NIH Jumps Into Genetic Variation Research

The field is given a boost by a widening of focus at the institutes as well as a report praising a major initiative. During the brief earthly tenure of the species Homo sapiens, the human genome seems to have accumulated just the right amount of variation to suit the purposes of geneticists. Single-nucleotide polymorphisms (SNPs), the DNA bases that vary systematically between subpopulations, are common enough to serve usefully as chromosomal markers but not so common as to make genetic analysis hopelessly complicated. As these SNPs (pronounced "snips") become easier to identify, they increasingly are being hailed as crucial tools not only for uncovering the genetic components of common diseases, but also for understanding human prehistory. 'LIGHTNING ROD': Penn State's Kenneth Weiss says the Human Genome Diversity Project introduced researchers to people "suspicious of science and/or genetics." Recent enthusiasm about SNPs has had two pronounced effects. Officials at the National Institutes of Health have undergone the bureaucratic equivalent of a frameshift as their focus widens from the small number of people whose DNA is being mapped by the Human Genome Project to the larger populations that research into genetic variation will involve. And the Human Genome Diversity Project (HGDP), an effort to chart evolution by cataloging genetic diversity among ethnic groups around the world, has gotten a boost in morale, though not in financing. To further its new push into genetic variation research, NIH has held a flurry of meetings, made plans to allocate funds to the area, and recruited geneticists to intramural programs. The benefit of studying genetic variation "seems to have been a realization that's hit everybody about the same time," says Irene Eckstrand, program director in genetics and developmental biology at the National Institute of General Medical Sciences (NIGMS). In 1993, Eckstrand tried unsuccessfully to organize a conference on the genetics of complex traits. Only the National Institute on Alcohol Abuse and Alcoholism (NIAAA) showed any interest. Last December, however, an NIGMS conference on the same topic drew more than 100 people and 40 speakers to Bethesda, Md. EUREKA: NIGMS's Irene Eckstrand says the benefits of genetic variation studies have become apparent to various constituences at "about the same time." The power of SNP analysis was noted by a National Research Council (NRC) panel that NIH and the National Science Foundation charged in 1996 with weighing the merits of the genome diversity project. In a report issued October 21, the 17-member NRC panel concluded "that a global assessment of human genetic variability has substantial scientific merit and warrants support, largely because of the insight that the data collected could provide into the origin and evolution of the human species." Conceived six and a half years ago, HGDP is already moving ahead to a limited extent in China, India, Pakistan, Europe, and the Sudan. Yet a swirl of ethical and political controversies has stalled its progress in the United States (K.Y. Kreeger, The Scientist, Oct. 14, 1996, page 1). According to HGDP proponents, these controversies have long frightened the U.S. government away from tackling human genetic variation. NIH officials maintain, to the contrary, that the analytical, technical, and sociopolitical prerequisites to studying variation have been in place only in the past year or so. Francis S. Collins, director of the National Human Genome Research Institute (NHGRI), and colleagues have characterized three such prerequisites (F.S. Collins et al., Science, 278:1580-1, 1997). First, they say, recent quantitative analyses suggest that, compared with linkage analysis, whole-genome association studies can more efficiently identify genes whose variants modestly increase disease risk. These less penetrant variants are likely to be implicated in common diseases. Second, methods for discovering SNPs have improved. Finally, the time has arrived when the public sector must identify SNPs, or companies will do so and then may restrict access to them. Much of the legwork for the genetic variation initiative has been done by Mark Guyer, assistant director for scientific coordination at NHGRI. Over the past few months, he has presided over meetings with colleagues from various NIH institutes. He also set up a December 9 workshop on creating common resources for human-polymorphism investigators. Some 25 researchers from such fields as genetics, anthropology, and philosophy attended. Guyer also is involved in writing requests for applications for variation research that NHGRI and other institutes plan to issue in early 1998. "The thrust of our efforts is basically discovery of common polymorphisms," he says. "There are two purposes. One is to use SNPs as a basis of a much higher-density genetic map of a few hundred thousand markers. The other purpose is to assemble a catalog of known sequence variations that can be screened for potential association with diseases." Given a high-density map, a whole-genome association study could identify a 50- to 100-kilobase interval between SNPs that harbors a susceptibility gene. The sense of urgency attending variation research results in part from recent successes in genetics, such as the discoveries of mutations underlying cystic fibrosis and Huntington's disease. "A lot of the more simple Mendelian disorders are getting solved," observes Steven Moldin, acting chief of the genetics research branch at the National Institute of Mental Health. "We're making so much progress there that now it's natural to shift the focus towards complex diseases, especially when we've got all these new technological developments." Advances are being made on many fronts, including sequencing devices and DNA hybridization buffers. But the most-touted new tool is the high-density DNA array developed by Affymetrix Inc. of Santa Clara, Calif. The array is a dime-size silicon chip to which hundreds of thousands of 20- to 25-base oligonucleotide probes are hybridized. With such a chip, "you can do high-throughput analysis," says Huber Warner, deputy associate director of the biology of aging program at the National Institute on Aging. "In other words, you can analyze thousands of genes on one little piece of glass, either looking for DNA differences or looking for levels-of-expression differences." Some observers worry that in the heady new atmosphere of genetics, researchers might not maintain their traditional skepticism toward findings. Robert Karp, program director for genetics at NIAAA, recalls that "there were some major mistakes made in the genetics of schizophrenia and bipolar disorder about 10 years ago." He continues: "Because there are so many uncertainties associated with the genetics of complex disorders such as alcoholism-and this is true for all complex disorders-no one finding is considered self-sufficient. It's very important to have multiple independent replication of results." As NIH pushes genetic variation research, institutes are responding by announcing initiatives, funding projects, and recruiting geneticists (see accompanying list). The National Institute of Environmental Health Sciences, for example, is trumpeting a plan to identify polymorphisms that render some people more vulnerable to pollutants and elements like lead and iron. L. Carl Barrett, scientific director of the institute's division of intramural research, says the Environmental Genome Project could cost $60 million over five years. Basic parameters, such as the number and identity of candidate genes, however, have yet to be established. National Cancer Institute Kenneth Buetow has been recruited from Philadelphia-based Fox Chase Cancer Center to become chief of NCI's laboratory of population genetics, starting in February. National Heart, Lung, and Blood Institute A collaborative effort led by Charles Sing of the University of Michigan was funded last summer to identify genetic variants underlying cardiovascular disease. The Collaborative Study on the Genetics of Asthma, whose grant was renewed last September, is searching for genes responsible for asthma susceptibility. Some investigators in the Family Blood Pressure Program, in the third year of a five-year grant, are studying genetic variation to find genes contributing to hypertension. National Institute on Alcohol Abuse and Alcoholism The long-standing Collaborative Study on the Genetics of Alcoholism is doing genome scans and has identified a few chromosomal regions with suggestions of linkage, according to Robert Karp, program director for genetics. A Special Emphasis Area (a designated priority area for research), "Genetic Linkage and Association Studies on Alcoholism," has been established. National Institute on Deafness and Other Communication Disorders Dennis Drayna, formerly at Menlo Park, Calif.-based Mercator Genetics Inc., has moved from NHGRI to NIDCD, where he will lead a large study of genes involved in stuttering. National Institute of Environmental Health Sciences For its Environmental Genome Project, NIEHS is trying to gain access to the approximately 17,000 DNA samples collected during the third Health and Nutrition Examination Survey (NHANES III) that was conducted by Centers for Disease Control and Prevention's National Center for Health Statistics. National Institute of Mental Health A recent reorganization has concentrated genetic research in one location; NIMH is also planning projects aimed at finding susceptibility genes for schizophrenia, bipolar disorder, and early-onset, recurrent depression, according to Steven Moldin, acting chief of NIMH's genetics research branch. National Institute of Neurological Disorders and Stroke A neurogeneticist is being recruited to set up a new laboratory, according to Judy Small, a health scientist administrator who leads the institute's genetics working group. Unlike earlier intramural research at NINDS on metabolic diseases, the laboratory will focus on discovering genes underlying complex diseases. -D.S. As NIH begins to fund projects studying genetic variation, HGDP-related applications will likely be submitted. At that point, the full weight of the NRC panel's report should be felt. The panel states that its recommendations "should be taken into account when considering the scientific merit of an individual request for support." In its most significant recommendation, the panel says that to ensure the anonymity of subjects donating genetic material, a diversity project should record only their locations, ages, and sexes, as well as the birthplaces of their parents. On the ethical front, the panel recommends that subjects' consent be obtained only after the purposes of a study are fully disclosed. The report also advises researchers to negotiate all financial arrangements with subjects before samples are collected. RESEARCH REQUIREMENT: Stanford's L. Luca Cavalli-Sforza notes that HGDP researchers will need to establish cell lines from subjects. When these recommendations first came out, some observers were confused by contradictory headlines in Science (E. Pennisi, "NRC OKs Long-Delayed Survey of Human Genome Diversity," 278:568, 1997) and Nature (C. Macilwain, "Diversity project 'does not merit federal funding,'" 389:774, 1997). Nevertheless, NIH and NSF officials, as well as members of HGDP's North American committee, soon professed their general satisfaction with the report. (Nature later acknowledged in an editor's note that its headline was "misleading" [390:221, 1997].) L. Luca Cavalli-Sforza, the Stanford University geneticist who cofounded the project, says, "I have been waiting for it [the report] for two years, and so I was very happy to see it and to see that it was quite favorable." Given the numerous scientific and organizational issues covered in the 102-page document, quibbles with some of the panel's recommendations come as no surprise. Cavalli-Sforza says that since the diversity project eventually will track thousands of genetic markers, investigators will need to establish cell lines from subjects. Citing increased costs and higher mutation rates in transformed cells, the panel counsels against developing cell lines except when a small population is in danger of disappearing. Since new technologies such as the DNA chip will soon render thousands of genetic markers available for study, the panel advises a diversity project not to mandate a core set of markers. But according to Dennis O'Rourke, program director for physical anthropology at NSF, geneticists have long discussed "establishing a standardized set of markers that all investigators would, at least, minimally use, so that there would be broad comparability across samples." John Moore, an anthropologist at the University of Florida, Gainesville, and a member of the North American committee, criticizes the panel's half-year delay in issuing its report. Having recently received requests for ethnographic questionnaires developed by HGDP, he fears that the recipients of these forms have already embarked on field work without being schooled in all the protocols developed by the committee. "The tragedy, I think, is that the critics of the project did not succeed in postponing the field work at all," he says. "All they did was to delay the committee's activities, so that now the project is going ahead in a very disorganized way." With the NRC report issued, the diversity project "goes back to where it should be, which is in the political arena, trying to find funding," maintains Kenneth Weiss, an anthropologist at Pennsylvania State University and another member of the North American committee. He estimates the final tab for HGDP could be in the tens of millions of dollars. The financial burden would largely fall on the U.S. government, since many of the populations targeted by the project live in poor countries. The goal of tracing human evolution and migration, unfortunately, places the diversity project squarely in the bailiwick of NSF rather than in the richer biomedical precincts of NIH. Over the past year, NSF has been funding eight HGDP pilot projects, but, according to O'Rourke, these cost only about $600,000 and the future of the program is unclear. Kenneth Kidd, a Yale geneticist and North American committee member, says, "I can make a strong argument-but it hasn't been made in print very much-that there is tremendous biomedical relevance in knowing how populations are related and how they diverged through recent evolutionary history." Judith Greenberg, director of genetics and developmental biology at NIGMS, has a different perspective. The diversity project is "in principle, a good thing to do, and if we had all the money in the world, we certainly would go out and do it," she says. "But I think that it has to be weighed against all of NIH's other priorities-in this particular case, weighed against what other ways there might be to get similar, if not precisely the same kind of data." CRITIC: Activist Debra Harry contends that "all the ethics go out the window when it comes to researchers coming in to indigenous communities." In the wake of the favorable NRC report, some nongovernmental and indigenous peoples' organizations are still calling for a global moratorium on collections of human DNA samples. Debra Harry, a coordinator of the Indigenous Peoples Coalition on Biopiracy in Nixon, Nev., charges that though HGDP has written model ethical protocols, "all the ethics go out the window when it comes to researchers coming in to indigenous communities to take collections." Field workers will offer subjects money or basic medical care in exchange for blood samples, she says. Members of the North American committee seem to have become sensitized to such concerns. "I think that the committee needs to develop relations with indigenous communities to the state where there is a mutual trust," says Marcus Feldman, a Stanford biologist. But he acknowledges that such trust "takes years and years to develop on the whole." "The Human Genome Diversity Project was the lightning rod that attracted all the attention of people who were suspicious of science and/or genetics," Penn State's Weiss recalls. "It hasn't been fun, but it was a useful thing for the organizers to see the level of suspicion that's out there." The lesson has also not been lost on scientists unconnected to the project. Asked whether he anticipates political and ethical problems as NIH moves into genetic variation research, NHGRI's Guyer replies: "I hope not. Let's just say that, as with the rest of genome research, we are trying to anticipate and address potential issues of that sort in advance." Douglas Steinberg is a science writer based in New York.

NIH Jumps Into Genetic Variation Research

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