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Annu. Rev. Genet. 2001. 35:785–800
c 2001 by Annual Reviews. All rights reserved
Copyright °
INFORMED CONSENT AND OTHER ETHICAL
ISSUES IN HUMAN POPULATION GENETICS
Henry T. Greely
Stanford Law School, Stanford University, Stanford, California 94305-8610;
e-mail: [email protected]
Key Words population genetics, genetics, ethics, law, society
■ Abstract Human population genetics has entered a new era of public interest, of controversy, and of ethical problems. Population genetics raises novel ethical problems because both the individuals and the populations being studied are, in
effect, “subjects” of the research. Those populations are collectively subject to possible benefits and harms from the research and have interests, somewhat different
from those of the individuals, that must be considered from both ethical and practical standpoints. The chapter first describes the new setting for research in human
population genetics. It then examines the most controversial ethical issue in population genetics—whether researchers must obtain the informed consent of both the
individual subjects and the group as a collectivity. Other vexing issues, including
special problems caused by researchers’ commercial interests, confidentiality, control
over research uses and materials, and return of information to the population are also
considered.
CONTENTS
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
THE NEW HUMAN POPULATION GENETICS . . . . . . . . . . . . . . . . . . . . . . . . . . . .
INFORMED CONSENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Individual Informed Consent and Iceland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Group Informed Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
A Special Case of Group Consent—Federally Recognized
Indian Tribes and Other Governments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OTHER ISSUES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Commercialism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Confidentiality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Control of Research Uses and Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Return of Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONCLUSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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INTRODUCTION
Although genetics has been a highly visible and controversial field for the past
century, population genetics has been scarcely visible to the public eye. Neither
its mathematical abstractions nor its hordes of collected fruit flies made much
impression on public consciousness. In recent years, however, the increased ability of researchers to examine large numbers of genetic variations in humans and
to draw conclusions of anthropological, historical, medical—and commercial—
interest from them has increased public knowledge of this kind of research. This
heightened ability of research in human population genetics to affect human societies has brought with it not only notoriety but also new ethical problems.
These ethical problems are in addition to the long-discussed ethical issues of
more traditional individual or family-centered human genetics research (13). Each
of the individual subjects of human population genetics research is an individual
human subject, protected by governmental rules on informed consent and ethical
review boards. What makes genetic research on populations different, and novel,
is that the populations being studied are also, in effect, “subjects” of the research.
Those populations are collectively subject to possible benefits and harms from the
research. These collective risks are beginning to be discussed by researchers and
ethicists, but have yet to be well addressed by regulators.
This review first describes the new setting for research in human population
genetics. It then examines the ethical concerns affecting this research. It discusses
first the most important, most controversial, and most debated issue—whether
researchers must obtain the informed consent of the whole group. The chapter
then discusses other vexing issues that have received much less attention. Those
include special problems caused by researchers’ commercial interests, confidentiality, control over the uses of the research and materials, and return of information
to the population. All of these issues, including informed consent, are just beginning to be discussed. In the ethics of human population genetics, at this point hard
questions are much more common than clear answers.
THE NEW HUMAN POPULATION GENETICS
The study of genetic differences between human populations dates back to the First
World War and pioneering studies of the frequency of the different ABO blood
groups among various ethnic groups (17, 31). But progress was slow. Phenotypic
markers clearly linked to genetic variations were difficult to find and data were
expensive to collect. Over the decades, a great deal of information did accumulate
about particular classical markers in some populations (3). In the 1990s, however,
the ability to test DNA directly for variations and the decreasing cost of that testing
made it feasible to consider studying large numbers of markers in large samples.
Some researchers interested in human population genetics seized the scientific opportunity provided by the new technologies—and the apparent political
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opportunity provided by the Human Genome Project—to launch the Human
Genome Diversity Project (HGDP) (2). While the Human Genome Project mapped
and sequenced one reference human genome, the HGDP was to sample over 500
populations, preserve the samples both as cell lines and as extracted DNA, analyze
the samples, and make their results publicly available through a computer database
(18). Over the past decade, the HGDP has generated more controversy than samples (it remains largely in the planning process with very limited funding), but it
did draw the attention of researchers, ethicists, and activists to the problems raised
by population-wide genetic research (11, 15, 29).
Although the HGDP’s interests were academic and largely non-medical, easier and cheaper analysis of genetic markers made population genetics of interest
to biomedical researchers. Most research on genetic diseases had focused on extended families with a high rate of the specific disease. Researchers would examine
the genomes of family members, both affected and unaffected, to see which genetic variations they shared. Some researchers argued that genes linked to disease
would be easier to spot in populations that had high incidence of the disease and
were relatively genetically homogenous. Academics and biotechnology firms both
began “gene hunting” for disease-linked genes in these isolated populations. The
involvement of the biotechnology firm Sequana in research on the genetics of
asthma among the people of Tristan da Cuhna was well-known, and controversial
(1, 30), but similar research was undertaken among a wide variety of populations.
Eventually, interest moved beyond research on particular diseases in small populations. Scientists and firms began to discuss the collection of large amounts of
phenotypic data, usually from clinical medical information, and genetic data, from
DNA samples, on entire populations. These population-wide “genotype/phenotype
resources” became feasible as the costs of genetic analysis and computing power
continued to decline. They were made attractive by the limited results from more
traditional, family-focused research. Good evidence exists that many common diseases such as heart disease, asthma, non-insulin dependent diabetes, and schizophrenia, have substantial links to shared genetic variations. Although family studies
have found the genetic variations linked to many rare diseases, they have largely
failed to establish links to these more common disorders. Researchers hoped that
statistical mining of a “genotype/phenotype resource” on a whole population might
reveal weak, but still important, associations between variations in one or more
genes and disease.
The first attempt to create such a population-wide resource has been made by
deCODE Genetics in the Republic of Iceland. deCODE, founded by an Icelandic
scientist, plans to create linked databases of clinical medical records, genotypes,
and genealogical data on all 280,000 Icelanders (14). The company was founded
in 1996; by 1998 it had convinced the government of Iceland to support legislation
that would allow a private firm to create a “health sector database” made up of clinical medical records from all Icelanders. The law passed in December 1998, and
deCODE was named the “licensee” under the Act and was empowered to create
the database in January 2000. The firm has created the genealogical database and
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plans to create the genetic database without further government support (5). Although deCODE has not yet proven that its resource will be effective—the health
sector database remains stalled in controversy—similar initiatives to create genotype/phenotype resources with large populations samples have been announced
in Estonia, Sweden, Tonga, Newfoundland, and the United Kingdom (16). These
resources are extremely expensive to create; most of the plans, like deCODE’s,
rely on commercial funding.
Thus, research on the genetics of human populations has become a high-profile
business. These groups may have their own benefits, risks, and interests with
respect to research that are somewhat different from those faced by individuals
within the groups. But the regulation of research on human subjects has focused on
individuals, not on groups. The existing federal regulations in the United States,
the so-called Common Rule (35), do not recognize a role of groups; they deal
only with individuals (24). Nongovernmental groups have made tentative proposals for guidelines that take group interests into consideration in research, notably
in epidemiological standards promulgated by the Council for International Organizations of Medical Sciences and in the Model Ethical Protocol for Collecting
DNA Samples of the North American Regional Committee of the HGDP (4, 26).
The process of addressing the ethical issues of human population genetics is thus
under way, but there is as yet no consensus—nor governmental regulation.
INFORMED CONSENT
Informed consent has raised the most controversy regarding the ethics of human
population genetics. Although some have questioned the application of even individual informed consent in some parts of this research, the more interesting
question, and the source of a burgeoning academic literature, is whether some
form of consent should be required from the group as a whole.
Individual Informed Consent and Iceland
The individual informed consent of a human research subject is generally required
by law in the United States and in most other countries and by relevant international
guidelines, such as the Helsinki Declaration of the World Medical Association (34).
Exceptions involve research with no significant risk; research involving children
and the mentally incompetent (whose parents or guardians must give consent); and,
in a very few cases, research that by its nature cannot be conducted with informed
consent, such as research on patients brought unconscious to hospital emergency
departments after heart attacks. The patient (or guardian) need not only consent,
but must do so after being informed of the nature of the research and of the specific
benefits and risks it might hold for him. The requirement for informed consent grew
from both respect for the individual’s autonomy and the belief that an individual’s
informed consent would be one check on overly dangerous research (7).
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Iceland’s Health Sector Database has been controversial in part because its
authorizing legislation does not require that Icelanders give their informed consent
before their clinical medical records are included in the database. Instead, the
legislation gives living Icelanders a chance to opt out. They can file a form with
the government stating that they do not wish to participate in the database. The
form will prevent the addition of any new data on them to the database, although
it will not lead to the removal of any data that has already been entered. There is
no requirement that Icelanders be told of the specific research uses of their data.
The use of this “presumed consent” in place of informed consent has caused
great unease. In Iceland, this has been a major objection by Mannvernd, an Icelandic
organization on research ethics founded in response to the Health Sector Database
law (22). It has also prompted denunciations from the World Medical Association
and from various ethicists (6). Iceland and deCODE defend the lack of informed
consent by comparing the planned uses of the Health Sector Database to epidemiological research, which typically proceeds without informed consent when it uses
clinical medical data from which personal identifiers have been removed (5, 19).
It notes that it plans to get individual informed consent for the genetic samples it
collects. Critics of deCODE counter that the Health Sector Database should not be
viewed in isolation from the genetics and genealogical databases; it is, they argue,
a crucial part of this broader plan and should not follow the precedents of purely
epidemiological research. Finally, deCODE points out that under ten percent of
the Icelandic population has, in fact, opted out of the database. The Health Sector
Database remains tied up in disputes in Iceland; it is not yet clear whether it will
proceed as currently planned. Interestingly, the other proposed population-wide
genotype/phenotype resources have made it clear that they will proceed only with
full individual informed consent.
Group Informed Consent
The more interesting consent problem in human population genetics concerns the
consent of the population. Should some kind of consent or at least consultation
with a population as a whole be required, in addition to individual informed consent, before researchers study the genetic variations in that population? At least
three positions have appeared—one in favor of a group consent requirement, one
opposed to such a requirement, and one intermediate position that favors group
consultation.
THE CASE FOR GROUP CONSENT The case for a group consent requirement is
based on both a principled and a pragmatic argument. The principled argument is
that the population itself is, in effect, the research subject and should be treated
as such. Research done on, for example, the Irish may have benefits and costs
to everyone identified as Irish, whether or not that person ever consented. The
risks may be quite concrete, such as an increased chance of discrimination in
employment or insurance. They could be more stigmatic, if someone were to
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claim, for example, that the population had a high level of a genetic variation
associated with alcoholism. Or risks could be more cultural in nature, as where the
anthropological or historical uses of population genetics undercut a population’s
own history or even their political or legal claims to certain territories.
The pragmatic argument is that research in the midst of a population will often require the approval of the population’s governance structure or leadership.
This de facto group consent requirement often appears in some kinds of research.
Without the cooperation of the local officials, the relevant religious figures, or the
educational or medical professionals, much epidemiological research would not
happen. Without the approval of the studied population, either formal or informal, ethnographic research would be impossible; without at least tacit consent,
the ethnographer would never gain access to the population to study it. The shift
from studying genetic variations in families with high rates of disease to studying
genetic variations in communities will often force researchers to deal with some
kind of collective consent. The pragmatic argument also has a political aspect;
groups might not oppose certain types of research if they were confident that they
would only be included in the research with their collective consent.
Some Native American tribes and indigenous organizations have asserted that
group consent is required, and some organizations have, to a greater or lesser extent,
agreed (33). The research organization that has been most active in endorsing group
consent is the North American Regional Committee of the HGDP (on which the
author serves). In 1996 that group completed a draft “Model Ethical Protocol for
Collecting DNA Samples” (13, 26). That document aimed to give broad ethical
and practical guidance to researchers and others in collecting DNA samples for
the Project. Among other things, it stated that, in addition to individual informed
consent:
[T]he HGDP requires that researchers participating in the HGDP show that
they have obtained the informed consent of the population, through its culturally appropriate authorities where such authorities exist, before they begin
sampling. If, for example, the Navajo Nation decided that it would not participate in the HGDP, the HGDP would not accept samples taken from members
of that population.
The Model Protocol recognized that there would be difficulties in implementing
its group consent requirement. It foresaw two major problems in recognizing the
“culturally appropriate authorities” and in defining the relevant group.
Who can provide consent? The Model Protocol singles out “culturally appropriate authorities.” These are the people or groups whose authority the community
recognizes. The Protocol notes that determining who the actual authorities are will
often be difficult. For example, a federally recognized tribe will have a tribal government, which clearly would be at least one of the authorities. But it may also have
people or organizations—elders, religious leaders, traditional leading families or
clans—whom the members obey. In those cases, many different groups might
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be culturally appropriate authorities. Alternatively, in some cases, particularly
in small populations, a community consensus, and not a discrete person or group,
might be the relevant authority.
The problem of defining the group stems from the common lack of a formal
or universally accepted definition of a group or its members. For ethnic groups or
other communities, this has both a horizontal and a vertical component. Where
does one draw the boundary between similar groups? Are two Cree bands living
close together but on separate reservations one group or two groups? Do “the Irish”
include only citizens of the Republic of Ireland or also the British subjects who live
in Northern Ireland? The vertical component asks at what level a group is defined.
Is the relevant group a particular village in the Navajo Nation (the proper term
for the Navajo Reservation)? Is it the entire Navajo Nation? Is it all Southwestern
Native Americans who speak languages related to Navajo, thus encompassing the
Apache? Is it all Native Americans who speak a language in the NaDene language
family, from inland Alaska to the Southwest? Or is the relevant group all Native
Americans? Are Irish-Americans a group or is the relevant group all those with
Irish ancestry?
The Model Protocol took an empirical approach to this issue. It recommended
starting by assuming that the “group” was the community in which the research
was being done. That population should then be asked its definition of its “group”
for purposes of both the horizontal and the vertical definitions. The Model Protocol
stated with respect to the vertical issue that
Ultimately, the question of the levels at which consent should be sought is
one that only the population can answer. Consent must be sought at higher
levels if the population believes it is meaningfully part of such a higher level
grouping and if there are entities operating at that level whose decisions on
the population’s participation in the research would be accepted by the local
population as authoritative.
The definition of the group raises another dilemma not expressly addressed in
the Model Protocol. What kinds of human organizations should count as “groups”
(12)? The ethnic or religious communities that the Model Protocol describes are
culturally meaningful entities whose members are expected to have genetic similarities through their genealogical connections. But other kinds of groups have also
been the subjects of genetics research. Families have been the classic locus of genetics research. Should they count as “groups” for which group consent is needed?
Similarly, many genetic (and nongenetic) diseases have spawned “disease organizations,” entities advocating for those with the disease. Would the American
Lung Association or the Cystic Fibrosis Foundation be a group whose consent
would be required for research in their fields? The Model Ethical Protocol did
not address these questions because the HGDP was not interested in those “populations,” but, like ethnic groups, members of a family or victims of a particular
disease all face some benefits and some risks from research in that family or on that
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disease. The logic behind group consent might extent to them, but the problems
of implementation seem more daunting.
The Model Protocol recognized that neither identification of “culturally relevant
authorities” nor definition of the relevant group would always be easy. It said that
each question could only be answered “in the detailed factual context of a population,” and it recommended that researchers come with the expertise, the funding,
and the time to make informed determinations. The North American Regional
Committee, in the Protocol and elsewhere, also recognized that there sometimes
would not be any “culturally relevant authorities.” Who, for example, would be
a culturally appropriate authority for Irish-Americans or the Ashkenazim? The
Model Protocol pointed out that
In cases where communities do not have a culturally appropriate authority,
there still may be institutions that provide a useful focus for community discussions and consensus. For example, in a Catholic parish in Seattle that
served a largely Irish-American population, the parish priest would certainly
not be a culturally appropriate authority to give permission to work with that
population. But the priest might be a useful and knowledgeable figure with
whom to discuss the community’s participation and the parish might provide
the best focus for the community. Through its auspices the researcher may
be able to present information and seek approval from active members of the
community.
In such situations, even the authors of the Model Protocol recognized that
“group consent” was impossible. They required such consent only where it was
feasible and settled for consultation and discussion in other circumstances.
THE CASE AGAINST GROUP CONSENT The concept of group consent has not been
widely adopted by researchers. Although adopted by the North American Regional
Committee of the HGDP, it has not even been adopted by the entire HGDP. No
doubt some of the reluctance is purely practical—why would a researcher take on,
voluntarily, a new obligation that promises to be expensive and time consuming
(27, 28)? Even the drafters of the Model Protocol acknowledge that its implementation will be difficult. But there are also more theoretical objections.
One common objection is that this concept favors group rights over individual
rights. If a mentally competent adult wishes to participate in research, why should
her right to do so be overruled by a collective decision, particularly where the group
definition or the identification of culturally appropriate authorities is uncertain?
Although, on occasion, a few U.S. courts have implied that the First Amendment
includes a right to engage in scientific research, there is no precedent for finding a
legal right to be a research subject. In fact much of the federal regulation of human
subjects research is aimed at keeping people from being research subjects. The
Common Rule, where it applies, requires not only informed consent but also review
and approval of research protocols by ethics committees called Institutional Review
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Boards (IRBs). IRBs are required to determine whether the research is appropriate,
including whether its potential benefits justify its risks. If an IRB concludes that
the proposed research does not meet that standard, the research may not take place
no matter how much an individual wants to be a research subject. There seems
little principled difference between an IRB making a decision, in opposition to a
potential research subject’s wishes, that the risks to her of the research are too high
for it to proceed and a “culturally appropriate authority” determining that the risks
to a population are too high for it to proceed.
Two other objections are less easily countered. Both were made by a National
Research Council committee to study the HGDP (25) and by bioethicist Eric
Juengst, who served on that committee (20, 21). The first objection is a version
of the vertical problem of defining the relevant group. Juengst points out that all
groups are nested within other groups. Ultimately, information about the genetic
make-up of any human group, or human being, provides some information about
every human group and every individual. This information then carries with it both
potential benefits and potential risks. Indeed, given the strong similarity between
many human and nonhuman genes, research with other animals could be said to
trigger an obligation to seek group consent of all humans.
Juengst’s other argument focuses on the possible effects of group consent. Although the scientists involved in the HGDP argue that genetic differences between
ethnic groups are trivial and that human races have no genetic meaning, he points
out that requiring “group consent” for genetic research implies that groups, including races, do have a genetic basis. Otherwise, why should genetic research in
particular be subject to a group consent requirement? A group consent requirement
could thus reinforce scientifically inaccurate and socially dangerous beliefs about
genetics and race.
Juengst does recognize the reasons that have led some to argue for group consent. He proposes that, as a partial solution, members of the group be reminded,
during their individual informed consent process, that the results of the research
might have implications, good or bad, for all members of the group.
GROUP CONSULTATION—AN INTERMEDIATE POSITION Other ethicists have opted
for an intermediate position, endorsing group consultation but usually not requiring
formal consent by the group. Morris Foster has been the leading proponent of
this position, along with Richard Sharp (8, 9, 32). Drawing from his work with an
Indian community in Oklahoma, Foster concludes that group consent is too difficult
to implement. Researchers, he argues, should have an obligation to inform the
community widely and to consult with it. This may have the same effect as a group
consent requirement—if substantial community opposition develops, the research
may not be able to proceed—but without the difficulties of formally identifying
the group and its culturally appropriate authorities. Like both the North American
Regional Committee and Juengst, Foster calls in addition for more attention to
group considerations by IRBs that review population genetics proposals.
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A Special Case of Group Consent—Federally Recognized
Indian Tribes and Other Governments
In the United States, one set of groups does have a special status in consenting
to research: the roughly 550 federally recognized Indian tribes and Alaska Native
villages. These groups are political sovereignties, predating the United States and
recognized by the United States as having political authority. Tribal governments
have powers similar to those of states, including the power to make and enforce
laws on the territories as long as they are not inconsistent with federal law. Some
other countries recognize similar political powers in their indigenous groups.
At least within its territorial jurisdiction, therefore, a federally recognized tribal
government has the power to make a collective decision whether to allow particular population genetics research in that jurisdiction. Some U.S. tribes have been
exercising that jurisdiction, either through the regular mechanisms of their tribal
governments, through tribal IRBs, or through use of an IRB established by the
Indian Health Service (10). This application of group consent is not only legal,
but it avoids some of the concept’s implementation problems. The tribal government in this case is a culturally appropriate authority and its membership is clearly
and legally defined. In the United States, Native American tribes, along with some
tightly endogamous European religious groups such as the Amish or the Hutterites,
are among the populations of most interest to researchers, for both biomedical and
anthropological reasons. With respect to federally recognized tribes, group consent
may be a fairly simple, and legally binding, requirement in the United States for
much human population genetics research.
Similarly, in some cases a national government may be able to give group consent for its citizens. The deCODE project in Iceland, though it may lack individual
informed consent, seems to meet the group consent requirement. A universally
recognized (and democratic) government passed legislation approving the plan
after substantial parliamentary and public discussion and debate. Many national
governments, including Iceland’s, accomplish similar ends through requiring approval of human subjects research by governmental bodies or the equivalents of
IRBs. Those governments arguably are in a position to assess the overall risks and
benefits to their people and to authorize, or veto, particular research projects.
The group consent concept does cause some difficulties even with national governments and federally recognized tribes. First, both national and tribal governments sometimes represent more than one population. Most countries have ethnic
or cultural minorities. In some cases tribal governments encompass several different tribes, including sometimes communities with separate languages and cultures. Here the national or tribal governments may not be good representatives of,
or “culturally appropriate authorities” for, their minorities. Consider, for example,
the moral authority of the Nazi government to consent to research on German Jews.
Second, both tribal and national governments may have limited power over
group members outside their territorial jurisdiction. The Navajo Nation may not
learn of, or be able to control, research voluntarily undertaken by Navajos living
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in Los Angeles. The People’s Republic of China, which recently adopted detailed
regulations governing the export of “Chinese DNA,” has little or no power over
the vast Chinese diaspora worldwide. Unless the researchers themselves are bound
to respect group consent, the territorially based power of governments may prove
unable to enforce this principle.
OTHER ISSUES
Group consent has received the most attention, but the group nature of population
genetics raises other special issues or, in some cases, raises conventional issues
in unusual ways. At least four deserve mention: commercialism, confidentiality,
control of research uses and materials, and return of information. These topics
have only rarely been discussed in the scholarly literature (16) but are likely to be
of increasing importance in human population genetics, at least with some groups.
They have been the subject of much conversation at conferences with Native
American leaders and researchers; the following analysis is drawn heavily from
those discussions. Ethical questions are raised concerning a researcher’s obligation
to protect research subjects from unfair treatment or harm. There are also practical
considerations that may well involve difficult negotiations between researchers
and groups.
Commercialism
Biomedical research has become more commercial in the past two decades; even
academic researchers often have connections with for-profit companies. For some
research subjects, the increased commercialization strains the altruistic basis for
their participation. When the researchers hope to make millions of dollars from
stock options from the application of their findings, the subjects may find it hard to
accept satisfaction at helping humanity as their only reward. This conflict is even
more pronounced with associational research. When genetics research is based on
disease families, research subjects have a strong motivation to participate to help
themselves and their kin. Associational genetic research, because of the weakness
of the connections its seeks, has no such direct link to the health of a research subject
or his family. At the same time, the high cost of genotype/phenotype resources
makes it very likely that commercial firms are performing the research.
In only a few instances have research subjects sought a share of the financial
value of research, with the case of John Moore being the most prominent (23).
Claims to share in future financial benefits may be more common with populationbased research for several reasons. First, any one individual is unlikely to be crucial
to an important genetic discovery. The discovery of BRCA1, for example, relied
on thousands of people, affected and unaffected, with mutant genes and normal
ones. Each was important to the collective result, but no single person was crucial.
In research with a population at high risk for a disease, no individual member is
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crucial, but the population itself may be. To the extent that group consent or other
forms of permission or consultation are involved, the population may have more
awareness of the potential commercial value of the research than an individual
would and may be better placed to negotiate for a share. This may be particularly
true for governments. The Chinese regulations on export of DNA require some
profit sharing with institutions in China. After much criticism, deCODE agreed
to give the Icelandic health system a share of its profits (though capped at about
$1 million per year). And recently a disease organization, the Canavan Foundation,
has sued the hospital that holds the patent on the gene linked to the disease,
claiming that its participation in the research gave it rights with respect to the
gene’s commercial use.
At the same time the group nature of population genetics makes financial claims
more likely, it also makes financial sharing more feasible. Providing a benefit for
participation in research is a tricky matter, as the benefit should not be inappropriate
or so great as to be coercive, a matter of great concern to IRBs in reviewing research
protocols. With population-based research, a share of the proceeds might be used in
a way that benefits the entire relevant population. This would reward all those whose
participation was important in the discovery rather than one individual whose DNA
happened to be used to clone or sequence the relevant genetic variation. The dilution
of the financial incentive this strategy would cause could have an added benefit. If
an individual were promised a profit share for his participation, he might be unduly
influenced to take part in the research, motivated by the speculative value of that
share rather than a careful weighing of the possible medical benefits and the risks.
The HGDP, both in North America and worldwide, committed itself to providing
a fair share of any financial benefits to the participating populations. That example
has not been widely followed, but organized populations may well demand such
guarantees from researchers. Whether and on what conditions IRBs will permit
such sharing of financial benefits remains unclear.
Confidentiality
Individual subjects usually want, and receive, assurances that their identities will
be kept confidential. This restriction often involves using false names in publications, obscuring photographs, and sometimes even doctoring pedigrees so that
individuals cannot be identified. Communities may have similar concerns. Thus,
whereas a population might be willing to participate in research on a stigmatizing condition that is unusually common among its members, it might not want
to be publicly identified. On the other hand, some populations might want their
participation heralded.
Group identities, like individual identities, can be obscured. A geographical
location can be referred to in broad terms; a population can be defined by language family rather than language. The Navajo, for example, could be described
as a Southwestern tribe or as a tribe speaking a NaDene language. Either description would leave a reader uncertain just which tribe had participated. Such group
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confidentiality does have its costs, though. For example, obscuring the identity of
the population may make it impossible to replicate the research. Or subsequent
researchers may not be able to make good use of the initial publications for lack
of an exact identification. Although the chances of a particular individual, or even
family, being the subject of study by several research teams will usually be small,
populations may well be studied by many researchers over many decades.
Again, little guidance exists on this issue. Researchers should discuss with the
population and its leaders what kind of group identification they would like. At
all costs, researchers should avoid unpleasant surprises to the research subject
population. Unexpected publicity could well leave the group embittered, violating
their expectations of the present researchers and making them less willing to
participate in future research.
Control of Research Uses and Materials
Individual research subjects will have little knowledge of the possible uses of the
results, data, and biological materials involved in the research. Populations may
have more knowledge and greater ability to bargain about their uses and disposition.
Based on conversations with members of Native American groups, three classes of
safeguards emerge as particularly important to them: prior approval of publication,
control over subsequent uses (and users) of data and materials, and the ultimate
return of data and materials.
Some Indian tribes have demanded prior review and approval of all publications.
They seek this in order to make sure that the publication accurately reflects tribal
understandings and does not harm the tribe’s interests. The tension caused by
this demand is likely to grow. Researchers are understandably reluctant to put
their findings into the hands of non-scientists for review. The potential for their
results to be delayed, or entirely lost, certainly exists. On the other hand, tribes
are becoming increasingly sensitive to unanticipated negative effects of research
publications; the Navajo, in particular, were outraged that the Hanta virus outbreak
of the late 1990s was initially termed the Navajo virus. One aspect of publication
review is acutely susceptible to misunderstanding: the definition of what constitutes
“publication.” The researcher may be prepared to submit a draft article for review,
but a tribal government might believe that all presentations of the data, including
talks and posters, should be reviewed in advance. Prior review and approval may
be contentious in many negotiations for group participation in research; the one
universal goal should be to ensure that whatever agreement is reached is clearly
and mutually understood.
Tribal governments have also come to understand that data and biological materials do not necessarily remain with one researcher. A tribe may have built a
relationship of trust with a particular scientist but may be upset to discover that
“their” data and materials have been transferred to other researchers. Apprehension
may be particularly acute when biological materials are transferred to widely accessible repositories, such as the American Type Culture Collection or the repositories
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at the Coriell Institute. Tribes may increasingly demand the power to approve, or
deny, any transfer of materials to different researchers, inside or outside of the lead
researcher’s institution. Such restriction on sharing data and materials does not fit
easily into current research methods. To some extent, restricted access may even
violate a researcher’s perceived obligation to help colleagues in other laboratories
try to verify or falsify his results. At the very least, transfer would become slower
and more cumbersome, hence likely to be another charged subject of negotiation.
Finally, tribal governments may require the data and biological materials to be
returned to their custody after a fixed period. Such a provision for return is some
guarantee that the data and materials will not be transferred or used without their
permission. For biological materials, return will also be consistent with traditions
concerning the disposition of human materials, where relevant. Researchers, on
the other hand, are likely to resist the return or destruction of data and materials.
Once gone, the data or materials can no longer be used for confirming the initial
results or for extending the earlier research.
Return of Information
One of the most difficult ethical issues concerning individual research subjects is
whether, or to what extent, a researcher should return significant information gained
in the research to the subject. Population-based research faces similar issues.
On the one hand, tribal leaders often complain that their people never learn
the results, if any, from the research conducted with them. Mailing a reprint of
a scientific article does not constitute effective communication, even where the
population’s first language is English. Some tribes are now asking for return visits to
discuss results or for translations of articles resulting from research into colloquial
English or into their own languages. On the other hand, populations may not want
to receive some kinds of information. A group might be willing to participate in
research that could lead to results inconsistent with its own histories and myths on
the condition that such inconsistent information not be returned to the population.
Once again, the only sure advice is to discuss these issues with the group in advance,
reach a clear agreement, and keep that agreement.
CONCLUSION
Genetic variations are both individual and collective. Except for monozygotic
twins, every human being has an entirely unique genome, a combination of genetic variations never before seen in the history of our species. But we share half
of our genetic variations with our siblings, parents, and children. And as families extend into ethnic groups, the commonality, although diluted, continues. As
genetic research moves increasingly into groups—communities, ethnic groups,
tribes, nations—researchers and research subjects are confronting the uncomfortable reality that groups, like people, face potential benefits and harms from their
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participation. Serious ethical and practical challenges are involved in protecting
the interests of groups—and of the people who constitute them. But the challenges
must be met, for the protection both of the people whose participation makes
research possible and, in the long run, for science itself. Embittered and angry
research subjects are unlikely to participate themselves in future research or to
provide political support for research. Given the potential of population genetics
research for relieving human suffering, such an outcome would be tragic.
Visit the Annual Reviews home page at www.AnnualReviews.org
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