of signification, "a mixed denomination, fruitful but ambiguous," as AnneMarie Moulin put it. "Nature does not spontaneously fabricate chimeras, it is man's way to integrate nature and culture ... it is the greatest source of productivity," Bastide insists. 53 It is in this sense that the genomic Book of Life may be viewed as a chimera, a production of nature and culture. As Ja-

In the Beginning Was the Wor(l)d?

319

cob wrote, "The genetic message, the programme of the present-day organism, therefore, resembles a text without an author, that a proof-reader has been correcting for more than two billion years, continually improving, refining and completing it, gradually eliminating all imperfections." 54 Part nature, part culture, the chimera of the book of life has accommodated the overload of meanings through which that book became an authorless creation. Thus the simultaneous transportation of cybernetic and informational representations into both linguistics and molecular biology in the 19 sos propelled the striking analogies between the two fields. As in other disciplines, through the circulation of the information discourse their objects of study were (separately) reconfigured anew, and then emerged, not entirely surprisingly, with some parallel features. And it is this simultaneous dematerialization of both language and life that soon formed the conditions of possibility for envisioning the word (information of the DNA sequence) as the origin of self-organization, the ontological unit of life and evolution. This vision, elaborated by Manfred Eigen in the 1970s, set the stage for simulating and engineering life with computer-generated mathematical modeling, creating the theoretical possibility of an evolutionary biotechnology, a postgenomic future. On the more pragmatic, short-term level, DNA linguistics has promised to fashion a powerful tool for uplifting the coding sequences from the morass of so-called junk DNA (the 97 percent of noncoding sequences), for extracting semantics out of syntax. In the 1970s, as Jakobson's influence waned, the study of the linguistic properties of DNA would be revisited with the Chomskian paradigm, but still subject to the same critique about the unwarranted extrapolation from linguistic analogy to ontology.

EVOLUTION OF THE WOR(L)D

Manfred Eigen's (b. 1927) excursions into life science began in the early 196os, soon after the breaking of the genetic code, and were stimulated by his regular participation in Schmitt's Neuroscience Research Program (NRP) gatherings. Even before his Nobel Prize (shared in 1967 with Ronald Norrish and George Porter) and directorship of the Max-Planck Institute for Biophysical Chemistry in Gottingen he began applying his expertise in ultrashort chemical reactions to biomolecular systems. He treated nucleic acid and enzyme reactions as information transfer systems, as molecular learning, storage, and retrieval. By the end of the decade these excursions had coalesced into a focused research program on the origin of life as information: self-organization of matter; molecular evolution; and the beginning of what

320

In the Beginning Was the Wor(l)d?

F IG URE

43.

Manfred Eigen, 1985. Courtesy of Manfred Eigen.

would grow into DNA linguistics. Eigen's project bestowed new meanings on Gamow's originary random sequence, Shannon's statistical communications, Wiener's vision of the individual as the word, and von Neumann's dream of self-reproducing automata: they now merged into biological algorithms grounded in the rules of neo-Darwinian evolution, reconfigured as information-based game theory.5 5

In the Beginning Was the Wor(l)d?

32 r

Eigen argued there is no need to get snagged up in chicken-and-egg conundrums about the origin of life-which came first, nucleic acids or proteins? (DNA cannot replicate without enzymes; enzymes cannot be made without DNA.) If "information" is substituted for nucleic acids and "function" for proteins, then the relation between the two is a closed loop: function is predicated on information; information acquires meaning only through function. Fully aware of the absence of meaning in information theory, Eigen viewed semantics as the dynamic and functional properties resulting from a pre biotic interplay between nucleic acids and proteins. Consequently, there was no need for viewing the emergence of life as one enormously unlikely accident (some estimate it on the order of ro - 255 ) but as random effects that were able to feed back to their origin and became themselves the cause of amplified action. As Eigen put it, they formed a communication system of sufficient legislative and executive powers. Under certain external conditions such a multiple interplay between cause and effect built upthrough hypercycles-to a macroscopic functional organization, including self-reproduction, selection, and evolution to a level of sophistication where the system could escape the prerequisite of its origin and change the environment to its advantage. Thus genetic information arose selectively by selforganization of a material system. In Eigen's cosmogony, "Life is neither creation nor revelation. It is neither the one nor the other, because it is both at once." His theory was not entirely novel; Henry Quastler had proposed an information-theoretical Darwinian model for biological organization in the early 1960s (Eigen and his colleagues did not seem to be aware of it). 56 But Eigen went much further, elaborating and quantifying the features of this evolutionary model and its putative linguistic properties toward futuristic visions of postgcnomic biopower. "Von Neumann's idea of a self-reproducing automaton has stirred mathematicians' interest [among them S. Ulam and J. H. Conway] in a particular category of games simulating proliferation and growth," Eigen recounted. 57 But he modified these statistical "life games"-colored glass beads and dice shaped as platonic solids, played on specially constructed boards-by introducing an element of randomness. Any molecular reproduction process was subject to randomly occurring "errors" and these "mutations," if properly selected, would be the source of new information. Beginning with a sequence of letters (e.g., AGUUCCGCAGGCU), the game's objective is to arrive at a specified sequence (say, GCUGGCUACUAGC) by random variation of single digits under the guidance of certain selection rules that favor survival, namely, the conservation of information or "ur-semantics." Sequences supplying further information for enhancement of speed or fidelity of reproduction or protection against decomposition possess selective advantage. In this sto-

3 22

In the Beginning Was the Wor(l)d?

chastic universe of molecular Darwinism the analogue of species is a "quasispecies," defined as a given distribution of macromolecular species with closely interrelated sequences. External constraints enforce the selection of the best-adapted distribution, referred to as the wild-type. 58 The lessons Eigen drew from those glass bead games were that Darwinian selectional behavior was attained by fulfillment of certain preconditions, which became unalterable once the complexity of the system had become so great that all the alternatives could not be represented at the same time. As long as the game started with simple preconditions to be fulfilled for large classes of substance in unlimited concentration ranges, only one definite combination of strategies-metabolism, self-reproduction, and mutageneityapplied for Darwinian selectional values. In this manner natural selection yielded a quality grounded in the properties of matter and readily checked by independent experiments; the model thus circumvented the proverbial tautology inherent in the Spencerian dictum "survival of the fittest," where fitness was assessed through survival rates, thus leading to the "survival of the survivor." Beyond theoretical prowess, the model suggested the possibility of building an "evolution machine"-von Neumann's dream of genetic simulacra extended even beyond Baudrillard's apocalypse-automatically controlling and maintaining the specified condition and leading to selfevolving molecular systems. A decade later Eigen would outline the kinetics of evolutionary molecular engineering of RNA replication in terms of models tested by computer simulations; he also sketched the basic features of an evolution reactor. Not purely of a theoretical import, this work has attracted the support of biotechnology companies (e.g., Bayer, Hoechst, and Hoffmann La Roche). An implosion of technologic and biologic, evolutionary biotechnology has since become a symbol of future biological machines and industrial ecology in what Kevin Kelly forecasted as the rise of neobiological civilization. 59 To ascend from survival at the macromolecular to the protocellular level Eigen postulated an ordering principle in the form of the emergence of the hypercycle (closed loop of nucleic acids and proteins). As a prerequisite for self-organization, nucleic acids provide legislative powers: complementary instructions for code formation using binary or quaternary digit system. But their recognition power is not sufficiently high for the accumulation of a large and still reproducible information content in single chains. Proteins, on the other hand, possess enormous executive powers, namely, functional and recognitive diversity and specificity. Via catalytic couplings they can link many information carriers and build up large information capacity; however, they lack the prerequisite for evolution-instructions. A combination of legislative and executive powers, or complementary instruction with cat-

In the Beginning Was the Wor(l)d?

323

alytic coupling, will lead to nonlinear selection behavior as the simplest mechanism of functional coupling, or a self-reproductive hypercycle. Those fluctuations in the system that lead to unique translation and its reinforcement via the formation of a hypercycle offer an enormous selective advantage. Thus the emergence of life occurs through selective reiterations. Rather than being a fluke, the origin of life's information turns out to be an inevitable event. By the mid-r970s this information-theoretical molecular Darwinism acquired a linguistic dimension. Jakobson had articulated a point of departure, but with the shift from structuralism to Chomsky's program-syntactic structures, generative grammar, and transformational rules-a handful of molecular biologists began exploring the so-called genetic language within the new paradigm. Rather than being a system grounded in differential phonemic attributes, "language" now meant a set of sentences, meaningful constructions of finite length but infinite possibilities, built from a finite set of elements by means of concatenation. It was defined by applying to its alphabet (set of elements) a finite set of rules (grammar) for generating all sentences and by imposing a set of punctuation marks, or strings of alphabetical signs, functioning as punctuations. 60 Drawing on such preliminary explorations Eigen and his collaborator, Ruthilde Winkler, outlined a rationale for studies of evolutionary biomolecular linguistics. They observed: The existence of a "language" is equally important to the material self-organization of living beings, to the communication between men, and the evolution of ideas. The essential precondition for the development of a language is the assignment of unambiguous meanings to symbols. In molecular languages, this assigning takes the form of definite physical and chemical interactions; in communication between human beings, it is based on the assignment of meaning to phonemes and on their graphic representation. The assignment of meaning to combinations of symbols, as well as the interrelationships between such combinations, arises from an evolutionary process based on functional evaluation. According to Noam Chomsky, the deep structures of all languages-just like the genetic language that has emerged from molecular mechanics-have common elements that reflect the functional logic inherent in the operations of the central nervous system. The parallels between molecular genetics and the generative grammar of linguistic communication make the rules affecting evolutionary processes eminently clear.

With this dialectic of language and matter, word and act, Eigen circumvented the Faustian dilemma raised by St. John's gospel: life is neither act nor word, neither creation nor revelation; it is both at once. In accordance with

3 24

In the Beginning Was the Wor(l)d?

the view of emergent life as a concatenation of hypercycles, as a communication between legislative and executive powers, semantics was assigned to proteins. As in human languages twenty alphabetical symbols (amino acids), having specific functions, formed cooperative units of words and sentences, the authors argued; the legislative language of nucleic acids was analogized to formal machine language, pure (syntactic) information processing. 61 But Eigen's linguistic distinction between DNA syntax and protein semantics did not take root. After all, what would be the incentive of investing efforts in linguistic analysis of known entities instead of operationalizing the predictive process for deriving biological meaning (functionality) from opaque genomic syntax? The quest for genetic meaning intensified as it became clear in the r98os that only a small fraction of human DNA (about 3 percent) specified the manufacture of proteins; this search gained urgency as the visions of sequencing the entire human genome took shape. Edward Trifonov and Volker Brendel in the mid-r98os first began applying operationally the rules of Chomskian grammar to genomic language, christening it "Gnomic" as their predictive tool. Words treated as internally correlated strings of limited size were the basis for future linguistic analysis of nucleotide sequences, they argued. "Bearing in mind the importance of information contained in these texts on living matter, its functions and malfunctioning, one could envisage that Gnomic will soon become a most intensively studied language, and most intriguing reading as it is already." 62 DNA linguistics did not become a scientific movement, but it did gather momentum and emerged as a visible subspecialty within theoretical, or computational, molecular biology. For example, inspired by Jakobson and Jacob, Julio Collado-Vides has been a champion of DNA linguistics. According to Collado-Vides, one of the biggest problems in biology is the accumulation of enormous amounts of data in the absence of appropriate theoretical frameworks. Generative grammar, he explained in 1989, could provide a broad and flexible framework for constructing a global paradigm for understanding genomic organization and gene expression regulation. Linguists' criticisms of the validity of this project notwithstanding, theoretical biologists continue to sharpen their linguistic tools on prokaryotic and eucariotic systems in quest of biological meaning. 63 "Biologists Seek the Words in DNA's Unbroken Text," announced a 1991 New York Times article. The reporter explained: Now, in an effort to decipher the great helical string of biochemical letters that make up the book of life, a handful of particularly imaginative biologists are applying the techniques of linguistics to the study of DNA.... The idea of thinking of genes as language is not really new. After all, said Dr. Konopka

In the Beginning Was the Wor(l)d?

325

[mathematical biologist at the National Cancer Institute], the science of molecular biology first burst to life in the 194os, which happened to be the time when social scientists were exploring the nature of communication and language. "This obviously influenced our thinking .... Most biologists were mentally ready to think of the genome as a communication system." ... Biolinguists are trying to find a method for picking up the core three percent from the biochemical background noise and they are trying to spot the words without having to worry about what those words say. 64

No longer taken as a metaphor, the chimera of the Book of Life, with all its incongruities and aporias, has become the dominant icon in the quest of biopower, genomic mastery predicated on "DNA literacy," and control of the word; it professes both creation and revelation.

Conclusion

The imagery of information written in the genomic Book of Life, which awaits reading and editing, has proved to be scientifically productive and culturally compelling. Each day on the average a new gene is identified; genetic sequence data is cascading exponentially as market stocks soar. But what does all this information mean? As several scientists have argued, these genomic visions are simplistic, promising a great deal more than can be reasonably delivered. For even if one grants these slippery scriptural analogies, the Book of Life cannot be read or edited unambiguously. As in literary creations, transliteration differs from translation and cannot capture the nuances of meaning. Transliterated DNA sequences would be polysemic and context-dependent; even "context" is by no means simple to define. Many biologists acknowledge that these large-scale sequencing initiatives, although useful, are based on faith in the predictive powers of genomic sequences, a view presupposing straightforward correspondence between genes, structures, and functions; a "genetic program." But with transposons, exons, and introns, and with splicing and posttranslation modification, the relation is plastic, context-dependent, and contingent. In several laboratories around the world, genomics is now moving beyond monogenetic and polygenetic determinism, even beyond functional genomics, toward a phase concerned with nonlinear, adaptive properties of complex dynamic systems, where visions of linear causality would be replaced by analyses of networks interacting with the environment and operating across levels of regulations: genetic, epigenetic, morphogenetic, and organismal. Indeed, most known human disorders (about 98 percent) are polygenetic (involving the participation of several genes) and multifactorial (influenced by somatic and environmental interactions). Only about 2 percent of known human disorders are monogenetic, as in the simplest paradigmatic case of cystic fibrosis where to date nearly five hundred mutations of the CF gene have been tracked down, although some mutations may never express, or manifest in only a mild form. And gene therapy has been forbiddingly costly and difficult to effect. Experts acknowledge that as a standard medical inter-

Conclusion

32 7

vention, gene therapy, even if eventually successful for a limited number of disorders, lies far in the future. At a rate of one per year, recombinant-DNA drugs (variously referred to as "gene therapy") have been slow to reach the market. In the meantime, driven by global capital, the human genome projects are generating voluminous "raw" genetic information, only some of it useful, and copious diagnostics of genetic predispositions, which are beginning to alter employment practices, family planning, educational policies, insurance practices, investment portfolios, and cultural attitudes. A fount for journalistic hype, human genome projects offer only little in the way of therapeutics. Their current medical prowess and their economic and cultural potency inheres mainly in their geneticization of society, in the ways genetic information is reconfiguring our notions of self, health, and disease. Well ahead of medical technologies, social technologies have already been set in motion. Indeed, the Human Genome Project is the vision of biopower of the information age. The possession of a genetic map and the DNA sequence of a human being will transform our lives, so we are told. For Leroy Hood, working at the vanguard of the Human Genome Project, the creation of the encyclopedia of life is essentially a technological process, which begets more powerful technologies, especially computer techniques for inputting, storing, and accessing the three billion base pairs, and fast microchips for pattern recognition in the hunt for anomalies. An article, "Hacking the Mother Code," in the September I 99 5 issue of Wired magazine reports on Hood's expansive genomic visions, his forecasts backed by the fortunes of software magnate Bill Gates. Gates's own excitement derives from the belief in the enormous possibilities inhering in the most sophisticated program of all: the genome. Molecular biologist and Nobel laureate Walter Gilbert too sees the essence of ourselves in terms of genetic information, predicting that soon one will be able to identify one's self by the information contained on a single compact disk (CD). Thus beyond control of bodies and populations, in all their material messiness and physical contingencies, genomic biopower promises new levels of control over life through the pristine metalevel of information: through control of the word, or the DNA sequence. While these human genome projects (in the United States, Europe, and Japan) were launched only in the past decade, the technoscientific imaginary and the discursive practices that have animated them, specifically the textual and linguistic representations of the genome, are quite old. In their (post?)modern form they first emerged in the late I940s and were then fully elaborated within the work on the genetic code in the I 9 sos and I 96os. Through that work DNA was conceptualized as programmed information, as a Book of Life of the nascent information age. Although these informational representations of genetic phenomena were imprecise, sometimes self-

3 28

Conclusion

negating, and often metaphorical, they proved remarkably seductive and productive both operationally and culturally. They aided the scientific imagination in the process of meaning making, in and beyond the laboratory. And they linked molecular biology with other realms of postwar technoculture shaped by the new communication sciences. Thus this study could be viewed as a kind of genealogy of the future, tracing the material, discursive, and social practices that contributed to the emergence and instantiations of the informational/scriptural vision of life, representations of heredity which animate the genomic future. But it is also a study of an epistemic rupture from purely material and energetic to an informational view of nature and society. We have seen that genes did not always transfer information, that these informational modes of reasoning were historically contingent. Up until around 19 so molecular biologists (supported mainly by the Rockefeller Foundation) described genetic mechanisms without ever using the term information (some, in fact, resisted its usage well into the r96os and beyond); what had been transferred across biological space and time earlier was biological and chemical specificity. An overarching theme in the life sciences, specificity originated in an earlier historical epoch, a different biological world picture, and within the discourse of organization. Though often interchangeable, the two concepts-specificity and information-did not directly map onto each other; being historically situated, discourses seldom do. The discrepancies resided in the categorical difference between the two: specificity denoting material and structural properties; information denoting nonmaterial attributes, such as soul, potentialities, and form (telos), previously captured by the notion of organization and plan (logos). The genetic code had been widely viewed as the key to life's secret logos. The early attempts to explain genetic specificity through the permutations of nucleic acids (which some have viewed as protocodes), were formulated without notions of information. In fact, and at the risk of posing a historical counterfactual, had the coding problem been studied in the 1930s, its representations would most likely look very different. After all, the twenty amino acids were known since the turn of the century, and the four DNA (and RNA) bases were identified already in the 1920s. That the theoretical correlations of the nucleic acid bases with amino acid did not even constitute an interesting biological problem derived from the prevailing belief in the protein view of life: from the conviction that the genetic material was a protein. Had DNA and RNA been of genetic interest in the 1930s, the problem of their correlations with amino acids would have probably assumed central importance. But then the terminology and modes of reasoning would have not been informational and scriptural, since the information discourse had not yet come into being.

Conclusion

3 29

This picture changed radically at the end of the I94os; World War II and the subsequent militarization of science and culture in the cold war played a significant role in this shift. Several leaders of the information revolution had a major impact on the biological sciences and social sciences, including molecular biology {still within the protein paradigm of heredity). Though the mathematical aspects of these works did not influence the technical content and experimental agenda of molecular genetics (as many information theorists had predicted) the discursive framework-the information discoursethat it stimulated did endure. Information, partially displacing the concept of specificity, became a guiding metaphor, or rather a metaphor of a metaphor, in molecular biology and in the work on the genetic code. We have seen how astrophysicist George Gamow, following up on Watson and Crick's DNA structure, articulated what became known as the coding problem: how the DNA bases, taken three at a time, specified the assembly of twenty amino acids. Gamow thus initiated the first phase of the genetic code: the formalistic phase, I 9 53-6 r. Envisioning the code as a military cryptogram and as a system of command and control, he enlisted some of the leading physicists, mathematicians, and communications experts (several working at the hub of weapons design) for its solution. The work consisted of viewing protein synthesis as a black box, and decoding the DNA input based on the protein output. Through these contributions and those of Gamow's RNA Tie Club, notably the studies of Francis Crick and Sydney Brenner, the genetic code was constituted as an information system and linguistic communication. This approach did not lead to "breaking the code," since from linguistic and cryptanalytic standpoints the genetic code is not a code. It was during the formalistic phase (as studies moved from overlapping to nonoverlapping codes) that the scriptural representation of the genetic code as text, reading, alphabet, and words was introduced; they served as the conceptual framework and as analytical tools for establishing the correlations between nucleotide triplets and amino acids. And despite the definitional slippages (down to the very definition of code), tautologies, empirical contradictions, and against the objections of information theorists these communication tropes were instantiated as the discursive framework of molecular biology. And as we have seen, by I 9 59 it even reoriented the thinking of biochemists. By I96o the genetic code was viewed as the arbiter of genetic information, the central problem in molecular biology; many researchers in American and European laboratories were racing to crack the code of life. The information discourse also assumed a pivotal role in the researches of Jacques Monod and Fran