oxford handbook of bioethics

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to found a new future for medicine, as rich as the Kingdom of the Grail to which Parzival is transported after the completion of his quest (Barber 2004).

Unlike Parzival’s discovery, however, the achievement of the Human Genome Project does not offer immediate access to the Grail Kingdom, or to the Grail’s reputed other benefits of health, longevity, and abundance. In fact, the Holy Grail of human biology is simply a set of tools for the further questing that must be done before the Fisher King can be cured of his reproductive wound and the Wasteland can be reclaimed. Armed with improved genomic maps and DNA sequencing technologies, the goal now is to pursue a new generation of projects comparing human genomes to better understand our similarities, differences, and patterns of relationship at the molecular level. These comparative quests are critical to the development of successful medical applications of genomic research but they also take our genomic knights down some particularly perilous roads. This chapter is the tale of two such perils, concerning first how best to pursue such comparisons and then how best to use their results, when they are made at the level of human populations. The dangers in both adventures are the risks of social harms that might come to people as a consequence of being members of those populations, if the groups are socially defined and the scientific stories told about them undermine their social interests. If genetic populations become identified with both political communities and stigmatizing biological claims, they can tap into our oldest social tensions — tribalism, racism, and suspicion of the ‘other’ — to open the door to volatile new forms of genetic discrimination. In the end, the ethical challenge for both research and practice in comparative genomics is a fundamental one: how can we preserve our commitment to human moral equality in the face of our growing understanding of human biological diversity?

POPUL AT ION GENOMIC RESEARCH

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Since the beginning of the Human Genome Project, there have been calls to map the genetic variation within our species (Cavalli-Sforza et al. 1991). The initial interest was primarily genealogical: physical anthropologists and population geneticists would use comparative genotyping to produce the molecular clues they need to reconstruct more completely the global history of human migration and differentiation. But interest in the ways in which human groups vary at different genetic loci has grown much broader within biomedicine, as scientists apply the fruits of genome research to their work in epidemiology, molecular diagnostics, pharmacogenetics, and the analysis of complex genetic traits (Collins et al. 1997; Risch and Merikingas 1996). Much of this interest is driven by the prospect of a ‘genomic medicine’, in which diagnostic protocols, therapeutic interventions, and preventive measures could be tailored to each patient’s genetic profile (Guttmacher

and Collins 2004). This prospect attracts clinicians concerned about adverse patient reactions to medications, public health officials interested in preventing disease through public risk education and behavior change, and health policy-makers concerned with the persistent health disparities between different population groups.

Whatever its focus, all population genomic research involves collecting DNA samples from individual members of different human groups, genotyping them (through marker mapping or DNA sequencing) at one or more loci, and comparing the results. This immediately raises an important conceptual question for this research: how should scientists define and identify the relevant comparison groups within our species? The initial attempt to use genomic tools in a large-scale study of human variation, the so-called Human Genome Diversity Project, followed the accepted practice of physical anthropologists and epidemiologists of describing its target groups in ethnic, linguistic, and geographical terms, and was called to task by both biologists and social scientists for using socially constructed categories that would obfuscate rather than illuminate underlying patterns of gene flow within our species (Gannet 2001; Reardon 2005). Rather than reifying various human political histories by looking for ‘ethnic-affiliation markers’ in human DNA, some suggested a random global sampling strategy blinded to social identifiers (National Research Council 1998). The US National Institutes of Health (NIH) followed this approach in developing a major genetic variation research resource — a databank of known single nucleotide variants in human DNA — and was in turn called to task by public health and pharmacogenomic researchers for omitting ‘phenotypic data’ about the distribution of the DNA variants across different populations (Altshuler and Clark 2005). As a result, the subsequent international effort to produce a variation-measuring ‘haplotype map’ of the human genome intentionally collected samples from groups defined by their ‘continents of origin’ (International Hapmap Consortium 2003). Critics charge that this strategy returns population genomics to a set of outmoded racial categories that human scientists of all stripes have repudiated as biomedically meaningless and socially pernicious (Duster 2005). Counterclaims that, nevertheless, research framed in this way has identified patterns of genetic variation that cluster along racial lines, and that these variations may be the key to ‘population specific’ public health interventions or even ‘race-based medicine’, have only lent fuel to this conceptual debate (Kahn 2004).

As a result, genetic research has an increasingly complicated message for our inclinations to identify ourselves in terms of larger human populations and ethnic groups. At the same time that we are learning just what a relatively young and genetically homogenous animal species we are, health disparities researchers, physical anthropologists, and forensic scientists continue to bear down on the rare genetic differences that seem to differentiate the social categories of race, ethnicity, people, and nationality (Burchard et al. 2003). Social categories, by definition, provide identities by segregating their members from other people. It

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is not surprising that research that threatens to drive scientific wedges into the social cracks that already divide people from their neighbors should carry very high moral stakes. Thus, comparative human genetic variation research which continues to use these categories or their proxies (i.e. ‘continents of origin’ for race) continues to be ethically and scientifically controversial (Cooper et al. 2003). On the one hand, no one wants to reify categories that were created and used in contexts of social oppression. Yet for those who have been marginalized and oppressed by the categories in the past, justice seems to demand increased access to whatever benefits genetic research might yield their group when it is framed in terms of this ascriptive identity (Zilinkas and Balint 2001). The need to recognize these categories in redressing injustice becomes particularly acute where health disparities are part of their legacies. At the same time, the claim that those disparities are also genetic — that racism has helped exacerbate genetic differences between specific human superfamilies — have to be very carefully made and evaluated, if they are not to fuel the very social problem they are intended to address.

The second challenge facing population genomic research follows from the first. Assuming that, for the foreseeable future, the definition of comparison groups in population genomics will be informed by socially constructed criteria at some level of resolution (either familial, tribal, ethnic, racial, or regional), how should the interests of group members be protected?

Almost by definition, a complicating feature of many population genomic studies is the fact that this research is increasingly cross-cultural and international. Large genetic variation studies like the Haplotype Mapping Project are increasingly collaborative efforts between scientists in different countries who collect and compare DNA from populations chosen for their phenotypic diversity. Even genetic studies that involve mainstream American immigrant communities, such as African Americans or the Ashkenazim can quickly take investigators all across the globe. As a result, cultural, linguistic, and socioeconomic factors complicate population genetics research in much the same way they complicate international epidemiological research, raising questions about the collective interests of the human groups being studied, and their decision-making role in this context.

Outside of groups with clear political sovereignty, like Native American nations, most targets of genetic analysis have ambiguous moral standing. Is it ethically important for scientists to attempt to discuss their plans with groups at the collective level before recruiting individual group members into genetic variation studies? Some argue strongly that a principle of ‘respect for community’ needs to supplement our traditionally individualistic principles of research ethics in these contexts, if only because individuals gain so much of their identity through their community memberships and their genetic lineages (Weijer 1999). Others argue that, at least for genetic studies, extensive efforts at community engagement are disingenuous and guaranteed to fail, given the mismatch between genetic

populations and the politically defined communities available for consultation ( Juengst 1998).

At the crux of this debate is the role of community membership in the personal identity of individuals who participate in genome research. Common bonds of religion, culture, or history can create defining identities for members of groups ranging from global diasporas to nations to local voluntary organizations and support groups. Unlike families or clans, however, genetic relationships are not the basis for the vast majority of these human communities. Despite the interests of population geneticists in identifying human examples of the ‘founder effect’, human communities that can count as ‘genetic isolates’ like the Galapagos finches are exceedingly rare. This means that for the fluxuating memberships of human communities like nations, cities, religions, political movements, and social classes, the ‘gene pool’ does not provide a commons that can be effectively exploited for the good of those communities. Despite the local appeal of promoting the ‘unique genomic research resources’ of communities like Iceland, Newfoundland, Estonia, the Han Chinese, or the castes of India, members of those communities should not expect research results that differentially benefit their own health.

Since no human communities define unique human genetic populations, moreover, the legitimacy of identifying socially defined communities with genetic populations and the propriety of giving community leaders this gate-keeping role becomes controversial, and complicated questions of loyalty arise for members of those communities (Marshall and Rotimi 2001). Any biomedical research that seeks to recruit research participants through the communities in which they live must always walk a tightrope between the values of group solidarity and individual autonomy. For genetic research, however, the local trust-building virtues of community gate-keeping are offset by a serious hazard: the danger of reinforcing the ultimately vicious impression that the communities being consulted are coincident with the genetic populations under study and therefore biologically distinct from their neighbors.

The discussion of how best to protect communities has moved through several stages. Most regulatory bodies have recognized that since genetic populations are not the sorts of groups that can claim autonomy as moral communities, it makes no sense to hinge the recruitment of their members on some corporate permission. Thus, for example, the ‘Points to Consider for Population-Based Genetic Research’ developed by the NIH stresses that: ‘community consultation is not the same as consent . . . . community consultation is a vehicle for hearing about the community’s interests and concerns, addressing ethical issues and communicating information about the research to the community’ (NIH 2002).

This interpretation of community engagement places much more emphasis on preserving the special values and cultural lifeways of a given population than on treating the population as a politically autonomous entity. The purpose of this interchange, NIH says, is to solicit the study population’s help in identifying any

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‘intra-community or ‘culturally specific’ risks and potential benefits, so that the research can be designed in ways that best protect the group’s interests (Foster et al. 1999). As Marshall and Rotimi point out, this can be difficult:

Despite the obvious benefits of community advisory boards, there are limits and constraints on their ability to represent the values of diverse community members. . . . In some cases community leaders on advisory boards may be politicians. Community activists represent another powerful group who might serve on such boards. Religious leaders or local celebrities also might be asked to participate on the boards. Investigators must be sensitive to the social and political agendas of members on community advisory boards and try to minimize the potential for addressing priorities that may be relevant to only a minority of the local population (Marshall and Rotimi 2001: 261).

Of course, the increasing dispersion of human populations around the world means that in fact most human superfamilies no longer share common ‘culturally specific risks’ and benefits. This leads even the staunchest advocates of community engagement to the counterintuitive point of arguing that, for study populations like ‘general ethnic, racial or national populations, e.g. Ashkenazi Jews, American Indians, Puerto Ricans, etc.’, the lack of distinctive common interests and structured social interaction means that ‘community review may not be required’ and even for geographically dispersed populations that share distinctive beliefs and practices, like the Amish or the Hmong, ‘limited social interactions between members of the study population make intra-community risks unlikely’ (Sharp and Foster 2000).

Diverse, dispersed genetic superfamilies of the sort useful to genetic variation studies will not often enjoy the level of organization that can make representative consultations possible. For these cases, Sharp and Foster suggest that all that may be required is the form of community engagement they call ‘community dialogue’: ‘‘an effort to interact with the local communities and institutions at the specific site from which members of a given genetic population will be recruited, in order to acquaint them with the investigators’ mission in advance of individual subject enrollment’’ (Sharp and Foster 2000).

The key move in this interpretation is to acknowledge the complexity of human population structure by sacrificing the ambition to protect all members of a genetic population from the potential harms of the research, and to refocus on the particular families and locale from which investigators hope to solicit DNA samples. Instead of attempting to respect the genetic population as a moral community, or attempting to protect all its individual members from potential harm, the practice of community engagement is reinterpreted to be simply a matter of establishing a viable political collaboration with the local community in which the recruitment of individuals for DNA sampling is to take place.

Narrowing the focus from broad study populations to localized communities does make the prospect of community engagement more plausible. Localized communities will be able to produce representatives authorized to speak for their

membership more easily than unorganized populations. Local communities are more likely to face common ‘intra-community risks’ and needs that might be usefully communicated in designing the research at that site. And to build trust and negotiate access to community members, it will be much more effective to work at the local level.

Nevertheless, it remains important to appreciate the limits of this approach. The study populations of the kinds that are of most interest to genetic variation researchers, the international human population groups whose genetic variations disclose the patterns of disease susceptibilities within the species, will be those least well served by the practice of community engagement. If the concern was to give those larger population groups some involvement in research that may affect them, even negotiating a full-blown ‘community partnership’ with one localized subset of the population is as likely to be an example of the problem rather than a step toward justice: to the extent that the researcher does not confine his or her scientific claims to the local community at hand, that community’s decisions about participation have preempted the interests of the rest of the population.

Moreover, for these same reasons, investigators cannot honestly let local communities speak for the population, and cannot promise that local research designs will protect the communities from population-related harms incurred by studies at other locales. Thus, in this most attenuated model of community engagement, even the local communities to whom the principle of ‘respect for community’ might apply cannot be afforded the level of involvement in the research decision-making that the principle’s proponents advocate.

Finally, there is the interesting twist that the idea of community genetic identity gives the discussion of the commercialization of genetic information. While the first wave of contemporary literature on this topic portrayed genetic information as ‘the common heritage of humankind’ (Ossario 1999) and thus unsuited to ownership and exploitation by subsets of the species, the organization of genetic research in terms of community membership is shifting the tone of the ownership debate dramatically. While the ownership framework continues to be debated in international policy circles ( Thorsteindottir et al. 2003), as human communities have come to be (mistakenly) identified with unique human superfamilies they seem to have begun to accept the idea that their genes are akin to the natural resources under their local control (Merz et al. 2004). Complaints of ‘bio-piracy’, and pleas for ‘benefit sharing’ and ‘reciprocity’ on behalf of communities under genetic study, as well as charges of unfairness and neglect by those left out of genetic diversity research, all suggest a rising sense that, in fact, subsets of the species do have claims on the genetic information that distinguishes them, and should be compensated appropriately for its use by others (Christie 1996).

The idea that populations are materially invested in their genetic information in economic ways is actually one with a long history in the science of human genetics. It is, however, a conceptually mistaken idea, and one with dangerous

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(Coughlin 1999). This resurgence raises a number of bioethical issues for public health policy-makers and the health professionals involved in delivering genetic services: questions about the limits of public health authority in this domain, the justice of population-based genetic interventions, the social costs of such screening, and the ethical allegiances of the clinicians involved. All of these issues are animated by the same conceptual issue that lay behind the eugenicists’ efforts to purify the human gene pool: the problem of defining ‘prevention’ for the purposes of a ‘public health genetics’.

Mass genetic screening programs have a relatively long history amongst modern genetic services, starting with the screening of newborns for prophylactic therapy against metabolic disorders in the 1960s and continuing into adult carrier testing programs for recessive genetic diseases such as Tay-Sachs (Blitzer and McDowell 1992), sickle cell disease (Bowman 1977), and the thalassemias (Angastiniotis et al. 1986) in specific at-risk populations in the 1970s. The early adult screening programs shared two features that warranted, and garnered, significant attention within bioethics and health policy (National Academy of Sciences 1975; President’s Commission 1983). First, they targeted specific socially defined populations, which raised issues of group-specific stigmatization and discrimination (Kenan and Schmidt 1987; Markel 1992). Second, the information about carrier status the screens provided was primarily useful for reproductive rather than therapeutic decision-making, raising issues of parental autonomy, paternalism, and procreative choice ( Thomson et al. 1993).

The 1980s witnessed a second wave of adult genetic screening programs, aimed at detecting pregnant women at risk of delivering children with genetic birth defects and chromosomal abnormalities (Cunningham and Kizer 1990; Haddow et al. 1992; Palomaki 1994). These programs are intended to have universal application within populations, and have been routinized into the obstetrical care of pregnant women in many countries, raising issues of voluntariness and informed consent (Press and Browner 1995; Marteau 1995). They have also provoked an outspoken reaction from the community of people with disabilities, who argue that such programs work against attempts to reform social attitudes about disability (Parens and Asch 2000).

Today these three ‘traditional’ forms of population genetic screening — newborn screening, risk-group carrier testing, and pregnancy screening — continue to make up the vast bulk of population genetic screening activities that are funded and evaluated as state public health initiatives. At the same time, the disease targets of these screening efforts have changed, as public health programs see rationales for shifting specific tests from one form of testing to another. Thus, many states have added sickle cell testing to their universal newborn screening panels (Olney 1999), and calls have been made for universal screening of pregnant women for maternal phenylketonuria (Kaye et al. 2001) and fetal hemoglobinopathies (Cuckle 2001). Moreover, genetic tests originally reserved for clinical use in families at risk