Background and Significance
1. Background: Why genetic research ethics?
When the original ELSI working group met in 1989 to identify
the most urgent issues for attention as the Human Genome Project
got underway, it produced a nine-item agenda, subsequently organized
into three "high priority areas": 1.) issues in the
clinical integration of new genetic knowledge; 2.) genetic privacy
and discrimination issues; 3.) public education about both of
the above. These priorities reflected the working group's concern
for the impact of genomic research on the larger society, and
the agenda consequently emphasized issues in the application
and use of new genetic information, downstream from the conduct
of basic human genomic research itself.1 This anticipatory orientation
was justified in part by the reassuring fact that human geneticists
had been active participants in the bioethical discussions of
research ethics in the 1970s and 1980s, and their clinical ethos
already showed a strong commitment to the values of shared decision
making, patient autonomy, and informed consent that those discussions
promoted.2 Against this history, "ELSI problems" were
expected to emerge primarily after any new genetic information
left the relatively civilized jurisdictions of the labs.
As the ELSI program pursued its initial agenda through the
1990s, however, a very interesting thing happened. As the program's
grantees worked with human geneticists to conduct pilot studies
of genetic testing, develop adequate protections against genetic
discrimination, and assess the educational needs of different
communities, issues emerged that raised new questions about
conventional practices in human genetic research: Should potential
insurance risks be disclosed in obtaining informed consent for
family studies? Should genetic testing research be expedited
through IRB review simply because of its minimal physical risks?
Should blanket consents to research with identified pathology
specimens license gene-hunting studies without recontact? How
should families and more extended groups be recruited into genetic
studies, given our commitments to privacy and voluntariness?
To what extent can confidentiality be protected when the principal
means of conveying a study's results in publication is through
a detailed diagram of the participant's family tree? Initial
ELSI-funded inquiries into these questions revealed a plethora
of home-grown strategies within the scientific community, based
on moral convictions that were often mutually shocking to their
respective scientific advocates.3 By 1995, the general area
of "human genetic research ethics" had been added
to the program's list of "high priority areas." It
has gained prominence in subsequent program plans as ELSI program
activities and grantees have elevated other specific issues,
such as consent for stored tissue research4 and family member
privacy,5 to the level of national debate and policy making.
Meanwhile, of course, human genome research itself has been
taking the genetic research community into new territory with
extraordinary speed. As new genomic tools have made DNA-based
strategies useful across a wider range of biomedical fields,
research ethics questions have emerged for which there are no
clear conventional answers. How should the "right to withdraw
from research" apply to DNA banking and repository studies?
How can participant privacy be protected in research that places
individual genetic profiles into public databases, against which
any personally identified new DNA samples could be matched?
What does informed consent require in studies in which the participant's
whole genome will be scanned for multiple markers with uncertain
functional connections with the phenotype in question? How should
research be conducted on plieotropic polymorphisms that already
have had clinical testing protocols established for some of
their associations? How should population studies of genomic
variation be designed if they are to avoid stigmatizing the
participating communities, and how should those communities
be involved in that process? What is the appropriate role of
various translational incentives, from commercial prospects
for researchers to benefit-sharing agreements with participants,
in the design of basic human genetic studies? How does one design
the research to test the utility or efficacy of putative "enhancement"
interventions without facilitating their exploitation? These
questions are critical to the genomic community's ability to
successfully accomplish the ambitious scientific goals it has
set for itself, and are coming up across the board in biomedicine
as genomic tools are applied to research agendas in different
fields.
The genomics community has been assiduous in underlining the
significance of these issues in its planning for the next phase
of human genetic research. The ELSI program at NHGRI has already
been responsive in funding relevant individual research projects,
cross-disciplinary fellowships, research consortia, and policy
workshops. Investigators at CWRU have had the opportunity to
be active at all these levels of activity. However, like many
topics under the ELSI Program's umbrella, the challenge of developing
intellectually-sound, evidence-based recommendations for scientific
practice and public policy in this area requires more than a
piece-meal response.
In the grand scheme of things, the ethics of genetic research
with human subjects may seem a relatively narrow window on the
ELSI landscape. But the tower of genetic research is tall enough
that the view through this window covers a very wide domain
of ELSI issues. To make sense of this view at the level of integration
required to produce useful advice to those on the ground requires
more than the focused telescopes of individual studies or the
episodic overflight reconnaissance of conferences. It requires
sustained conversation by an interdisciplinary mix of observers
living and working together in that window's room, like air
traffic controllers or forest fire tower rangers.
This team needs to be "in each other's business"
regularly enough to be able to ask the right questions to address
current issues and to look in the right directions for new hotspots,
which can be difficult if collaborators are geographically scattered.
Moreover, to interact effectively enough to offer the rapid
responses sometimes required of such observers, the ideal team
will have to be comfortable with blunt communication and working
together under stress -something inhibited by the formalities,
tensions, and mutual education inherent in completely new collaborations.
The purpose of the CGREAL is to build and equip just such an
observation post for genetic research ethics, peopled by scientists
and ELSI scholars whose existing working relationships can allow
them to hit the ground arguing (amicably) about the issues.
This proposal is its blueprint.
2. Aim-specific rationales: What research questions need answers
in genetic research ethics?
Our team of investigators has been meeting regularly since
the release of the CEER RFA to develop the CGREAL blueprint.
One of the rewards of those meetings has been the emergence
of several useful new conceptual heuristics for our work. The
first of these now serves to ground the CGREAL's Center-wide
specific aims. This is the hypothesis that an adequate overall
account of genetic research ethics should include considerations
from four perspectives: 1. the role of cultural meanings brought
to genetic research by its participants (and the public) in
shaping research risks and benefits; 2. the role of social values
held by scientists (and the public) in driving the pace and
direction of the science; 3. the role of scientific (and public)
moral imagination in anticipating the implications of genetic
research; 4. the role of responsible, evidence-based scientific
(and public) policy building in optimizing genetic research
outcomes (Fig.1). Each of these corners of genetic research
ethics offers an interesting vantage point on the others, and
each has its devotees amongst ELSI researchers. Each has also
been identified before as key elements in the ethics of genetic
research. Celeste Condit focuses on the impact of genetic research
on those it describes in her insightful analyses6; Anders Nordgren
emphasizes the role of scientific social values;7 Daniel Callahan
has underscored the importance of moral imagination;8 Ben Wilfond
and Kathleen Nolan have demonstrated the value of evidenced-based
thinking for responsible policy-making on genetic issues.9 When
viewed collectively from above, however, two things become clear:
First, none of these perspectives is privileged: each plays
a necessary but insufficient part in the ethical design, conduct,
and evaluation of genetic research. Second, there are important
unmet informational needs in each quarter of genetic research
ethics for many kinds of genetic research. Our Center-wide research
aims reflect these needs.
What does it mean to participate in human genetic research?
Our first Center-wide aim is to improve our understanding of
the relationship between human genetic research and the humans
it seeks to benefit by elucidating the cultural values and beliefs
that influence different people's reactions to and experience
of genetic research participation. As a wider range of biomedical
fields embrace genetic and genomic research, increasing numbers
of individuals, families, communities, and populations will
find themselves being invited to participate in genetic studies.
Their responses to those invitations and their experiences as
research participants will be influenced heavily by their beliefs
about the meanings of genetic information and among those beliefs
their interpretations of the meaning of genetic research findings
for their identities as people will be critical.
The literature generated by ELSI-funded research to date suggests
that four overlapping aspects of personal identity are implicated
in genetic findings and animate many of the specific ethical
issues that genetic researchers and participants must face:
Future Potential
Many human beings define themselves in terms of what they expect
to become as much as they do in terms of what they have been.
This is why genetic information that is considered predictive
of future experience is so potent - it seems to offer a preview
of upcoming chapters in people's life stories that threaten
their own authorship.10 By the same token, the prospect of improving
upon the phenotypes outlined in the first genetic drafts of
those stories is what makes the potential for intervention at
the genetic level so appealing to so many.11
Ancestral Origins
Human beings are also familial animals. Our expectations of
the future are set against a background of kin relationships
that define our origins and shape our personalities. This is
why the impact on familial harmony is the most ubiquitous of
the various social risks of genetic research participation that
ELSI research has illuminated.12 It is also, of course, why
genetic studies that promise to confirm, enrich, or extend the
lineage stories through which families understand themselves
are of such interest, and why the interpretation and communication
of their results can be so controversial.13
Community Memberships
Our identities are also influenced significantly by the communities
in which our families live. Common bonds of religion, culture,
or experience can create defining identities for members of
groups ranging from global diasporas to local caregiver support
groups. For some, those identities are defined precisely by
their rejection of the community's beliefs and values. This
is why genetic 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.14 At the same time, it is this sense of corporate
identity that animates the debates over ownership and authority
in the commercialization of genetic research, as genetic research
redefines communities in terms of the unusual genotypes that
can be found amongst them.15
Ethnic affiliations
Finally, 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 segregate the social
categories of race, ethnicity, tribe, and nationality. Social
categories, by definition, provide identities by differentiating
their members from other people. It 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.16 Yet for those who have been marginalized
by those categories in the past, justice seems to demand increased
access to whatever benefits genetic research participation might
yield.17
These four features of identity-Future potential, Ancestral
origin, Community membership, and Ethnic affiliation-make up
the genetic "FACE" of the individual.18 It is no coincidence
that they raise issues for genetic research ethics. For the
last 300 years, the moral significance of the FACE in determining
human rights and obligations has been the central moral controversy
within democracy's Diaspora. This background debate is what
animates the contemporary discussion of specific genetic research
issues and gives them such profound significance. Over the last
decade, ELSI research has helpfully illuminated many of these
specific issues, but no group has had the breadth or stability
to reflect adequately on the significance of the fact that genetic
research is always about our most socially important feature-the
human FACE.
2. What social values should help steer genomic research?
Our second Center-wide aim is to improve our understanding
of the relationship between human genetic research and the human
benefits it promises by elucidating the influence of translational
incentives, ranging from commercial prospects and specific benefit-sharing
agreements to general public health goals on the design and
conduct of basic genetic research. Scholars of the culture of
science have long noted that social values and incentives shape
the research agendas of the basic sciences, including molecular
biology. Since its beginning, the genome science community has
been explicit in citing human health benefits as the ultimate
end of its efforts to accomplish the Human Genome Project and
bring genomic tools to biology and medicine. Two recent phenomena
are testing the limits of that conviction, and have yet to be
adequately examined.
The first development is the logical conclusion of a long-standing
argument. One of the persistent tensions within the genome community
has been the conflict between the moral commitment to public
benefit and the interests of individual genome scientists in
capitalizing on their work for private academic or financial
gain. The result is a remarkable history of data-release agreements
and public disputes over intellectual property policies, culminating
in the famous "race" between the public and private
sectors to complete the human genome sequence. This tension
has not been a high priority issue for the ELSI research community,
although ELSI-funded studies of the relationships between genome
scientists and commercial concerns document the alacrity with
which the community has "transferred technology" to
commercial concerns.19 Now, however, economic logic has brought
some genomic entrepreneurs to realize that the biggest markets
for their tools are not in health care at all, but in various
kinds of genomic consumer products, such as ancestral racial
profiling or individually customized skin creams. While agencies
like the FDA and FTC are being pressed to address these developments
as consumer protection issues, underneath that concern is a
moral uncertainty within the genomics community about the values
for which it should stand.
Meanwhile, as the human participants in genetic and genomic
research become more organized, they become more insistent about
gaining access to the benefits of research, challenging scientists
to think about the limits of their obligations to help those
they study. What should geneticists make of demands of patient
groups for access to unfinished results, such as inadequately-evaluated
genetic risk tests? In order to secure the participation of
a particular group, should investigators be willing to graft
health services onto research projects that could otherwise
promise no benefits but knowledge-or is that literally a form
of graft? How should public-spirited scientists respond to research
participants who seek to privatize their own genotypes? Despite
rhetorical and exhortatory appeals to "benefit-sharing"
as a consideration in the design and conduct of genetic research,20
there has been little effort spent distinguishing and assessing
these very different scenarios.
A common scientific metaphor for the process of translating
basic genome research into health benefits is the "pipeline,"
and a famous complaint about the ELSI research community is
its putative role in "constricting the pipeline."21
In fact, the gauge and orientation of that translational pipeline
depend on many factors, including the interests of both genome
scientists and those they work with as research participants.
If these factors are to be addressed in ways that reinforce
and improve the flow of biomedical benefits, they must be better
understood, and that is the point of this aim of our collaborative
work.
3. What will be the challenges of $1,000 genome as a research
tool?
Our third Center-wide aim is to anticipate the research ethics
and science policy issues raised by new advances in genetic
research by analyzing the confluence of human variation research,
computational genomics, sequencing technologies, and gene transfer
techniques through the lenses of contemporary research regulations
and norms.
During the development of the NHGRI's new strategic plan for
genome research, one of the aspirational goals cited for sequencing
technology was to be able to sequence an entire human genome
for $1,000, making whole genome sequencing a practical tool
for human biomedical research. Already, DNA chip-based gene
detection technologies are making whole genome scanning approaches
to research feasible, and opening up increasingly complex polygenic
human traits to analysis. At the same time, population-based
repositories and DNA databanks are making thousands of human
genome samples available for comparative analysis of the polygenic
profiles that complex phenotypes yield. As computational genomic
techniques improve our ability to interpret the variation between
individuals and populations in such profiles, clues to the environmental
and genetic manipulation of these phenotypes will begin to emerge.
As the phenotypes under study begin to overlap with socially
important human characteristics, such as our longevity, our
behaviors, our cognitive and physical abilities, and our FACE
identities, researchers and participants will increasingly and
inevitably be challenged with questions about the moral boundaries
of genetic research that contemporary research norms do not
adequately address.
For example, the consortium of studies funded by the NIH in
1997 to study the informed consent process in human subjects
research recently published a cumulative analysis of their results,
under the leadership of Laura Siminoff (cf. Appendix A). This
consortium, which included studies of consent to genetic research,
documented the fact that as biomedical studies become more removed
from immediate individual health care concerns, participant
understanding of the research drops-regardless of which approach
to obtaining informed consent is used.22 As others have pointed
out, this problem will be magnified by genetic studies with
multiple possible outcomes at both population and individual
levels, particularly when the research has no bearing on the
health of the individual participants. This situation suggests
the need for new models of ethical research participant recruitment
and authorization.23
In fact, our standard approaches to living up to all three
of the Belmont Report's famous principles for research ethics-respect
for persons, beneficence, and justice-will be challenged by
this coming wave of genomic and genetic research. Traditionally,
for example, our obligation of beneficence has been interpreted
in terms of minimizing research risks and maximizing its benefits
to subjects. For research designed to improve upon some socially-valued,
non-medical trait, however, measuring the benefits of participation
becomes problematic.24 If , for example, a study of the safety
of biosynthetic growth hormone in short normal children succeeds
in increasing their stature, should that mitigate any physical
risks involved? The controversy over that example only foreshadows
what is to come in many other parts of biomedicine as research
assessing the safety and efficacy of putative "enhancement"
interventions begins.25
Finally, the principle of justice in research ethics has traditionally
provoked concerns about either the exploitation or exclusion
of people as research subjects, rather than concerns about the
content of the research itself. As we begin to investigate and
manipulate human traits that seem to implicate our equality
as persons-such as our social abilities, physical strengths,
or personal virtues, scientists and their research participants
will have to consider whether certain scientific projects themselves
can promote injustice, and how to minimize that risk.26 The
thrust of our work towards this specific aim will be to gather
the information necessary to develop these new research ethics
models.
4. What are responsible options in designing and conducting
human genetic research?
The fourth overall aim for our Center is to harness ongoing
scholarship on genetic research ethics for practical application
by providing evidence-based policy options for use by the scientific
community, institutional review boards, and national research
regulatory bodies in seeking to improve participant protections
in the design and conduct of human genetic research.
One of the early criticisms of the ELSI research community
was that there is little efficient feedback from the extramural
research community to those who frame policy for genomic and
genetic research.27 In large part, this critique has been by
history. The fact that this research community has succeeded
in establishing a remarkable dialogue with the scientific community
is demonstrated by the rise of genetic research ethics as a
priority within the ELSI program, the integration of ELSI considerations
into the design of major initiatives such as the international
HapMap project, the prominence of ELSI concerns in the latest
NHGRI strategic plan, and even, ironically, complaints about
the ELSI community's power to "constrict the pipeline"
of genome research.28 Nevertheless, it is true that there is
no institutionalized program devoted to distilling and collating
the results of ELSI research in order to identify gaps, extend
the knowledge necessary to ground reasonable policy options
for genetic research issues, and communicate that evidence to
science policy makers. As a result, most new issues continue
to be debated and addressed in an extemporaneous rather than
an evidentiary fashion,9 and valuable ELSI research can become
buried in the academic woodwork. There are six forms of genetic
and genomic research that are currently experiencing these extemporaneous
debates and are particularly important examples of the need
for a more consolidated approach:
Genetic family studies
Genetic studies of twins and their families have a venerable
history in human genetics, suggesting a settled set of research
practices and norms. In 2001, however, the father of an adult
twin participating in such a study created a national debate
by claiming that a questionnaire asking his daughter for information
about his history of alcoholism and the shape of his genitals
was an invasion of his privacy and made him an involuntary human
research subject.29 Extemporaneous deliberations by institutional
and, finally, federal review groups agreed, effectively creating
a new regulatory category of "secondary subjects"
warranting human subjects protections in genetic family studies.
Devising clever ways of recruiting family members without first
learning about them through probands has subsequently become
a cottage industry within family studies research, with little
significant assessment of the alternative approaches or the
ethical issues involved. Similar debates surround other issues
in family research as well, such as the disclosure of interim
results to families, the publication of family pedigrees, and
the authorizing scope of "blanket" consents to tissue
research.
Community-based studies
Genetic epidemiologists have recently been enjoined by international
guidelines30 and NIH committees31-32 to practice "community
consultation" in advance of recruiting individual volunteers
from the communities in which their research is to be conducted.
The ideal organization, content, and outcomes of such consultations
are unclear, however, because their purpose is ambiguous. Ethical
arguments are marshaled to support them as ways of respecting
the collective autonomy of the targeted groups, but experience
suggests that their main utility is in increasing research enrollment
by improving relations with the community's opinion leaders.
More evidentiary analysis of both the social dynamics and moral
significance of these consultations will be required if this
practice is to become a clear and meaningful norm for genetic
research ethics.
Comparative population genomics
Since the debacle of the proposed "Human Genome Diversity
Project" in the early 1990s, the field of population genetics
has been awash in reports, manifestos, and admonitions about
how best to study human genetic variation without exploiting,
stereotyping, or stigmatizing the human populations being compared.
Debates over the definition of those populations and their relationship
to the identity issues described above have been central to
these deliberations. Although excellent work on these issues
has been funded by the ELSI program over the last five years,
it has not been developed into practical resources or recommendations
for genetic variation research.
Genome-Wide Research
The ethics of human research has conventionally revolved around
hypothesis-driven research, relegating scientific "fishing
expeditions" with human subjects to the margins as too
ill-formed to allow adequate risk/benefit calculations and meaningful
informed consent disclosures. With the whole-genome research
approaches made possible by the Human Genome Project and DNA
chip technology, however, scientific FISHing is no longer a
random angling but a powerful comprehensive sieving of the entire
genomic sea-bed. This raises the risks of unanticipated findings
well beyond the inadvertent discoveries of mis-identified paternity
or chromosomal mosaicism, and challenges the traditional conception
of what should go into an adequate informed consent.
Commercial Genetic Research
The interplay of scientific creativity and entrepreneurial thinking
has been examined to date by science policy makers primarily
as a matter of intellectual property rights in the basic research
setting. Less attention has been paid to that interplay as a
feature of the culture of contemporary science. As the scientific
debate over the entrepreneurial aspirations of some molecular
biologists of aging has shown over the last several years, however,
the dynamics of that interplay can be of professional ethical
concern within the scientific community even where intellectual
property claims are not at stake.33 With most public and institutional
policy in the U.S. actively encouraging the commercialization
of science, there is a relative vacuum of guidance for scientists
concerned with the influence of profit making in their fields.34
Enhancement Genetic Research
For human gene transfer research, scientific policy has traditionally
accepted a distinction between the use of genetic interventions
to treat disease and their use in attempting to improve upon
healthy human traits as a boundary line for acceptable research.
The recent report of the President's Council on Bioethics affirms
and extends this conviction to a much broader range of scientific
research efforts, from pharmacogenomics to anti-aging medicine.35
But ELSI-funded scholarship is showing just how difficult it
is to use that distinction as a regulatory tool in these molecular
genetic contexts, since there are always legitimate therapeutic
purposes toward which any potential enhancement can be aimed.36
Moreover, as enhancement uses of new medical tools become publicly
(and therefore commercially) attractive, it will be important
to be able to conduct the human research necessary to assess
their safety and efficacy in healthy people. As our genetic
understanding of, and capacity to manipulate, an increasing
range of complex, non-pathological human traits grows, it will
be increasingly important to have a more nuanced and scientifically-grounded
approach to managing this form of research.
The CGREAL's research and training activities are designed
to address these needs by surveying existing ELSI research on
these six forms of genetic and genomic studies, conducting new
studies to address the open questions in that ELSI research,
and channeling our efforts into a series of concrete projects
providing resources for professional and public policy making
on genetic research ethics issues.
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