Research with Human Embryonic Stem Cells: Ethical Considerations.
by Karen Lebacqz , Micheal M. Mendiola , Ted Peters , Ernle W. D. Young , Laurie Zoloth-Dorfman On 5 November 1998 Geron Corporation announced that scientists working in collaboration with Geron had succeeded in establishing cell culture lines of human embryonic stem (hES) cells. Because these cells are considered pluripotent (capable of being the precursors to a variety of human cell types) and immortal (sustainable in culture and reproducing themselves indefinitely), they represent a major breakthrough in scientific research, with potential for significant advances in tissue transplantation, pharmaceutical testing, and embryology. Prior to the November announcement, the Geron Ethics Advisory Board developed "A Statement on Human Embryonic Stem Cells"[1] as a set of guidelines for hES research. [See Box.] This essay provides an expansion and elaboration of the particular warrants and moral reasoning for that statement. The EAB did not offer a carte blanche approval of research on hES cells undertaken by Geron or any other entity. The board unanimously affirmed that such research can be undertaken ethically, contingent upon meeting a range of qualifying conditions. The initial work of the board has been to specify such conditions; its continued work will consist of assessing Geron's developing research in light of them. Hence here we also include some preliminary reflections on ethical issues in human embryonic germ cell (hEG) research. Moreover, the EAB perceived the need for and urged continued public discussion of the complex ethical issues emerging from such research. Thus the statement and this companion essay should be seen not only as an initial clarification of the EAB's own position, but also as an effort to contribute to and invite that public discourse. We enumerate some specific questions for further reflection at the end of this essay. 1. "The blastocyst must be treated with the respect appropriate to early human embryonic tissue." The creation of hES cells involves isolation of cells from the blastocyst.[2] The blastocyst consists of an outer cellular layer, which would develop as the placenta, and an inner cell mass, which would develop as the body of the fetus. The outer layer is dissolved and the resulting mass of cells is used for research. Thus a central ethical issue is the moral status of the blastocyst. To raise the matter of "moral status" is to ask, Does a given entity possess the requisite qualities or characteristics that entitle it to moral consideration and concern? "Moral status" thus functions as a threshold idea: entities with moral status should be treated in a manner differently from entities without that status. The EAB affirms that the blastocyst has moral status and hence should be treated with respect.[3] What sort of moral status does the blastocyst have? This question has riveted political, religious, and ethical attention, and profound and substantial disagreement is based not only on contending biological interpretations but also on deeply held philosophical and theological considerations. Some have argued for conception as the relevant consideration, others for the development of the "primitive streak" (the precursor to the spinal cord of an individual fetus) as a defining moment, and some for utilizing implantation as the crucial threshold for moral status.[4] Reviewing the complex literature on this topic, Ted Peters, following Daniel Callahan, distinguishes three basic schools of thought.[5] The genetic school locates the beginning of human personhood, and thus claims of moral status and dignity, at the genetic beginning--that is, at conception, at the point where one's individual genome is set. Here, a criterion for moral status (human genetic heritage) is linked to a particular point in human life (conception). The developmental school while granting that human life begins at conception, holds equally that human personhood--and hence full moral status-is a later development. Here, moral status is understood developmentally: as the conceptus develops from blastocyst to fetus and beyond so too does moral status grow (although proponents differ on when exactly the threshold of moral status is reached). The social consequences school shares with the developmental school the belief that human personhood is a process and an achievement over time. Advocates deny, however, that personhood is achieved at any particular moment. Rather, "personhood" is a matter of definition rather than biological fact, based on socially constructed norms. In its work, the National Institutes of Health Human Embryo Research Panel focused less on the time when moral status might be acquired and more on the criteria for its determination. The panel noted two broad approaches in the debates: one proposes a single criterion as constitutive of moral personhood, while a second, "pluralistic," approach emphasizes a number of different, interacting criteria. As the panel noted | |
Among the qualities considered under a pluralistic approach are those
mentioned in single-criterion views: genetic uniqueness, potentiality for
development, sentience, brain activity, and degree of cognitive
development. Other qualities often mentioned are human form, capacity for
survival outside the mother's womb, and degree of relational presence
(whether to the mother herself or to others). Although none of these
qualities is by itself sufficient to establish personhood, their developing
presence in an entity increases its moral status until, at some point, full
and equal protectability is required.[6]
| | The panel proposed the pluralistic approach as the more adequate of the two, with moral status (and hence protectability) understood developmentally, culminating at birth in full and equal personhood.[7] Drawing upon this wealth of philosophical and theological reflection and situating ourselves relative to it, the EAB affirmed our understanding of moral status as developmental and consonant with the pluralistic approach. This developmental view is in accord with Jewish tradition,[8] with the views of many Roman Catholics[9] (although not the Vatican), and with the majority of Protestant traditions as well as with legal traditions that provide different protections at different stages of fetal development. We hold that a fundamental principle of respect for human life applies at all stages of human development. The developmental view that we affirm does not mean that the principle of respect can be ignored; it means that the principle requires different considerations and entails different obligations at different developmental stages. For example, Lisa Sowle Cahill argues that "Few doubt that there exists from conception some form of `human life' in the literal sense; the crucial question is whether from conception or at any subsequent time during pregnancy that life deserves the same respect and protection due an infant."[10] Once there is evidence of capacity for sensation, for example, respect requires minimization of pain. In this very early embryonic tissue there is no capacity for sensation; thus minimization of pain does not apply. Rather, early embryonic tissue is respected by ensuring that it is used with care only in research that incorporates substantive values such as reduction of human suffering.[11] We believe that the purposes of the hES research--its potential to contribute to fundamental knowledge of human development and to medical and pharmaceutical interventions to alleviate suffering--provide such substantive values. A second source of cells is human embryonic germ (hEG) cells derived from gamete ridge tissue removed from early fetal tissue following elective abortion. These cells have been cultured using similar but not identical methods as are used for the hES cells, and may have both properties of pluripotency and immortality. However, this research raises ethical questions distinct from those in the use of the early blastocyst. The tissue is taken (much as cadaver organs might be taken) from an aborted fetus within the first eight weeks after conception. At stake in this debate is whether licit use can be made of tissue collected after abortion in a society in which the act of abortion is seen by some as murderous and by others (and by law) as acceptable. The EAB cannot resolve the contentious abortion debate. We are developing guidelines for hEG research. Preliminary reflections suggest at least the following concerns: First, all agree that the demise of the fetus is not caused by the research procedures. Second, the moral obligation to save life may be a sufficiently strong warrant to justify certain uses of the tissue of the dead and hence to support such research. Third, the tissue of the dead must be used with respect. Respect for tissue taken from a dead fetus would take into account the need for closure, grief, and ritual that families might have in these cases. Respect would include the confidential and dignified handling of the tissue when collected and used. Finally, issues of informed consent would apply with the same stringency required in the case of hES research (see below). 2. "Women/couples donating blastocysts produced in the process of in vitro fertilization must give full and informed consent for the use of the blastocysts in research and in the development of cell lines from that tissue." Human embryonic stem cells are derived from embryos produced for clinical purposes and then donated for research purposes. Hence of crucial ethical significance is the character and quality of the consent given by women and couples to such donation. As with the issue of moral status, the ethical and legal literature on consent and refusal is voluminous.[12] What is needed for valid consent to donate embryonic tissue for research purposes? Tom Beauchamp and James Childress argue that the core meaning of informed consent is an autonomous authorization of a medical intervention or involvement in research. An informed consent occurs "if and only if a patient or subject, with substantial understanding and in substantial absence of control by others, intentionally authorizes a professional to do something."[13] Thus informed consent or refusal is not simply a matter of what the professional should disclose to the patient, but is a matter of ensuring that the conditions necessary for autonomous authorization are met--i.e., that consent is intentional, with substantial understanding, and without controlling influences. Authority for participation in research, expressed in an informed consent, resides with and is to be exercised by the subject. Consent to utilize embryos for clinical purposes of IVF does not therefore suffice as consent for their use in research and cell-line development. Explicit consent must be elicited for such use. We concur with Arthur Caplan that "when research is the goal, whether for profit or not, those whose materials are to be used have a right to know and consent to such use."[14] Other commentators agree that fairness and respect for persons dictate that explicit information be provided to patients regarding the use of their tissues and cells, especially when those may be used for commercial purposes.[15] For these reasons, the EAB determined that women/ couples donating embryos for this research should understand clearly the nature of the research and also should understand whether there are commercial implications and if so, whether they hold any proprietary rights in the tissue lines developed from embryonic cells.[16] Moreover, we believe that the context of embryo donation within the process of IVF renders the need for careful consent even more important. The IVF process is often physically painful, emotionally burdensome, and financially costly. These factors may make IVF patients particularly vulnerable.[17] Such possible vulnerability demands careful and consistent efforts on the part of researchers not to exercise a controlling or coercive influence over these patients. A recent study of patients who consented to participate in therapeutic research found that "Physicians' recommendation were ... powerful factors influencing patients' decisions to become research subjects.[18] Authors of the study recommended that research ethics "be enriched with a sensitivity to the profound trust participants place in researchers and the research enterprise" (p. 27). The context of a study regarding participation in therapeutic research is clearly different from the context of IVF embryo donation for hES cell research. In the latter context, the consent is "twice removed": women/couples are not consenting to therapeutic research, nor does the research involve their own bodies or persons. Nevertheless, even in the IVF context some measure of trust in the researchers may be involved and this possibility raises a warning regarding the ways in which trust can be manipulated to researchers' advantage, thus possibly leading to undue influence over subjects. Moreover, while this research does not involve their own bodies, it does involve entities that they may well consider as potential progeny, a factor that must be considered in this research. Informed consent also requires "substantial understanding." Hence the EAB requires certain informational elements in the context of embryo donation for hES cell research. First, as the derived hES cells are of significant market potential, donors should understand those potential market implications. Second, they should be advised as to whether there are any proprietary rights in the tissue. The achievement of substantial understanding requires a process that builds trust over time, an admittedly difficult requirement yet one that will be critical in all stages of this research for it to be carried out ethically.[19] Adequate time for eliciting and answering donor questions is necessary, as is ensuring that donors are genuinely free to refuse as well as to consent. In the course of our deliberations, we reviewed an exemplary form used in soliciting consent for embryo donation for research.[20] This form states explicitly: "cells that may be derived from embryos donated for this research could have clinical and commercial value in the event that the study is successful." It further specifies: | |
This research will not benefit your clinical care, and you will not benefit
financially from it. The physicians/clinicians involved in your care will
not benefit financially from this study. The investigators conducting this
study could benefit financially from clinical or commercial values that may
result from it. The cells derived in this study may be shared with Geron
Corporation, located in Menlo Park, CA, as part of the study. Geron
Corporation may benefit financially from the development and clinical use
of the cells derived in this study.
| | Such explicit statements embody well the kinds of financial disclosure that a consent form should contain. 3. "The hES research will not involve any dolling for purposes of human reproduction, any transfer to a uterus, or any creation of human chimeras or human-animal hybrids." Corporate representatives have stated clearly to the EAB that human reproduction was not a goal, purpose, or intent of Geron's research on hES (and hEG) cells. Any effort to produce a living being out of this research would raise a host of ethical issues, in particular the risk of harms to potential offspring,[21] to parenting women and couples, and to the human community itself through genetic manipulation and transmission. Because Geron is not engaged in these activities, and has made clear its intention not to do so, the EAB did not take them up for extended assessment in its deliberations. Should Geron consider initiating any such activities, the EAB will undertake the necessary ethical analysis. 4. "Acquisition and development of the feeder layer necessary for the growth of hES cells in vitro must not violate accepted norms for human or animal research." To keep hES cells in an undifferentiated state, they are cultured and maintained on layers of nutrients called "feeder layers." Currently, irradiated mouse embryonic fibroblast feeder layers are utilized, but it is possible that other tissues would be used in the future. The acquisition and development of the feeder layers must be in accord with norms for research appropriate to the source from which the feeder layers are drawn.[22] Geron's use of mouse embryonic cells would seem to fall well within a judgment of ethical use of animal tissue. The research holds great potential therapeutic value. In addition, mouse embryos fall below the threshold of sentience (the ability to experience pain) or of other capacities of organic animal being and activity. Nevertheless, we mandate continued attention to animal welfare. 5. "All such research must be done in a context of concern for global justice." One of the primary justifications of hES research is beneficence based: its therapeutic potential to alleviate human suffering and to promote the health and well-being of human populations. However, to justify a practice on the basis of its benefits makes moral sense only if people in need actually have access to those benefits. Hence the justification gains credibility only when it is wedded to a commitment to justice, rooted in "a recognition of our sociality and mutual vulnerability to disease and death."[23] The EAB considers concerns about social justice in public health to be of overriding importance. Thus in the EAB's judgment, it is morally paramount that research development include attention to the global distribution of and access to these therapeutic interventions. Two features of Geron's research render this commitment to just access particularly challenging. First, the research is undertaken in the private sector--in the context of market forces, patenting of products, interests of shareholders and investors, and a consideration of profit. These varied interests may compete with--but should not override--a concern for equitable access.[24] Second, the research is highly technological and expensive, as well as under the proprietary rights of a U.S. company. How to ensure adequate access for insured, underinsured, and noninsured patients in the United States, let alone on a global basis, will be an ethically and financially challenging task. The EAB will continue to work with geron on these matters. 6. "All such research should be approved by an independent Ethics Advisory Board in addition to an Institutional Review Board." At its own initiative, Geron established the EAB. Given the kinds of ethical issues already emerging from hES research and those yet to come, the EAB reaffirmed the necessity of an independent board for ethical analysis and consultation. In addition, the research undertaken should receive IRB review and approval in order to protect subjects involved. Issues Requiring Further Deliberation A indicated above, the EAB wishes to generate public discourse on a wide range of issues related to emerging research arenas. Among those are some that surfaced during our discussions but are not reviewed in this essay: 1. Who should exercise control over the disposition of fetal or embryo tissue? In our discussion of consent, we refer to both "women" and "couples." The appropriate locus of consent/refusal may be disputed. 2. What is the proper relationship of ethicists to proprietary companies? Who should constitute an ethics board, and who should serve on it? Under what conditions (e.g., remuneration, stock options, etc.)?[25] 3. As noted above, how can difficult issues of global justice and fair distribution be handled in research involving private enterprise? 4. What is the role of consensus in a society that is both pluralistic and often deeply divided over appropriate norms? How can we develop appropriate language for public debate and decisionmaking while remaining respectful of differences and accountable to substantive moral disagreements?[26] Research with Embryonic Stem Cells An Ethics Advisory Board, whose members represent a variety of philosophical and theological traditions with a breadth of experience in health care ethics, was created by Geron Corporation in 1998. The Board functions as an independent entity, consulting and giving advice to the corporation on ethical aspects of the work Geron sponsors. Members of the board have no financial interest in Geron Corporation. The Geron Ethics Advisory Board is unanimous in its judgment that research on hES cells can be conducted ethically. In order for such research to be conducted ethically in the current context, some conditions must pertain. In addition, further public discourse will be needed on a range of ethically complex questions generated by this research. The conditions are: 1. The blastocyst must be treated with the respect appropriate to early human embryonic tissue. 2. Women/couples donating blastocysts produced in the process of in vitro fertilization must give full and informed consent for the use of the blastocysts in research and in the development of cell lines from that tissue. 3. The research will not involve any cloning for purposes of human reproduction, any transfer to a uterus, or any creation of chimeras. 4. Acquisition and development of the feeder layer necessary for the growth of hES cell lines in vitro must not violate accepted norms for human or animal research. 5. All such research must be done in a context of concern for global justice. 6. All such research should be approved by an independent Ethics Advisory Board in addition to an Institutional Review Board. References [1.] The statement was drafted in September 1998 by Karen Lebacqz, revised by the EAB, and was finalized on 20 October 1998. [2.] The blastocyst is approximately 140 cells, fourteen days post-conception. [3.] Michael M. Mendiola, "Some Background Thoughts on the Concept of `Moral Status' Relative to the Early Embryo." Background paper for the EAB. [4.] Jacques Cohen and Robert Lee Hotz, "Toward Policies Regarding Assisted Reproductive Technologies," in Setting Allocation Priorities: Genetic and Reproductive Technologies, ed. Robert H. Blank and Andrea Bonnicksen (New York: Columbia University Press, 1992), pp. 228-29. [5.] Ted Peters, For the Love of Children (Louisville, KY: Westminster/John Knox Press, 1996), pp. 96-100. [6.] National Institutes of Health, Report of the Human Embryo Research Panel (Bethesda, Md.: National Institutes of Health, 1994), p. 49. Mary Anne Warren offers a critique similar in structure, arguing for a "multi-criterial" view of moral status, instead of "uni-criterial" approaches. Mary Anne Warren, Moral Status: Obligations to Persons and Other Living Things (Oxford: Clarendon Press, 1997). [7.] National Institutes of Health, Report of the Human Embryo Research Panel, pp. 49-51. Cohen and Holtz echo this position: "New life does not appear suddenly; it is created gradually, with each new phase differing from that which preceded it." Cohen and Holtz, "Toward Policies Regarding Assisted Reproductive Technologies," p. 230. [8.] Laurie Zoloth-Dorfman, "The Ethics of the Eighth Day: Jewish Bioethics and Genetic Medicine." Background paper for the EAB. [9.] See, for example, Thomas A. Shannon and Allan B. Wolter, "Reflections on the Moral Status of the Pre-Embryo," Theological Studies 51 (1990): 603-626. [10.] Lisa Sowle Cahill, "Abortion," in The Westminster Dictionary of Christian Ethics, ed. James E Childress and John Macquarrie (Philadelphia: The Westminster Press, 1986), p. 3. [11.] Ernle W. D. Young, "The Moral Status of Human Embryonic Tissue." Background paper for the EAB. The EAB holds that "substantive" values are those supported by prima facie moral duties such as nonmaleficence. [12.] See Ruth R. Faden and Tom L. Beauchamp, A History and Theory of Informed Consent (New York: Oxford University Press, 1986), for a good overview of the historical development and philosophical treatment of informed consent in the clinical and research contexts. [13.] Tom L. Beauchamp and James F. Childress, Principles of Biomedical Ethics, 4th ed. (New York: Oxford University Press, 1994), p. 143. [14.] Arthur L. Caplan, "Blood, Sweat, Tears and Profits: The Ethics of the Sale and Use of Patient Derived Materials in Biomedicine," Clinical Research 33, no. 4 (1985): 448-51, at 451. [15.] See, for example, George J. Annas, "Outrageous Fortune: Selling Other People's Cells," Hastings Center Report 20, no.6 (1990): 36-39; also George J. Annas, "Whose Waste Is It Anyway? The Case of John Moore," Hastings Center Report 18, no. 5 (1988): 37-39. [16.] The most celebrated legal case dealing with the issue of use of tissue without consent is that of Moore v. Regents of the University of California (51 Cal 3rd 120, 1990). For an extended discussion, see E. Richard Gold, Body Parts: Property Rights and the Ownership of Human Biological Materials (Washington, D.C.: Georgetown University Press, 1996). [17.] Judith Lorber has argued that IVF may also involve a coercive element for women when undertaken to treat male infertility. Such women may have to strike a "patriarchal bargain" to maintain a relationship and have a child within the constraints of monogamy, the nuclear family, and the valorization of biological parenthood. Judith Lorber, "Choice, Gift, or Patriarchal Bargain? Women's Consent to In Vitro Fertilization in Male Fertility," in Feminist Perspectives in Medical Ethics, ed. Helen Bequaert Holmes and Laura M. Purdy (Bloomington: Indiana University press, 1992), pp. 169-80. [18.] Nancy E. Kass, Jeremy Sugarman, Ruth Faden, Monica Schoch-Spana, "Trust: The Fragile Foundation of Contemporary Biomedical Research," Hastings Center Report 26, no. 5 (1996): 25-34, at 26. [19.] Mark G. Kuczewski, "Reconceiving the Family: The Process of Consent in Medical Decisionmaking," Hastings Center Report26, no. 2 (1996): 30-37, at 32. [20.] The form was developed by Roger Pedersen, Ph.D., of the Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, and is used with permission. [21.] It is for this reason that the NIH Human Embryo Research Panel distinguished between research on embryos intended for and not intended for transfer. Research on the former must include consideration of potential harms to the future child--a concern not raised by the latter. (National Institutes of Health, Report of the Human Embryo Research Panel, pp. 51-52.) It should also be noted that hES cells are derived cells and are not the cellular equivalent of an intact embryo. Even if transferred, hES cells would not form an embryo because they lack other cells necessary for implantation and embryogenesis. [22.] The current usage of mouse embryo cells raises ethical concerns about the use of animals in hES research. A number of criteria have been proposed to weigh ethical versus unethical uses of animals in biomedical research. However, as Strachan Donnelley notes, no single, unambiguous standard or guideline exists for assessing each and every use of animals in science. Ethical attention must be directed to the specific purposes, types, and contexts of animal use. See Strachan Donnelley and Kathleen Nolan, eds., "Animals, Science, and Ethics" [Special Supplement], Hastings Center Report 20, no. 3 (1990), pp. S11-S12. [23.] Larry R. Churchill, Rationing Health Care in America: Perceptions and Principles of Justice (Notre Dame: University of Notre Dame Press, 1987), p. 135. [24.] Zoloth-Dorfman, "The Ethics of the Eighth Day." [25.] Members of the EAB receive a very modest honorarium for the time spent in scheduled meetings with Geron staff and officers. We are not compensated for time spent in research, writing, or other conversations with Geron, nor does any of us hold any stock in the corporation. [26.] See, for example, Alta Charo, "The Hunting of the Snark: The Moral Status of Embryos, RighttoLifers, and Third World Women," Stanford Law and Policy Review 6, no. 2 (1995): 11-38. Geron Ethics Advisory Board, "Research with Human Embryonic Stem Cells: Ethical Considerations," Hastings Center Report 29, no. 2 (1999): 31-36. Karen Lebacqz is the Robert Gordon Sproul Professor of Theological Ethics at the Pacific School of Religion in the Graduate Theological Union, Berkeley, California. She served on the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, was a member of the ELSI group convened by the Center for Theology and the Natural Science at the GTU, and has written extensively on research ethics as well as ethics and genetics. Michael M. Mendiola is assistant professor of Christian ethics at Pacific School of Religion, Graduate Theological Union, Berkeley, California and project director of the Bay Area Faith and Health Consortium. He has published on the role of religious ethics in public discourse and is working on a book on suffering and its implications for ethics in the health care arena. Ted Peters teaches systematic theology at Pacific Lutheran Theological Seminary and the Graduate Theological Union and pursues research at the Center for Theology and the Natural Sciences in Berkeley, California. He is editor of Genetics.' Issues of Social Justice (Pilgrim Press, 1998) and author of Playing God? Genetic Determination and Human Freedom (Routledge, 1997. Ernle W. D. Young is codirector of Stanford University's Center for Biomedical Ethics and clinical professor of ethics in the Department of Medicine and Pediatrics of Stanford University School of Medicine and is the clinical ethics consultant both to Stanford University Hospital and to Veterans' Affairs hospitals in Palo Alto and Fresno, California. He has published widely on issues in bioethics. Laurie Zoloth-Dorfman is associate professor of social ethics and director of the Program in Jewish Studies at San Francisco State University and cofounder of The Ethics Practice, a group that has provided bioethics consultation and education services to health care providers and health care systems nationally. She has published frequently on topics in bioethics, religion, and health care. |
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