StemCell Therapy

Abstract

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, Parkinsons 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.

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)

V.

Fetal Stem Cells

VI.

Induced Pluripotent Stem Cells (iPS Cells)

VII.

Stem Cell Clinical Trials

VIII.

Institutional Oversight of Stem Cell Research

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, Parkinsons 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 pluripotent 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.

TABLE 1

Ethical issues at different phases of stem cell research

TABLE 1

Ethical issues at different phases of stem cell research

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.

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.

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.

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. Furthermore, 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).

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 politically controversial because it involves the destruction of human 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 embryos have the potential to become human beings; if implanted into a womans 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 perspective, 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 opposition to abortion and with the pro-life movement. However, 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).

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 destruction 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 Bushs 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 pluripotent, 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 transplantation 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 experts, 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 transplantation (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 laboratory space may not be used for research on nonapproved hESC lines. Both the derivation of new hESC lines and research 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 programs 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 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. However, 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, 11).

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 informed consent from the woman or couple donating the embryo, consent from gamete donors involved in the creation of the embryo, and the confidentiality of donor information.

Since the Nuremburg Code, informed consent has been regarded as a basic requirement for research with human subjects. Consent is particularly important in research with human 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 research. For instance, 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). Obtaining informed consent for potential future uses of the donated embryo respects this diversity of views. Additionally, people commonly place special emotional and moral significance on their reproductive materials, compared with other tissues (15).

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 possible to carry out embryo and stem cell research on deidentified 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 discarded. These materials could be deidentified and then used by researchers. Furthermore, if infertility patients have frozen 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 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 discard such frozen embryos, it is logistically feasible to deidentify them and give them to researchers.

However, the ethical justifications for allowing deidentified 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 offended or feel wronged if their frozen embryos were used for research that they did not consent to. Deidentifying the materials would not address their concerns.

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 required 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 research. Little is known about the wishes of sperm donors concerning research.

There are substantial practical differences between obtaining 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 stimulation and retrieval. However, most ART clinics obtain donor sperm from sperm banks and generally have no direct contact with the donors. Furthermore, sperm is often donated anonymously to sperm banks, with strict confidentiality 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 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 embryos are people or that gametes or embryos are research subjects.

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). 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, concerns about confidentiality may deter some donors from agreeing to be recontacted.

Recently, confidentiality of personal health care information 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 equivalent system, that records each entry. Audit trails of access to the information should be routinely monitored for inappropriate 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).

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 human SCNT lines were fabricated. In addition to scientific fraud, the scandal involved inappropriate payments to oocyte 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 medical complications from oocyte donation (2224). 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.

The medical risks of oocyte retrieval include ovarian hyperstimulation syndrome, bleeding, 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 number 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 research 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 procedure 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 research injuries has been recommended by several U.S. 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.

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 proximate 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 connected 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 insurance. 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.

If women in infertility treatment share oocytes with researcherseither their own oocytes or those from an oocyte donortheir prospect of reproductive success may be compromised because fewer oocytes are available for reproductive purposes (21). In this situation, the physician carrying out oocyte retrieval and infertility care should give priority to the reproductive needs of the patient in IVF. The highest quality oocytes should be used for reproductive purposes (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 researchers. 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 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 donate materials for research.

Many jurisdictions have conflicting policies about payment to oocyte donors. Reimbursement to oocyte donors for out-of-pocket expenses presents no ethical problems because donors gain no financial advantage 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 occurred in the Hwang scandal. Such concerns about undue influence, however, may be addressed without banning payment. 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 materials 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 criticized 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.

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 appreciate 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 detailed consent forms (32). CIRM thus reasons that disclosure, while necessary, is not sufficient to guarantee informed consent. 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 because 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 comprehension has also been carried out with respect to oocyte donation for clinical infertility services.

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, reprogramming 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).

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).

There are several compelling objections to using SCNT for human reproduction. First, because of errors during reprogramming of genetic material, cloned animal embryos fail to activate key embryonic genes, and newborn clones misexpress hundreds 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, fundamental 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 development and use for basic research should be banned.

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 chimerasmythical beasts that appear part human and part animal and have characteristics 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 concerned 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 immutable but empirical and pragmatic (4042). Animal-animal hybrids of various sorts, such as the mule, exist and are not considered morally objectionable. Moreover, in medical research, human cells are commonly injected into nonhuman animals and incorporated into their functioning tissue. Indeed, 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. 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 disagree over what is repugnant, and their views might change over time. Blood transfusion and cadaveric organ transplantation were originally viewed as repugnant but are now widely accepted practices. Furthermore, after public discussion and education, many people overcome their initial concerns.

Pluripotent stem cells can be derived from fetal tissue after abortion. However, use of fetal tissue is ethically controversial because it is associated with abortion, which many people 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 womans decision to terminate pregnancy might be influenced by the prospect of contributing tissue to research. Currently there is a phase 1 clinical trial in Battens disease, a lethal degenerative disease affecting children, using neural stem cells derived from fetal tissue (43, 44).

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 encoding for transcription factors, using retroviral vectors. Researchers have been trying to eliminate safety concerns about inserting oncogenes and insertional mutagenesis. Reprogramming has been successfully accomplished without known oncogenes and using adenovirus vectors rather than retrovirus vectors. 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, 48). Not only was reprogramming 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 embryonic stem cell research because embryos or oocytes are not used. Furthermore, because a skin biopsy to obtain somatic cells is relatively noninvasive, there are fewer concerns about risks to donors compared with oocyte donation. The Presidents Council on Bioethics called iPS cells ethically unproblematic and acceptable for use in humans (39). Neither the donation of materials to derive iPS cells nor their derivation raises special ethical issues.

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 derivatives, using common and well-accepted scientific practices, such as:

Genetic modifications of cells

Injection of derived cells into nonhuman animals to demonstrate 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 commercial 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 materials are not explicitly informed of these research procedures, 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 demonstrate that they are pluripotent. Large-scale genome sequencing will yield insights about the pathogenesis of disease and identify new targets for therapy. Injection of human stem cells into the brains of nonhuman animals will be required for preclinical testing of cell-based therapies for many conditions, such as Parkinsons disease, Alzheimers disease, and stroke.

However, some downstream research could also raise ethical concerns. For example, large-scale genome sequencing may evoke concerns about privacy and confidentiality. Donors might consider it a violation of privacy if scientists know their future susceptibility to many genetic diseases. Furthermore, 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, 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 developing 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 developing 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 additional 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 totipotent entities.

Because these concerns about consent for sensitive downstream research also apply to other types of stem cells, it would be prudent to put in place similar standards for consent 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.

Transplantation of cells derived from pluripotent stem cells offers the promise of effective new treatments. However, 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 hematopoietic 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, typically for large sums of money, but without credible scientific rationale, transparency, oversight, or patient protections (58). Although supporting medical innovation under very limited circumstances, the International Society for Stem Cell Research has decried such use of unproven 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. Additional 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.

The risks of innovative stem cell-based interventions include tumor formation, immunological reactions, unexpected 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 relevant 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 Parkinsons disease, transplanted cells failed to improve clinical outcomes (60, 61). Indeed, about 15% of subjects receiving transplantation late developed disabling dyskinesias, with some needing 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 intended neurotransmitters, appropriately regulated physiological function was not achieved. Participants in phase I trials may not thoroughly understand the possibility that hESC transplantation might make their condition worse.

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 clinical trials reveal that the information in consent forms generally is adequate. However, in early phase I gene transfer clinical trials, researchers descriptions of the direct benefit to participants commonly were vague, ambiguous, and indeterminate (64).

Participants in phase I stem cell-based clinical trials might overestimate their benefits and underestimate the risks. The 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 manner. Researchers need to communicate the distinction between 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 transplantation, 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 intervention 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 originated 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 participants 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 participants understanding of the study has been recommended more broadly in contexts in which misunderstandings 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 (6668). The resulting ethical controversies brought about negative publicity and delays in subsequent clinical trials.

Human stem cell research raises some ethical issues that are beyond the mission of institutional review boards (IRBs) 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.

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Ethical Issues in Stem Cell Research | Endocrine Reviews ...

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