Preliminary Studies and Collaborations
1. Why Case Western Reserve University?
Case Western Reserve University already enjoys the research
track record and the working interdisciplinary collaborations
necessary to be recognized as a "center for excellence
in ELSI research" with respect to issues in genetic research
ethics. The establishment of the CGREAL would enable us to capitalize
on this experience to integrate our efforts and accomplish the
specific intellectual aims we have described above in a concerted
way. In this section, we describe our experience and the ways
in which it prepares us to be successful in addressing our focal
theme (Also, see Appendix L for examples of publications by
members of the research team).
Over the last decade, only six institutions across the country
have impressed peer reviewers enough to receive more than five
NIH grants in support of research on ethical, legal, and social
issues in genomics. In most places, these studies have been
thematically scattered. Even among the institutions with recognizable
research concentrations, CWRU is the only site to have developed
a significant focus on issues in research ethics. Since 1994,
investigators across CWRU have been awarded ten RO1 research
grants on this theme alone. Moreover, the training opportunities
made possible by this level of activity have led to an unrivaled
number of successful grants for cross-disciplinary training
in research ethics-i.e., six to date, ranging from individual
KO1 career development awards and F32 senior fellowships to
multi-year R25 projects like our international research ethics
training program, co-funded by the NIH Fogarty International
Center and NHGRI. (See Appendix B for the details of this history).
The collaborative relationships that have emerged from this
concentration of research interests are, however, more important
than the numbers. Close ties already exist between the School
of Medicine's Department of Bioethics, the Department of Genetics'
Center for Human Genetics, the Law School's Law-Medicine Center,
University Hospitals' Center for Pediatric Ethics, and the University
Center on Memory and Aging, and have produced the collaborative
projects and co-authored publications, joint degree programs,
secondary faculty appointments, and shared conference series
that are described below. With this cooperative network already
in place, it has not been difficult to cultivate the new collaborations
with our other colleagues from CWRU and the Cleveland Clinic
that we propose for the CGREAL.
2. The CGREAL's progenitors at Case Western Reserve University
The relationships that have been nurtured within our institutional
context position us to begin the work of the CGREAL immediately
upon funding. Our progress will be jump-started by the integration
of four ongoing lines of NIH-funded ELSI research and five families
of scientific research.
a. Existing ELSI Research Heritage
Human subjects Research Issues
Three recent CWRU initiatives on ethical issues in the recruitment
of human participants for biomedical research will provide important
starting points for our research. Two of these were empirical
studies funded by NIH as part of the NIH Informed Consent Consortium,
which recently published its cumulative findings under the editorship
of Laura Siminoff (See appendix A.). Dr. Siminoff's own project
for the Consortium examined the dynamics and content of the
informed consent process in four different biomedical research
settings ranging from oncology to neurology. Eric Kodish's Consortium
study examined the process of subject recruitment in the pediatric
research setting. The third project, for which Jessica Berg
was the lead author, was the first major legal study of the
informed consent doctrine in the last decade.37
For these investigators, the creation of the CGREAL will provide
the opportunity to extend their research into the genetic research
setting, and to examine the challenges raised for our conventional
research ethics practices in new contexts such as genome-scanning
and population-based research. For other CGREAL faculty, these
studies bring important baseline data and preliminary insights
about the informed consent issues, as well as providing access
to other investigators' methodological expertise and research
tools and contact with the wider national network of Informed
Consent Consortium researchers.
Cross-Cultural Genetic Research Issues
CWRU has also sponsored an ongoing cluster of research efforts
on ethical issues in cross-cultural and community-based genetic
research that gives the CGREL a significant head start on its
interests in issues of personal identity in genetic research.
This cluster also includes a mixture of empirical research and
ethical/legal analysis. The former is represented by Patricia
Marshall's two ELSI R01 studies of informed consent to genetic
epidemiological research on hypertension and colorectal cancer
amongst African Americans and Nigerians, and her role on an
ELSI-funded project to design and assess community engagement
processes in Kenya, Nigeria, and South Africa for the international
Haplotype Mapping Project. All three of these studies are parts
of the ELSI Program's Consortium on Genetic Variation Research.
Important data have been and will be collected on beliefs about
the implications of genetic research for personal health and
individual and group identity, as well as individuals' motives
to participate in genetic research. Results of these studies
have the potential to contribute to the growing literature on
the meaning of genetic research for individuals and communities
of African heritage. Dr. Marshall is working with Dr. Georgia
Wiesner, Dr. Charles Rotimi, Director of Genetic Epidemiology
at the National Human Genome Center at Howard University, and
Drs. Adebowale Adeyemo, Department of Pediatrics, and Clement
Adebamowo, Department of Surgery, at the University of Ibadan,
Nigeria.
On the ethical/legal side, Eric Juengst and Dena Davis have
ongoing lines of scholarship addressing the issues raised by
genetic research with named populations, and Sharona Hoffman
is currently conducting a legal analysis of the implications
of population genetics for the law's uses of racial categories.
The creation of the CGREAL will make it possible for these
investigators to advance both the empirical and theoretical
studies in novel ways by expanding the range of scientific and
cultural cases they can consider and the disciplinary resources
they can draw upon. The participation of the rest of the CGREAL
faculty will provide important preliminary data for the development
of new studies of cross-cultural issues, as well as access to
the deliberations and findings of both the national Genetic
Variation Consortium and the international Haplotype Mapping
Project.
Alzheimer Disease (AD) Genetic Research Issues
A third line of ELSI research at CWRU includes studies that
have examined issues in the development and introduction of
new genetic risk assessments for late-onset disease, taking
AD as the focal example. Again, this includes both empirical
and policy analysis work. Empirically, Peter Whitehouse serves
as a site P.I. for a national ELSI-funded pilot study of APOE4
testing for AD risk assessment, gathering both quantitative
and qualitative data about participant experiences in that research.38
Barber, Juengst, Post, and Gaines have also been involved in
that research as co-investigators or consultants. This project
was preceded by an ELSI-funded national consensus development
project, for which Stephen Post was the P.I., which identified
the special issues of conducting genetic research with demented
patients and their families, the premature commercialization
of genetic testing services, and the need for evidenced-based
guidelines in this area.39 Juengst, Whitehouse, Mehlman, Gaines,
and Binstock all contributed as co-investigators to that project.40
Through a major supplement to his ELSI R01, Post also spent
a year working intensively with the AD community conducting
genetic issue dialogues issues in every state in the continental
U.S. Related work by Atwood Gaines has also examined international
and cross-cultural dimensions of AD research.41
The CGREAL provides an opportunity to test the results of these
studies against other cases of emerging genetic research with
commercial prospects, and to investigate issues in AD genetics
that cross professional specialty lines, such as the use of
APOE4 markers for risk assessment in cardiology. These investigators'
insights into the dynamics of genetic research with a diagnostically-defined
population will provide important points of comparison for other
CGREL studies.
Enhancement and Anti-Aging Research
Finally, a fourth line of NIH-funded ELSI research is represented
by the series of three projects addressing issues in the development
of genetic enhancement and anti-aging interventions, for which
Eric Juengst has served as P.I. These studies, involving Maxwell
Mehlman, Thomas Murray, Stephen Post, Robert Binstock, and Peter
Whitehouse, have all used the interpretive methods of philosophy,
political theory, and law to extrapolate from current human
experience with attempts to use medical technologies to improve
on human form and function to identify the ethical implications
of genetic research with enhancement applications. In addition,
we have hired Jennifer Fishman, a young sociologist of science
whose research on the social and political dynamics behind the
development and marketing of Viagra has already won the Nicholas
Mullin Award from the Society for the Social Studies of Science.42
One of the major findings of our enhancement research is the
observation that most genetic enhancement interventions will
initially be developed and approved as therapeutic tools, even
when public attitudes and commercial prospects predict their
wider use for non-medical purposes. This drives our interest
in the broader social forces that influence the pace and direction
of such research, and creates a need for the social scientific
expertise that the CGREAL can provide. Moreover, as medical
tools begin to be used for enhancement purposes, scientific
research explicitly designed to evaluate those uses will need
to be conducted. Exploring the questions that such research
would pose within the contemporary framework for research regulation
is a natural next step for this inquiry. In turn, our work to
date in attempting to explicate the ethical and social implications
of enhancement will help generate research questions for our
social scientific colleagues, and help inform the analysis of
the beliefs and attitudes their studies reveal.
While all four families of ELSI research at CWRU have been
multi-faceted and overlapping, it is interesting to note that
each of them has been centered in a different quadrant of genetic
research ethics. Our informed consent studies have been aimed
at contributing to the development of responsible, evidence-based
research policies and practice. Our cross-cultural and community-based
studies have been designed to improve our understanding of the
cultural meanings of genetic research. The AD studies have focused
primarily on the social forces shaping the pace and direction
of genetic research. The enhancement research projects have
been driven by the need to exercise moral imagination in anticipating
the implications of genetic research. By reweaving these legacies
into new collaborations, CGREL will provide a level of integration
that none of its predecessor initiatives could have attained
alone through continued ELSI RO1 support.
b. Existing Scientific Research Heritage
In addition to our ongoing lines of ELSI research, the CGREAL
will also benefit from the participation of five scientific
research initiatives at Case Western Reserve University and
the Cleveland Clinic Foundation.
Department of Genetics' Genetic Family Studies
The Family Studies Core in the Department of Genetics, administered
by Anne Matthews, was established to provide a link between
investigators and faculty and the individuals and families with
whom genetic family research is being conducted. Since 1996,
the Core has been involved with the enrollment of over 2500
individuals from more than 900 families from across the USA
in genetic family studies. The Core staff are responsible for
screening potential study participants, answering participants'
questions about the research, recruitment, obtaining informed
consent, verifying phenotype by obtaining medical records, and
arranging blood and tissue sample collection. This extensive
experience guides the Core's consultation with investigators
on the ethical and practical conduct of genetic family studies,
including composition of informed consent documents, applications,
amendments, and renewal of IRB protocols, HIPAA authorization
for genetic studies, database issues related to genetic family
studies, family contact and recruitment procedures, pedigree
drawing, and confidentiality of private information.
Participating in the CGREAL will provide the Family Studies
Core with opportunities to advance its own mission by collaborating
on research designed to address the open policy questions that
participants, investigators, and IRBs all bring to its staff,
but which it does not have the research resources to answer.
In turn, the Family Studies Core can provide CGREAL investigators
(appropriately negotiated!) access to research families and
the lessons of its experience to help frame and conduct this
research.
Center for Jewish Genetic Diseases' Community-Based Genetic
Research
The Center for Jewish Genetic Disease, located at the CWRU
Center for Human Genetics and University Hospitals of Cleveland,
was created in 2002 with funding from the Mt. Sinai Legacy Foundation,
a local Jewish charitable organization. Under the leadership
of Georgia Wiesner, the Center houses education, genetic testing
and counseling, health services research programs related to
the use of genetic services by the Jewish community, and scientific
research on diseases of high prevalence among people of Ashkenazi
Jewish ancestry.
The Center has used community dialogue exercises to conduct
initial studies of public experiences with and receptiveness
to genetic services, but lacks the social scientific expertise
to conduct the more robust ELSI projects its faculty would like
to pursue as part of the proposed CGREAL. For other CGREAL investigators,
the collaboration of the Center for Jewish Genetic Diseases
provides an opportunity to conduct research with a well-educated,
relatively high SES, ethnically-defined community of families
participating in studies of single gene disorders and genetic
disease risks that are framed in terms of their religious identity-an
important comparison group with unique issues of its own.
Cleveland Clinic Genebank/GeneQuest Projects' Patient-Based
Genetic Research
The Department of Cardiovascular Medicine of the Cleveland
Clinic Foundation initiated the Genebank study in July 2001,
under the leadership of Eric Topel. This program's main goal
is to develop a database and repository of specimens (serum,
plasma and DNA). In addition, a concise general medical history,
demographic data, ECG, echo, laboratory data, and comprehensive
genetic screening history targeted to "categories"
of disease to which each individual patient may be predisposed
are collected. There are currently over 7,000 patients enrolled.
The GeneQuest Project started in 1995 with a grant to collect
sibships with familial, premature coronary atherosclerotic disease
and myocardial infarction. Pedigree discovery work through GeneQuest
still continues. See Appendix C for more details on these projects.
The Genebank/GeneQuest research team is interested in improving
the experiences of patients and their families participating
in these genetic research projects, and in developing models
of good practice for research in cardiovascular genetics. The
research collaborations that the CGREAL will make possible provide
a welcome opportunity to be able to pursue these interests.
The GeneBank/GeneQuest projects offer other CGREAL faculty an
excellent opportunity to conduct research with a clinically-defined
community of families participating in studies defining genetic
susceptibility to common, multifactorial, acute disease-an increasingly
important class of genetic family studies that raise different
issues from traditional pedigree studies of single-gene disorders.
CWRU's Population-Based Genome Scanning Research
There is a growing interest amongst biomedical scientists at
CWRU in using genome-scanning techniques to propel our understanding
of human biology, and a number of investigators are doing so
for traits and conditions that have traditionally been paradigmatic
of non-genetic, environmentally-controlled phenotypes: infectious
and parasitic diseases such as tuberculosis (Whalen); malaria
(Zimmerman); filiarisis (Kazura); acquired traits, such as human
physiological adaptations to high altitude (Beall) and academic
success (Thompson). Moreover, each of these investigators conducts
their research in cross-cultural settings, either locally or
internationally, with participants ranging from Peru, Kenya,
Uganda, and Tibet all the way to inner-city Cleveland.
These investigators are all interested in improving their abilities
to work effectively with their research participants in addressing
the social and ethical challenges that emerge in their research.
They view the CGREAL's research plan as an opportunity to gather
the information they need. Other CGREAL faculty, in turn, welcome
their collaboration as providing opportunities to advance our
understanding of the issues involved in a uniquely global cross-section
of international and cross-cultural genetic research, genetic
research on non-medical human traits and environmental health
problems, and research utilizing whole-genome analytic approaches.
Center for Computational Genomics' Genome-Wide Analysis Research
The CWRU Center for Computational Genomics, under the leadership
of Joseph Nadeau, is a University-wide research center aimed
at developing improved algorithmic, heuristic, and database
tools to enhance genomic analysis methods. Current projects
include the development of computational tools for identifying
regulatory regions within human DNA, constructing gene expression
profiles, and the analysis of complex human phenotypes (cf.
www.genomics.cwru.edu
for more information).
The CCG is, in some respects, the most abstract of the scientific
initiatives participating in the CGREAL: its work is primarily
mathematical and is conducted by computer scientists and molecular
biologists who may never see a human genetic research participant
as part of their work. Nevertheless, the CCG faculty appreciate
the impact that their work could have on individuals, families,
and communities as it is used to better understand and control
complex genetic traits, and consider it a natural part of their
work to collaborate in attempting to anticipate and assess those
implications. In turn, the CCG's collaboration provides other
CGREAL faculty an invaluable window onto cutting-edge genomics,
and the opportunity to consider its challenges early in the
research process.
Just as our collective ELSI research to date brings experience
from all four corners of genetic research ethics to the CGREAL,
CGREAL's collective scientific endowment prepares it to address
the full spectrum of human genetic research, from traditional
family studies of single gene conditions to the mathematical
modeling of pharmacogenomic enhancement interventions. This
provides an excellent observation post on genetic research ethics:
we have the radar screens, binoculars, sensors, and charts we
will need to accomplish our aims. Now, how should the room be
organized so that it actually works?
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