The Century of the Gene

Evelyn Fox Keller, Evelyn Fox KELLER

• Publisher: Harvard University Press
• Year: 2002
• Print ISBN: 9780674008250, 9780674003729
• eBook ISBN: 9780674254855
• Topic: Biological Sciences
• Subtopic: Genetics & Genomics
• Index: Biological Sciences

In a book that promises to change the way we think and talk about genes and genetic determinism, Evelyn Fox Keller, one of our most gifted historians and philosophers of science, provides a powerful, profound analysis of the achievements of genetics and molecular biology in the twentieth century, the century of the gene. Not just a chronicle of biology's progress from gene to genome in one hundred years, The Century of the Gene also calls our attention to the surprising ways these advances challenge the familiar picture of the gene most of us still entertain.

Keller shows us that the very successes that have stirred our imagination have also radically undermined the primacy of the gene—word and object—as the core explanatory concept of heredity and development. She argues that we need a new vocabulary that includes concepts such as robustness, fidelity, and evolvability. But more than a new vocabulary, a new awareness is absolutely crucial: that understanding the components of a system (be they individual genes, proteins, or even molecules) may tell us little about the interactions among these components.

With the Human Genome Project nearing its first and most publicized goal, biologists are coming to realize that they have reached not the end of biology but the beginning of a new era. Indeed, Keller predicts that in the new century we will witness another Cambrian era, this time in new forms of biological thought rather than in new forms of biological life.

1

MOTORS OF STASIS AND CHANGE: THE REGULATION OF GENETIC STABILITY

How can we, from the point of view of statistical physics, reconcile the facts that the gene structure seems to involve only a comparatively small number of atoms . . . and that nevertheless it displays a most regular and lawful activity—with a durability or permanence that borders upon the miraculous?

Let me throw the truly amazing situation into relief once again. Several members of the Hapsburg dynasty have a peculiar disfigurement of the lower lip (“Hapsburger Lippe”) . . . Fixing our attention on the portraits of a member of the family in the sixteenth century and of his descendant, living in the nineteenth, we may safely assume that the material gene structure responsible for the abnormal feature has been carried on from generation to generation through the centuries, faithfully reproduced at every one of the not very numerous cell divisions that lie between . . . How are we to understand that it has remained unperturbed by the disordering tendency of the heat motion for centuries?

ERWIN SCHROEDINGER, What Is Life? (1944)

If the Mendelian revolution marked the turning point of twentieth-century biology, then surely the Darwinian revolution was the great watershed of the nineteenth century. The realm of living organisms could no longer to be fitted into a great “Chain of Being”; it required its own figuration: more of a tree than a chain, and as much a succession of becoming as of beings. The living world became a world in time, and both its occupants and its relational structure were reconfigured as products of its evolutionary history. After the publication of On the Origin of Species in 1859, few could be found among the scientifically literate who still believed in the fixity of species. Moreover, Darwin’s evolutionary theory offered his readers a mechanism for the origin and transformation of species—natural selection acting upon individual variation. Yet, for all the power of that theory, a fundamental mystery remained. If change is the essence of life, how are we to account for the remarkable stability with which, in each generation, organisms develop and grow true to the type of their particular species, and with a certainty that endures over the lifetime of that species?

Viewed from the perspective of geological time, species transform and evolve. Yet viewed from the perspective of historical time, they display an unmistakable constancy in form and function. But on this matter—on the “stability of type” (to borrow a phrase from Francis Galton) that is so conspicuously maintained over the course of generations— Darwin’s theory was silent. However eloquently and powerfully the theory of evolution by means of natural selection might account for changes in biological form and function occurring over eons and reflected in the geological record, it could not begin to explain the reproducibility of that same form and function over the shorter spans of genealogical time. Nor could it offer any account of the persistence of particular individual features from generation to generation, of the clearly recognizable family resemblances that are passed on from parents to offspring.

Of course, Darwin was not privy to the insights of genetics, nor could he have been. He shared with his contemporaries a belief in “blending heredity”—the view that the characteristics of an offspring are, somehow, a blend of the parents’ characteristics—but he had nothing to say about how such distinctive features as the Hapsburg lip might endure without dilution. Nor could he offer any kind of answer to the dilemma that was later to plague Schroedinger: How can we understand the reproduction of individual features, generation after generation, with such fidelity as to lend them a “durability or permanence that borders upon the miraculous?”

The fact is that Darwin’s preoccupations were different. Throughout his life, he focused his attention on mechanisms of transformation; the mechanisms required for conservation eluded both his understanding and, for the most part, his interest. And while he acknowledged that “our ignorance of the laws of variation is profound” and devoted considerable attention to the ways in which the variation essential to natural selection might arise, nowhere did he express concern about a corresponding ignorance of the laws of constancy.¹

The task of searching for the laws of constancy—that is, of accounting for intergenerational stability—thus fell to Darwin’s heirs. Indeed, the century of the gene begins with this task—or more specifically with efforts to account for the persistence of individual traits through the generations. Of course, just as with any collective endeavor, the science of genetics arose out of multiple needs and a variety of different interests, and these have been well chronicled by many historians. My focus here, in Chapter 1, is on the particular force that the search for constancy of individual traits exerted on the origins of the very concept of the gene. A crucial component of that concept, I argue, enters the history of genetics even before the word gene was coined, and it enters with the supposition that underlying each individual trait is a hereditary unit so stable that its stability can account for the reliability with which such traits are transmitted through the generations. In other words, the problem of trait stability was answered by assuming the existence of an inherently stable, potentially immortal, unit that could be transferred intact through the generations.

In the first part of this chapter, I trace the increasing hold this assumption of the intrinsic stability of hereditary elements came to have on geneticists in the first part of the century, its apparent vindication in the middle of the century, and its gradual dissolution over the last few decades. To be sure, genetic stability remains as remarkable a property as ever, and it is clearly a property of all known organisms. The difficulty arises with the question of how that stability is maintained, and this has proven to be a far more complex matter than we could ever have imagined. Furthermore, we will see that the maintenance of genetic stability turns out to be inextricably bound up with the generation of variability. Thus, in the second part of this chapter, I return to Darwin’s concerns, taking up the companion issue of transformation and discussing some of the surprising challenges that new research on mechanisms of conservation pose to the simple neo-Darwinian picture of evolution by the cumulative operation of natural selection on randomly generated small mutations.

Finally, a word about the relation between the stability of “type” (that is, the stability with which organisms, in each generation, develop and grow true to the type of their particular species) and the stability of individual traits. For a long time, it was assumed that genes are as capable of explaining the development of individual traits as they are of explaining the development of whole organisms, and therefore that genetic stability sufficed to account for what I will later on in this book call developmental stability. I use the term to refer to the reliability with which organisms of a particular species undergo the passage from fertilization to maturity, generation after generation, each time reproducing a phenotype that is clearly recognizable as characteristic of that “type.” Thus, while genetic stability is a property of all organisms, developmental stability is a term primarily applicable to multicellular organisms that pass through embryonic stages of development—that is, metazoan organisms. The differences between these two kinds of stability may be significant, but discussion of such differences must be deferred until after I have said more about the relation between genes and development. Accordingly, in my fourth and final chapter I return to the particular challenges raised in attempting to account for developmental stability.

EXPLAINING GENETIC STABILITY

August Weismann (1834–1914)—one of the great zoologists of the latter part of the nineteenth century—put the problem succinctly: “When we find in all species of plants and animals a thousand characteristic peculiarities of structure continued unchanged, through long series of generations; when we even see them in many cases unchanged throughout whole geological periods; we very naturally ask for the causes of such a striking phenomenon . . . How is it that . . . a single cell can reproduce the tout ensemble of the parent with all the faithfulness of a portrait?”² In these brief remarks, written in 1885, Weismann defined the challenge for a science of heredity—indeed, one might read the entire history of genetics as an attempt to answer the question he posed. But Weismann did more than pose the question: he also proposed something of an answer, and the form of his answer helped set the science of heredity on the particular track it would follow for the next sixty years or more.

Whatever the mechanism by which a single cell reproduces the traits of the parent, Weismann assumed the existence of particulate, self-reproducing elements that “determine” the properties of an organism; appropriately enough, he called these elements determinants. This assumption was hardly unique to Weismann—in fact, Darwin himself had hypothesized the existence of some such elements (his gemmules). The Dutch botanist Hugo de Vries, a near-contemporary of Weismann’s (1848–1935), also hypothesized the existence of elementary hereditary units. As he wrote, “Just as physics and chemistry are based on molecules and atoms, even so the biological sciences must penetrate to these units in order to explain by their combinations the phenomena of the living world.”³ De Vries called his units pangens, a term he introduced in 1889 in an effort to salvage the best of both Darwin’s gemmules and Weissman’s determinants.

But Weismann assumed more than the existence of elementary hereditary units. In order to explain the remarkable fidelity with which such traits were reproduced generation after generation, he further hypothesized the sequestration of a full complement of these elements in a substance “of a definite chemical, and above all, molecular composition.” He called this substance the “germ-plasm” and argued that a germ-plasm, insulated from the ravages of individual mortality, could be transferred, intact, from one generation to another. Thus he wrote, “I have attempted to explain heredity by supposing that in each ontogeny, a part of the specific germ-plasm contained in the parent egg-cell is not used up in the construction of the off-spring, but is reserved unchanged for the formation of the germ-cells of the following generation.”⁴ Weismann’s theory traveled wide and fast. In his influential textbook published only a few years after Weismann’s work had appeared in English, the American zoologist E. B. Wilson wrote, “As far as inheritance is concerned, the body is merely the carrier of the germ-cells, which are held in trust for coming generations.”⁵

Experimental biology was still in its infancy at the end of the nineteenth century, and Weismann had no way of knowing what these hereditary elements might be. Nor did de Vries, or any other student of heredity at that time. This was a period of grand speculations, and Weismann’s were among the grandest. As he explained his philosophy, “Biology is not obliged to wait until Physics and Chemistry are completely finished; nor have we to wait for the investigation of the phenomena of heredity until the physiology of the cell is complete . . . Science is impossible without hypotheses and theories; they are the plummets with which we test the depth of the ocean of unknown phenomena and thus determine the future course to be pursued on our voyage of discovery.”⁶ Given how little they had to go on in the way of concrete evidence, it comes as small surprise to find how much (or how sharply) these early thinkers about heredity differed from one another both in their characterization of hereditary elements and in their conjectures about how these elements could impress their various characteristics on the formation of particular cells and tissues. What is more surprising is how much they shared. Underlying all their differences were two enduring articles of faith.

The first of these was that, just as atoms and molecules provided the fundamental units of explanation in physics and chemistry, so too would particulate hereditary elements serve as the fundamental units of biological explanation. These units might themselves be some kind of atom or molecule, or they might be made up of molecules, but the important point was that they were elemental, the primitive units with which the study of heredity must begin.

The second article of faith was closely related, and it held that responsibility for intergenerational stability inhered in the fixity of these material elements, taken either as individual units or in their collective composition. For Weismann, the burden of stability lay in the sequestration of a certain substance “of a definite . . . molecular composition” in a protected lineage of germ cells, where they would be held inviolate for future generations. For de Vries, it lay in the sequestration of the individual particles in the nucleus of each and every cell, with one particle representing one hereditary characteristic. But once sequestered, whether in the germ-plasm or in the nucleus, the fixity of the elements themselves was simply taken for granted, accepted as part of their definition.

The rediscovery of Mendel’s rules of inheritance in 1900 marked the beginning of an end to the era of grand speculation in the study of heredity. Indeed, Johannsen’s aim in coining the term gene in 1909 was to mark a break with the preconceptions of his predecessors. “The word ‘gene,’ he wrote, “is completely free from any hypotheses.”⁷ But it takes more than a new word to effect a complete break with the past. Weismann’s determinants and de Vries’ pangens were still the direct precursors of the gene, and inevitably some of the preconceptions underlying these earlier concepts carried over. Genes were hypothetical entities, but, like their precursors, they were particulate entities (Mendel himself had called his factors Elemente). Furthermore, whatever they were made of—indeed, even for those who thought of them as no more than a bookkeeping device—the capacity for faithful transmission from generation to generation remained built into the very notion, as it were, by definition.

No student of heredity, either before or after the watershed of 1900, thought of these hereditary elements literally as atoms, but the analogy with the fundamental units of physics and chemistry continued to lurk in people’s minds. As E. B. Wilson wrote in 1923...

Table of contents

• Cover
• Title
• Copyright
• 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
• Index