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Endocrine Reviews 30(3):204 –213 Copyright © 2009 by The Endocrine Society doi: 10.1210/er.2008-0031

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 myocardial infarction. However, human stem cell (hSC) research also raises sharp ethical and political controversies. The derivation of pluripotent stem cell lines from oocytes and embryos is fraught with disputes about the onset of human personhood. The reprogramming of somatic cells to produce induced pluripotent stem cells avoids the ethical problems specific to embryonic stem cell research. In any hSC research, however, difficult dilemmas arise regarding sensitive downstream research, consent to donate materials for hSC research, 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)

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

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 pluripotent 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 difficult dilemmas, including consent to donate materials for hSC research, early clinical trials of hSC therapies, and oversight 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

TEM 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 myocardial infarction (1). Pluripotent stem cells perpetuate themselves in culture and can differentiate into all types of specialized cells. Scientists plan to differentiate pluripoFirst Published Online April 14, 2009 Abbreviations: ART, Artificial reproductive technology; hESC, human 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://, the foremost professional society serving the endocrine community.


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 alternative to bone marrow transplantation.
B. Adult blood stem cells

Adult stem cells occur in many tissues and can differentiate into specialized cells in their tissue of origin and also transdifferentiate into specialized cells characteristic of other tissues. For example, hematopoietic stem cells can differentiate into all three blood cell types as well as into neural stem cells, cardiomyocytes, and liver cells.

such opposition to stem cell research is not monolithic. believe that the embryo or blastocyst is just a clump of cells that can be used for research without restriction. However. for example that the embryo becomes a person in a moral sense at a later stage of development than fertilization. A. However. or were not available for shipping.S. Sen. 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. Embryonic Stem Cell Research Pluripotent stem cell lines can be derived from the inner cell mass of the 5. including several known to predispose to cancer. Senator Orrin Hatch. They are already used to treat hematological malignancies and to modify the side effects of cancer chemotherapy. 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. For example. Currently. an embryo has interests and rights that must be respected. who holds strong pro-life views. President Bush. In addition. To me. This policy was a response to a growing sense that hESC research held great promise for understanding and treating degenerative diseases. It is not disputed that embryos have the potential to become human beings. May 2009. the majority of these lines were not suitable for research. How- In 2001. However. using only existing embryonic stem cell lines is scientifically problematic. In the United States. The tragedy would be in not using these embryos to save lives when the alternative is that they would be discarded” (6). the morality of the situation dictates that these embryos. by former First Lady Nancy Reagan and by U. had become contaminated. including the Director of the NIH under President Bush. However. Ethical issues at different phases of stem cell research Phase of research Ethical issues Endocrine Reviews. From this perspective. allowed federal National Institutes of Health (NIH) funding for stem cell research using embryonic stem cell lines already in existence at the time. however. an embryo could implant. for example. believe that an embryo is a person with the same moral status as an adult or a live-born child. Allowing research to be carried out on the stem cell lines might allow some good to come out of their destruction. President Bush’s rationale for this policy was that the embryos from which these lines were produced had already been destroyed. they were not truly pluripotent. Their use in several other conditions has not been validated or is experimental. however. while still opposing further destruction of human embryos. Protecting reproductive interests of women in infertility treatment Conflicting legal and ethical standards Risks and benefits of experimental intervention Informed consent Use of stem cell lines derived at another institution Stem cell clinical trials ever. “I believe that human life begins in the womb. Hatch states: “The support of embryonic stem cell research is consistent with pro-life. According to this view. careful oversight. . As a matter of religious faith and moral conviction. human embryonic stem cell (hESC) research is ethically and politically controversial because it involves the destruction of human embryos. . these lines may not be safe for transplantation into humans. for example. be used to improve and save lives. the question of when human life begins has been highly controversial and closely linked to debates over abortion. therapeutic breakthroughs would be less likely. Payment to oocyte donors 2. and long-standing lines have been shown to accumulate mutations. Furthermore. they believe that “human life begins at conception” and that an embryo is therefore a person. and become a live-born child. Originally. 22 hESC lines are eligible for NIH funding. . not a Petri dish or refrigerator . As of January 2009. lines from a wider range of donors would allow more patients to receive human leukocyte agent matched stem cell transplants (9). which are routinely discarded. Existing embryonic stem cell lines Adult stem cells can be isolated through plasmapheresis. profamily values. This view is 7-d-old blastocyst. the NIH announced that over 60 hESC lines would be acceptable for NIH funding. develop into a fetus. 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. autologous stem cells are being used in clinical trials in patients who have suffered myocardial infarction. Medical risks of oocyte retrieval 3. Both the derivation of new hESC lines and re- . NIH-funded equipment and laboratory space may not be used for research on nonapproved hESC lines. despite some claims to the contrary (3). Opposition to hESC research is often associated with opposition to abortion and with the “pro-life” movement. 30(3):204 –213 205 Donation of biological materials Research with hESCs Informed and voluntary consent Destruction of embryos Creation of embryos specifically for research purposes 1. without a strong basic science platform. taking a blastocyst and removing the inner cell mass to derive an embryonic stem cell line is tantamount to murder (4). III. while prohibiting NIH funding for the derivation or use of additional embryonic stem cell lines. Many other people have a different view of the moral status of the embryo. if implanted into a woman’s uterus at the appropriate hormonal phase. On his Senate website. Some people. 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. and informed consent from the woman or couple for donating the embryo for research (5). concerns have been raised about the consent process for the derivation of some of these NIH-approved lines (7). The vast majority of scientific experts. believe that a lack of access to new embryonic stem cell lines hinders progress toward stem cell-based transplantation (8).Lo and Parham • Ethical Issues in Stem Cell Research TABLE 1. Few people.

they are routinely contacted by the IVF program to decide whether they want to continue to store the embryos (and to pay freezer storage fees). The disposition of these frozen embryos is often a difficult decision for them to make (12). 2. In one study. and many people in the United States oppose embryo research. oocytes that fail to fertilize or embryos that fail to develop sufficiently to be implanted are ordinarily discarded. their wishes regarding stem cell derivation should be determined and respected (13). with strict confidentiality provisions. Again. for example. As a matter of respect for gamete donors. Frozen embryos may be created with sperm or oocytes from donors who do not participate any further in assisted reproduction or childrearing.206 Endocrine Reviews. it is logistically feasible to deidentify them and give them to researchers. 3. including the derivation of new embryonic stem cell lines. B. However. If a patient chooses to discard the embryos. 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. consent from gamete donors involved in the creation of the embryo. ART clinics can readily discuss donation for research with oocyte donors during visits for oocyte stimulation and retrieval. Obtaining informed consent for potential future uses of the donated embryo respects this diversity of views. Several ethical concerns come into play when a frozen embryo is donated. if infertility patients have frozen embryos remaining after they complete treatment. Some consider all embryo research to be unacceptable. Some choose to donate these remaining embryos to research rather than giving them to another couple for reproductive purposes or destroying them. sperm is often donated anonymously to sperm banks. Still another possibility involves frozen embryos from patients who do not respond to requests to make a decision regarding the disposition of frozen embryos. has allocated $3 billion over 10 yr to stem cell research. 11). However. there can be no breach of confidentiality. For example. gamete donors who are willing to help women and couples bear children may object to the use of their genetic materials for research. 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). A second rationale is that people would not object to having their materials used in such a manner if they were asked. May 2009. including informed consent from the woman or couple donating the embryo. 1. In the United States. a number of states have established programs to fund stem cell research. it would be possible to instead remove identifiers and use them for research. Such donors might be offended or feel wronged if their frozen embryos were used for research that they did not consent to. 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 . Some people argue that consent from gamete donors is not required for embryo research because they have ceded their right to direct further usage of their gametes to the artificial reproductive technology (ART) patients. the ethical justifications for allowing deidentified biological materials to be used for research without consent do not always hold for embryo research (13). this assumption does not necessarily hold in the context of embryo research. Because of these restrictions on NIH funding. Additionally. However. Under President Obama. it is expected that federal funding 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 couple using in vitro fertilization (IVF) has determined they are no longer needed for reproductive purposes. Some IVF practices have a policy to discard such embryos and inform patients of this policy when they give consent for the IVF procedures. rather than discard such frozen embryos. others only support some forms of research. California. most ART clinics obtain donor sperm from sperm banks and generally have no direct contact with the donors. Consent is particularly important in research with human embryos (13). A 2007 study found that 49% of women with frozen embryos would be willing to donate them for research (12). compared with other tissues (15). Furthermore. This percentage is not unexpected because reproductive materials have special significance. to donate them to another infertile woman or couple. Consent from gamete donors. 25% of women who donated oocytes for infertility treatment did not want the embryos created to be used for research (17). However. informed consent has been regarded as a basic requirement for research with human subjects. and the confidentiality of donor information. For instance. Waiver of consent. logistically it would be possible to carry out embryo and stem cell research on deidentified materials without consent. There are substantial practical differences between obtaining consent for embryo research from oocyte donors and from sperm donors. Informed consent for donation of materials for stem cell research. For example. a person might consider infertility research acceptable but object to research to derive stem cell lines or research that might lead to patents or commercial products (14). Little is known about the wishes of sperm donors concerning research. Members of the public and potential donors of embryos for research hold strong and diverse opinions on the matter. These materials could be deidentified and then used by researchers. Furthermore. Deidentifying the materials would not address their concerns. or to discard them. during IVF procedures. federal 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. people commonly place special emotional and moral significance on their reproductive materials. 30(3):204 –213 Lo and Parham • Ethical Issues in Stem Cell Research search with hESC lines not approved by NIH may be carried out under nonfederal funding. However. which is the main concern in this type of research. Since the Nuremburg Code. Gamete donors who are willing to help women and couples bear children may object to the use of their genetic materials for research. Thus. one rationale for allowing the use of deidentified materials is that the ethical risks are very low.

To protect information from subpoena. some legislators and members of the public have charged that infertility clinics downplay the risks of oocyte donation (19). in which widely hailed claims of deriving human SCNT lines were fabricated. 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 reproductive purposes (21). 19). in IVF programs some oocytes fail to fertilize. bleed- . the state agency funding stem cell research (18. Any computer storing such files should be locked in a secure room and password-protected. For the donation of fresh embryos for research. To protect the reproductive interests of donors. The computer storing these data should not be connected to the Internet. Because severe hyperovulation syndrome may require hospitalization or surgery. CIRM has put in place several protections for women donating oocytes in state-funded stem cell research. women who undergo an invasive procedure for the benefit of science and who are not receiving payment beyond expenses should not bear any costs for the treatment of complications. In California. as we next discuss (21). The rationale for making research institutions responsible 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 coverage to other research injuries. 2. concerns about confidentiality may deter some donors from agreeing to be recontacted. the embryologist should not know Concerns about oocyte donation specifically for research are particularly serious in the wake of the Hwang scandal in South Korea. or equivalent system. To avoid any conflict of interest. investigators should obtain a federal Certificate of Confidentiality.Lo and Parham • Ethical Issues in Stem Cell Research Endocrine Reviews. through break-ins by computer hackers. and through loss or theft of laptop computers. hESC research using fresh oocytes donated for research raises several additional ethical concerns as well. the determination by the embryologist that an embryo is not suitable for implantation and therefore should be discarded is a matter of judgment. The medical risks of oocyte retrieval include ovarian hyperstimulation syndrome. Audit trails of access to the information should be routinely monitored for inappropriate access. As a matter of fairness. Medical risks of oocyte retrieval. 30(3):204 –213 207 has been adopted by the California Institute for Regenerative Medicine (CIRM). The term “direct and proximate” is a legal concept to determine how closely an injury needs to be connected to an event or condition to assign responsibility for the injury to the person who carried out the event or created the condition. Files containing the identities of persons whose gametes or embryos were used to derive hESC lines should be protected through heightened security measures (20). interviews. with one of the keys held by a high-ranking institutional official who is not involved in stem cell research. Commercial insurance policies are available to cover short-term complications of oocyte retrieval. As discussed in Section B. her premiums might be prohibitive. The files with identifiers should be copyprotected and double encrypted. and complications of anesthesia (25). and if she later applied for individual-rated health insurance. and some embryos fail to develop sufficiently to be implanted. The personnel responsible for maintaining this confidential database and contacting any donor should not be part of any research team. and training. Such materials may be donated to researchers. the scandal involved inappropriate payments to oocyte donors. copayments and deductibles might be substantial. The United States does not have universal health insurance. and an unacceptably high incidence of medical complications from oocyte donation (22–24). Confidentiality must be carefully protected in embryo and hESC research because breaches of confidentiality might subject donors to unwanted publicity or even harassment by opponents of hESC research (20). the determination that an oocyte has failed to fertilize and thus cannot be used for reproduction is a judgment call. C. that records each entry. several safeguards should be in place (20). In California. In this situation. panels (26) but has not been adopted because of difficulties calculating long-term actuarial risk and assessing intervening factors that could contribute to or cause adverse events. careful monitoring of the number of developing follicles. Requiring free care for short-term complications of oocyte donation is feasible. CIRM allows state stem cell grants to cover the cost of such insurance. with access limited to a minimum number of individuals on a strict “need-to-know” basis. 2. infection. The highest quality oocytes should be used for reproductive purposes (21). May 2009. confidentiality of personal health care information has been violated through deliberate breaches by staff. Confidentiality of donor information. Entry to the computer storage room should also be restricted by means of a card-key. serious deficiencies in the informed consent process. 1.S. Human factors in breaches of confidentiality should also be considered. Personnel who have access to these identifiers might receive additional background checks. Similarly. Protecting the reproductive interests of women in infertility treatment. Even if a woman has health insurance. Ethical concerns about oocyte donation for research ing. research institutions must ensure free treatment to oocyte donors for direct and proximate medical complications of oocyte retrieval in statefunded research. This consent requirement need not imply that embryos are people or that gametes or embryos are research subjects. 4. women donating oocytes for research should be protected against the costs of complications of hormonal stimulation and oocyte retrieval (19). In addition to scientific fraud. Recently. Compensation for research injuries has been recommended by several U. Although identifying information about donors must be retained in case of audits by the Food and Drug Administration as part of the approval process for new therapies. and adjusting the dose of human chorionic gonadotropin administered to induce ovulation or canceling the cycle (25). undue influence on staff and junior scientists to serve as donors. the physician carrying out oocyte retrieval and infertility care should give priority to the reproductive needs of the patient in IVF. These risks may be minimized by the exclusion of donors at highrisk for these complications.

2. 4. First. and screen potential new therapies. In rebuttal. Informed consent for oocyte donation. Many jurisdictions have conflicting policies about payment to oocyte donors. Objections to creating embryos specifically for research. some argue that pluripotent entities created through SCNT are biologically and ethically distinct from embryos (36). Objections to human reproduction using SCNT. some object that such payments induce women to undertake excessive risks. According to testimony presented to CIRM. For example. the technique that produced Dolly the sheep. A cloned child would have only one genetic parent and would be the genetic twin of that parent. research participants often fail to understand the information in detailed consent forms (32). as occurred in the Hwang scandal. the treating infertility physicians should not know whether or not their patients agree to donate materials for research. some contend that it is unfair to ban payments to donors of research oocytes. Also. Somatic Cell Nuclear Transfer (SCNT) Pluripotent stem cell lines whose nuclear DNA matches a specific person have several scientific advantages. 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). 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 materials are bought and sold like commodities (14. 30(3):204 –213 Lo and Parham • Ethical Issues in Stem Cell Research whether a woman has agreed to research donation and also should receive no funding from grants associated with the research. such as liver biopsy. denying women the authority to make decisions for themselves (31). and cultural values (34). 38). even if SCNT could be carried out safely in humans. Stem cell lines matched to persons with specific diseases can serve as in vitro models of diseases. In this view. without such payment. religious. is not sufficient to guarantee informed consent. Furthermore. oocyte donors must be asked questions to ensure that they comprehend the key features of the research (19). CIRM thus reasons that disclosure. In California. dollars to undergo the same procedures to provide oocytes for infertility treatment (29). 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. it is very difficult to recruit oocyte donors for research. Use of animal oocytes to create SCNT lines using human DNA.S. May 2009. 35). such as in HIV prevention trials in the developing world (33). Second. Furthermore. both men and women. particularly poorly educated women who have limited options for employment. 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. 28). 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. The risk of severe congenital defects would be prohibitively high in humans. cloned animal embryos fail to activate key embryonic genes. while allowing women to receive thousands of U. because of errors during reprogramming of genetic material. however. some object that it violates human dignity and undermines traditional. Reimbursement to oocyte donors for out-of-pocket expenses presents no ethical problems because donors gain no financial advantage from participating in research. Lines matched to specific individuals also offer the promise of personalized autologous stem cell transplantation. Moreover. In CIRM-funded research. In SCNT. creating human SCNT stem cell lines has not only been scientifically impossible to date but is also ethically controversial (34. One approach to creating such lines is through SCNT. its development and use for basic research should be banned. while necessary. cloning would violate “the natural boundaries between generations” (34). IV. and jurisdictions have conflicting policies that may also be internally inconsistent (27. some people argue that because the technique of SCNT can be used for reproduction. As discussed previously. evaluation of comprehension has also been carried out with respect to oocyte donation for clinical infertility services. bans on payment for oocyte donation for research have been criticized as paternalistic. For these reasons. Good arguments can be made both for and against paying donors of research oocytes more than their expenses (29). On the one hand. however.” Furthermore. Such concerns about undue influence. However. Ethical concerns about SCNT 1. These so-called “cytoplasmic hybrid embryos” raise a number of ethical concerns. fundamental moral. elucidate the pathophysiology of diseases. may be addressed without banning payment. The major ethical issue is whether donors appreciate key information about oocyte donation. payment to oocyte donors in excess of reasonable out-of-pocket expenses is controversial. A. are paid to undergo other invasive research procedures. CIRM has instituted heightened requirements for informed consent for oocyte donation for research (19). and newborn clones misexpress hundreds of genes (37. However. There are several compelling objections to using SCNT for human reproduction. Evaluating comprehension is feasible because it has been carried out in other research contexts. Because of the shortage of human oocytes for SCNT research. healthy volunteers. reprogramming is achieved after transferring nuclear DNA from a donor cell into an oocyte from which the nucleus has been removed. in other research settings. cloning for reproductive purposes is widely considered morally wrong and is illegal in a number of states.208 Endocrine Reviews. Some opponents fear the creation of chimeras—mythical beasts . 30). 3. some scientists wish to use nonhuman oocytes to derive lines using human nuclear DNA. Moreover. On the other hand. Payment to oocyte donors. The CIRM regulations go beyond requirements for disclosure of information to oocyte donors (19). careful monitoring and adjustment of hormone doses can minimize the risks associated with oocyte donation (25). On a pragmatic level. 3. not simply whether the information has been disclosed to them or not. for research purposes.

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). 30(3):204 –213 209 that appear part human and part animal and have characteristics of both humans and animals (39). A further step was the recent demonstration that human embryonic fibroblasts can be reprogrammed to a pluripotent state using a plasmid with a peptide-linked reprogramming cassette (47. using common and well-accepted scientific practices. Finally. Some people view such hybrid embryos as contrary to a moral order embodied in the natural world and in natural law. The President’s Council on Bioethics called iPS cells “ethically unproblematic and acceptable for use in humans” (39). Pluripotent stem cells can be derived from fetal tissue after abortion. Blood transfusion and cadaveric organ transplantation were originally viewed as repugnant but are now widely accepted practices. and • Patenting scientific discoveries and developing commercial tests and therapies. Because of unresolved problems with iPS cells. supporters of such research point out that the biological definitions of species are not natural and immutable but empirical and pragmatic (40 – 42). VI. 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. Furthermore. Moreover. • Large-scale genome sequencing • Sharing cell lines with other researchers. In this view. Currently there is a phase 1 clinical trial in Batten’s disease. some people regard repugnance per se an unconvincing guide to ethical judgments. However. donors of biological materials are not explicitly informed of these research procedures. Alzheimer’s disease. for example to characterize the lines and to demonstrate that they are pluripotent. and stroke. including the injection into the brains of nonhuman animals. in medical research. Opponents may feel deep moral unease or repugnance. Fetal Stem Cells searchers have been trying to eliminate safety concerns about inserting oncogenes and insertional mutagenesis. Such studies are of fundamental importance in stem cell biology.Lo and Parham • Ethical Issues in Stem Cell Research Endocrine Reviews. Not only was reprogramming accomplished without using a virus. Injection of human stem cells into the brains of nonhuman animals will be required for preclinical testing of cell-based therapies for many conditions. May 2009. Others view such research as an inappropriate crossing of species barriers. exist and are not considered morally objectionable. Finally. without articulating their concerns in more specific terms. Induced Pluripotent Stem Cells (iPS Cells) Somatic cells can be reprogrammed to form pluripotent stem cells (45. a lethal degenerative disease affecting children. Indeed. using neural stem cells derived from fetal tissue (43. Animal-animal hybrids of various sorts. with appropriate confidentiality protections. after public discussion and education. because a skin biopsy to obtain somatic cells is relatively noninvasive. Reprogramming has been successfully accomplished without known oncogenes and using adenovirus vectors rather than retrovirus vectors. there are fewer concerns about risks to donors compared with oocyte donation. People disagree over what is repugnant. each species has a particular moral purpose or goal. this is widely done in research with all types of stem cells to demonstrate that cells are pluripotent or have differentiated into the desired type of cell. most scientists urge continued research with hESC (49). iPS cells avoid the heated debates over the ethics of embryonic stem cell research because embryos or oocytes are not used. 53). human cells are commonly injected into nonhuman animals and incorporated into their functioning tissue. 44). 46). such as the mule. such as Parkinson’s disease. Under federal regulations. which should be an immutable part of natural design. Neither the donation of materials to derive iPS cells nor their derivation raises special ethical issues. In addition. which many people object to. Generally. but the transgene can be removed after reprogramming is accomplished. A. using retroviral vectors. although such disclosure is now proposed for whole genome sequencing (52. V. 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. with no sharing of royalties with donors (51). Large-scale genome sequencing will yield insights about the pathogenesis of disease and identify new targets for therapy. These standard research techniques are widely used in other types of basic research. for example prohibiting reproductive uses of these embryos and limiting in vitro development to 14 d or the development of the primitive streak. called induced pluripotential stem cells (iPS cells). some concerns can be addressed through strict oversight (40). which mankind should not try to change. In rebuttal. use of fetal tissue is ethically controversial because it is associated with abortion. 48). This requirement minimizes the possibility that a woman’s decision to terminate pregnancy might be influenced by the prospect of contributing tissue to research. Re- . Early iPS cell lines were derived by inserting genes encoding for transcription factors. including research with stem cells from other sources. Furthermore. and their views might change over time. The ultimate goal is to induce pluripotentiality without genetic manipulation. iPS cells will be shared widely among researchers who will carry out a variety of studies with iPS cells and derivatives. many people overcome their initial concerns. some are concerned that there may be attempts to implant these embryos for reproductive purposes. which currently preclude their use for cell-based therapies. limits that are widely accepted for other hESC research. such as: • Genetic modifications of cells • Injection of derived cells into nonhuman animals to demonstrate their function.

for example hematopoietic stem cell transplants for leukemia and epithelial stem cell-based treatments for burns and corneal disorders (58). In older clinical trials of transplantation of fetal dopaminergic neurons into persons with Parkinson’s disease. Some stem cell therapies have been shown to be effective and safe. limited experience in humans. 55). 30(3):204 –213 Lo and Parham • Ethical Issues in Stem Cell Research However. Participants in cancer clinical trials commonly expect that they will benefit personally from the trial. Although the transplanted cells localized to the target areas of the brain. it may be possible to reidentify the donor of a deidentified large-scale genome sequence using information in forensic DNA databases or at an Internet company offering personal genomic testing (54. appropriately regulated physiological function was not achieved. including appropriate balance of risks and benefits and informed. oversight. Although supporting medical innovation under very limited circumstances. However. Indeed. Donors might consider it a violation of privacy if scientists know their future susceptibility to many genetic diseases. because of the highly innovative nature of the intervention and limited experience in humans. and ensure publication of negative findings (59). and the high hopes of patients who have no effective treatments. about 15% of subjects receiving transplantation late developed disabling dyskinesias. Even with these safeguards. These measures are appropriate because of the highly innovative nature of the intervention. However. with some needing ablative surgery to relieve these adverse events (60. immunological reactions. For example. transplanted cells failed to improve clinical outcomes (60. however. The injection of human neural progenitor cells into nonhuman animals has raised ethical concerns about animals developing characteristics considered uniquely human (56. These clinical trials should follow ethical principles that guide all clinical research. unexpected behavior of the cells. 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. The . Risks and prospective benefits in stem cell clinical trials The risks of innovative stem cell-based interventions include “tumor formation. some downstream research could also raise ethical concerns. 57). entific rationale. For example. B. transparency. coordinate scientific and ethics review. and indeterminate (64). which can be resolved during the process of obtaining consent for the original donation of materials. Participants in phase I trials may not thoroughly understand the possibility that hESC transplantation might make their condition worse. engrafted. 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). such transplantation also involves great uncertainty and the possibility of serious risks. 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 additional research because the somatic cell donor objected. A. in early phase I gene transfer clinical trials. typically for large sums of money. and functioned to produce the intended neurotransmitters. and unknown long-term health effects” (58). voluntary consent. Informed consent in early stem cell clinical trials VII. May 2009. Donors could also be offered the option of consenting to additional specific types of sensitive but not fundamental downstream research. 61). the International Society for Stem Cell Research has decried such use of unproven hSC transplantation. 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).210 Endocrine Reviews. Analyses of cancer clinical trials reveal that the information in consent forms generally is adequate. Evidence of safety and proof of principle should be established through appropriate preclinical studies in relevant animal models or through human studies of similar cell-based interventions. but without credible sci- Problems with informed consent are well documented in phase I clinical trials. Thus there may be a tension between respecting the autonomy of donors and obtaining scientific benefit from research. researchers’ descriptions of the direct benefit to participants commonly were vague. it would be prudent to put in place similar standards for consent to donate materials for derivation of other types of stem cells. unanticipated serious adverse events may occur. “there are some clinics around the world already exploiting patients’ hopes by purporting to offer effective stem cell therapies for seriously ill patients. 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. Furthermore. verify that participants understand key features of the trial. This tendency to view clinical research as providing personal benefit has been termed the “therapeutic misconception” (32. although the primary purpose of phase I trials is to test safety rather than efficacy (62). However. large-scale genome sequencing may evoke concerns about privacy and confidentiality. Additional ethical requirements are also warranted to strengthen trial design. 61). Participants in phase I stem cell-based clinical trials might overestimate their benefits and underestimate the risks. However. Because these concerns about consent for sensitive downstream research also apply to other types of stem cells. or patient protections” (58). or they may have religious objections to the mixing of human and animal species. Stem Cell Clinical Trials Transplantation of cells derived from pluripotent stem cells offers the promise of effective new treatments. ambiguous. Still other donors may not want cell lines derived from their biological materials to be patented as a step toward developing new tests and therapies. Other donors may object to their cells being injected into animals. such as allogenic transplantation into other humans and reproductive research involving the creation of totipotent entities. 63). they may oppose all animal research.

A. the relevant information concerns the nature of the intervention being studied and the risks and prospective benefits. explicit . In early clinical trials of organ transplantation. 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. Participants in phase I studies need to understand that the intervention has never been tried before in humans for the specific condition. Several measures may enhance informed consent in early stem cell-based clinical trials (59). as well as public members. Second. May 2009. Researchers and SCROs need to distinguish core ethical standards that are accepted by international consensus—informed consent and an acceptable balance of benefits and risks—from standards that vary across jurisdictions and cultures. In addition. However. that researchers do not know whether it will work as hoped. Other dilemmas arise with hESC lines derived from embryos using gamete donors. and oversee stem cell research (18. as well as the expertise of IRB members. 69. in cases of animal research. but rather what the participants in clinical trials understand. should be convened at each institution to review. The crucial ethical issue about informed consent is not what researchers disclose in consent forms or discussions. with the Institutional Animal Care and Use Committee. for example the concern that transplanting human stem cells into nonhuman animals might result in characteristics that are regarded as uniquely human. some researchers have ensured that participants understand the key features of the trial by assessing their comprehension. highly optimistic press coverage might reinforce unrealistic hopes. and somatic cells used. 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. The resulting ethical controversies brought about negative publicity and delays in subsequent clinical trials. and gene transfer. The stem cell research oversight committee (SCRO) An institutional SCRO with appropriate scientific and ethical expertise. In HIV clinical trials in developing countries. the implantable totally artificial heart. Although this intervention might benefit them medically. B. The review process should focus on those types of hSC derivation that raise heightened levels of ethical concern (71). As previously discussed. Institutional Oversight of Stem Cell Research to protect human subjects. Third. undue influence. and setbacks to the reproductive goals of a woman undergoing infertility treatment. Some ethical issues in hESC research do not involve human subjects’ protection. 70). 30(3):204 –213 211 scientific rationale for hSC transplantation and preclinical results may seem compelling. such individuals might regard it as complicit with an immoral action. We urge that such tests of comprehension be carried out in phase I trials of hSC transplantation (58. ethical concerns arise if researchers work with lines that were derived in other jurisdictions under conditions that would not be permitted at their home institution. the occurrence of serious adverse events led to allegations that study participants had not truly understood the nature of the research (66 – 68). However. where it has been alleged that participants did not understand the trial. 59). 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. approve. However. IRBs usually do not carry out indepth scientific review. Using lines whose derivation violated core standards would erode ethical conduct of research by providing incentives to others to violate those standards. Individuals who regard the embryo as having the moral status of a person would likely have strong objections to receiving hESC transplants. Such payments. researchers should verify that participants have a realistic understanding of the clinical trial (59). Careful attention to consent in highly innovative clinical trials might prevent controversies later. Researchers need to communicate the distinction between the long-term hope for effective treatments and the uncertainty inherent in any phase I trial. Thus researchers in clinical trials of hESC transplantation should inform eligible participants that transplanted materials originated from human embryos. researchers should describe the risks and prospective benefits in a realistic manner.Lo and Parham • Ethical Issues in Stem Cell Research Endocrine Reviews. investigators in hESC clinical trials should discuss a broader range of information with potential participants than in other clinical trials. nonmedical issues may be prominent or even decisive for some participants. VIII. There should be a sound scientific justification for using human oocytes and embryos to derive new human stem cell lines. In other contexts. Such direct assessment of participants’ understanding of the study has been recommended more broadly in contexts in which misunderstandings are likely (26). are not an inducement for hESC research (71). Use of stem cell lines derived at another institution Human stem cell research raises some ethical issues that are beyond the mission of institutional review boards (IRBs) Sharing stem cells across institutions facilitates scientific progress and minimizes the number of oocytes. The SCRO will need to work closely with the IRB and. Generally. which were carried out before donation for research was actually considered. 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). hSC lines derived using fresh oocytes and embryos require in-depth review because of concerns about the medical risks of oocyte donation. embryos. and most important. For example. and that the great majority of participants in phase I studies do not receive a direct benefit. First. in hESC transplantation. many researchers are now testing each participant to be sure he or she understands the essential features of the research (33). the SCRO should include nonaffiliated and lay members who can ensure that public concerns are taken into account. Because of the sensitive nature of hSC research.

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