The ability to isolate and culture human embryonic stem (ES) cells, which was first reported in 1998, has opened a promising area of medical research (1Thomson J.A. Itskovitz-Eldor J. Shapiro S.S. Waknitz M.A. Swiergiel J.J. Marshall V.S. et al.Embryonic stem cell lines derived from human blastocysts.Science. 1998; 282: 1145-1147Crossref PubMed Scopus (11805) Google Scholar). Derived from the inner cell mass of blastocyst-stage embryos, pluripotent ES cells give rise to all cell types in the human body and are thought to be able to proliferate indefinitely in an undifferentiated state (2American Association for the Advancement of Science and Institute for Civil Society. Stem cell research and applications: monitoring the frontiers of biomedical research. Washington, DC: American Association for the Advancement of Science, 1999:3.Google Scholar). Researchers predict that, if coaxed to differentiate in culture, ES cells can be used to create specialized cells to treat a wide range of diseases and conditions, including Parkinson’s disease, Alzheimer’s disease, cancer, spinal cord injury, and juvenile-onset diabetes. Other envisioned uses of ES cells include research to understand cell specialization and the development and testing of new drugs (3National Institutes of Health. Office of the Director. Stem cells: a primer. May 2000. Available at http://www.nih.gov/news/stemcell/primer.htm. Accessed on November 2, 2000.Google Scholar). Human ES cell research has provoked considerable discussion about ethics and policy. Among other commissions, the National Bioethics Advisory Commission considered the question of federal funding of ES cell research in 1999 and recommended that the government fund both the derivation and use of ES cells from spare, donated embryos. The Clinton administration proposed funding only the use of ES cells, and the National Institutes of Health subsequently issued guidelines to oversee the process. Before any grants were made, however, a change of administration occurred. After further review of the issue, President Bush announced on August 9, 2001, that the administration would consider for funding only those proposals using human ES cells from cell lines that had been derived and cultured by August 9, 2001 (4The White House. Office of the Press Secretary. Radio address by the President to the nation. Bush Ranch, Crawford, Texas, August 11, 2001. Available at http://www.whitehouse.gov/news/releases/2000. Accessed on February 5, 2002.Google Scholar). Although this decision opened the door to fundable research, many scientists have questioned whether the preexisting cell lines would be adequate for the research or therapies to which they might lead. Privately funded investigators are likely to seek additional donated embryos in order to obtain new ES cell lines for research in their own laboratories. New sources of embryos will enable investigators to study the derivation process itself, secure more cells from the initial embryo source if necessary, and culture cell lines from varied genetic sources. In addition, the human ES cells derived before August 9, 2001, were cultured in their undifferentiated state on a feeder layer of embryonic mouse cells, which will render these cell lines unacceptable for clinical trials. Presumably, new cell lines will be needed for clinical trials to commence. A primary source of embryos for future ES cell research is likely to be embryos donated by couples undergoing IVF who no longer want or need their embryos for fertility treatment. We consider here the conditions under which fertility clinics and other facilities that store embryos may ethically make embryos available for researchers seeking ES cells. This consideration is preceded by a summary of differing perspectives about the ethics of embryo research. Human embryo research has elicited diverse and conflicting perspectives since the early days of in vitro fertilization. Discussions about the human embryo are frequently framed in terms of the embryo’s moral status. An important distinction arises between those who regard the embryo as a person, with all the protections accorded fellow members of the human community, and those who regard the embryo as deserving respect as a potential human being but not the same respect accorded persons. Those who believe the embryo has the moral status of persons expect that the embryo should be accorded all the rights of these individuals. Under this perspective, the embryo is vulnerable and needs protection. Some believe this status begins during fertilization, when the DNA from the female and male gametes combines to create an entity with a novel genetic composition. Others believe the status begins later, when the primitive streak begins to develop approximately l4 days after fertilization and when the embryo will, if it survives, develop into a single individual. Most of those who believe that the embryo has a lesser status than adults and children regard the embryo as a potential human being worthy of special respect but not entitled to the same rights as persons. According to this perspective, the embryo used in research ranges in size from a single cell to hundreds of cells with no nervous system and a limited chance of developing to birth. The possibility of twinning or regression to a nonviable entity up to the 14th day after fertilization is consistent with the notion that the embryo lacks individuality. Moreover, according to this point of view, the early embryo lacks the criteria traditionally equated with human status. The Ethics Committee of the American Society for Reproductive Medicine (ASRM) has consistently held to the second perspective, which regards the embryo as a potential human being worthy of special respect (5Ethics Committee of the American Fertility SocietyEthical considerations of the new reproductive technologies.Fertil Steril. 1986; 46: 1SPubMed Google Scholar, 6Ethics Committee of the American Fertility SocietyEthical considerations of the new reproductive technologies.Fertil Steril. 1990; 53: 1SPubMed Google Scholar, 7Ethics Committee of the American Fertility SocietyEthical considerations of assisted reproductive technologies.Fertil Steril. 1994; 62: 1SPubMed Google Scholar, 8Ethics Committee of the American Society for Reproductive MedicineInformed consent and the use of gametes and embryos for research.Fertil Steril. 1997; 68: 780-781Abstract Full Text PDF PubMed Scopus (14) Google Scholar). The ASRM Ethics Committee regards embryo research as ethically acceptable if it is likely to provide significant new knowledge that will benefit human health and if it is conducted in ways that accord the embryo respect. The Ethics Committee, along with commissions and advisory bodies from around the world, has developed core expectations about how research using embryos may ethically be conducted (8Ethics Committee of the American Society for Reproductive MedicineInformed consent and the use of gametes and embryos for research.Fertil Steril. 1997; 68: 780-781Abstract Full Text PDF PubMed Scopus (14) Google Scholar, 9ESHRE Task Force on Ethics and LawI. The moral status of the pre-implantation embryo.Hum Reprod. 2001; 16: 1046-1048Crossref PubMed Google Scholar). Among other things, couples must give informed consent to donate their spare embryos for research, embryos should not be kept cleaving more than 14 days after fertilization, and there should be no buying and selling of embryos. It is also expected that the investigator bears the burden of justifying the worthiness of the research, uses the smallest possible number of embryos, submits proposals to review by an institutional review board, has no satisfactory alternative to using embryos, and expects important clinical data to accrue from the research. The ability of scientists to isolate and culture human ES cells has evoked renewed discussions about the ethics of embryo research. Advocates of ES cell research argue that preimplantation embryos will be discarded in any event and it is appropriate to gain some benefit from the act. In light of the potentially significant impact on regenerative medicine, they argue it may even be morally obligatory to pursue this research. They also note that donation for embryo research is an extension of the couple’s authority over the disposition of embryos. Critics, on the other hand, argue that research causing the destruction of embryos is wrong. In addition, they argue that adult stem cells also hold potential for diagnostics and therapy. They also express concern that the research will lead to the treatment of embryos as commodities and, consequently, to diminished respect for embryos. The matter of whether embryos may ethically be created for ES cell research through in vitro fertilization or somatic cell nuclear transfer remains a topic of continued debate and elusive consensus (10ESHRE Task Force on Ethics and LawIV. Stem cells.Hum Reprod. 2002; 17: 1409-1410Crossref PubMed Google Scholar, 11United Kingdom Department of HealthGovernment response to the recommendations made in the Chief Medical Officer’s Expert Group report, “Stem Cell Research: Medical Progress with Responsibility.”. 2000Google Scholar, 12Australian Academy of ScienceOn human cloning. Australian Academy of Science, Canberra1999Google Scholar, 13National Bioethics Advisory CommissionEthical issues in human stem cell research. National Bioethics Advisory Commission, Rockville, MD1999Google Scholar, 14National Institutes of HealthDraft National Institutes of Health guidelines for research involving human pluripotent stem cells.Fed Regist. 1999; 64: 67576-67579PubMed Google Scholar, 15Canadian Institutes of Health ResearchHuman stem cell research. Canadian Institutes of Health Research, Ottawa2001Google Scholar). A distinct feature of ES cell investigations is the intent to derive cell lines that may continue to divide indefinitely and be used by researchers for many years to come. Cell lines eventually may have considerable commercial value. In addition, they may potentially be traced to donors (10ESHRE Task Force on Ethics and LawIV. Stem cells.Hum Reprod. 2002; 17: 1409-1410Crossref PubMed Google Scholar). For these and other reasons, it is appropriate to revisit guidelines about what should be conveyed to couples in the donation process, when, and by whom. These guidelines aim to protect the autonomous interests of couples faced with deciding the disposition of embryos they no longer want or need. Informed consent is a basic requirement for the ethical conduct of all human subjects research, including studies using human embryos. Couples who donate embryos for research should be told of the risks and benefits of donation. For example, a risk might arise if the couple were later to wish they still had the embryos available for their fertility efforts. A benefit might be the satisfaction of knowing they have contributed to research designed to advance medical therapies. Couples should also be told of the purpose and nature of the research and of whether the research is expected to have commercial value. They should be told that they may change their minds about donation at any time until the experiment begins, that their status in the infertility program will not be affected if they do not donate spare embryos, and that no embryos used in the study will be transferred for pregnancy (8Ethics Committee of the American Society for Reproductive MedicineInformed consent and the use of gametes and embryos for research.Fertil Steril. 1997; 68: 780-781Abstract Full Text PDF PubMed Scopus (14) Google Scholar). In the case of donation for ES cell research, other considerations may also be relevant. Given the wide range of uses to which ES cells may be put, couples should be informed of the specific research project, if known, or at least of the category of anticipated research, such as reproductive research, development of therapies for disease, or product development. Couples should also know that ES cell research typically involves deriving cells from the inner cell mass of an embryo at the blastocyst stage, which leads to the embryo’s destruction. Potential donors also should be informed that the cell lines might exist indefinitely. They should be told that stem cells from embryos may have commercial value for a wide range of research and clinical purposes and that they as donors will not share in the commercial value. The clinic should develop a policy on privacy and confidentiality of donations and present this as part of the consent process. If identifiers are attached to the cell lines, the donors must be informed of this and of steps taken to assure their anonymity. The male and female partners must agree on the disposition of their spare embryos. If they cannot jointly agree to donate embryos for research, the embryos should not be used for research. It is important that couples decide to donate embryos for research only after they have decided not to continue storing their embryos. Making separate decisions about no longer using embryos and donating them for research guards against pressure placed on couples to donate embryos. When embryos are created, couples often stipulate what should be done with their frozen embryos in the event of future contingencies, such as death, divorce, or no contact with the clinic. These directives usually involve donating the embryos to another couple, donating them for research, or discarding them. If no death or divorce occurs, the couple makes a separate decision about what should be done with the unused embryos when their fertility needs are met or they end their reproductive efforts with these embryos. At this point, the investigator has the opportunity to discuss more thoroughly the option of donating embryos for research. Using only frozen embryos for research ensures that time passes between the creation of embryos for conception and their donation for research. Still, it is reasonable to expect questions eventually to arise about the donation of fresh but supernumerary embryos (16National Institutes of HealthNational Institutes of Health guidelines for research using human pluripotent stem cells.Fed Regist. 2000; 65: 69951Google Scholar). Donation of fresh embryos raises the possibility that a physician might induce a patient to allow insemination of extra eggs so that they may be donated for research. Moreover, this increases the chance that decisions will be made quickly and later regretted by couples. Without evidence that fresh embryos are significantly preferable to frozen embryos for ES cell use, it is appropriate to use only spare embryos that have been frozen. The number of embryos created and frozen should be determined by the clinical needs of the infertile couple. In some situations, couples with stored embryos cannot be contacted despite efforts on the part of the clinic. The Ethics Committee has previously concluded that programs may consider embryos abandoned if clinics have taken diligent steps to contact the couple, no written instructions exist, and more than 5 years have elapsed without contact with the couple (17Ethics Committee of the American Society for Reproductive MedicineDisposition of abandoned embryos.Fertil Steril. 1997; 67: 1SPubMed Google Scholar). Abandoned embryos may be discarded, but they should not be used for research or donated to another couple without prior consent. In some cases, however, couples may have given consent to use spare embryos for research but were not informed of the possibility of ES cell research. The singular features of ES cell research make it advisable not to use such embryos for ES cell research unless couples have given specific advance consent for this purpose, in case they cannot later be reached for a decision. Advance permission to use abandoned embryos for research may thus prevail for ES cell studies if the couple has been informed of the possibility of ES cell research. Several advisory bodies have recommended that a person other than the fertility specialist secure consent to donate embryos (2American Association for the Advancement of Science and Institute for Civil Society. Stem cell research and applications: monitoring the frontiers of biomedical research. Washington, DC: American Association for the Advancement of Science, 1999:3.Google Scholar, 13National Bioethics Advisory CommissionEthical issues in human stem cell research. National Bioethics Advisory Commission, Rockville, MD1999Google Scholar). The rationale is that this will ensure that the couple’s reproductive needs are foremost and avoid conflicts of interest when the fertility specialist is also the investigator. In some circumstances, however, this guideline may be difficult to follow. It is possible, for example, that the fertility specialist who knows the couple and is trusted by them may be better able to have a frank discussion with the couple about donation for research and may secure more informed consent. Moreover, using a separate person to secure consent may be difficult if the physician is part of the research team. The possibility of undue influence by the physician will be lessened if the request for a donation is made after the couple decides to dispose of their embryos. Still, the fact that the physician is also a researcher is relevant information and should be conveyed to the couple along with a statement about financial incentives, if any, the physician has in the research. The rule that the number of embryos created and frozen must be determined by the clinical needs of the couple and not by research goals is especially pertinent when the physician is both the fertility specialist and investigator. The Ethics Committee believes it is ethically acceptable to derive and use ES cells in research to develop cell replacement therapies and to further other medical uses. This research should take place only within guidelines in place for embryo research in general and only under conditions that protect the free and informed consent of couples. At a minimum, guidelines for informed consent include the following about what should be conveyed to couples, when, and by whom. 1.The consent process should inform donors of the nature of ES cell derivation; the specific research project, if known; source of funding; potential commercial value; and anticipated clinical applications. Policies on confidentiality and maintenance of the donors’ privacy should be developed by the clinic and presented as part of the consent process.2.The final decisions on the donation of embryos to ES cell or other research must occur after the couple’s infertility needs are met or the couple discontinues therapy, except in rare cases where the couple is not available and has given explicit written directions in advance for use of their embryos in ES cell research.3.Whenever possible, someone other than the treating infertility specialist should make requests for embryos for research purposes. Couples should be informed that refusal to participate will not affect medical care and that embryos used for research will not be transferred to a woman’s uterus for possible pregnancy. They should be informed of financial incentives, if any, that the physician has in the research.4.Embryos should not be bought or sold with a monetary exchange. Reasonable fees may be charged for laboratory processing or for handling, storage, or transport of embryos. Reply: The physical properties of seminal fluid-reproducibility and intrasubject variation?Fertility and SterilityVol. 84Issue 6PreviewWe appreciate the interest and comments of Dr. Amelar with regard to our recent article (1). It is important to bear in mind that our results were published as Correspondence and subject to space limitations. Full-Text PDF