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BOOK REVIEW

Hype and Hope

Robert Cook-Deegan

Cracking the Genome: Inside the Race to Unlock Human DNA. Kevin Davies. ix + 310 pp. The Free Press, 2001. $25.

Transducing the Genome: Information, Anarchy, and Revolution in the Biomedical Sciences. Gary Zweiger. xiii + 272 pp. McGraw-Hill, 2001. $24.95.

Abraham Lincoln's DNA and Other Adventures in Genetics. Philip R. Reilly. xx + 339 pp. Cold Spring Harbor Laboratory Press, 2000. $25.

Talk of genetics is everywhere now, from the laboratory and classroom to the boardroom and the living room. The 1990s may be remembered as the decade in which genetics became a part of our general culture. As if to remind us, publishers are filling library and store shelves with books on gene themes, works that we can hope will inform the debates sparked by the rapid pace of current discovery.

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The widening awareness is exquisitely appropriate, for genetics has come of age. Once the study of how traits are inherited, the field has expanded its domain to the understanding of how information encoded in DNA is translated inside cells. This transformation has been driven by technologies for analyzing the structure of DNA and proteins as well as for determining DNA and polypeptide sequences and the three-dimensional shapes of nucleic acids and proteins. Rapid technological development has propelled molecular biology to the vanguard of biomedical research and given it growing roles in agriculture, criminology, ecology, population studies and paleontology. Thus the works now reaching the bookshelf span a wide range, from Luigi Luca Cavalli-Sforza's magisterial survey of genetics in human populations to Kevin Davies's rollicking good tale about an enduring intellectual monument—the creation of a reference sequence of the human genome that was The Great Genome Race of 2000.

The growing speed and power of genetic technologies is quite real. Yet its rapidly emerging social and economic importance does not mean genetics is well understood by the general public, or even the genetic commentariat. Genetics and genomics (gene mapping and sequencing) seem poised on the precipice of a rhetorical cliff. The technologies will continue to improve, but the current genohype risks promising more than the tools of molecular genetics can deliver, no matter how powerful they become. The unfolding story of the great race is an exemplar. In Cracking the Genome, published close on the heels of the events it recounts, Davies has the first book fully chronicling the race.

Molecular biologists know that, in a way, the great White House human-genome announcement on June 26, 2000, was a nonstory. It was (as the practitioners of Orwell's Newspeak might say) tremendously unimportant that Craig Venter and Francis Collins not uncross the nonfinish line together; any other outcome would have been doubleplus ungood. The story of this uncrossing is a horror-show narrative deserving a treatment by Anthony Burgess or Orwell himself. Davies's book is a straightforward account of extraordinary accomplishment. The zippy narrative suffers an awkward and imprecise title, but the book deserves the audience it will garner by winning the race to cover The Race. Others treading the same ground in subsequent books will have to work hard to improve the story.

Do not envy Davies his task. At the announcement of the near-completion of a reference sequence for the human genome, Collins and Venter, heads respectively of the Human Genome Project and Celera Genomics, basked with President Clinton in deserved public adulation. The two scientists boast other accomplishments that stand tall: Collins in identifying disease genes and Venter in a succession of DNA-sequencing landmarks. Collins is the public spokesman for the "public" genome program, Venter the perpetual bad boy who rattles its cage. Despite their fame, however, each is notoriously thin-skinned. This poses a problem for Davies, executive editor of Current Biology; he cannot burn his bridges. His solution: Quote-to-quote combat carries the story of the genome race, Davies's voice intruding only to describe the technical underpinnings that he so clearly relishes. The reader has to do the work, but the story is there.

The goodspeak suppression of talk about rivalry and competition makes the politics of the genome race all the more apparent. The quest for Nobel gold is a backdrop to the public theater and no doubt weighed heavily in the ultimate decision to have a show of public comity in the White House. Collins is the salient figure in an effort that has expended more than $2 billion of public funds; Venter has spent a half-billion dollars of other people's money. Both work prodigiously to keep political machinations out of public view.

The American genomics champions lack the pristine scientific zeal of the United Kingdom's genome hero, John Sulston, whose individual efforts in tracing the lineage of every cell in the nematode Caenorhabditis elegans and then proceeding to map its genome overshadow even the achievements those two brought to the genome project. Sulston's moral fervor about openness in science perpetuates the values of Cambridge molecular biology, carrying the spirit of Frederick Sanger into a new generation. From Davies we learn how the Wellcome Trust stepped in to fuel the Cambridge group when the U.K. government proved too shortsighted to do so sufficiently; he touches lightly—too lightly—on substantial contributions from other parts of Europe and Asia.

No artful first-person narrative as candid as James Watson's The Double Helix seems apt to emerge. It will likely fall to another author to puncture the sanctimony, the rhetorical Millennium Dome constructed around genomics. The genome story of 2000 recalls what a brilliant gem Helix remains as the account of an even more august accomplishment.

The genome-race story underscores the emerging importance of the private sector, even in research that once would have been called "basic." Since 1994, private genomics investment has exceeded government funding in the United States. In 1999, research and development reported by publicly traded genomics startup firms alone exceeded government genomics funding and nonprofit spending put together. In Transducing the Genome, to be published in February, Gary Zweiger, a scientist-executive at Incyte Genomics, provides a bracing insider's account of why gene structure matters to science and commerce. His focus is on transducing the information content of DNA into useful form. He teases out a powerful theme of genomics: its focus on methods of creating massive databases quickly. This contrasts with and augments the tradition of hypothesis-driven experiment in molecular biology.

The gods in Zweiger's pantheon are mathematicians, computer scientists, technology developers and database mavens. Molecular biologists enter the story, but mainly those with an avidity for technology and an appetite for large scale. Zweiger weds his enthusiasm for large-scale genomics to an anarchist theory of innovation that entails substantial contributions by private firms. No one is in charge, and that is a Good Thing.

Zweiger is persuasive about the virtues that private interests bring, but in his enthusiasm he gives less credence to future problems in commercial genomics than critics will be willing to tolerate. The practical problems raised by tens of thousands of DNA patents are seen as a business problem that will be solved.

The future of industrial genomics may well be smoother than the past of automobile and aircraft-engine manufacture and telecommunications, but then again it may not. Garrett Hardin's notion of a collective commons has been used to explain why some shared resources are overused. In a seminal 1998 article (Science 280:698–701), Michael Heller and Rebecca Eisenberg foresaw a potential anticommons—the tendency to underuse scarce resources—in gene patenting. The problems have already begun to surface and are apt to grow. Incyte, which holds more DNA-based patents than any other entity except the U.S. Government, will be a player in future negotiations. We can hope that Zweiger's optimism is borne out, but we can also keep a watchful eye. Trust in Allah, but tether your camel.

The technical complexity of genetics, one of the obstacles to public understanding, is a veil that can be penetrated by good writing: for example, by interesting stories about people and practical uses of genetics. In this spirit, Philip Reilly contributes 24 lovely essays about diverse uses of genetic technologies in Abraham Lincoln's DNA.

Reilly is a geneticist, physician and lawyer whose 1977 book on genetics and public policy presaged the systematic study of social, legal and ethical issues related to genetics. His essays are designed well for use in teaching or public speaking. American audiences will warm to discussions about Abraham Lincoln's DNA and what it can and cannot help us understand about our most important president. Europeans may be more interested in using DNA to investigate the Romanov family massacre in Russia or the passage of genetic disease through royalty—or the origins of genetically modified crops and animals.

Reilly plunges right into some of the most vexing and controversial areas in genetics. He makes his opinions plain and is usually appropriately tentative. Some of those opinions will not go down well in Reilly's hometown Boston, headquarters for the "not in our genes" academic left. Some missteps in his handling of behavioral genetics, in particular, will surely draw fire, in at least one case deservedly so. In a section on personality he says, "The implications of attributing such a large fraction [a 40 to 50 percent heritability of 'sense of well-being'] are immense. It suggests, for example, that parenting style, economic status and education have relatively little impact on the child's sense of well-being." He goes on to quote University of Michigan psychologists David Lykken and Auke Tellegan, who speculated in their analysis of twin studies that "trying to be happier [may be] as futile as trying to be taller and therefore is counterproductive." The problem here is careless interpretation. There is a persistent conceptual virus that conflates heritability with immutability, and this passage of Reilly's book needs to go into quarantine.

The seemingly intractable confusion is frustrating in the extreme. It starts with a false dichotomy: whether nature or nurture is the more important determinant of a phenotype. This frame is especially procrustean when imposed on genes and behavior or genes affecting the nervous system. The brain has evolved to be exquisitely adaptable to environmental change. The inheritance of a trait says little about how malleable it is and therefore how effective interventions might be. The evidence Reilly presents about personality and intelligence addresses trait heritability and trait stability, not malleability. Do we really believe that Romanian orphan babies left alone in their beds will have the same potential for happiness as those raised by caring parents of ample means? That is precisely what quotes such as those above will be taken to imply.

The book provides sufficient examples to counter the confusion. Reilly discusses height, for example, and notes it is highly heritable. Yet study after study has shown very significant population differences in height with nutrition (most famously, Japanese reared in the United States). Some short stature is caused by growth-hormone deficiency, which can be treated and so is both inherited and highly malleable. Until gene therapy becomes commonplace, genes will not be malleable, but the traits they influence generally will be malleable. Genetic population studies, twin studies and other approaches do attempt to control for obvious differences, but unless they are designed as intervention studies (such as a clinical trial), they cannot assess trait malleability. At the very least, statements for public consumption need to be couched with extreme care.

This confusion is partly explained by long-standing ideological battles between the right and left. Reilly reviews some of this history, going back to Francis Galton's 19th-century suggestion that the familial clustering of various forms of social success was best explained by genetics, when the much more plausible explanations were personal networks, wealth and social advantage. The left's standard attack on such views has been to deny that genes have a role, but again the dichotomy is false: It is possible to use genetics to define the role genes actually play in specific instances and to place them in perspective. Sometimes, as in the case of Huntington's disease, genes will do much of the work in explaining a disease or trait; most of the time, genes will help explain one small part of a far more complicated story.

The 20th century opened with a rediscovery of Mendelian genetics; it closes having laid the technological foundation for understanding how, when and why genes matter. These books show the many different ways that genetics is building knowledge and finding practical use. Genetics is not a revolution in the sense of overturning our fundamental beliefs, or even our scientific theories. Darwin still stands strong, if refined. Genetics is a revolution, however, in the sense of the cumulative impact of technological change. And no end of that change is in sight. As genetics becomes ubiquitous, genetic literacy is becoming a civic virtue. These books should promote such literacy, despite the occasional miscue and penchant for hype. In 10 years' time, genetics will surely have helped solve some problems. Genetics has long since become something that schoolchildren have to learn in their science classes, and so an object of schoolroom tedium and resistance. We can all use a few lively stories. The books a decade hence are apt to be more about how genetic tools were used and less about how they were constructed; we can hope they will be as interesting.


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