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Leslie J. Raffel, M.D. Professor of Pediatrics,
  • Program Director, General Clinical Research
  • Associate Director, Common Disease Genetics
  • Former Executive Chair, Institutional Review
  • Cedars-Sinai Medical Center

Genetics and Stem Cell Research
Do they really need to be such explosive issues?
Genetics Research - Whats All the Fuss About?
  • Reasons why genetic research is treated
  • 1. Concern for Discrimination/Stigmatization
  • Potential to identify individuals at risk before
    disease develops
  • Potential for insurance and/or employment
  • Risk of suicide/depression
  • Can affect both those who are found to carry a
    mutation and those who do not

Genetics Research - Whats All the Fuss About?
  • Reasons why genetic research is treated
  • 2. Information obtained from one individual may
    have predictive value for other family members
  • May adversely impact family relations

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Genetics Research - Whats All the Fuss About?
  • Reasons why genetic research is treated
  • 3. Genetics is new and most people do not
    understand it
  • Fear makes for good news stories
  • We shun what we fear

Body Bazaar The Market for Human Tissue in the
Biotechnology Age by Lori Andrews
Exploding the Gene Myth by Ruth Hubbard and
Elijah Wald
Categories of Genetics Research Activities
1. Research involving collection of pedigrees
(family trees)
  • Research involving recruitment of family members
  • Research involving specific racial/ethnic groups
    or other defined populations
  • 4. Research involving collection of specimens
    for DNA isolation and storage
  • 5. Research that is really part of clinical
  • 6. Research involving gene therapy

Pedigree collection Vital for the research, but
does collection of information about family
members who have not consented to participate
constitute invasion of privacy?
Who owns your family history?
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  • Maintenance of confidentiality of family history
    information is paramount
  • Investigators must provide the IRB with detailed
    descriptions of how the privacy of these records
    will be protected
  • Consideration should be given to obtaining a
    Certificate of Confidentiality
  • Some types of information (such as sexual
    orientation, drug use, abortion history) may be
    of such a sensitive nature as to be inappropriate
    to collect even in an indirect fashion without
    the consent of all subjects

2. Research involving recruitment of family
  • Can investigators collect contact information for
    family members without their consent?
  • If the IRB requires written information
    containing phone numbers for the investigators to
    be distributed to family members, with the family
    member initiating contact, what is the chance
    that anyone will call, even if they are
    interested in the research?
  • Can the index case (proband) contact family
    members and obtain verbal consent to release
    contact information to investigators? What is
    the potential for coercion?

  • Research involving specific racial/ethnic groups
    or other defined populations
  • Population stigmatization
  • Cultural differences in consent
  • Dealing with different perceptions in
    non-Westernized cultures

Jewish leaders seek genetic guidelines...
…a growing list of mutations in the Ashkenazi
population linked to disease, including Tay
Sachs, Gaucher's and the 185delAG mutation
associated with breast and ovarian cancer. Such
findings, which have already led to Jewish groups
being targeted as a potential market for
commercial genetic tests, could create the
perception that Jewish people are unusually
susceptible to disease, says Rutkin. As a
result, she warns, anyone with a Jewish-sounding
last name could face discrimination in insurance
and employment as companies struggle to keep down
health-care costs.
Nature 389, 322 (25 September 1997)
Community Dimensions of Consent …in many
developing country settings, consent may be
invalid if it does not have a familial or
communal dimension...However, tension may arise
between individual and community consent for
example, if community elders decide that research
should be participated in but individuals are
unwilling, or if community leaders withhold
consent but individuals want to participate.
Chokshi DA, Thera MA, Parker M, Diakite M, Makani
J, et al. (2007) Valid Consent for Genomic
Epidemiology in Developing Countries. PLoS Med
4(4) e95 doi10.1371/journal.pmed.0040095
Consent in non-Westernized Cultures
  • Is it appropriate to apply the same standards for
    informed consent in all cultures?
  • How do you explain concepts such as genetic
    testing to someone from a primitive society?
  • Who gives consent in a culture in which a womans
    father or spouse is viewed as having the
    authority to determine what she can or cannot do?
  • Even if you attempt to obtain consent directly
    from such a woman, how can you know if the
    consent is coerced?

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  • 4. Research involving collection of specimens
    for DNA isolation and storage
  • Sharing of specimens with other investigators
  • Long term storage of specimens
  • Dealing with potentially clinically relevant

  • Many research studies involve long term storage
    of DNA samples or cell lines
  • This may be beneficial for subjects (multiple
    studies may be performed without the need to
    request additional samples) and investigators
    (ability to perform freezer studies to test new
    candidate genes, etc.)
  • But what types of safeguards are needed to
    protect subject privacy?
  • Who decides for what studies a given specimen can
    be used?

The Chinese Restaurant Menu Approach
Permission to share my sample(s) with other
researchers? If you agree, your sample may be
shared with other researchers, performing
research on your condition or on other
conditions. Please note your preferences
below I give permission for the research team
to share my sample with the individuals noted
below YES ? NO ? Researchers at CSMC
studying (state disease) YES ? NO ?
Researchers at other institutions studying
(state disease) YES ? NO ? Researchers at
CSMC studying any disease YES ? NO ?
Researchers at other institutions studying any
disease YES ? NO ? In addition, I agree
to be contacted in the future to receive
information on other research
studies investigating (state
  • Do research subjects really understand the
  • Who do they want to make decisions about the
    future use of their samples?
  • Will the decisions they make be respected?

If an intent of the study is to share samples
with non-CSMC institutions and researchers
studying the same disease as described in the
consent form, insert the following paragraph.
As part of this research, we will make your
sample available to researchers at non-CSMC
institutions who are studying the same disease as
described in this consent form. Your sample will
be shared with insert name of institution(s).
Insert applicable option The sample will be
labeled with a unique study number that will link
your identity so that only the research team can
recognize you. OR The sample will not contain any
information that could be used to identify you.
Note to researcher In the future, requests to
share samples with non-CSMC institutions not
listed below or requests to perform other
research on the sample, will require either
re-consent or a waiver of consent. IRB approval
must be obtained for these types of requests.
Genome Wide Association
  • Tests if a specific gene is likely to be involved
    in the disease process, or is very close to the
    causative gene
  • Takes advantage of the linkage disequilibrium
    that exists as a reflection of human history
  • Disequilibrium covers much shorter distances
    (typically several LD blocks within a gene) than
    typically observed with family-based linkage
  • Typically entails genotyping 300,000 to 1
    million snps

Ikram M et al. N Engl J Med 20093601718-1728
  • Genome Wide Association generates a huge amount
    of data on each subject
  • It has been proposed that making this data widely
    available will produce more rapid advances in
    understanding the genetic basis of many disorders

The NIH Policy on Genome Wide Association Data
If genome wide association is performed with NIH
funding, the investigators are obligated to
deposit the data in the NIH GWA data repository,
where it can be made accessible to other
In order to minimize the risks to study
participants, data will be submitted to the GWAS
data repository without identifiable information
and using a random, unique code.
OHRP considers private information or specimens
not to be individually identifiable when they
cannot be linked to specific individuals by the
investigator(s) either directly or indirectly
through coding systems. Research does not
involve human subjects if the following
conditions are both met (1) the private
information or specimens were not collected
specifically for the currently proposed research
project through an interaction or intervention
with living individuals and (2) the
investigator(s) cannot readily ascertain the
identity of the individual(s) to whom the coded
private information or specimens pertain
The Fallacy Is DNA de-identifiable?
Amy L. McGuire and Richard A. Gibbs
SCIENCE 312370-371 APRIL 21, 2006
….an individual can be uniquely identified
with access to just 75 single-nucleotide
polymorphisms (SNPs) from that person.
NIH Background Fact Sheet on GWAS Policy
Update August 28, 2008
A research team, led by David W. Craig, Ph.D. at
the Translational Genomics Research Institute
(TGen) in Phoenix AZ, has developed a new
bioinformatics method that allows the detection
of a single persons SNP profile in a mixture of
1,000 or more individual DNA samples. In other
words, bioinformatics techniques have progressed
to the point that with enough genomic data on an
individual from another source, it is now
possible to determine whether that individual
participated in a study by analyzing only the
pooled summary data.
15-year-old Boy Tracks Down His Anonymous Sperm
Donor Father
  • A woman became pregnant using a sperm donor
  • She knew donors birth date, birth place, and
    college degree
  • At 15, her son decided to try to learn about his
  • For 296, the boy sent a cheek swab to, an online genealogy
    DNA-testing service
  • Contacted by 2 men with closely matched Y
  • 50 chance that all 3 had the same father,
    grandfather, or great-grandfather
  • Both men had the same surname, but with different
  • He purchased the names of everyone born in the
    same place on the same day from
  • One man had the surname he was looking for, and
    within 10 days he had made contact

Dealing with potentially clinically relevant
results What about recontacting subjects?
  • At the time that many studies are initiated, the
    likelihood of finding clinically relevant results
    in the near future is small
  • If such results are generated, what is the
  • Obligation to recontact study subjects?
  • Ethical right to recontact study subjects?
  • What should the investigator do if the research
    turns up something that is clinically relevant,
    but far different from what was expected?

Willingness to receive results of testing
performed as part of research YES ? NO ? I
wish to receive information about the testing
conducted on my sample YES ? NO ? I
wish to receive general information about the
study results. I understand that this
will not include specific information on
the testing completed on my sample. YES ? NO
? Should information that may be important to
my health become available in the future,
I would like to be contacted and given an
opportunity to learn of this information.
I understand that it is my responsibility
to update any changes to my address
Can research participants really make an informed
decision about their wish to receive results when
those results may come may years later and when
they nature of the results may not be predictable?
  • 5. Research that is really part of clinical
  • Genetic testing that is only available in
    research labs

  • Many genetic diseases are rare conditions -
  • Mutation detection is becoming available for many
    genetic disorders
  • Few are available through clinical laboratories
    and the only option for many is to send samples
    to a research lab studying the disorder
  • How does the clinical investigator obtain local
    IRB approval for these rare tests, when there are
    hundreds of them and there is no way of
    predicting when a patient will present with any
    one of them?
  • Since these studies are being done in research
    laboratories (non-CLIA approved), can the results
    be given to subjects?
  • Who is responsible for providing the appropriate
    counseling? Should the subject be billed for

6. Research involving gene therapy
  • Gene Therapy holds the potential both for curing
    and preventing diseases that we will otherwise
    never be able to treat effectively
  • Gene therapy is risky - the technology is new and
    there is much we still do not understand
  • gene regulation
  • the impact of random vector insertion into the
  • the impact of germ line insertions of recombinant

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The Truth About Stem Cell Research
Everyone has a strong opinion on the topic …….but
there is no consensus
I find nothing in the Bible that tells me that
cells in a lab dish are people. What I do find
in the Gospels is an emphasis on healing
relieving people of their suffering. John
Danforth, Former U.S. Senator and Episcopal priest
The children here today remind us that there is
no such thing as a spare embryo. Every embryo is
unique and genetically complete, like every other
human being. George Bush
Embryonic Stem Cells
  • Pleuripotent cells that can differentiate into
    any tissue type
  • Retain this plasticity in cell culture in the
  • Can divide almost indefinitely while
  • ESCs may not elicit the same kind of immune
    response that is associated with transplantation
    of more mature cells or tissues

Figure 1. Generation of human embryonic stem
cells. A few-celled embryo gives rise to the
blastocyst, a structure comprised of an outer
cell layer, the trophoectoderm, and the inner
cell mass. The inner cell mass is harvested and
plated on feeder cells to yield a population of
embryonic stem cells. Meier JJ, Bhushan A,
Butler PC. Pediatr Res. 2006 Apr59(4 Pt
Approaches to Producing Embryonic Stem Cells
  • Donation of ova and sperm in vitro fertilization
    specifically for the purpose of research
  • Single cell embryo biopsy similar to what is used
    for preimplantation genetic diagnosis (PGD)
  • a cell can be removed from an 8 cells stage
    embryo (blastomere), without interfering with
    embryonic development
  • Altered nuclear transfer (ANT)
  • variation of nuclear transfer that creates
    abnormal nuclear transfer blastocysts that are
    unable to implant into the uterus but are capable
    of generating ES cells
  • variation on cloning
  • Use of left over embryos generated in IVF

Are Adult Somatic Stem Cells an Alternative?
  • Many mammalian tissues including bone marrow,
    skin, gut lining, blood vessels, endocrine
    glands, mammary gland, prostate, lung, retina,
    and parts of the nervous system contain stem cell
  • Already standardly used in bone marrow
  • By using a persons own stem cells, can avoid the
    problem of immune rejection
  • Problems in isolation and culture that must be
  • Level of self-renewal and degree of
    differentiation varies drastically between
    somatic tissues

Induced pluripotent stem (iPS) cells
Stem cell lines derived by introducing sets of
genes into somatic cells
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Embryonic and iPS Stem Cells - Problems that Must
be Overcome
  • Derivation of hES and iPS cell lines devoid of
    animal contaminants and retroviruses
  • Maintenance of normal karyotypes
  • Assuring there is no potential to form tumors

U.S. Policy on Stem Cell Research
Under the Bush administration, there was no
federal funding for human embryonic stem cell
research, unless one of a handful of existing
stem cell lines that have been authorized was
  • On March 9, 2009, President Obama issued
    Executive Order 13505, entitled "Removing
    Barriers to Responsible Research Involving Human
    Stem Cells."

Current NIH Guidelines on Human Stem Cell
  • Applicants proposing research using hESCs derived
    from embryos donated in the U.S. on or after the
    effective date of these Guidelines may use hESCs
    that are posted on the new NIH Registry or they
    may establish eligibility for NIH funding by
    submitting an assurance of compliance with
    Section II (A).

hESCs should have been derived from human embryos
  • 1. created using IVF for reproductive purposes
    and were no longer needed
  • 2. donated by individuals who sought reproductive
    treatment and who gave voluntary written consent
    for the embryos to be used for research purposes

3. for which it can be documented that 1. All
options pertaining to embryos no longer needed
for reproductive purposes were explained 2. No
payments, cash or in kind, were offered for the
donated embryos. 3. Neither consenting nor
refusing to donate embryos for research would
affect the care provided. 4. There was a clear
separation between the donors decision to create
human embryos for reproductive purposes and the
decision to donate human embryos for research
purposes. 5. The donors were informed
  • 1. the embryos would be used to derive hESCs for
  • 2. what would happen to the embryos in the
    derivation of hESCs
  • 3. hESCs might be kept for many years
  • 4. the donation was made without any restriction
    or direction regarding who may receive medical
    benefit from the use of the hESCs
  • 5. the research was not intended to provide
    direct medical benefit to the donors
  • 6. research using the hESCs may have commercial
    potential, and that the donors would not receive
    financial benefits
  • 7. whether information that could identify the
    donors would be available to researchers.

  • 2. Existing hESCs investigators can submit
    materials to a Working Group of the Advisory
    Committee to the Director that demonstrate that
    the hESCs were derived from human embryos
  • 1) that were created using in vitro fertilization
    for reproductive purposes and were no longer
    needed and
  • 2) that were donated by donors who gave voluntary
    written consent for the embryos to be used for
  • The Working Group will make recommendations
    regarding eligibility for NIH funding to its
    parent group, the ACD. The ACD will make
    recommendations to the NIH Director, who will
    make final decisions about eligibility for NIH

Some research using hESCs and/or human induced
pluripotent stem cells is still ineligible for
NIH funding
  • 1. Research in which hESCs or human iPS cells are
    introduced into non-human primate blastocysts.
  • 2. Research involving the breeding of animals
    where the introduction of hESCs or human induced
    pluripotent stem cells may contribute to the germ
  • 3. Derivation of stem cells from human embryos
    (Section 509, Omnibus Appropriations Act, 2009),
    otherwise known as the Dickey Amendment.
  • 4. Research using hESCs derived from other
    sources, including somatic cell nuclear transfer,
    parthenogenesis, and/or IVF embryos created for
    research purposes.

About CIRM The California Institute for
Regenerative Medicine ("The Institute" or "CIRM")
was established in early 2005 with the passage of
Proposition 71, the California Stem Cell Research
and Cures Initiative. The statewide ballot
measure, which provided 3 billion in funding for
stem cell research at California universities and
research institutions, was approved by California
voters on November 2, 2004, and called for the
establishment of a new state agency to make
grants and provide loans for stem cell research,
research facilities and other vital research
California Code of Regulations Title 17.Public
Health Division 4 California Institute For
Regenerative Medicine Chapter 2 Date January 26,
Specifically, the regulation embodies five
principles (1) Unrestricted donation There are
no restrictions on who may receive tissue (2)
Disclosure of interest The attending physician
should disclose any interest in the research
using fetal tissue (3) Timing of abortion The
proposed research should not influence a womans
decision to continue her pregnancy. (4) Medical
management of abortion No alteration of the
timing, method, or procedures used to terminate
the pregnancy should be made solely for the
purposes of obtaining the tissue and (5)
Legality of abortion The abortion should be
performed in accordance with applicable State and
Federal law.
Prohibition on Compensation While permitting
reimbursement of expenses, the CIRM regulations
prohibit compensation to research donors (a human
who donates biological materials for research
purposes after full disclosure and consent)
Now, it is your turn to talk……… Case Scenarios
1. Susan Jones, a 25 year old woman, was still
living at home with her parents, as was her twin
brother. Susan learned about a research study
that was being conducted at a local university,
which involved completing a questionnaire asking
details of her medical history, along with
information about her relatives. She thought
this might be interesting, contacted the research
team and, after hearing details about the study,
agreed to participate. The investigator mailed a
copy of the questionnaire to Susan to fill out.
However, before Susan got home from work, her
father, Tom Jones, opened the envelope, even
though it was addressed to her. He became upset
when he saw the type of questions that were being
asked. In particular, he was upset when he saw
questions asking whether her parents had ever
suffered from depression or if they had abnormal
The father contacted university officials, who
assured him that the study had been reviewed by
the IRB and that his daughter had provided
informed consent when she enrolled in the study.
However, the father was not satisfied and
contacted the Office for Protection from Research
Risks (OPRR now the Office for Human Research
Protections), which investigated his complaint.
OPRR ruled that the IRB should have considered
whether family members were human subjects of
this research based on their relationships to the
enrolled subjects, as well as the nature of the
family information being collected. After review
of the IRB procedures, the OPRR and the Food and
Drug Administration suspended human subject
research at the university, stating that the IRB
had inadequately documented its monitoring of
research protocols.
  • Did the researchers have the right to include
    questions of this nature in the questionnaire?
  • What if, instead of asking about psychiatric
    history and genitalia, the questions asked for
    parental history of hypertension and what their
    occupations were?
  • In a medical setting, it is standard to ask
    information about family history of disease. Why
    might it be legitimate for her doctor to ask
    Susan these questions, but inappropriate for a
    researcher to ask them?

  • What constitutes private information?
  • What defines identifiable information? If
    Susan did not live at home with her parents, was
    married and used Smith as her last name, not
    Jones, would the information collected on her
    parents still be identifiable?
  • Suppose the investigators had wanted to contact
    Susans parents and siblings to invite them to
    participate in the research. How should they
    have done so?

2. A large, multicenter clinical trial comparing
a variety of treatments in patients with
congestive heart failure was performed. The
treatment tested in one arm of the study involved
a combination of two cardiovascular medications,
isosorbide dinitrate and hydralazine. Both of
these medications have been FDA approved and used
in treating heart failure for many years.
Subjects in the other arm received enalapril.
Analysis of the data indicated that enalapril was
associated with a lower mortality rate than the
combination of isosorbide dinitrate/hydralazine.
However, a subsequent analysis comparing African
American subjects and Caucasian subjects in the
isosorbide dinitrate/hydralazine group indicated
that African American subjects had substantial
benefit from this therapy, while it was of little
benefit to Caucasians.
These data subsequently were used by a
pharmaceutical company to support an application
to the FDA for approval of a isosorbide
dinitrate/hydralazine combination pill. The FDA
rejected approval of this combination for all
heart failure patients, but approved it for
treatment of heart failure in African Americans.
  • What explanations have been put forward to
    explain observed differences in disease
    prevalence and outcome in individuals of
    different ethnic/racial backgrounds?
  • Is it justified to use race or ethnicity
    subgrouping for analysis of clinical trial data?
  • Some people argue that, even if there are genetic
    differences in response to treatment, use of race
    as a surrogate to identify such differences is
    unwarranted because it reinforces racist
    attitudes and does more harm than good. Do you
    agree or disagree? Are there ways to minimize
    the potential for adverse affects?

3. With our increased knowledge of the human
genome, a number of genes have been identified
that influence muscle function and endurance.
Myostatin mutation associated with gross muscle
hypertrophy in a child.
Photographs of the Child at the Ages of Six Days
and Seven Months (Panel A), Ultrasonograms (Panel
B) and Morphometric Analysis (Panel C) of the
Muscles of the Patient and a Control Infant, and
the Patient's Pedigree (Panel D)
Schuelke M et al. N Engl J Med 20043502682-2688
(No Transcript)
  • Should athletes who are willing to take the risks
    of experimental therapy be allowed to use gene
    therapy to enhance their performance?
  • How can society regulate the use of novel
    therapies for non-medical purposes?
  • What, if any, restraints should be placed on
    physicians in terms of assisting with
    non-therapeutic use of genetic methodologies?
  • Is this any different from athletes taking growth
    hormone or erythropoietin?

4. Subjects have participated in a national,
multicenter study to find the genes responsible
for Type 2 (adult onset) diabetes. One of the
goals of the study was to establish a cell line
bank of EBV-transformed lymphoblastoid cell lines
so that DNA can be given to many investigators
involved in Type 2 diabetes research. The
samples are coded and, when DNA is distributed,
no direct identifiers are given out, but the
national bank retains the link that matches the
code with the original subjects identity.
Shortly after this cell line bank was
established, the gene responsible for
hemochromatosis was identified. Hemochromatosis
is a disease of iron overload that can cause
diabetes, cirrhosis of the liver, hepatic cancer,
and cardiac failure.
An investigator who had requested and received
samples from the bank was asked by a colleague
whose lab was across the hall from hers if he
could look for hemochromatosis mutations in the
diabetes samples, since nobody had a clear idea
of how often patients with hemochromatosis were
misdiagnosed as having garden-variety type 2
diabetes. The first investigator gave the DNA to
her colleague, thinking this was a good
scientific question. A few months later, her
colleague comes back, saying that he has
identified 12 cases of hemochromatosis and
wonders what they should do with the results.
They draft a letter listing the ID numbers that
were found to carry hemochromatosis mutations and
send it to the tissue bank.
  • What should be done with this information?
    Should the original subjects be notified? If so,
  • Can the reliability of these findings be assured?
  • What might be done to avoid problems in the

5. The Hermans are a couple with two young
children, ages 3 and 5. They are thrilled to
have these two healthy children, as they had
endured years of infertility before finally
succeeding in becoming pregnant using in vitro
fertilization. At the time their first child was
conceived, several rounds of IVF were necessary
before successful implantation was achieved and
all of the embryos that had been produced were
used. When they returned for IVF again, they
became pregnant during the first cycle and 8
embryos were frozen for possible future
pregnancies. The couple has now decided that
their family is complete and they have called the
fertility clinic to discuss what should be done
with the remaining embryos.
  • Options that are presented include
  • a) maintaining the embryos in the freezer because
    they might change their minds and want more
  • b) donating the embryos to be given to another
    infertile couple,
  • c) destroying the embryos, and
  • d) donating the embryos for stem cell research
  • Should all of these options be presented?
  • What, if any, are the ethical issues raised by
    these options?

The Hermans are sure that their family is
complete and they will not wish to have any
further pregnancies, as they are both now in
their 40s. In addition, they have decided
against donation to another couple, as the idea
that their biological child would be born into
and raised by another family makes them
uncomfortable. They are therefore trying to
decide whether to have the embryos destroyed or
to donate them for stem cell research. Mrs.
Herman asks if they could find out which
investigator might get the embryos, so that they
can learn about the research and decide if they
think it is a worthwhile project. Dr. Taylor,
the IVF specialist who assisted the Hermans in
becoming pregnant, tells them that he is himself
involved in embryonic stem cell research aimed at
developing a treatment for muscular dystrophy and
they could donate the cells to his work.
  • Is this an acceptable option?
  • What type of conflict of interest may exist in
    this situation?
  • What other approaches might be ethically more