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Defying Genomania

Rob Dorit

It Ain't Necessarily So: The Dream of the Human Genome and Other Illusions. Richard Lewontin. xxv + 330 pp. New York Review Books, 2000. $24.95.

The Triple Helix: Gene, Organism and Environment. Richard Lewontin. 136 pp. Harvard University Press, 2000. $22.95.

Unless you are living in a cave (without an Internet connection), you know that the first draft of the human genome, the single most impressive outpouring of information in the history of the natural sciences, has now been completed. And yet, as Richard Lewontin points out in these two thoughtful and provocative books, the achievement only takes us so far: Piling fact on fact does not necessarily lead to enlightenment. Overblown claims notwithstanding, the time has not come (nor may it ever) when we can turn out the lights, go home, break out the champagne and stop doing science.

The sequencing of the human genome is unquestionably a great achievement. It has spurred clever inventions and spawned useful computational tools. The patent disputes it will engender will keep lawyers gainfully employed for the next 30 years. Yet, as Lewontin's books make clear, with the success of the Human Genome Project, the era of naive reductionism—the very perspective that promoted an almost exclusive emphasis on genome sequencing over the past decade—may take its final bow.

For the past three decades, molecular biology has been a phenomenally productive branch of the natural sciences. Successes have come in part from a commitment to the notion that complex organisms can best be understood by examining their parts. The advent of DNA sequencing promised to reduce life to its simplest components, the units of inherited information. Decoding the sequence of DNA (soon rechristened "the master molecule") seemed to promise the resolution of the most recalcitrant problems in biology. Yet as soon as significant amounts of sequence began to accumulate, it became obvious that things were not as simple as we might have hoped. My molecular biologist colleagues have voiced their frustration and bewilderment at discovering just how unintuitive, disorganized and plain inefficient genomes have turned out to be (an outcome less surprising to evolutionary biologists). Nonetheless, despite this messiness, molecular biologists have kept the faith—at least in public—by arguing that the sequence was incomplete, with key bits missing, or was the wrong kind of sequence. Those excuses no longer hold.

The completion of the Human Genome Project means we will soon have to confront the fact that, fascinating and useful as the complete genome of a complex eukaryote is, sheer information will not resolve the central questions in human biology. Personally, I find it comforting to think that our mission as biologists goes beyond the tedious accumulation of sequence (sequencing being one of the more numbing activities in our profession). After all, it confirms that the difficult problems in our field are conceptual—more data are always welcome, but not in lieu of thought.

For some time now, Lewontin has been warning that the pieces of the human puzzle will not all simply fall into place when the sequencing is done. The Triple Helix and It Ain't Necessarily So take clear and direct aim at the way much of biology is now being done. Lewontin's claim is radical and convincingly argued: The world is complicated, and the current way we approach that world is in subtle ways defective. These essays make clear that the problem has never been insufficient data, but rather insufficient understanding of that data, and specifically of the relationship between parts and whole in living systems.

Much has been written about the tension in biology between holistic and atomistic perspectives. Unfortunately, critiques of reductionism have often suffered from a certain romantic longing for a more mysterious, less explainable world. Lewontin will have none of it. From the outset, these books make clear that a commitment to material explanation is not negotiable, nor is it automatically a vote for the reductionist approach. Lewontin makes a riveting case for the interactionist perspective, based on the notion that living systems arise at the intersection of multiple weak forces. That postulate carries with it profound ontological implications: No single force, factor or source of data is likely to explain fully the world as we see it. Equally important, if the interaction of many weak forces dominates outcomes in living systems, we cannot learn much by isolating a single factor and studying it intensively, since in so doing we obscure the very interactions that we wish to understand. Lewontin's version of the uncertainty principle is that the emphasis of reductionist biology on parts, on holding everything constant while we tweak a single variable, destroys precisely what we need to examine.

The Triple Helix takes the argument further by suggesting that our notion of an external environment posing "challenges" that successful organisms "solve" has hindered any real understanding in evolutionary and population biology. Here again, the logic is compelling: Organisms alter and define their environments as profoundly as environments shape and cull organisms. Miss the interaction and any true understanding of the system evaporates. And throughout the book, Lewontin argues convincingly that dominant ideas in contemporary biology—the primacy of the gene, the adaptive character of living organisms, indeed the very rise of biology as the dominant mode of explanation for every disease, syndrome, behavior or social phenomenon—are reflections of the economic and social context in which they arise. The argument has come full circle: The outside world shapes the practice of science no less powerfully than science shapes the outside world. With a sharp eye and a sharp wit, these books remind us that we cannot understand one without the other.

The pieces in It Ain't Necessarily So, written between 1981 and 1998 for The New York Review of Books, should be read by anyone wishing to understand the intellectual history of biology over the past four decades. Opinionated? You bet, but also brilliant, and just about impossible to put down. The author is (bliss to a reader) impeccably candid about his point of view. The essays have been reprinted as they first appeared (a wise decision), and each is followed by an update. Years, sometimes decades later, many of Lewontin's arguments seem prescient.

This being the decade of biology, the critique presented in these books is likely to be willfully misunderstood, dismissed as part of some agenda or, perhaps worst of all, patronized as a necessary but ultimately irrelevant antidote to the prevailing ethos of our age. Such reactions would all be grave mistakes. It is precisely now, when we have just finished sequencing the human genome, that we need to take a step back. The assumptions underlying the way we do biology have always made for lively intellectual repartee. The sequencing of the human genome now makes the debate literally personal.

Anyone wishing to engage in this discussion, which is far too important to be left to the professionals, should read these two books. Together they cast new light on the coming age of biology. When I was a member of Lewontin's laboratory, we would claim, partly in jest, that his epistemological stance could be summarized in a single sentence: "Anything knowable is uninteresting; anything worth knowing is unknowable." Taken at face value, this seems like counsel of despair. But there is no despair in these books—only the deeply humanistic reminder that the world is a complicated and interesting place, and we have much work yet to do if we wish both to understand it and to change it.

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