Some disarming honesty here from J. Craig Venter, president of the Celera Corp., who delivered the genome text to Science:
**"We don't know shit about biology."**
- Something to balance against some of the techno-optimists who feature below. Brave's review is particularly good on one of these - biotech promoter and "libertarian" Matt Ridley:
"Ridley shows himself quite willing to jettison his unstinting rhetorical devotion to the individual when it conflicts with a technology or corporate policy that he favors. Ridley will not allow his much-championed free individual to stand in the way of Monsanto's unilateral decision to genetically alter the world's food."
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Decoding the genome
Six new books tackle human biology's Holy Grail, but each fights its own crusade.
By Ralph Brave Jan. 9, 2001
The text of the human genome -- those 3 billion-plus bits of DNA that contain the basic instructions for constructing and operating a human body -- is now in the hands of editors at Science magazine and is due to be published early this year. An astonishing scientific accomplishment, all acknowledge. But equally astonishing is how little of that text we are currently capable of reading. It's as if we had a list of all words in the English language but lacked a dictionary to tell us what they mean.
No one knows how quickly we will decipher this "code of codes," the Holy Grail of human biology. Both the biotech industry, which has a considerable investment at stake, and scientists, who seek to alleviate suffering, to secure a place in history and to make their own molecular millions, want to move rapidly. Yet, facing a genome that contains thousands of genes, coding for a million or more different proteins (the biochemical powerhouses that do much of the work in making a human and guiding its functioning), they have a long road ahead. And we know even less about the proteome (the entire array of human proteins) than we do about the genome. That's why J. Craig Venter, president of the Celera Corp., who delivered the genome text to Science, told a science writer earlier this year, "We don't know shit about biology."
This strange moment, in which we hold the genetic keys but have no idea which doors they open, has given rise to a peculiar literature. Writers naturally want to tout the very real importance of their subject, but when it comes to what it all signifies, they don't have much solid data to work with. The result is a series of books that walk a tightrope between the minutiae of biochemical structures and mechanics, with their attendant technical vocabularies, and the most open-ended speculation about how a new era of genomics will affect humanity.
It's hard to single out any one of these books for recommendation. The authors have varying strengths and weaknesses in making the science accessible, and when it comes to sketching the outer reaches of scientific possibility, the human genome currently functions as a kind of Rorschach inkblot. Each author's beliefs and politics determine much of what he or she thinks the genome can tell us. And there are some big questions at stake here: When we fully understand the genome, will we know ourselves? Will this knowledge require a revolution in our understanding of what it means to be human? If so, do we even possess the cognitive capacity to grasp it? What limits can and should be drawn around what we do with that knowledge? And who shall decide?
The most recent addition to the shelf of books on the Human Genome Project (and the first account to include the completion of the project), "Cracking the Genome: Inside the Race to Unlock Human DNA" by Kevin Davies, is also the most disappointing. Davies is a clear and competent writer, and his book doesn't contain any inaccuracies or gross distortions -- all of which are great virtues in science writing. But for a book with the word "Inside" in its title, "Cracking the Genome" contains very little inside to speak of. Instead, it's an entirely derivative artifact, cobbled together from secondary sources, with only a few original interviews, none of them providing anything remotely resembling behind-the-scenes revelations. Even a casual but consistent reader of the coverage of the genome project by the New York Times' Nicholas Wade or the Washington Post's Rick Weiss would spend $25 on Davies' book to learn nothing new. The author tacitly, if not guiltily, admits as much in his acknowledgments when he thanks Wade, "whose superb coverage of all aspects of this story has been invaluable." (We can only hope Davies has enough integrity to also share with Wade whatever fee he received to write the book.)
An accomplished science editor and writer with a Ph.D. in genetics from Oxford, Davies says his goal was "to capture the excitement, intrigue, mystery and majesty of the quest for biology's holy grail" and not to pen "the definitive record" of the genome project. In that, alas, he also fails. He breaks up his narrative of "the race" to sequence the genome with sections and even entire chapters that address subjects that, while often interesting, are only indirectly related to the project. Any approximation of excitement or mystery he generates is quickly dissipated by the padding.
More significant, while Davies continually reminds the reader that this is "the defining moment in the evolution of mankind," he hypercautiously avoids bringing a critical or even a personal eye to what we have done and where we are going. He makes passing mention of findings that suggest that a person's overall sense of happiness may have a genetic component, and of a "remarkable attempt to go nature one better" by expanding the repertoire of proteins for which DNA can code. Davies even refers to physicist Stephen Hawking's conjecture that the genome project may ultimately enable an increase in human brain size at faster rates than the glacial pace of evolution.
But Davies never asks what these advances might mean for our understanding of ourselves as a species or a culture. In fact, the innovative Ethical, Legal and Social Issues program of the National Institutes of Health genome project gets only a single paragraph near the beginning of the book. The Davies who is the editor of technical scientific articles repeatedly trumps the essayist and the thinker. Nevertheless, as a compendium of the major media stories on genetics and genomics over the past decade (with a bit of historical background), "Cracking the Genome" might serve as a useful guide for beginners.
If Davies avoids adopting any viewpoint, science writer Matt Ridley goes to the other extreme, putting forth a thinly disguised political treatise in "Genome: The Autobiography of a Species in 23 Chapters." "Genome" was chosen as one of the eight notable books of 2000 by the editors of the New York Times Book Review, which will no doubt give the curious novice the unfortunate impression that this is a definitive work on the subject.
But what is most notable about "Genome" is that Ridley makes the scientific advances he writes about serve as mules for his beliefs, which are those stereotypically libertarian views to be expected in a former science editor and Washington correspondent for the Economist. Nevertheless, Ridley can certainly write. His accomplished prose shines as he takes us through complicated biochemistry with exceptional ease. His four-page "Primer" on genetics (in the book's preface) is among the clearest and most succinct summaries of the subject available. Ridley has designed his 23 chapters to correspond with each of the 23 chromosomes that contain the human genome. He identifies a particular gene on each chromosome and uses it to illuminate an aspect of genetics and human life. So Chromosome 6 is entitled "Intelligence," Chromosome 15 is "Sex" and Chromosome 22 is "Free Will," and in each case Ridley shows how science connects intimately with human experience.
Not too surprisingly, though, in "Genome" human experience and genetics connect to demonstrate the truth of Ridley's political stance. For example, Chapter 18 (about Chromosome 18) tackles "Cures" and provides Ridley with the opportunity to hold forth on genetic therapy, which is necessarily a form of genetic engineering. That leads him to the topic of agricultural biotechnology and genetically modified organisms (GMOs), of which he declares, "The opposition to genetically modified crops, motivated more by hatred of new technology than love of the environment, largely chooses to ignore the fact that tens of thousands of safety trials have been done with no nasty surprises." He offers no footnoted reference to a peer-reviewed scientific paper discerning hatred as the basis for opposition to GMOs.
Pursuing the issue further, Ridley asserts that "the politicization of the issue [of GMOs] has had absurd results." He relates that a corporation abandoned a transgenic soybean project because the gene inserted into the soy came from Brazil nuts and therefore was allergenic to those susceptible. "This [abandonment] was despite the fact that calculations showed that the new soya-bean allergy would probably kill no more than two Americans a year," Ridley declares, "and could save hundreds of thousands worldwide from malnutrition." Putting aside the question of the causes and cures for malnutrition -- opinions vary on the effectiveness of GMOs in alleviating it -- it's worth noting here that Ridley shows himself quite willing to jettison his unstinting rhetorical devotion to the individual when it conflicts with a technology or corporate policy that he favors. Ridley will not allow his much-championed free individual to stand in the way of Monsanto's unilateral decision to genetically alter the world's food. The two American individuals killed annually are a small and acceptable price to pay to allow corporate agriculture free rein.
"An absurd attitude to risk," Ridley later declares, regarding a similar case. Though he doesn't explicitly say so, Ridley accepts an actuarial evaluation of risk, like those performed by the insurance industry: The most unlikely possibilities, which tend to be the most catastrophic, are to be given the least consideration. Of course, many people who are mindful of the consequences of a "highly unlikely" Chernobyl- or Bhopal-type catastrophe suggest that when it comes to irrevocable genetic experiments, we might want to proceed on a more precautionary basis. Ridley, of course, would dismiss this as mere hatred of new technology.
In his final two chapters, "Eugenics" and "Free Will," Ridley most fully elaborates his philosophy that the social environment and particularly government are the greatest evils facing humankind, much more to be feared than any genetic determinism. After all, he says, while genes may do much to determine who we are, at least they are our personal genes. He even claims that Aldous Huxley's "Brave New World" demonstrates "how hellish a world in which nurture [rather than nature] prevailed would actually be." For Ridley, the notion of the individual is uncomplicated and the individual's relation to the social world can only be one of unending antagonism and defensiveness -- except of course when they are abstract individuals to be sacrificed to the actuarial tables of science and industry. In the end, perhaps what's most enlightening, and depressing, about Ridley is how willing he is to limit his obvious intellectual capacities in the service of his ideological predilections. In the preface he asserts, "I genuinely believe that we are living through the greatest intellectual moment in history." Yet when he surveys the meaning of this moment, it requires no adjustment of his mind-set -- instead it all uncannily mirrors what he already believes.
The left sees the genome as confirming its views just as readily as the right does. You can't find a better example of this than the curmudgeonly brilliance of Richard Lewontin, Aggasiz Research Professor at the Museum of Comparative Zoology at Harvard University and longtime opponent of genetic determinism. Lewontin is one of the central objects of scorn for Ridley and his ilk, who loathe anyone who challenges their vision of the perfect alignment of genetics and capitalism or questions a sociobiology that proves that people like them are born to run the world. No one has questioned and belittled the potential of the Human Genome Project as persistently as Lewontin has. Equally famed as a geneticist and for his neo-Marxist approach to science (titles of his earlier works include "The Dialectical Biologist" and "Not in Our Genes"), Lewontin has repeatedly argued that biology is a lot more complicated than the A, T, C and G nucleotides of DNA and, further, that many important realities of our social lives can't be found there. "They still haven't found the gene for unemployment," Lewontin sarcastically told me in an interview about the genome project several years ago.
In his latest book, "The Triple Helix: Gene, Organism and Environment" (based on a series of three lectures with an added final chapter), Lewontin lays out his position with devastating clarity; the science in the book should be accessible to most laypersons. However much our DNA may tell us about individual diseases, he says, ultimately reductionism provides a simplified and therefore false picture of both the interactions between the genes of any cell and the other parts of the cell and the interactions between a cell and all the other cells of an organism. By extension, that false picture also undermines a true understanding of any organism's interaction with its environment.
Lewontin says that all biologists know this to be the case, but are rewarded for pursuing scientific investigations as if it were otherwise. Dangerously, "science as we practice it solves those problems for which its methods and concepts are adequate, and successful scientists soon learn to pose only those problems that are likely to be solved. Pointing to their undoubted successes in dealing with the relatively easy problems, they then assure us that eventually the same methods will triumph over the harder ones. If the determination of DNA sequence has solved the problem of how information about protein structure is stored in the cell, then surely the determination of the structure of some molecules, perhaps even DNA itself, will solve the problem of how information about social structure is stored in the brain." The argument is not against genetic reductionism per se, he says. Sometimes parts of the genome are causal elements, sometimes they're not, "depending upon which genetic differences in which species living in which circumstances are considered. There are no universal rules for cutting up organisms," he informs us. Just as during the recent election Americans were educated about the differences in the election laws among the 50 states, Lewontin writes, "so too in biology, it depends upon the jurisdiction."
Lewontin claims that a correct understanding of gene, organism and environment would stress that they function as a whole. He's not suggesting that we escape into a holistic mysticism beyond analytic grasp, but that we recognize that genes function in organisms and organisms function in environments, and each plays a role in "co-creating" the other, reciprocally. Co-evolution of organism and environment, says Lewontin, is demonstrably the most accurate scientific account of the world. Rather than reducing life to physical-chemical systems, such as the molecular chemistry of DNA, biologists need to stand by their knowledge of the open, ongoing interaction between organism and environment, and to design methodologies that take this into account.
Lewontin's arguments are sound, but his perpetual "Yes, but ..." qualifications may not offer the kind of progress people get with reductionist science. Certain genes do seem capable of causing certain diseases, no matter what the environment. Lewontin wouldn't disagree with that, smart scientist that he is. But someone suffering from a genetic disorder wouldn't necessarily want to wait it out while Lewontin's methodologies produce a cure. Lewontin is also unabashedly derisive when it comes to the contribution of science and medicine to the redress of human suffering. The primary causes of death in the third world are overwork and undernourishment, he says, a product of "an anarchic scheme of production that was developed by industrial capitalism and adopted by industrial socialism." Though he admits that an old-style red future is not the answer, he's equally unenthusiastic about the Red Cross, even one armed with genetic medicine, as a solution to the massive ill health and early death caused by international inequities and injustice.
Lewontin scorns efforts by the left to incorporate the methods and even some of the findings of genetics, but one of the most influential and controversial contemporary philosophers, Peter Singer, argues the opposite tack. He proposes that the left regroup in the wake of the collapse of Marxist regimes. The left is, Singer says, "in need of a new paradigm." Though Singer's new book, "A Darwinian Left: Politics, Evolution and Cooperation," weighs in at a mere 64 pages, it is one of the few genuinely stimulating meditations on the topic, and one whose perspectives have implications far beyond the considerations of the left. Although the precise details of genomics are of only tangential concern to Singer's project here, you need a basic understanding of genetics and its role in human life to appreciate the book.
Singer, as usual, presents his case with straightforward simplicity, an absence of jargon and an apparently self-evident logic. As Singer sees it, Marx got it exactly backward, and the left needs to correct itself with that in mind. Marx believed that the individual emerges entirely from his or her social reality. Change the social reality, and you change the person; the human being is completely malleable. The problem, says Singer, is that the opposite is closer to the truth: There is a bedrock biological human nature that contributes mightily to the structure of our social lives. "To be blind to the facts of human nature is to risk disaster," writes Singer, holding up Stalin's gulag, Mao's China and Pol Pot's Cambodia as evidence.
The kernel of Singer's corrective is that "it is time for the left to take seriously the fact that we are evolved animals, and that we bear the evidence of our inheritance, not only in our anatomy and our DNA, but in our behavior, too." The left's continual rejection of this notion emerges from the idea that human beings are perfectible, an assumption that Singer says Marxism shares with Christianity. And that idea originates in the assumption that human beings are separate from -- and more valuable than -- animals. Singer, famous for his 1990 book "Animal Liberation," long ago rejected that notion. Singer doesn't wholly reject Marx's insights on the role economics plays in shaping culture and ideas; he wants to make them "part of a larger picture." The failure of egalitarian revolutions does not mean "that hierarchy is good, or desirable, or even inevitable," writes Singer, "but it does show that getting rid of it is not going to be nearly as easy as revolutionaries usually imagine."
Singer's larger picture includes an understanding that humans are biologically driven to act out of self-interest and should not be asked to act against their self-interest. But self-interest, as it has evolved, includes cooperative and even altruistic impulses as well as competitive ones. If we increase our understanding of how our human nature interacts with our environment, we can begin to systematically emphasize, build and reinforce our noncompetitive traits.
Singer is a self-described "consequentialist," a descendant of John Stuart Mill's utilitarianism and William James' pragmatism. Utilitarianism's guiding belief is that reason can determine which actions will result in the greatest happiness for the greatest number of people. Singer's reason informs him that his own self-interest is best served by this ethical approach, not only toward all people but toward all sentient beings. Singer also believes that we should not fear scientifically based programs of genetic improvement but instead ask how they might contribute to the greatest happiness. Genetic improvement, says Singer, holds out the prospect "of a new kind of freedom." After all, if human nature is the major obstacle to creating a better society, then the solution may ultimately lie in altering that genetically based nature.
What makes Singer so provocative is that he takes up the left's commitment to fighting injustice and at the same time urges scientists to pursue the knowledge and control of our biological makeup to the furthest reaches. He synthesizes, in a way, the determinism of Ridley with the social commitment of Lewontin. But, at least in this work, he doesn't clarify who'll be in charge of deciding which policies will lead to the greatest happiness for the most people -- a key question, particularly given Singer's controversial advocacy of euthanasia for those born with severe mental disabilities. In Singer's preferred social order, molecular biologists like James Watson would be free to do what they wanted. To see why this is troubling, look to Watson himself and the other contributors to "Engineering the Human Germline: An Exploration of the Science and Ethics of Altering the Genes We Pass to Our Children." This book of essays, compiled and edited by UCLA neurobiologist John Campbell and the director of the UCLA Medicine, Technology and Society Program, John Stock, also contains the fascinating transcript of a 1998 panel discussion about how far we should go in modifying genes in the sperm and eggs we use to produce future generations -- what scientists call the "human germline." Currently, almost all clinical trials of genetic therapy are directed at specific parts of the body and affect only the patient involved; germline therapy would alter the genes passed on to all future generations. Earlier this year, the American Association for the Advancement of Science issued a report recommending that any effort to proceed with germline engineering, whether in the public or private sector, be regulated.
Watson, the co-discoverer of the double helix structure of DNA, appears in his catalytic prime here, casting aside what he views as the "prejudices" of social and moral concerns in order to advance science and medicine. Not only should we "try germline therapy without completely knowing that it's going to work," Watson says, but "if we could make better human beings by knowing how to add genes, why shouldn't we do it? What's wrong with it? Who is telling us not to do it? I mean, it just seems obvious now."
Watson suggests that just as we might find benefit from putting a Brazil nut gene in a soybean to enhance its nutritional value or an Arctic fish gene in a strawberry to help it resist damage from freezing weather, so too the human genome might be improved with the implantation of a plant gene or an animal gene or perhaps even an artificially devised gene. After all, Watson says, "we [molecular biologists] should be proud of what we're doing and not worry about whether we're destroying the genetic patrimony of the world, which is awfully cruel to too many people." While some voices in "Engineering the Human Germline" recommend a less ambitious approach to modification of the human genome, Watson's fellow panelists and many of the book's essays mostly echo his views.
Ian Wilmut, the leader of the team of scientists who cloned the sheep Dolly and a scientist who nearly equals Watson in stature, proposes a moral alternative. As coauthor of "The Second Creation: Dolly and the Age of Biological Control," Wilmut shows a humility in the face of our potential ability to alter the genome that's the opposite of Watson's brashness in every way. Wilmut has always insistently opposed the cloning of human beings, and in this book he repeats that objection; he views human cloning as an unwarranted imposition on the new person brought into being. On the same grounds (except in the case of correcting single-gene diseases), Wilmut opposes attempts to enhance the human genome to promote any particular physical or mental quality.
His book, written with fellow Dolly project biologist Keith Campbell and science writer Colin Tudge, sets the record straight on the history and impetus behind cloning research, relates the scientific journey to the creation of Dolly and provides an insider's view of the cutting edge of biotechnology. But the core of the book is its final section, "The Age of Biological Control." Here Wilmut squarely confronts the dilemmas of an era in which, inevitably, we will achieve nearly total control over the creation and development of any and all biological organisms, including humans. While Celera Corp.'s Venter is right that we currently "don't know shit about biology," knowing all of it -- or close to all of it -- could happen within a few generations.
"Cloning and genetic engineering are conceptually linked," Wilmut explains, "because they are technically linked." The real purpose behind cloning, after all, was to allow for precise genetic alteration and duplication. The traditional path of a fertilized egg, Wilmut tells us, "is a hit-and-miss affair, offering only limited possibilities." "But when cells are cultured by the million, and laid out in a dish for months at a stretch," Wilmut says, "genetic engineers can work their full repertoire." What shall be done to these cells? Who shall decide?
In a chapter called "Cloning People," authored by Wilmut alone, the scientist looks at many of the perspectives found in the other books covered in this essay. He endorses Lewontin's argument for a more complex understanding of the interaction of genes, organisms and environments because "the genes operate in constant dialogue with their surroundings," which in turn affect how genes function. That's part of the reason even biological clones would still be different people. In response to the libertarianism advocated by Ridley and deeply embedded in American culture, Wilmut suggests that when it comes to risk, we need to look beyond statistical calculations and ask, "Risk to whom?" and "Risk of what?" The manipulation of our genetics involves more than just one individual. Even basic genetic test results have implications for all the blood relatives of the person undergoing the test.
For this reason, Wilmut insists that market forces alone should not determine how genetic technologies get applied. "Worldwide, we may perceive a trend toward libertarianism," he observes, but "various societies in recent years have shown that they can resist new technologies of many kinds, whatever the market forces." He cites nuclear power, high-rises and genetically modified organisms as examples.
To his credit, Wilmut claims no greater authority for his positions than that of a well-informed citizen. These issues are human and moral and not merely scientific. Coauthor Tudge adds, in an individually penned epilogue, "How, in general, can we ensure that ... we don't stop scientists from following their noses -- but that on the other hand we are not encumbered with technologies that offend us, or lower our quality of life, or simply hand over life's controls to powerful companies?"
Wilmut, Campbell and Tudge don't pretend to have final answers. They urge that "if we are serious -- if we are not simply trying to score political points or to underplay what has been achieved so far -- then we should think in serious intervals of time." They suggest 200 to 500 years as the block of time during which the age of biological control will be realized. If they're right -- and unless we are satisfied with the alternatives offered by Ridley's libertarianism, Lewontin's interactive constructionism, Singer's consequentialism or Watson's naturalism -- then a book that helps us think in just those terms is the book that urgently needs to be written next.
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About the writer Ralph Brave is a science writer who lives in Davis, Calif. Sound Off
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Philip L. Bereano Professor Department of Technical Communication College of Engineering Box 352195 University of Washington Seattle, Wash. 98195
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