The Human Genome Diversity Project: medical benefits versus ethical concerns

The Human Genome Diversity Project: medical benefits versus ethical concerns By the year 2005 the entire human genome should have been sequenced and the genes identified. But the resulting genomic sequence, although a marvelous accomplishment, will be a composite of just a handful of individuals selected at random. The Human Genome Diversity Project was , proposed as a means to overcome these limitations by obtaining genetic information from many diverse populations of the world. This would give medical geneticists a handle on ,the variations in susceptibility to disease among different populations, as well as being of anthropological value. But would such a project risk exploiting the indigenous populations involved? 3

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THE Human Genome Diversity Project (HGDP) is a proposal for an international collaborative effort to collect genetic material from a large number of indigenous peoples of the world and to make it available for systematic genetic studies. The project was first proposed in 1991 by Luigi Luca Cavalli-Sforza (Stanford University, CA, USA) and colleagues in a letter to the journal Genomicd. The original purpose of the project was to ‘understand human diversity, both normal variation and that responsible for inherited diseases’. Its focus was to be the collection of nuclear and mitochondrial DNA from isolated populations that were likely to be linguistically and culturally distinct, and surrounded by geographic barriers. In a series of meetings that followed the proposal, it was decided that the number of individuals to be studied would be between 10 000 and 100 000 from some 400-500 populations. For most of the study subjects, only small amounts of DNA would be prepared, stored and made available to qualified investigators from around the world. For approximately 10% of the sampled individuals, cells would be collected, transformed, and stored as,frozen cell lines. This latter strategy, it was reasoned, would allow for the production of additional DNA should it be needed for future studies. The original project envisioned that the collection of DNA would be supervised by regional committees, who would also collect a substantial amount of information regarding the people from whom the samples were collected. This information was to include: genealogical relationships among sampled individuals; Ibirthplace and place of residence of the individual and of his/her parents; if applicable, clan PII: S13S7-4310(97)01206-9

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of indi\ idual, 1‘.11/1~ and mother; and birthplace, ethnic affiliation and clan of spou\~: (unless both husband and wife have been sampled separately). Ethical guitlzlines were also agreed upon and included (1) obtaining informed consent before collecting samples, (2) respect for the privacy of individuals sampled, (3) encouraging the participation of the population in the development of study designs and (4) keeping them fully informed of the results of the various studies. The cost of the HGDP was estimated to be in the range of US 525-30 million - a mere one percent of the cost of the Human Genome Project. This might seem a gross underestimation when one considers that the Human Genome Project will only sequence one composite genome. However, much of the cost of the Human Genome Project is invested in developing the technology necessary to conduct massive-scale sequencing operations; by contrast, the costs of the HGDP are primarily for the collection of the genetic material, establishing a database of information on the study subjects and a system for the worldwide clistribution of samples to researchers.

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lations such as the Old Order Amish might be useful in identifying the genetic component of conditions such as mental illness?. Studies of Jews of Eastern European origin may contribute to an understanding of the genetics of Tay-Sachs and Gaucher’s disease and the 185delAG mutation associated with breast and ovarian cancer in Ashkenazi Jews5. The flip side: genes that protect from disease Greely also explains that some of the populations studied might possess genes that could be beneficial to the world population as a whole. Possible examples of such useful genes include those from the people of a village in Northern Italy who appear to be protected from some forms of heart disease, and prostitutes in Nairobi who appear to be immune to HIV infectionQ.

Biotechnology and indigenous populations

Although the leaders of the HGDP consistently downplay the commercial aspects of the project, several biotechnology companies are already funding their own miniature versions of the HGDP in the search for useful genes that could lead to commercial products. One How could the HGDP benefit medicinle? of these is Sequana Therapeutics Inc. (La Jolla, CA, USA) who, Although its primary purpose is anthropological, many of the per- along with its major pharma partner Boehringer Ingelheim ceived benefits of the project are medical, because the HGDP would (Ingelheim, Germany), is prospecting for genes related to asthma allow the assessment of the prevalence and distribution of disease from a variety of selected populations, including island populations genes in the populations of the world. in the south Atlantic, a Jewish community that was located in India for several thousand years, the Polynesian descendants that now occupy Easter Island, and large families in Brazil and China. These A better handle on genetic susceptibility to disease? Sir Walter Bodmer, former president of the Human Genome groups all have high incidences of asthma. Sequana hopes that an Organization, believes that one of the mo:jt important medical out- asthma gene can be identified, with the possibility that such a find comes of the HGDP will be a more detailed mapping of the location will lead to new commercially viable therapeutic approaches for of genetic markers in ‘normal’ population:; and their use in linkage treatment8. Compared with the HGDP, the level of controversy over disequilibrium studies. Such studies have already been used to iden- the efforts of these companies to collect genetic material has been tify some disease-causing genes, such as CFTR, the gene for cystic modest. This could be because the companies have the funds to quifibrosis. The approach is to use a set of gene markers to determine etly go about the business of collecting genetic material without the the degree of association of each marker with the disease of interest public debate that accompanies the use of government research funds in the population. By using a wide range of markers with known lo- for such activity. Other entrepreneurs have also been attracted by the potential comcations, the location of the unknown gene responsible for the disease can be narrowed down to an ever-small:r region of the genome, mercial bonanza of DNA from indigenous peoples. Kari Stefansson, eventually pinpointing its location. Bodmer points out that linkage a Harvard geneticist and native of Iceland, has recently established a disequilibrium studies have the potential ‘:o identify gene variations small company, decode Genetics, Inc. (Reykjavik, Iceland), whose involved in complex, multifactorial geneti’: conditions, such as alter- purpose is to collect DNA from the native population of Iceland to ations of angiotensin or angiotensin-converting enzyme in cardiovas- search for useful genes that will return a profit to the company and to cular disease, some forms of cancer, or v:.riable drug responses. But the local people’. Stefansson is counting on the geographic isolation of the islanders, long-established patterns of maintaining medical the key to the use of the technique is to understand, in the ‘normal’ population, the frequency and distribution of whatever markers are records, selection pressure from an epidemic of the bubonic plague being used. Such a study is necessary, says Bodmer, to allow one to in the 1400s and severe famine brought on by a volcanic eruption in say that the frequency of the marker in ihe disease is significantly the 17OOs,as well as the similar familial backgrounds, to have naturally selected for genes with commercial potential. Currently some different from that of the controls. 25 common diseases are under investigation at decode, including Henry Greely, Professor of Law at Stanford University (CA, USA), cites a number of other examples of possible medical benefits multiple sclerosis, psoriasis, pre-eclampsia, inflammatory bowel disof studying the DNA of indigenous populations*. One is likely to be a ease, aortic aneurysm and alcoholism. The company is looking for better understanding of the high incidence of adult-onset diabetes commercial partners to further its efforts in mining the genome of the through studies of narrowly defined populations such as the Pima Icelandic people. Stefansson also seems to have avoided much of the criticism fotribe in Arizona, the Old Order Amish, t!le ‘Gullah’ Islanders in the American Southeast and some West Africans, all of whom suffer cused on the HGDP, possibly because he is sampling a population of from an unusually high incidence of the disease. Studies have shown some 270 000 Icelandic citizens of which he is a member. In addithat diabetes within the Pima is ‘strongly familial, and probably of tion, decode’s approach to collecting samples goes to great lengths genetic origin, although the precise nature of the gene or genes re- to maintain the privacy of the donor and only uses samples obtained from volunteers who have been fully informed and who have freely mains unknown’3. Greely also suggests that studies of specific pop-

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given their consent. Finally, in his agreements with pharmaceutical companies, Stefansson insists that any drugs developed as a result of the genetic information obtained from his sample population be supplied for use to the Icelandic population free of charge during the life of the patient.

Opposition to the HGDP

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Reactions of indigenous peoples Much to the surprise of the organizers of the HGDP, many of the populations of the world recoiled in horror at the prospect of having their DNA collected and studied. David Maybury-Lewis (Professor of Anthropology, Harvard University, Boston, MA, USA) explains that many indigenous peoples ‘consider their land, the life forms on it and all aspects of their own persons - such as blood, hair and tissue, as well as DNA samples - to be sacred’8. He further points out that such beliefs are often also held by non-indigenous people who are opposed to commercial ownership and exploita.tion of such a fundamental element of life as DNA. Some populations are particularly concerned that useful DNA sequences found through the HGDP might be patented by US or European countries and exploited for commercial gain. RAF1 (The Rural Advancement Foundation International), a non-profit, private organization in Montreal, Canada, has emerged as the champion of the patent issue. RAF1 was originally involved in protesting against the worldwide collection of seeds by agricultural companies who selected for the most useful variants, obtained patent rights, and then attempted to sell them back to the countries of origin at a profit. RAF1 saw the HGDP as an extension of these practices and rallied many of the indigenous populations in opposition to the HGDP.

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Opposition from other scientists Some scientists also believe the HGDP is poorly conceived. One vocal critic is Jonathan Marks, a Visiting Associate Professor of Anthropology at The University of California at Berkeley (CA, USA) who holds graduate degrees in both molecul.ar genetics and anthropology. According to Marks, there are no ‘pristine’, genetically untouched, populations in the world. In his view, we are all mutts, and he doubts that the approach proposed by the HGDP will be as useful for studies of human evolution as proposed. He is concerned that the HGDP will encourage racism, and points ‘out the difficulty of maintaining the confidentiality of the individuals being sampled. ‘After all,’ he says, ‘if you have DNA then you have the ultimate identifier.’ Marks believes that a study of genetic diversity would be a good thing, but is opposed to the methods of the HGDP. In his view, we should collect DNA along with extensive phenotypic data, even photographs, but only from individuals who have given informed consent and fully understand the implications of donating their DNA to the project. Marks believes that this could only be possible after a great deal of anthropological groundwork when collecting from indigenous populations, who are likely to have different ideas about blood, human bodies and heredity.

Should the HGDP be funded? These issues recently came to a head when the National Research Council of the US National Academy of Sciences (NRC), which was asked to evaluate the proposed HGDP by the US National Science Foundation (NSF) and the NIH, published its recommendations9.Their report is the culmination of four meetings, attended by a committee of 15 experts formed by the Board of Biology of the National Research

international scene

Council.Threeof the meetingswereopento the public, andthe committeeheardfrom proponents of the projectaswell asfrom representativesof RAF1andindigenous peopleswhoopposedtheproject. The reportconcludedthat ‘The federalgovernmentshouldprovide fundingfor a globalsurvey on humangeneticdiversity.’ However,a statementfrom the committeethat accompanied the reportsaid‘The proposaldoesnot clearly explain the purposeof the project or provide thenecessarysafeguards for protectingparticipants.’Becauseof thislack of focusof the existingproposalfor the HGDP,the committee ‘choseto examinethe scientificmeritsandvalue of researchon humangeneticvariationandthe organizational,policy, andethicalissuesthat suchresearchposesin a more-general context.’The remainderof thereportis devotedto specificrecommendations for conducting the HGDP(summarized in Box l), someof which are similarto thoseoriginally envisionedby the organizersof the project, while others,suchasthe strongemphasison confidentiality,the ethicsof informedconsentandthe arrangements regardingpossiblefinancial return,go further thanthe originalHGDPproposal.

Different interpretations of the NRC rejport However, it would seemthat the report’s recommendations were opento interpretation.NaturelOand RAF1 tlook the report to be a 61

suggestionthat the recentNRC report might have broken through the impassein the USA on funding for studiesinto variation of the humangenome.

A revamped HGDP: but at what cost to medicine?

basis to understar&&& taken to deal wit

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There seemsto be little doubt that the HGDP, or an HGDP-like project under a different name, will soon move forward in the USA with funding of formal projectsfrom the NIH and the NSF. However,the NRC report hasimposedrestrictionsthat might decreasethe value of the DNA samplesfor medicalresearch.For example,it is difficult to understandhow the samplescouldbe usedto studyadult-onsetdiabetesin selectedpopulationsif it is not possible to record which samplescomefrom individualswith diabetes.The lack of pedigreeinformation and the requirementthat informed consentmustbe given for definedprotocolsmight alsoprove restrictive. The review committeemust have recognizedthat such restrictionslimit the medicalvalue of the samples,but concluded that therisk of exploitationwassufficientlygreatto requirea sacrifice of the medicalvalueof the samples. It remainsto be seenhow HGDPfunding agenciesin othercountries will respondto the report. Sir Walter Bodmernotesthat the NRC report ‘will havenothingto do with what might, or might not, go on elsewhere.’It is alsounlikely to have an affect on what goes on asbiotechnologycompaniesconducttheir own miniature,selffundedversionsof the HGDP.In the midst of all the conflict?they have quietly steppedin, and are quite likely to be the onesto reap the majormedicalbenefitsoriginally envisionedby the HGDP.

rejection of the HGDP’s proposal, but Stience” saw the report as supporting the project commenting that :.t ‘got a cautious nod of References approval from the National Research Ccuncil.’ William J. Schull 1 Cavalli-Sforza, L.L. et al. (1991) Call for a worldwide survey of human (University of Texas Health Center, Houston, TX, USA), the genetic diversity: a vanishing opportunity for the human genome pmject, Chairman of the NRC review committee, says that it was not the inGenomics 11; 490-498 tention of the committee to reject the proposal. In his words, the 2 Greely, H.T. (1996) Genes, patents, and indigenous peoples, Cultural Su~i!xzl ‘committee did not endorse or reject the HGDP.’ Instead, it looked Quarterly 20,54-57 3 Knowler, W.C. et al. (1993) Determinants of diabetes mellitus in Pima at the issue in a broad context to determine if the project has scientific merit and found that it has, but certain safeguards need to be Indians, Diabetes Care 16. 216-227 put in place. To make sure the safeguards are followed, the commit4 Risch, N. and Botstein, D. (1996) A manic depressive history, Nat. Gener. 12, tee recommended that initial funding be from US agencies only, 351-353 5 Lehrman, S. (1997) Jewish leaders seek genetic guidelines..., Nature 389.322 since that would give them the greatest control over how the HGDP projects will be conducted. This statement was reiterated in a letter 6 Fowke, K.R. et al. (1996) Resistance to HIV-1 infection among persistently semnegative prostitutes in Nairobi, Kenya, Lancel348, 1347-1351 to Nature12. 7 Marshall, E. (1997) Tapping Iceland’s DNA, Science 278,566 In December 1997, meetings were held at NIH and NSF with 8 Maybury-Davis, D. (1996) Science and sensibility, Cultural Survival Quarterly principal investigators who had received money for pilot projects related to techniques needed for the HGDP to go forward. The pur20, 3 9 Committee on Human Genome Diversity, Commission on Life Sciences. National pose of these meetings was to decide on the next step now that the Research Council (1997) Evaluating Human Genetic Diversity, National NRC report is in hand. According tc’ Mary Clutter, Assistant Academy Press, Washington, DC Director for Biological Sciences (Nation;.1 Science Foundation), the techniques to conduct the project are nova in hand and the investiga- 10 Macilwain, C. (1997) Diversity project ‘does not merit federal funding’, Nature 389,774 tors have designed proposals that will meet the recommendations put forth in the NRC report. Clutter belk.ves that the only approach 11 Pennisi, E. (1997) NRC Oks long-delayed survey of human genome diversity, Science 278,568 to the continued objection to the project by some populations is to 12 Schull, W.J. (1997) Support for Genetic Diversity Project. Name 390, 221 mount an education program to deal with the criticism. Francis Collins, Director of the National Human Genome 13 Collins, F.S., Guyer, M.S. and Chakravarti, A. (1997) Variations on a theme: cataloging human DNA sequence variation, Science 278,158s1581 Research Institute of the NIH, was recently the lead author of an article proposing a project to catalog human DNA sequence variation13. The proposed project bears a sl.riking resemblence to the HGDP; the article even cites the NRC report that endorses the HGDP project’, but nowhere is the terminology ‘Human Genome Diversity Project’ used. The appearance of this article is a further 62