Editors: Norio Fujiki, M.D. & Darryl R.J. Macer, Ph.D.
Robyn Yuri Nishimi
Senior Associate, Office of Technology Assessment, U.S. Congress, USA.
The Office of Technology Assessment (OTA), a research and analytic agency of the U.S. Congress, has examined a broad spectrum of ethical issues raised by applications of genetic research, including: human gene therapy, genetic monitoring and screening in the workplace, privacy considerations of DNA databases and databanks, population carrier screening for cystic fibrosis, and the commercialisation of products derived from genetic engineering research (1-7). OTA's analyses are largely reported in the context of the U.S. political system, but some reports draw on international experiences. Certainly, the general themes of most of these issues are generic to all countries. OTA also has examined the role of bioethics commissions in U.S. and international policy decision making.
Drawing on OTA's work in genetics and bioethics, this paper will briefly trace the history of genetics and bioethics in U.S. public policy, including a short discussion of the Ethical, Legal, and Social Issues Programs of the National Institutes of Health and the Department of Energy. It will then briefly examine the scope and breadth of bioethics activities in other countries or organisations that examine the ethical, legal, and social implications of genetic technologies and information, in order to explore the opportunities and mechanisms to enhance international research on these issues. Finally, I will discuss two particular topics that I believe could greatly benefit from future international research--namely the ethical issues raised by patenting human DNA sequences and the ethical issues raised by the Human Genome Diversity Project.
Concern about ethical issues related to genetic information is not a new phenomenon in the United States or elsewhere. From a public policy standpoint, one of the earliest, most broad, and widely disseminated documents was the 1975 report of the National Research Council of the U.S. National Academy of Sciences (8). This work was funded by the U.S. government (National Science Foundation) and made a critical impact in shaping future discussions, including the report on genetic screening and counseling that the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioural Research issued in 1983 (9). Both reports identified the ethical issues associated with genetic screening and laid the foundations for applications of genetic research. Still, the scale of interest and the scope of work now being undertaken has grown dramatically in recent years.
Since fiscal year 1988, the U.S. government has made a commitment explore the ethical, legal, and social aspects of the Human Genome Project. Since Dr. James Watson first suggested that 3 to 5 percent of federal funds for the Human Genome Project be set aside for grants related to ethical, legal, and social issues (10), over $21 million has been devoted to this purpose. In fiscal year 1993 alone, the National Institutes of Health spent over $5 million and the Department of Energy spent nearly $2 million. Additionally, the U.S. Congress has suggested that the National Institutes of Health and the Department of Energy establish a federal commission to address the ethical, legal, and social implications of our growing knowledge of human genetics. Of particular concern is the issue of privacy and confidentiality of genetic information (11). And of course, I have already mentioned the many issues explored by my agency, OTA.
Elsewhere around the world, the governments of several countries have established committees, held forums, or funded other efforts to analyze the ethical implications of genetic research. These countries, to name a few, include Australia, Canada, Denmark, China, France, Germany, Israel, Italy, Japan, the Netherlands, and Switzerland. In the United Kingdom, a private body, the Nuffield Council on Bioethics is completing a report on genetic screening. It is interesting to note that many of these efforts are performed via the work of bioethics commissions. In fact, OTA's recently released report, "Biomedical Ethics in U.S. Public Policy," reported that the governments of at least 27 nations on six continents have established national commissions of some type or currently have legislation pending to do so (12). This stands in contrast to the United States, which currently has no broad-based, government-sponsored bioethics commission, although congressional interest in establishing such a body surfaced at a recent hearing (13). In the coming months, as we in the United States struggle to reform our health care system, I believe the issue of bioethics, generally, as well as the ethical implications of genetic information, will receive some attention.
Multinational organisations also recognize the importance of attending to the ethical, legal, and social issues raised by the Human Genome Project. For example, the United Nations Educational, Scientific, and Cultural Organisation, the Council for International Organisations of Medical Sciences, the Council of Europe, the European Community, and the European Parliament all have funded initiatives in this area (12).
Thus, ongoing research on the ethical implications of the Human Genome Project is rich and varied. Yet, as each country or organisation moves forward with its research agenda, it will be guided, in many respects, by parochial interests. This is to be expected. It is even largely acceptable because much of the work is made possible by funds from taxpayers. Furthermore, since commonalities of concern exist, some of the work will be important in the global context. In the United States, for example, the National Institutes of Health aims to emphasize three areas over the next five years: the ethical, legal, counseling, and education issues that might arise with genetic tests for breast cancer or colon cancer risk issues that might arise with fetal cell sorting and prenatal diagnosis and social issues that new knowledge of genetic variation raises (for example in the area of behavioural genetics). And two foci of the Department of Energy will be privacy concerns and public education.
Nevertheless, as we attempt to identify future directions for international research related to bioethical considerations of the Human Genome Project, I believe multinational efforts can be particularly important to at least two topics. In fact, cross-cultural approaches are essential to these matters. As I mentioned, no single country can definitively articulate all of the ethical issues raised by (i) patenting human DNA sequences, or (ii) those raised by the Human Genome Diversity Project. In devoting the remainder of this paper to these topics, I emphasize that I can offer no answers to the difficult and complex questions raised. Rather, I hope to identify some of the principal questions in order to stimulate further discussion.
With respect to the first issue--patenting human DNA sequences--I'm sure all of you are familiar with the 1991 National Institutes of Health applications to patent expressed sequence tags, and so I will not dwell on the details. Suffice to say, however, that opposition from several quarters was swift and largely negative. In fact, opposition on ethical grounds surfaced against the whole concept of patenting human DNA sequences per se, including whole genes. Representative of this opposition is a statement adopted at the May 1992 North-South Human Genome Conference in Brazil:
This work has to be done with great respect for human dignity and with the understanding that the knowledge obtained should be the prized possession of all humanity. In order to reap those benefits it is essential to achieve a balance between the protection of intellectual property rights and the free exchange of information and materials needed for optimal international collaboration in carrying out the Human Genome Project. In order to achieve the desired balance, we urge that consideration be given to avoiding the patenting of naturally occurring DNA sequences. The protection of intellectual property should, in our opinion, be based on uses of sequences rather than on sequences themselves (14).
Thus, at least three moral questions would benefit from international debate, research, and analysis. First, is it appropriate to patent human DNA sequences per se if they are really part of humanity's common heritage and therefore should be in society's custody (14,15)? Second, is the patenting human genes, or human DNA sequences, compatible with respect for the dignity of human beings and human life (14-16)? And third, will patenting have an unfair impact on research and commercial efforts in developing nations (17)?
Turning to a second area that I believe looms on the horizon and would benefit from international dialogue, I would like to briefly mention some of the ethical questions raised by the Human Genome Diversity Project (18).
As we all recognize, the Human Genome Project is designed to produce a single reference map of composite information, yet it is genetic diversity that distinguishes each of us from the other. Additionally, genetic diversity clearly exists among populations around the world. The Human Genome Diversity Project proposes a systematic examination of human DNA sequence variation by sampling 20 to 25 unrelated individuals from each of 400 to 500 populations of historical interest. It would be undertaken with the expectation that fundamental questions about the origins, settlement, and migration of humans could be examined. As well, the project could elucidate why some populations are more, or less, susceptible to certain diseases.
As with patenting human DNA sequences, the issues of equity and justice for developing nations are important here, too--perhaps more so since the great majority of sampling would be of citizens in these countries. Other issues that arise are concerned chiefly with the fundamental ethical tenets that guide the conduct of research involving human subjects.
1. Will any benefits of the research accrue to the research subjects?
2. What are the risks-particularly social risks such as stigmatisation-to research subjects who participate? To those who decline to participate?
3. What about compensation--monetary or otherwise--for research subjects? What if a country seeks payment in return for the collection of biological samples from its citizens? What if a local leader demands compensation? If compensating individuals is an option, what happens to people not "chosen" as research subjects? What benefits realistically can be offered to participating communities, especially if they are small and isolated?
4. What about confidentiality of the samples collected? What limits are necessary? Who decides? Who will be responsible for ensuring confidentiality?
5. In addition to collecting samples for the Human Genome Diversity Project, what about testing blood samples for disease? In particular, special attention to HIV infection is an issue-- especially with blood samples from Africa, for example. Should samples be tested so that researchers can exercise greater caution when handling certain samples? Should the samples be tested anonymously to determine infection rates in these populations? Is it ethical to test these samples anonymously? If it is unethical, then how does a demand to link a sample with an individual for purposes of disease identification balance against the importance of confidentiality for other purposes? If anonymous testing is viewed favourably and HIV testing is deemed desirable for the safety of scientists or to analyze HIV infection in indigenous populations, how will pretest counseling for HIV be handled on top of informed consent for the Human Genome Diversity Project, generally?
6. The issue of informed consent raises its own questions: What constitutes meaningful informed consent in non-Western cultures? In fact, do Western notions of informed consent have any true relevance to some of the populations to be sampled? Nevertheless, informed consent, expressed in whatever form, is a minimum activity to demonstrate respect for a culture. And while Western notions of consent might differ drastically from those of the populations to be studied, the concept of respect surely persists.
Cross-cultural issues of informed consent could prove particularly difficult to resolve. For example, any research conducted with U.S. funds needs to comply with current U.S. regulations governing human subjects research, in addition to adhering to any local governmental rules. U.S. regulations lay out eight specific informed consent requirements, and of which at least three may result in a conflict between U.S. regulations and the practices, values, or beliefs in other societies. U.S. regulations require a written document, a clear explanation of the purposes of the research, and individual consent.
A written document is important because it endures as a record for the future -either as an instructive tool or for auditing purposes. Yet written documents will be an anathema in some populations. How can this be reconciled with Federal regulations?
Similarly, U.S. regulations require that a project's purposes be clearly explained. One of the goals of the Human Genome Diversity Project is to elucidate information about the origin of the sample population, as well as its relationship to other populations. On face value, this might easily be put in terms understandable to all cultures. However, some cultures have deeply rooted beliefs about their origins and would find this goal of the project insulting or offensive. What if this jeopardizes efforts to obtain samples from key communities? Would it be ethical to emphasize certain goals (for example, identifying disease susceptibility) over others (for example examining human origins) in order to facilitate consent and participation? Who decides if this is permissible?
Must informed consent be obtained from every individual in a community? Can local leaders and other central authorities decide for all members of a community? Consider for example, a situation where a local leader speaks for all members of his group. What if he agrees to the sampling, but researchers who are preparing to draw blood from a woman plainly see that the woman is distressed by the prospect? Do they proceed? Do they decide not to sample her blood? Will this now incur the wrath of her leader, who has "lost face" because he had given his word that all would participate? Will she be punished overtly? If not overtly, will this stigmatise her? Should the investigators try to gain her individual consent? Is any consent she might then give truly consent, or has it been coerced?
7. If protocols vary (for example, regarding compensation or consent) from culture to culture, as might be expected, who will arbitrate what's necessary to ensure the protection of the people involved? Will population-by-population approval be necessary? If individual protocol review is deemed cumbersome by researchers, is there a reasonable expectation that all contingencies can be identified prior to embarking on sample collection?
8. Finally, what about issues of genetic discrimination? What is the best mechanism to minimize misuse and misinterpretation of the data that are gathered? In particular, since genetic differences are the project's focus, concerns are raised about information being used to support notions of superiority of one group over another.
This list of issues is by no means an exhaustive one. Nevertheless, I reiterate that analyzing these considerations is especially critical because many of the populations that have been proposed for sampling are groups that historically have been vulnerable or exploited. Furthermore, it strikes me as especially important that an international approach be used to address these matters.
In conclusion, I believe we can take heart from the many efforts currently underway to examine the ethical, legal, and social issues of the Human Genome Project. At the same time, much work remains to be done, and undertaking this work will require increased international cooperation. Clearly, a balance must be struck between our intellectual desire to pursue interesting, exciting lines of scientific inquiry against our ethical obligation to respect and enhance the welfare of all people.
1. U.S. Congress, Office of Technology Assessment, Human Gene Therapy, OTA-BP-BA-32 (Washington, DC: U.S. Government Printing Office, 1984).
2. U.S. Congress, Office of Technology Assessment, Mapping Our Genes--Genome Projects: How Big, How Fast?, OTA-BA-373 (Washington, DC: U.S. Government Printing Office, 1988).
3. U.S. Congress, Office of Technology Assessment, New Developments in Biotechnology: Patenting Life, OTA-BA-370 (Washington, DC: U.S. Government Printing Office, 1989).
4. U.S. Congress, Office of Technology Assessment, Genetic Witness: Forensic Uses of DNA Tests, OTA-BA-438 (Washington, DC: U.S. Government Printing Office, 1990).
5. U.S. Congress, Office of Technology Assessment, Genetic Monitoring and Screening in the Workplace, OTA-BA-455 (Washington, DC: U.S. Government Printing Office, 1990).
6. U.S. Congress, Office of Technology Assessment, Cystic Fibrosis and DNA Tests: Implications of Carrier Screening, OTA-BA-532 (Washington, DC: U.S. Government Printing Office, 1992).
7. U.S. Congress, Office of Technology Assessment, The Human Genome Project and Patenting DNA Sequences (Washington, DC: U.S. Government Printing Office, planned for 1994).
8. National Research Council, Committee for the Study of Inborn Errors of Metabolism, Genetic Screening: Programs, Principles, and Research (Washington, DC: National Academy of Sciences, 1975).
9. President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, Screening and Counseling for Genetic Conditions (Washington, DC: U.S. Government Printing Office, 1983).
10. Cook-Deegan, R.M., The Gene Wars: Science, Politics, and the Human Genome (New York: W.W. Norton, 1994).
11. U.S. Congress, House of Representatives, Committee on Government Operations, Designing Genetic Information Policy: The Need for an Independent Policy Review of the Ethical, Legal, and Social Implications of the Human Genome Project, House Report 102-478 (Washington, DC: U.S. Government Printing Office, 1992).
12. U.S. Congress, Office of Technology Assessment, "International Bioethics Initiatives", pp. 43-60 in Biomedical Ethics in U.S. Public Policy, OTA-BP-BBS-105 (Washington, DC: U.S. Government Printing Office, 1993).
13. U.S. Congress, "Bioethics in U.S. Public Policy", hearing before the Committee on Labor and Human Resources, October 14, 1993.
14. McKusick, V.A. (1992) First South-North Human Genome Conference.Genomics 14: 1121-1123.
15. Macer, D. (1991) Whose Genome Project?. Bioethics 5: 183-211.
16. Commission of the European Communities, Amended Proposal for a Council Directive on the Legal Protection of Biotechnological Inventions. COM (92) 589 final-SYN 159, Dec. 16, 1992.
17. Curien, H. (1991) The Human Genome Project and Patents. Science 254: 710.
18. Nishimi, R.Y., testimony before the U.S. Senate, Committee on Governmental Affairs, April 26, 1993.