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Product Details
| ISBN-13: | 9780674039438 |
|---|---|
| Publisher: | Harvard University Press |
| Publication date: | 07/01/2009 |
| Sold by: | Barnes & Noble |
| Format: | eBook |
| Pages: | 192 |
| File size: | 303 KB |
About the Author
Evelyn Fox Keller is Professor of History and Philosophy of Science at MIT. She is the recipient of a MacArthur Fellowship and numerous honorary degrees.
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Introduction
The Life of a Powerful Word
In 1900 three papers appeared in the same volume of the Proceedings of the German Botanical Society—the first by Hugo de Vries, the second by Carl Correns, and the third by Erich von Tschermak. De Vries, Correns, and Tschermak had independently "rediscovered" the rules of inheritance that Gregor Mendel, at the time an obscure Austrian monk, had found forty years earlier in his solitary investigations of pea plants. Mendel's original paper may have failed to attract much attention, but these papers did not. Indeed, they are generally credited not only with rescuing Mendel from oblivion but also with launching the science that would soon be called "genetics," and with that new science the age I am calling "the century of the gene."
The actual term genetics was coined in 1906, when William Bateson informed the International Congress of Botany that "a new and well developed branch of Physiology has been created. To this study we may give the title Genetics." The term gene came along three years later, introduced by Wilhelm Johannsen. What was a gene? This no one could say. Johannsen himself wanted a new word so that it might be free of the taint of preformationism associated with such precursor terms as Darwin's gemmules (his units of "pangenesis"), Weismann's determinants, or de Vries' pangens. "Therefore," he wrote, "it appears simplest to isolate the last syllable, 'gene,' which alone is of interest tous ... The word 'gene' is completely free from any hypotheses; it expresses only the evident fact that, in any case, many characteristics of the organism are specified in the gametes by means of special conditions, foundations, and determiners which are present in unique, separate, and thereby independent ways—in short, precisely what we wish to call genes."
Two years later, Johannsen added, "The 'gene' is nothing but a very applicable little word, easily combined with others, and hence it may be useful as an expression for the 'unit factors,' 'elements' or 'allelomorphs' in the gametes, demonstrated by modern Mendelian researches ... As to the nature of the 'genes,' it is as yet of no value to propose any hypothesis; but that the notion of the 'gene' covers a reality is evident in Mendelism." A little word, perhaps-but a remarkably powerful one nonetheless. Indeed, this little word proved powerful enough to guide research in the science of genetics for the remainder of the century.
Not surprisingly, Johannsen's strictures against hypotheses about the material nature of the gene were rather less influential. As late as 1933, T. H. Morgan might claim, "There is no consensus opinion amongst geneticists as to what the genes are—whether they are real or purely fictitious." Yet for the majority of Morgan's colleagues (indeed, for Morgan himself), genes had by then become incontrovertibly real, material entities—the biological analogue of the molecules and atoms of physical science, endowed with the properties that would make it possible, as de Vries had written, "to explain by their combinations the phenomena of the living world."
For H. J. Muller, a student of Morgan's, the gene was not only "the fundamental unit of heredity" but "the basis of life." Thus, for Muller, as for many other geneticists of the time, the question that begged was crucial: Just what sort of entity is a gene? Perhaps it was some sort of chemical molecule, but what sort? What is it made of, how big is it, and, above all, from whence comes its miraculous power to determine the properties of a developing organism and, at the same time, ensure the stability of those properties from one generation to another?
For the first four decades of this century, progress in genetics was steady and cumulative, but it offered little in the way of answers to such basic questions as these. The beginnings of an answer to the question of what genes are made of came in 1943 with Avery, MacLeod, and McCarty's identification of DNA as the carrier of biological specificity in bacteria. At roughly the same time, the first hint of what a gene does was provided by the "one gene-one enzyme" hypothesis of George Beadle and Edward Tatum. But it was the triumphal announcement by James D. Watson and Francis Crick in 1953 which convinced biologists not only that genes are real molecules but also that they are constituted of nothing more mysterious than deoxyribonucleic acid. Thus, by midcentury, all remaining doubts about the material reality of the gene were dispelled and the way was cleared for the gene to become the foundational concept capable of unifying all of biology. Moreover, the identification of DNA as the genetic material spawned a new era of analysis, in which the powerful techniques of molecular genetics would replace those of classical genetics. As everyone knows, the ensuing progress has been spectacular, and it continues to accelerate.
In many ways, the advances of the last twenty-five years have been the most dramatic of the century (as well as the most publicized), and they have come largely as a consequence of, first, the advent of recombinant DNA technology in the mid 1970s and, second, the launching of the Human Genome Project (HGP) in 1990. Building on the phenomenal advances of molecular genetics, this enterprise—somewhat misleadingly named insofar as its mission has been to sequence not only the human genome but the genomes of other organisms of interest to biologists as well—has promised to reveal the genetic blueprint that tells us who we are. Indeed, it would be hard to imagine a more dramatic climax to the efforts of the entire century than the recent announcement that a draft of the entire sequence of the human genome will be completed in time to mark the centennial. At the very least, that announcement comes as a fitting climax to the career of the man who has been one of the prime movers behind this project: as Watson himself has put it, "Start out with the double helix and end up with the human genome."
When the Human Genome Project was first proposed in the mid 1980s, it evoked a great deal of skepticism. But today, as its pace exceeds all expectations, few skeptics remain. So far, the complete genomes of over twenty-five microbial organisms have been sequenced, including those of that illustrious bacterium Escherichia coli on which molecular biology first cut its teeth. Genomes of more sophisticated model organisms have also been sequenced: yeast was the first, followed in 1998 by the roundworm Caenorhabditis elegans—the first higher organism to be sequenced. The fruit fly Drosophila, the most famous of all model organisms in the history of genetics, made its debut in February 2000. The task of sequencing the human genome itself began relatively late, but its progress has been breathtaking: Less than 3 percent of the human genome had been sequenced by the end of 1997; by November 30, 1998, that number had risen to 7.1 percent; by September 5, 1999, it had reached 22 percent, and by the end of 1999, 47 percent. The expectation is that we should have a complete draft of the sequence of the human genome before the end of the year 2000.
I confess to having been one of the early critics. Like many others, I believed that so exclusive a focus on sequence information was both misguided and misleading. But today I am ready to share in the general enthusiasm for the HGP's achievements, although from a somewhat unusual perspective. What is most impressive to me is not so much the ways in which the genome project has fulfilled our expectations but the ways in which it has transformed them.
The aim of this book is to celebrate the surprising effects that the successes of this project have had on biological thought. Contrary to all expectations, instead of lending support to the familiar notions of genetic determinism that have acquired so powerful grip on the popular imagination, these successes pose critical challenges to such notions. Today, the prominence of genes in both the general media and the scientific press suggests that in this new science of genomics, twentieth-century genetics has achieved its apotheosis. Yet, the very successes that have so stirred our imagination have also radically undermined their core driving concept, the concept of the gene. As the HGP nears the realization of its goals, biologists have begun to recognize that those goals represent not an end but the beginning of a new era of biology. Craig Stephens writes, "Sequence gazing alone cannot predict with confidence the precise functions of the multitude of encoding regions in even a simple genome!" For this reason, he continues, "the era of genomic analysis represents a new beginning, not the beginning of the end, for experimental biology."
To see how progress in genomics has begun to transform the way many biologists think about genes and genetics, and even about the meaning of the genome project itself, it is useful to recall the expectations with which that project began. A decade ago, many biologists spoke as if sequence information would, by itself, provide all that was necessary for an understanding of biological function. Spelling out his "Vision of the Grail," Walter Gilbert wrote, "Three billion bases of sequence can be put on a single compact disc (CD), and one will be able to pull a CD out of one's pocket and say, 'Here is a human being; it's me!'" Today, almost no one would make such a provocative claim. Doubts about the adequacy of sequence information for an understanding of biological function have become ubiquitous, even among molecular biologists, and largely as a consequence of the increasing sophistication of genomic research. Instead of a "Rosetta Stone," molecular geneticist William Gelbart suggests that "it might be more appropriate to liken the human genome sequence to the Phaestos Disk: an as yet undeciphered set of glyphs from a Minoan palace ... With regard to understanding the A's, T's. G's, and C's of genomic sequence, by and large, we are functional illiterates."
Now that the genomes of several lower organisms have been fully sequenced, the call for a new phase of genome analysis—functional genomics rather than structural genomics—is heard with growing frequency. Hieter and Boguski define functional genomics as "the development and application of global (genome-wide or system-wide) experimental approaches to assess gene function by making use of the information and reagents provided by structural genomics." In their view, the sequence no longer appears as an end-product but rather as a tool: "The recent completion of the genome sequence of the budding yeast ... has provided the raw material to begin exploring the potential power of functional genomics approaches." In a similar vein, anticipation of the full sequence of the Drosophila genome found geneticists who study this organism girding for a long haul. As Burtis and Hawley put it, they are preparing for "the huge amount of work that will be involved in correlating the primary DNA sequence with genetic function ... This link is essential if we are to bring full biological relevance to the flood of raw data produced by this and other projects to sequence the genomes of 'model' organisms."
It is a rare and wonderful moment when success teaches us humility, and this, I argue, is precisely the moment at which we find ourselves at the end of the twentieth century. Indeed, of all the benefits that genomics has bequeathed to us, this humility may ultimately prove to have been its greatest contribution. For almost fifty years, we lulled ourselves into believing that, in discovering the molecular basis of genetic information, we had found the "secret of life"; we were confident that if we could only decode the message in DNA's sequence of nucleotides, we would understand the "program" that makes an organism what it is. And we marveled at how simple the answer seemed to be. But now, in the call for a functional genomics, we can read at least a tacit acknowledgment of how large the gap between genetic "information" and biological meaning really is.
Of course, the existence of such a gap had long been intuited, and not infrequently voices could be heard attempting to caution us. It is only now, however, that we begin to fathom its depths, marveling not at the simplicity of life's secrets but at their complexity. One might say that structural genomics has given us the insight we needed to confront our own hubris, insight that could illuminate the limits of the vision with which we began.
In the main body of this book, I review four of the more important lessons that molecular genomics has helped us learn. The first concerns the role of the gene in what may well be the most fundamental dynamic of the living world: maintaining the faithful reproduction of traits from generation to generation and providing the variability on which evolution depends—that is, ensuring both genetic stability and genetic variability. In the second chapter, I discuss the meaning of gene function and ask: What is it that a gene does? In the third, I examine the notion of a genetic program and contrast that idea with the concept of a developmental program. And in the fourth chapter, I argue for the importance of resiliency in biological development and consider the ways in which a search for design principles that would ensure developmental reliability and robustness exposes some of the limits of genetic analysis.
Throughout each of these chapters, my primary focus is on the ever-widening gaps between our starting assumptions and the actual data that the new molecular tools are now making available. These tools are themselves the direct product of the most recent advances in molecular genetics and genomics; yet at the same time, and in the most eloquent testimony to the prowess of science I can imagine, they have worked to erode many of the core assumptions on which these efforts were first premised. In the recent calls for a functional genomics, I read an acknowledgment of the limitations of the most extreme forms of reductionism that had earlier held sway. And even though the message has yet to reach the popular press, to an increasingly large number of workers at the forefront of contemporary research, it seems evident that the primacy of the gene as the core explanatory concept of biological structure and function is more a feature of the twentieth century than it will be of the twenty-first. What will take its place? Indeed, we might ask, will biology ever again be able to offer an explanatory framework of comparable simplicity and allure?
What, in short, will the biology of the twenty-first century look like? I have no crystal ball, but perhaps some indications of its shape can be seen in the new lexicon that begins to emerge as biologists turn their attention to "cross-talk" and "checkpoints," to genetic, epigenetic, and "post-genomic" metabolic networks, and even to multiple systems of inheritance. But will the new lexicon ever cohere into an explanatory framework providing anything close to the satisfaction that genes once offered? This I cannot say, and in any case, the answer will depend not only on what biologists find, not only on the adequacy of such terms and concepts to these findings, but also on the particular needs those explanations will be expected to satisfy in the coming decades.
Only three predictions seem safe to make about the character of biology in a post-genomic age. First, a radically transformed intra- and intercellular bestiary will require accommodation in the new order of things, and it will include numerous elements defying classification in the traditional categories of animate and inanimate. Second, biologists who seek to make sense of these new elements will have a considerably expanded array of conceptual tools with which to work. Third, even so, they are not likely to stop talking about genes-not, at least, in the near future.
Why is that? What is it that keeps the term alive? This question I take up in my conclusion, and, in brief, my answer is twofold. First, Johannsen's "little word" has become far too entrenched in our vocabulary for it to disappear altogether; and second, despite all its ambiguity, it has not yet outlived its usefulness. Thus, at the end of this book I turn to the question "What are genes for?" and argue that to ask this question is also, at least implicitly, to ask "What is gene talk for?" I point to several particularly important ways in which gene talk functions today.
Paramount among these is the convenience of gene talk as an operational shorthand for scientists working in specific experimental contexts. Furthermore, gene talk identifies concrete levers or handles for effecting specific kinds of change. And finally, gene talk is an undeniably powerful tool of persuasion, useful not only in promoting research agendas and securing funding but also (perhaps especially) in marketing the products of a rapidly expanding biotech industry. My rather brief comments about these functions are not intended as a recapitulation of the central arguments of the book but rather as a way of calling attention to some of the many questions and issues it does not address, and for which the interested reader will need to look elsewhere.
Table of Contents
Contents Introduction: The Life of a Powerful Word 1. Motors of Stasis and Change: The Regulation of Genetic Stability 2. The Meaning of Gene Function: What Does a Gene Do? 3. The Concept of a Genetic Program: How to Make an Organism 4. Limits of Genetic Analysis: What Keeps Development on Track? Conclusion: What Are Genes For? Notes References Acknowledgments IndexWhat People are Saying About This
In The Century of the Gene Evelyn Keller gathers together her considerable skills as a mathematician, physicist, historian and philosopher and applies them to the central problem of the last 100 years of biology, namely the relation of the genes to the building of an organism. The scholarship is masterly, not only because of her wide reading of the literature, but her deep, penetrating understanding of what she reads. To cap it all she writes clearly and elegantly so that the book is a pleasure to read. This is a conspicuously intelligent book.
In The Century of the Gene Evelyn Keller gathers together her considerable skills as a mathematician, physicist, historian and philosopher and applies them to the central problem of the last 100 years of biology, namely the relation of the genes to the building of an organism. The scholarship is masterly, not only because of her wide reading of the literature, but her deep, penetrating understanding of what she reads. To cap it all she writes clearly and elegantly so that the book is a pleasure to read. This is a conspicuously intelligent book.
— John Bonner, Princeton University
Evelyn Keller has the disturbing ability to make you think again from scratch about things you thought you had already understood. It is a long time since I have thought so hard about fundamental problems in genetics as I did when reading The Century of the Gene.
— Richard Lewontin, Harvard University
In this elegantly written book Evelyn Fox-Keller tells the fascinating story of how the heuristic power of genetic experimentation interacts with the narrative power of the word "gene." Both are built on and reinforce each other. I never saw an equally convincing and well informed narrative on how language mediates the interaction between experimental research and its social context.
— Günter P. Wagner, Yale University
Genes have captured the scientific and popular imagination. But in The Century of the Gene, Evelyn Fox Keller provides us with a powerful analysis of the limits of the gene as an explanatory concept. Indeed, the success of molecular biology and greater understanding of biological development have exposed the wide gap between genetic information and biological meaning, undermining the very concept of the gene. Yet gene talk with all its historical baggage persists in shaping both science and popular perceptions. Keller argues convincingly for a new language, for new concepts that will enable us to deal with the real complexity of biological organization. This is a critically important book to be very widely read.
— Dorothy Nelkin, New York University