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Ethical Issues in Stem Cell Research
Bernard Lo and Lindsay Parham
Program in Medical Ethics, the Division of General Internal Medicine, and the Department of Medicine, University of California San
Francisco, San Francisco, California 94143
Stem cell research offers great promise for understanding basic
mechanisms of human development and differentiation, as well as the
hope for new treatments for diseases such as diabetes, spinal cord injury,
Parkinson’s disease, and myo-cardial infarction. However, human stem
cell (hSC) research also raises sharp ethical and political controversies.
The der-ivation of pluripotent stem cell lines from oocytes and em-bryos
is fraught with disputes about the onset of human per-sonhood. The
reprogramming of somatic cells to produce induced pluripotent stem cells
avoids the ethical problems
I. Introduction
II. Multipotent Stem Cells
A. Cord blood stem cells
B. Adult blood stem cells
III. Embryonic Stem Cell Research
A. Existing embryonic stem cell lines
B. New embryonic stem cell lines from frozen embryos
C. Ethical concerns about oocyte donation for research IV.
Somatic Cell Nuclear Transfer (SCNT)
A. Ethical concerns about SCNT V.
Fetal Stem Cells
VI. Induced Pluripotent Stem Cells (iPS Cells)
A. Downstream research
VII. Stem Cell Clinical Trials
A. Risks and prospective benefits in stem cell clinical
trials
B. Informed consent in early stem cell clinical trials VIII.
Institutional Oversight of Stem Cell Research
A. The Stem Cell Research Oversight Committee (SCRO) B.
Use of stem cell lines derived at another institution
I. Introduction
S TEM CELL RESEARCH offers great promise for under-standing
basic mechanisms of human development and differentiation, as well
as the hope for new treatments for dis-eases such as diabetes, spinal
cord injury, Parkinson’s disease, and myocardial infarction (1).
Pluripotent stem cells perpet-uate themselves in culture and can
differentiate into all types of specialized cells. Scientists plan to
differentiate pluripo-
First Published Online April 14, 2009
Abbreviations: ART, Artificial reproductive technology; hESC, hu-man
embryonic stem cell; hSC, human stem cell; iPS cells, induced pluripotent
stem cells; IRB, institutional review board; IVF, in vitro fertilization; SCNT,
somatic cell nuclear transfer.
Endocrine Reviews is published by The Endocrine Society (http://
www.endo-society.org), the foremost professional society serving the
endocrine community.
204
Endocrine Reviews 30(3):204 –213
Copyright © 2009 by The Endocrine Society
doi: 10.1210/er.2008-0031
specific to embryonic stem cell research. In any hSC research, however,
difficult dilemmas arise regarding sensitive down-stream research,
consent to donate materials for hSC re-search, early clinical trials of hSC
therapies, and oversight of hSC research. These ethical and policy issues
need to be discussed along with scientific challenges to ensure that stem
cell research is carried out in an ethically appropriate manner. This
article provides a critical analysis of these issues and how they are
addressed in current policies. (Endocrine Reviews 30: 204 –213, 2009)
tent cells into specialized cells that could be used for
transplantation.
However, human stem cell (hSC) research also raises sharp
ethical and political controversies. The derivation of pluri-potent
stem cell lines from oocytes and embryos is fraught with disputes
regarding the onset of human personhood and human
reproduction. Several other methods of deriving stem cells raise
fewer ethical concerns. The reprogramming of somatic cells to
produce induced pluripotent stem cells (iPS cells) avoids the
ethical problems specific to embryonic stem cells. With any hSC
research, however, there are dif-ficult dilemmas, including
consent to donate materials for hSC research, early clinical trials
of hSC therapies, and over-sight of hSC research (2). Table 1
summarizes the ethical issues that arise at different phases of stem
cell research.
II. Multipotent Stem Cells
Adult stem cells and cord blood stem cells do not raise special
ethical concerns and are widely used in research and clinical care.
However, these cells cannot be expanded in vitro and have not
been definitively shown to be pluripotent.
A. Cord blood stem cells
Hematopoietic stem cells from cord blood can be banked and
are widely used for allogenic and autologous stem cell
transplantation in pediatric hematological diseases as an al-
ternative to bone marrow transplantation.
B. Adult blood stem cells
Adult stem cells occur in many tissues and can differen-tiate
into specialized cells in their tissue of origin and also
transdifferentiate into specialized cells characteristic of other
tissues. For example, hematopoietic stem cells can differen-tiate
into all three blood cell types as well as into neural stem cells,
cardiomyocytes, and liver cells.
Lo and Parham • Ethical Issues in Stem Cell Research Endocrine Reviews, May 2009, 30(3):204 –213 205

TABLE 1. Ethical issues at different phases of stem cell research
Phase of research
Donation of biological
materials
Research with hESCs
Use of stem cell lines derived
at another institution
Stem cell clinical trials
Ethical issues
Informed and voluntary consent
Destruction of embryos
Creation of embryos specifically
for research purposes
1. Payment to oocyte donors
2. Medical risks of oocyte
retrieval
3. Protecting reproductive
interests of women in
infertility treatment
Conflicting legal and ethical
standards
Risks and benefits of
experimental intervention
Informed consent
ever, such opposition to stem cell research is not monolithic. A
number of pro-life leaders support stem cell research using frozen
embryos that remain after a woman or couple has completed
infertility treatment and that they have decided not to give to
another couple. This view is held, for example, by former First
Lady Nancy Reagan and by U.S. Senator Orrin Hatch.
On his Senate website, Sen. Hatch states: “The support of
embryonic stem cell research is consistent with pro-life, pro-
family values.
“I believe that human life begins in the womb, not a Petri dish
or refrigerator . . . . To me, the morality of the situation dictates
that these embryos, which are routinely discarded, be used to
improve and save lives. The tragedy would be in not using these
embryos to save lives when the alternative is that they would be
discarded” (6).

Adult stem cells can be isolated through plasmapheresis. They
are already used to treat hematological malignancies and to
modify the side effects of cancer chemotherapy. Fur-thermore,
autologous stem cells are being used in clinical trials in patients
who have suffered myocardial infarction. Their use in several
other conditions has not been validated or is experimental, despite
some claims to the contrary (3).
III. Embryonic Stem Cell Research
Pluripotent stem cell lines can be derived from the inner cell
mass of the 5- to 7-d-old blastocyst. However, human embryonic
stem cell (hESC) research is ethically and politi-cally
controversial because it involves the destruction of hu-man
embryos. In the United States, the question of when human life
begins has been highly controversial and closely linked to debates
over abortion. It is not disputed that em-bryos have the potential
to become human beings; if im-planted into a woman’s uterus at
the appropriate hormonal phase, an embryo could implant,
develop into a fetus, and become a live-born child.
Some people, however, believe that an embryo is a person with
the same moral status as an adult or a live-born child. As a matter
of religious faith and moral conviction, they believe that “human
life begins at conception” and that an embryo is therefore a
person. According to this view, an embryo has interests and rights
that must be respected. From this perspec-tive, taking a blastocyst
and removing the inner cell mass to derive an embryonic stem
cell line is tantamount to murder (4).
Many other people have a different view of the moral status of
the embryo, for example that the embryo becomes a person in a
moral sense at a later stage of development than fertilization. Few
people, however, believe that the embryo or blastocyst is just a
clump of cells that can be used for research without restriction.
Many hold a middle ground that the early embryo deserves
special respect as a potential human being but that it is acceptable
to use it for certain types of research provided there is good
scientific justification, careful oversight, and informed consent
from the woman or couple for donating the embryo for research
(5).
Opposition to hESC research is often associated with op-
position to abortion and with the “pro-life” movement. How-
A. Existing embryonic stem cell lines
In 2001, President Bush, who holds strong pro-life views,
allowed federal National Institutes of Health (NIH) funding for
stem cell research using embryonic stem cell lines already in
existence at the time, while prohibiting NIH funding for the
derivation or use of additional embryonic stem cell lines. This
policy was a response to a growing sense that hESC research held
great promise for understanding and treating degenerative
diseases, while still opposing further destruc-tion of human
embryos. NIH funding was viewed by many researchers as
essential for attracting scientists to make a long-term commitment
to study the basic biology of stem cells; without a strong basic
science platform, therapeutic breakthroughs would be less likely.
President Bush’s rationale for this policy was that the embryos
from which these lines were produced had already been
destroyed. Allowing research to be carried out on the stem cell
lines might allow some good to come out of their destruction.
However, using only existing embryonic stem cell lines is
scientifically problematic. Originally, the NIH announced that
over 60 hESC lines would be acceptable for NIH funding.
However, the majority of these lines were not suitable for
research; for example, they were not truly plu-ripotent, had
become contaminated, or were not available for shipping. As of
January 2009, 22 hESC lines are eligible for NIH funding.
However, these lines may not be safe for trans-plantation into
humans, and long-standing lines have been shown to accumulate
mutations, including several known to predispose to cancer. In
addition, concerns have been raised about the consent process for
the derivation of some of these NIH-approved lines (7). The vast
majority of scientific ex-perts, including the Director of the NIH
under President Bush, believe that a lack of access to new
embryonic stem cell lines hinders progress toward stem cell-
based transplanta-tion (8). For example, lines from a wider range
of donors would allow more patients to receive human leukocyte
agent matched stem cell transplants (9).
Currently, federal funds may not be used to derive new
embryonic stem cell lines or to work with hESC lines not on the
approved NIH list. NIH-funded equipment and labora-tory space
may not be used for research on nonapproved hESC lines. Both
the derivation of new hESC lines and re-
206 Endocrine Reviews, May 2009, 30(3):204 –213
search with hESC lines not approved by NIH may be carried out
under nonfederal funding. Because of these restrictions on NIH
funding, a number of states have established pro-grams to fund
stem cell research, including the derivation of new embryonic
stem cell lines. California, for example, has allocated $3 billion
over 10 yr to stem cell research.
Under President Obama, it is expected that federal fund-ing
will be made available to carry out research with hESC lines not
on the NIH list and to derive new hESC lines from frozen
embryos donated for research after a woman or cou-ple using in
vitro fertilization (IVF) has determined they are no longer needed
for reproductive purposes. However, fed-eral funding may not be
permitted for creation of embryos expressly for research or for
derivation of stem cell lines using somatic cell nuclear transfer
(SCNT) (10, 11).
B. New embryonic stem cell lines from frozen embryos
Women and couples who undergo infertility treatment often
have frozen embryos remaining after they complete their
infertility treatment. The disposition of these frozen embryos is
often a difficult decision for them to make (12). Some choose to
donate these remaining embryos to research rather than giving
them to another couple for reproductive purposes or destroying
them. Several ethical concerns come into play when a frozen
embryo is donated, including in-formed consent from the woman
or couple donating the embryo, consent from gamete donors
involved in the cre-ation of the embryo, and the confidentiality of
donor information.
1. Informed consent for donation of materials for stem cell
research. Since the Nuremburg Code, informed consent has been
re-garded as a basic requirement for research with human sub-
jects. Consent is particularly important in research with hu-man
embryos (13). Members of the public and potential donors of
embryos for research hold strong and diverse opinions on the
matter. Some consider all embryo research to be unacceptable;
others only support some forms of re-search. For instance, a
person might consider infertility re-search acceptable but object
to research to derive stem cell lines or research that might lead to
patents or commercial products (14). Obtaining informed consent
for potential fu-ture uses of the donated embryo respects this
diversity of views. Additionally, people commonly place special
emo-tional and moral significance on their reproductive materials,
compared with other tissues (15).
2. Waiver of consent. In the United States, federal regulations on
research permit a waiver of informed consent for the research use
of deidentified biological materials that cannot be linked to
donors (16). Thus, logistically it would be pos-sible to carry out
embryo and stem cell research on deiden-tified materials without
consent. For example, during IVF procedures, oocytes that fail to
fertilize or embryos that fail to develop sufficiently to be
implanted are ordinarily dis-carded. These materials could be
deidentified and then used by researchers. Furthermore, if
infertility patients have fro-zen embryos remaining after they
complete treatment, they are routinely contacted by the IVF
program to decide whether they want to continue to store the
embryos (and to
Lo and Parham • Ethical Issues in Stem Cell Research
pay freezer storage fees), to donate them to another infertile
woman or couple, or to discard them. If a patient chooses to
discard the embryos, it would be possible to instead remove
identifiers and use them for research. Still another possibility
involves frozen embryos from patients who do not respond to
requests to make a decision regarding the disposition of frozen
embryos. Some IVF practices have a policy to discard such
embryos and inform patients of this policy when they give
consent for the IVF procedures. Again, rather than dis-card such
frozen embryos, it is logistically feasible to dei-dentify them and
give them to researchers.
However, the ethical justifications for allowing deidenti-fied
biological materials to be used for research without consent do
not always hold for embryo research (13). For example, one
rationale for allowing the use of deidentified materials is that the
ethical risks are very low; there can be no breach of
confidentiality, which is the main concern in this type of research.
A second rationale is that people would not object to having their
materials used in such a manner if they were asked. However, this
assumption does not necessarily hold in the context of embryo
research. A 2007 study found that 49% of women with frozen
embryos would be willing to donate them for research (12). Such
donors might be of-fended or feel wronged if their frozen
embryos were used for research that they did not consent to.
Deidentifying the ma-terials would not address their concerns.
3. Consent from gamete donors. Frozen embryos may be created
with sperm or oocytes from donors who do not participate any
further in assisted reproduction or childrearing. Some people
argue that consent from gamete donors is not re-quired for
embryo research because they have ceded their right to direct
further usage of their gametes to the artificial reproductive
technology (ART) patients. However, gamete donors who are
willing to help women and couples bear children may object to
the use of their genetic materials for research. In one study, 25%
of women who donated oocytes for infertility treatment did not
want the embryos created to be used for research (17). This
percentage is not unexpected because reproductive materials have
special significance, and many people in the United States oppose
embryo re-search. Little is known about the wishes of sperm
donors concerning research.
There are substantial practical differences between obtain-ing
consent for embryo research from oocyte donors and from sperm
donors. ART clinics can readily discuss donation for research
with oocyte donors during visits for oocyte stim-ulation and
retrieval. However, most ART clinics obtain do-nor sperm from
sperm banks and generally have no direct contact with the donors.
Furthermore, sperm is often do-nated anonymously to sperm
banks, with strict confidenti-ality provisions.
As a matter of respect for gamete donors, their wishes
regarding stem cell derivation should be determined and
respected (13). Gamete donors who are willing to help women
and couples bear children may object to the use of their genetic
materials for research. Specific consent for stem cell research
from both embryo and gamete donors was recommended by the
National Academy of Sciences 2005 Guidelines for Human
Embryonic Stem Cell Research and
Lo and Parham • Ethical Issues in Stem Cell Research
has been adopted by the California Institute for Regenerative
Medicine (CIRM), the state agency funding stem cell research
(18, 19). This consent requirement need not imply that em-bryos
are people or that gametes or embryos are research subjects.
4. Confidentiality of donor information. Confidentiality must be
carefully protected in embryo and hESC research because
breaches of confidentiality might subject donors to un-wanted
publicity or even harassment by opponents of hESC research
(20). Although identifying information about do-nors must be
retained in case of audits by the Food and Drug Administration as
part of the approval process for new ther-apies, concerns about
confidentiality may deter some donors from agreeing to be
recontacted.
Recently, confidentiality of personal health care informa-tion
has been violated through deliberate breaches by staff, through
break-ins by computer hackers, and through loss or theft of laptop
computers. Files containing the identities of persons whose
gametes or embryos were used to derive hESC lines should be
protected through heightened security measures (20). Any
computer storing such files should be locked in a secure room and
password-protected, with access limited to a minimum number of
individuals on a strict “need-to-know” basis. Entry to the
computer storage room should also be restricted by means of a
card-key, or equiv-alent system, that records each entry. Audit
trails of access to the information should be routinely monitored
for inap-propriate access. The files with identifiers should be
copy-protected and double encrypted, with one of the keys held
by a high-ranking institutional official who is not involved in
stem cell research. The computer storing these data should not be
connected to the Internet. To protect information from subpoena,
investigators should obtain a federal Certificate of
Confidentiality. Human factors in breaches of confidentiality
should also be considered. Personnel who have access to these
identifiers might receive additional background checks,
interviews, and training. The personnel responsible for
maintaining this confidential database and contacting any donor
should not be part of any research team.
hESC research using fresh oocytes donated for research raises
several additional ethical concerns as well, as we next discuss
(21).
C. Ethical concerns about oocyte donation for research
Concerns about oocyte donation specifically for research are
particularly serious in the wake of the Hwang scandal in South
Korea, in which widely hailed claims of deriving hu-man SCNT
lines were fabricated. In addition to scientific fraud, the scandal
involved inappropriate payments to oo-cyte donors, serious
deficiencies in the informed consent process, undue influence on
staff and junior scientists to serve as donors, and an unacceptably
high incidence of med-ical complications from oocyte donation
(22–24). In California, some legislators and members of the
public have charged that infertility clinics downplay the risks of
oocyte donation (19). CIRM has put in place several protections
for women donating oocytes in state-funded stem cell research.
1. Medical risks of oocyte retrieval. The medical risks of oocyte
retrieval include ovarian hyperstimulation syndrome, bleed-
Endocrine Reviews, May 2009, 30(3):204 –213 207
ing, infection, and complications of anesthesia (25). These risks
may be minimized by the exclusion of donors at high-risk for
these complications, careful monitoring of the num-ber of
developing follicles, and adjusting the dose of human chorionic
gonadotropin administered to induce ovulation or canceling the
cycle (25).
Because severe hyperovulation syndrome may require
hospitalization or surgery, women donating oocytes for re-search
should be protected against the costs of complications of
hormonal stimulation and oocyte retrieval (19). The United States
does not have universal health insurance. As a matter of fairness,
women who undergo an invasive pro-cedure for the benefit of
science and who are not receiving payment beyond expenses
should not bear any costs for the treatment of complications. Even
if a woman has health insurance, copayments and deductibles
might be substantial, and if she later applied for individual-rated
health insurance, her premiums might be prohibitive.
Compensation for re-search injuries has been recommended by
several U.S. panels
(26) but has not been adopted because of difficulties calcu-lating
long-term actuarial risk and assessing intervening fac-tors that
could contribute to or cause adverse events.
Requiring free care for short-term complications of oocyte
donation is feasible. In California, research institutions must
ensure free treatment to oocyte donors for direct and prox-imate
medical complications of oocyte retrieval in state-funded
research. The term “direct and proximate” is a legal concept to
determine how closely an injury needs to be con-nected to an
event or condition to assign responsibility for the injury to the
person who carried out the event or created the condition.
Commercial insurance policies are available to cover short-term
complications of oocyte retrieval. CIRM allows state stem cell
grants to cover the cost of such insur-ance. The rationale for
making research institutions respon-sible for treatment is that they
are in a better position than individual researchers to identify
insurance policies and would have an incentive to consider
extending such cover-age to other research injuries.
2. Protecting the reproductive interests of women in infertility
treatment. If women in infertility treatment share oocytes with
researchers— either their own oocytes or those from an oocyte
donor—their prospect of reproductive success may be
compromised because fewer oocytes are available for repro-
ductive purposes (21). In this situation, the physician carry-ing
out oocyte retrieval and infertility care should give pri-ority to the
reproductive needs of the patient in IVF. The highest quality
oocytes should be used for reproductive pur-poses (21).
As discussed in Section B. 2, in IVF programs some oocytes
fail to fertilize, and some embryos fail to develop sufficiently to
be implanted. Such materials may be donated to research-ers. To
protect the reproductive interests of donors, several safeguards
should be in place (20). For the donation of fresh embryos for
research, the determination by the embryologist that an embryo is
not suitable for implantation and therefore should be discarded is
a matter of judgment. Similarly, the determination that an oocyte
has failed to fertilize and thus cannot be used for reproduction is a
judgment call. To avoid any conflict of interest, the embryologist
should not know
208 Endocrine Reviews, May 2009, 30(3):204 –213
whether a woman has agreed to research donation and also should
receive no funding from grants associated with the research.
Furthermore, the treating infertility physicians should not know
whether or not their patients agree to do-nate materials for
research.
3. Payment to oocyte donors. Many jurisdictions have conflict-ing
policies about payment to oocyte donors. Reimburse-ment to
oocyte donors for out-of-pocket expenses presents no ethical
problems because donors gain no financial ad-vantage from
participating in research. However, payment to oocyte donors in
excess of reasonable out-of-pocket expenses is controversial, and
jurisdictions have conflicting policies that may also be internally
inconsistent (27, 28).
Good arguments can be made both for and against paying
donors of research oocytes more than their expenses (29). On the
one hand, some object that such payments induce women to
undertake excessive risks, particularly poorly educated women
who have limited options for employment, as oc-curred in the
Hwang scandal. Such concerns about undue influence, however,
may be addressed without banning pay-ment. For example,
participants could be asked questions to ensure that they
understood key features of the study and that they felt they had a
choice regarding participation (19). Also, careful monitoring and
adjustment of hormone doses can minimize the risks associated
with oocyte donation (25). A further objection is that paying
women who provide research oocytes undermines human dignity
because human biological materials and intimate relationships are
devalued if these ma-terials are bought and sold like commodities
(14, 30).
On the other hand, some contend that it is unfair to ban
payments to donors of research oocytes, while allowing women to
receive thousands of U.S. dollars to undergo the same procedures
to provide oocytes for infertility treatment (29). Moreover,
healthy volunteers, both men and women, are paid to undergo
other invasive research procedures, such as liver biopsy, for
research purposes. Furthermore, bans on payment for oocyte
donation for research have been criti-cized as paternalistic,
denying women the authority to make decisions for themselves
(31). On a pragmatic level, without such payment, it is very
difficult to recruit oocyte donors for research.
4. Informed consent for oocyte donation. In California, CIRM has
instituted heightened requirements for informed consent for
oocyte donation for research (19). The CIRM regulations go
beyond requirements for disclosure of information to oocyte
donors (19). The major ethical issue is whether donors ap-preciate
key information about oocyte donation, not simply whether the
information has been disclosed to them or not. As discussed
previously, in other research settings, research participants often
fail to understand the information in de-tailed consent forms (32).
CIRM thus reasons that disclosure, while necessary, is not
sufficient to guarantee informed con-sent. In CIRM-funded
research, oocyte donors must be asked questions to ensure that
they comprehend the key features of the research (19). Evaluating
comprehension is feasible be-cause it has been carried out in
other research contexts, such as in HIV prevention trials in the
developing world (33). According to testimony presented to
CIRM, evaluation of
Lo and Parham • Ethical Issues in Stem Cell Research
comprehension has also been carried out with respect to oocyte
donation for clinical infertility services.
IV. Somatic Cell Nuclear Transfer (SCNT)
Pluripotent stem cell lines whose nuclear DNA matches a
specific person have several scientific advantages. Stem cell lines
matched to persons with specific diseases can serve as in vitro
models of diseases, elucidate the pathophysiology of diseases,
and screen potential new therapies. Lines matched to specific
individuals also offer the promise of personalized autologous
stem cell transplantation.
One approach to creating such lines is through SCNT, the
technique that produced Dolly the sheep. In SCNT, repro-
gramming is achieved after transferring nuclear DNA from a
donor cell into an oocyte from which the nucleus has been
removed. However, creating human SCNT stem cell lines has not
only been scientifically impossible to date but is also ethically
controversial (34, 35).
A. Ethical concerns about SCNT
1. Objections to creating embryos specifically for research. Some
people who object to SCNT believe that creating embryos with
the intention of using them for research and destroying them in
that process violates respect for nascent human life. Even those
who support deriving stem cell lines from frozen embryos that
would otherwise be discarded sometimes reject the intentional
creation of embryos for research. In rebuttal, however, some
argue that pluripotent entities created through SCNT are
biologically and ethically distinct from embryos (36).
2. Objections to human reproduction using SCNT. There are
several compelling objections to using SCNT for human re-
production. First, because of errors during reprogramming of
genetic material, cloned animal embryos fail to activate key
embryonic genes, and newborn clones misexpress hun-dreds of
genes (37, 38). The risk of severe congenital defects would be
prohibitively high in humans. Second, even if SCNT could be
carried out safely in humans, some object that it violates human
dignity and undermines traditional, fun-damental moral, religious,
and cultural values (34). A cloned child would have only one
genetic parent and would be the genetic twin of that parent. In this
view, cloning would lead children to be regarded more as
“products of a designed manufacturing process than ‘gifts’ whom
their parents are prepared to accept as they are.” Furthermore,
cloning would violate “the natural boundaries between
generations” (34). For these reasons, cloning for reproductive
purposes is widely considered morally wrong and is illegal in a
number of states. Moreover, some people argue that because the
technique of SCNT can be used for reproduction, its devel-
opment and use for basic research should be banned.
3. Use of animal oocytes to create SCNT lines using human DNA.
Because of the shortage of human oocytes for SCNT research,
some scientists wish to use nonhuman oocytes to derive lines
using human nuclear DNA. These so-called “cytoplasmic hybrid
embryos” raise a number of ethical concerns. Some opponents
fear the creation of chimeras—mythical beasts
Lo and Parham • Ethical Issues in Stem Cell Research
that appear part human and part animal and have charac-teristics
of both humans and animals (39). Opponents may feel deep moral
unease or repugnance, without articulating their concerns in more
specific terms. Some people view such hybrid embryos as
contrary to a moral order embodied in the natural world and in
natural law. In this view, each species has a particular moral
purpose or goal, which mankind should not try to change. Others
view such research as an inappropriate crossing of species
barriers, which should be an immutable part of natural design.
Finally, some are con-cerned that there may be attempts to
implant these embryos for reproductive purposes.
In rebuttal, supporters of such research point out that the
biological definitions of species are not natural and immu-table
but empirical and pragmatic (40 – 42). Animal-animal hybrids of
various sorts, such as the mule, exist and are not considered
morally objectionable. Moreover, in medical re-search, human
cells are commonly injected into nonhuman animals and
incorporated into their functioning tissue. In-deed, this is widely
done in research with all types of stem cells to demonstrate that
cells are pluripotent or have dif-ferentiated into the desired type
of cell. In addition, some concerns can be addressed through strict
oversight (40), for example prohibiting reproductive uses of these
embryos and limiting in vitro development to 14 d or the
development of the primitive streak, limits that are widely
accepted for other hESC research. Finally, some people regard
repugnance per se an unconvincing guide to ethical judgments.
People dis-agree over what is repugnant, and their views might
change over time. Blood transfusion and cadaveric organ
transplan-tation were originally viewed as repugnant but are now
widely accepted practices. Furthermore, after public discus-sion
and education, many people overcome their initial concerns.
V. Fetal Stem Cells
Pluripotent stem cells can be derived from fetal tissue after
abortion. However, use of fetal tissue is ethically controver-sial
because it is associated with abortion, which many peo-ple object
to. Under federal regulations, research with fetal tissue is
permitted provided that the donation of tissue for research is
considered only after the decision to terminate pregnancy has
been made. This requirement minimizes the possibility that a
woman’s decision to terminate pregnancy might be influenced by
the prospect of contributing tissue to research. Currently there is a
phase 1 clinical trial in Batten’s disease, a lethal degenerative
disease affecting children, us-ing neural stem cells derived from
fetal tissue (43, 44).
VI. Induced Pluripotent Stem Cells (iPS Cells)
Somatic cells can be reprogrammed to form pluripotent stem
cells (45, 46), called induced pluripotential stem cells (iPS cells).
These iPS cell lines will have DNA matching that of the somatic
cell donors and will be useful as disease models and potentially
for allogenic transplantation.
Early iPS cell lines were derived by inserting genes en-coding
for transcription factors, using retroviral vectors. Re-
Endocrine Reviews, May 2009, 30(3):204 –213 209
searchers have been trying to eliminate safety concerns about
inserting oncogenes and insertional mutagenesis. Repro-
gramming has been successfully accomplished without known
oncogenes and using adenovirus vectors rather than retrovirus
vectors. A further step was the recent demonstra-tion that human
embryonic fibroblasts can be reprogrammed to a pluripotent state
using a plasmid with a peptide-linked reprogramming cassette
(47, 48). Not only was reprogram-ming accomplished without
using a virus, but the transgene can be removed after
reprogramming is accomplished. The ultimate goal is to induce
pluripotentiality without genetic manipulation. Because of
unresolved problems with iPS cells, which currently preclude
their use for cell-based therapies, most scientists urge continued
research with hESC (49).
iPS cells avoid the heated debates over the ethics of em-
bryonic stem cell research because embryos or oocytes are not
used. Furthermore, because a skin biopsy to obtain so-matic cells
is relatively noninvasive, there are fewer concerns about risks to
donors compared with oocyte donation. The President’s Council
on Bioethics called iPS cells “ethically unproblematic and
acceptable for use in humans” (39). Nei-ther the donation of
materials to derive iPS cells nor their derivation raises special
ethical issues.
A. Downstream research
Some potential downstream uses of iPS cell derivatives may be
so sensitive as to call into question whether the original somatic
cell donors would have agreed to such uses (50). iPS cells will be
shared widely among researchers who will carry out a variety of
studies with iPS cells and deriv-atives, using common and well-
accepted scientific practices, such as:
• Genetic modifications of cells
• Injection of derived cells into nonhuman animals to dem-
onstrate their function, including the injection into the brains
of nonhuman animals.
• Large-scale genome sequencing
• Sharing cell lines with other researchers, with appropriate
confidentiality protections, and
• Patenting scientific discoveries and developing commer-cial
tests and therapies, with no sharing of royalties with donors
(51).
These standard research techniques are widely used in other
types of basic research, including research with stem cells from
other sources. Generally, donors of biological ma-terials are not
explicitly informed of these research proce-dures, although such
disclosure is now proposed for whole genome sequencing (52,
53).
Such studies are of fundamental importance in stem cell
biology, for example to characterize the lines and to dem-onstrate
that they are pluripotent. Large-scale genome se-quencing will
yield insights about the pathogenesis of dis-ease and identify new
targets for therapy. Injection of human stem cells into the brains
of nonhuman animals will be re-quired for preclinical testing of
cell-based therapies for many conditions, such as Parkinson’s
disease, Alzheimer’s disease, and stroke.
210 Endocrine Reviews, May 2009, 30(3):204 –213
However, some downstream research could also raise eth-ical
concerns. For example, large-scale genome sequencing may
evoke concerns about privacy and confidentiality. Do-nors might
consider it a violation of privacy if scientists know their future
susceptibility to many genetic diseases. Further-more, it may be
possible to reidentify the donor of a dei-dentified large-scale
genome sequence using information in forensic DNA databases or
at an Internet company offering personal genomic testing (54,
55). Other donors may object to their cells being injected into
animals. For example, they may oppose all animal research, or
they may have religious objections to the mixing of human and
animal species. The injection of human neural progenitor cells
into nonhuman animals has raised ethical concerns about animals
develop-ing characteristics considered uniquely human (56, 57).
Still other donors may not want cell lines derived from their
biological materials to be patented as a step toward devel-oping
new tests and therapies. People are unlikely to drop such
objections even if the cell lines were deidentified or even if many
years had passed since the original donation. Thus there may be a
tension between respecting the autonomy of donors and obtaining
scientific benefit from research, which can be resolved during the
process of obtaining consent for the original donation of
materials.
It would be unfortunate if iPS cell lines that turned out to be
extremely useful scientifically (for example because of robust
growth in tissue culture) could not be used in addi-tional research
because the somatic cell donor objected. One approach to avoid
this is to preferentially use somatic cells from donors who are
willing to allow all such basic stem cell research and to be
contacted for future sensitive research that cannot be anticipated
at the time of consent (50). Donors could also be offered the
option of consenting to additional specific types of sensitive but
not fundamental downstream research, such as allogenic
transplantation into other humans and reproductive research
involving the creation of totipo-tent entities.
Because these concerns about consent for sensitive down-
stream research also apply to other types of stem cells, it would
be prudent to put in place similar standards for con-sent to donate
materials for derivation of other types of stem cells. However,
these concerns are particularly salient for iPS cells because of the
widespread perception that these cells raise no serious ethical
problems and because they are likely to play an increasing role in
stem cell research.
VII. Stem Cell Clinical Trials
Transplantation of cells derived from pluripotent stem cells
offers the promise of effective new treatments. How-ever, such
transplantation also involves great uncertainty and the possibility
of serious risks. Some stem cell therapies have been shown to be
effective and safe, for example he-matopoietic stem cell
transplants for leukemia and epithelial stem cell-based treatments
for burns and corneal disorders (58). However, “there are some
clinics around the world already exploiting patients’ hopes by
purporting to offer effective stem cell therapies for seriously ill
patients, typ-ically for large sums of money, but without credible
sci-
Lo and Parham • Ethical Issues in Stem Cell Research
entific rationale, transparency, oversight, or patient pro-tections”
(58). Although supporting medical innovation under very limited
circumstances, the International Soci-ety for Stem Cell Research
has decried such use of un-proven hSC transplantation.
These clinical trials should follow ethical principles that guide
all clinical research, including appropriate balance of risks and
benefits and informed, voluntary consent. Addi-tional ethical
requirements are also warranted to strengthen trial design,
coordinate scientific and ethics review, verify that participants
understand key features of the trial, and ensure publication of
negative findings (59). These measures are appropriate because of
the highly innovative nature of the intervention, limited
experience in humans, and the high hopes of patients who have
no effective treatments.
A. Risks and prospective benefits in stem cell clinical trials
The risks of innovative stem cell-based interventions in-clude
“tumor formation, immunological reactions, unex-pected
behavior of the cells, and unknown long-term health effects” (58).
Evidence of safety and proof of principle should be established
through appropriate preclinical studies in rel-evant animal models
or through human studies of similar cell-based interventions.
Requirements for proof of principle and safety should be higher if
cells have been manipulated extensively in vitro or have been
derived from pluripotent stem cells (58).
Even with these safeguards, however, because of the highly
innovative nature of the intervention and limited experience in
humans, unanticipated serious adverse events may occur. In older
clinical trials of transplantation of fetal dopaminergic neurons
into persons with Parkinson’s dis-ease, transplanted cells failed to
improve clinical outcomes (60, 61). Indeed, about 15% of
subjects receiving transplan-tation late developed disabling
dyskinesias, with some need-ing ablative surgery to relieve these
adverse events (60, 61). Although the transplanted cells localized
to the target areas of the brain, engrafted, and functioned to
produce the in-tended neurotransmitters, appropriately regulated
physio-logical function was not achieved. Participants in phase I
trials may not thoroughly understand the possibility that hESC
transplantation might make their condition worse.
B. Informed consent in early stem cell clinical trials
Problems with informed consent are well documented in phase
I clinical trials. Participants in cancer clinical trials commonly
expect that they will benefit personally from the trial, although
the primary purpose of phase I trials is to test safety rather than
efficacy (62). This tendency to view clinical research as providing
personal benefit has been termed the “therapeutic misconception”
(32, 63). Analyses of cancer clin-ical trials reveal that the
information in consent forms gen-erally is adequate. However, in
early phase I gene transfer clinical trials, researchers’ descriptions
of the direct benefit to participants commonly were vague,
ambiguous, and inde-terminate (64).
Participants in phase I stem cell-based clinical trials might
overestimate their benefits and underestimate the risks. The
Lo and Parham • Ethical Issues in Stem Cell Research
scientific rationale for hSC transplantation and preclinical results
may seem compelling. In addition, highly optimistic press
coverage might reinforce unrealistic hopes.
Several measures may enhance informed consent in early stem
cell-based clinical trials (59). First, researchers should describe
the risks and prospective benefits in a realistic man-ner.
Researchers need to communicate the distinction be-tween the
long-term hope for effective treatments and the uncertainty
inherent in any phase I trial. Participants in phase I studies need
to understand that the intervention has never been tried before in
humans for the specific condition, that researchers do not know
whether it will work as hoped, and that the great majority of
participants in phase I studies do not receive a direct benefit.
Second, investigators in hESC clinical trials should discuss a
broader range of information with potential participants than in
other clinical trials. The doctrine of informed consent requires
researchers to discuss with potential participants information that
is pertinent to their decision to volunteer for the clinical trial (65).
Generally, the relevant information concerns the nature of the
intervention being studied and the risks and prospective benefits.
However, in hESC transplan-tation, nonmedical issues may be
prominent or even decisive for some participants. Individuals
who regard the embryo as having the moral status of a person
would likely have strong objections to receiving hESC
transplants. Although this in-tervention might benefit them
medically, such individuals might regard it as complicit with an
immoral action. Thus researchers in clinical trials of hESC
transplantation should inform eligible participants that
transplanted materials orig-inated from human embryos.
Third, and most important, researchers should verify that
participants have a realistic understanding of the clinical trial
(59). The crucial ethical issue about informed consent is not what
researchers disclose in consent forms or discussions, but rather
what the participants in clinical trials understand. In other
contexts, some researchers have ensured that par-ticipants
understand the key features of the trial by assessing their
comprehension. In HIV clinical trials in developing countries,
where it has been alleged that participants did not understand the
trial, many researchers are now testing each participant to be sure
he or she understands the essential features of the research (33).
Such direct assessment of par-ticipants’ understanding of the
study has been recom-mended more broadly in contexts in which
misunderstand-ings are likely (26). We urge that such tests of
comprehension be carried out in phase I trials of hSC
transplantation (58, 59).
Careful attention to consent in highly innovative clinical trials
might prevent controversies later. In early clinical trials of organ
transplantation, the implantable totally artificial heart, and gene
transfer, the occurrence of serious adverse events led to
allegations that study participants had not truly understood the
nature of the research (66 – 68). The resulting ethical
controversies brought about negative publicity and delays in
subsequent clinical trials.
VIII. Institutional Oversight of Stem Cell Research
Human stem cell research raises some ethical issues that are
beyond the mission of institutional review boards (IRBs)
Endocrine Reviews, May 2009, 30(3):204 –213 211
to protect human subjects, as well as the expertise of IRB
members. There should be a sound scientific justification for
using human oocytes and embryos to derive new human stem cell
lines. However, IRBs usually do not carry out in-depth scientific
review. Some ethical issues in hESC research do not involve
human subjects’ protection, for example the concern that
transplanting human stem cells into nonhuman animals might
result in characteristics that are regarded as uniquely human.
A. The stem cell research oversight committee (SCRO)
An institutional SCRO with appropriate scientific and eth-ical
expertise, as well as public members, should be convened at each
institution to review, approve, and oversee stem cell research (18,
69, 70). The SCRO will need to work closely with the IRB and, in
cases of animal research, with the Institutional Animal Care and
Use Committee. Because of the sensitive nature of hSC research,
the SCRO should include nonaffil-iated and lay members who
can ensure that public concerns are taken into account.
B. Use of stem cell lines derived at another institution
Sharing stem cells across institutions facilitates scientific
progress and minimizes the number of oocytes, embryos, and
somatic cells used. However, ethical concerns arise if researchers
work with lines that were derived in other ju-risdictions under
conditions that would not be permitted at their home institution.
Researchers and SCROs need to dis-tinguish core ethical
standards that are accepted by interna-tional consensus—
informed consent and an acceptable bal-ance of benefits and risks
—from standards that vary across jurisdictions and cultures.
Using lines whose derivation vi-olated core standards would
erode ethical conduct of re-search by providing incentives to
others to violate those standards.
The review process should focus on those types of hSC
derivation that raise heightened levels of ethical concern (71).
hSC lines derived using fresh oocytes and embryos require in-
depth review because of concerns about the medical risks of
oocyte donation, undue influence, and setbacks to the
reproductive goals of a woman undergoing infertility treatment.
Dilemmas occur when donors of research oocytes receive
payments in excess of their expenses and such payments are not
permitted in the jurisdiction where the hSC cells will be used. For
example, the United Kingdom enacted an explicit policy to allow
such payment after public consultation and debate and provided
reasons to justify its decision (72–75). Jurisdictions that ban
payments should accept such carefully considered policies as a
reasonable difference of opinion on a complex issue. Concerns
about payment should be less if lines were derived from frozen
embryos remaining after IVF treatment and donors were paid in
the reproductive context. Such payments, which were carried out
before donation for research was actually considered, are not an
inducement for hESC research (71).
Other dilemmas arise with hESC lines derived from em-bryos
using gamete donors. As previously discussed, explicit
212 Endocrine Reviews, May 2009, 30(3):204 –213
consent for the use of reproductive materials in stem cell research
should be obtained from any gamete donors as well as embryo
donors (13, 76). An exception may be made to “grandparent”
older lines derived from frozen embryos cre-ated before such
explicit consent became the standard of care, for example before
the 2005 National Academy of Sciences guidelines (76). Use of
such older lines is appropriate because it would be unreasonable
to expect physicians to comply with standards that had not yet
been developed (71). It would also be acceptable to grandparent
lines if gamete donors agreed to unspecified future research or
gave dispositional control of frozen embryos to the woman or
couple in IVF. However, the derivation should be consistent with
the ethical and legal standards in place at the time the line was
derived.
In summary, hSC research offers exciting opportunities for
scientific advances and new therapies, but also raises some
complex ethical and policy issues. These issues need to be
discussed along with scientific challenges to ensure that stem cell
research is carried out in an ethically appropriate manner.
Acknowledgments
Received July 10, 2008. Accepted March 10, 2009.
Address all correspondence and requests for reprints to: Dr. Bernard Lo,
University of California San Francisco Program in Medical Ethics, 521
Parnassus Avenue, Suite C-126, San Francisco, California 94143. E-mail:
bernard.lo@ucsf.edu.
This work was supported by National Institutes of Health (NIH) Grant 1
UL1 RR024131-01 from the National Center for Research Re-sources
(NCRR) and NIH Roadmap for Medical Research and by the Greenwall
Foundation. Its contents are solely the responsibility of the authors and do not
necessarily represent the official view of NCRR or NIH.
B.L. is co-chair of the California Institute for Regenerative Medicine
Scientific and Medical Accountability Standards Working Group.
Disclosure Summary: The authors have no conflicts of interest to declare.
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