Human Embryonic Stem Cells

James A. Thomson

Human embryonic stem (hES) cells capture the imagination because they are immortal and have an almost unlimited developmental potential. After many months growing in culture dishes, these rather nondescript cells maintain the ability to form cells ranging from muscle to nerve to blood, and potentially any cell type that makes up the body. Their proliferative and developmental potential promises an essentially unlimited supply of specific cell types for transplantation in disorders ranging from heart disease to Parkinson's disease to leukemia.

The Basic Science

To understand hES cells, it is necessary to understand something about the basic properties of early human embryos (figure 2.1). Fertilization normally occurs in the oviduct, and during the next few days a series of cleavage divisions occurs as the embryo migrates down the oviduct and into the uterus. All of the cells (blastomeres) of these cleavage-stage embryos are undifferentiated; that is, they do not look or act like the specialized cells of the adult, and the blastomeres are not committed to becoming any particular type of differentiated cell. Indeed, each blastomere has the potential to form any cell of the body. The first differentiation event occurs at about five days of development when an outer layer of cells committed to becoming part of the placenta (trophectoderm) separates from the inner cell mass (ICM). The ICM cells maintain the potential to form any cell type of the body. Because an isolated ICM lacks the trophectoderm layer, which mediates implantation, it would not be able to develop into a child if transferred to a woman's uterus.

Figure 2.1: Human preimplantation development. After fertilization, the one-cell embryo undergoes a series of cleavage divisions and forms a blastocyst at about six days of development. The blastocyst is composed of an inner cell mass and a trophectoderm. Embryonic stem cells are derived from the inner cell mass.

A hallmark of these early mammalian embryonic stages is a remarkable developmental plasticity. If a preimplantation embryo is separated into halves, each half has the ability to develop normally to term. Because of the embryo's self-regulatory abilities, the resulting twins are born a normal size and have normal life expectancies. Conversely, if two separate cleavage-stage embryos are pushed together, blastomeres can intermingle to form a single embryo that can develop to term. Such an individual would be composed of cells with different genotypes and, indeed, could have four different parents. Nonetheless, the individual could be completely normal. Thus, because of their plasticity, the concept of "individual" as applied to the adult does not apply in a straightforward way to early mammalian embryos. It is the developmental plasticity of early mammalian embryos that allows the derivation of embryonic stem (ES) cells.

A stem cell replaces itself through proliferation for prolonged periods (self-renewal) and gives rise to one or more differentiated cell types. In the adult, tissue-specific stem cells sustain tissues with a high turnover rate, such as blood, intestinal epithelium, and skin. In these tissues there is a careful balance among stem cell self-renewal, differentiation, and cell death so that tissues remain in a steady state. Adult stem cells are restricted to forming only a limited number of cell types, and some tissues, such as the heart, completely lack stem cells. In the intact embryo, cells of the ICM have the potential to form any cell type of the body, but they proliferate and replace themselves only briefly. After implantation, ICM cells differentiate to other cell types with a more restricted developmental potential. Thus, in the intact embryo, ICM cells function as precursor cells, but not as stem cells. If mammalian development were very rigid, with developmental decisions inflexibly tied to a specified number of cell divisions, ICM cells placed in culture would also just differentiate to more restricted lineages and not replace themselves, regardless of culture conditions. However, because of developmental plasticity of mammalian embryos, if the ICM is taken out of its normal embryonic environment and cultured under appropriate conditions, ICM-derived cells can proliferate and replace themselves indefinitely, yet maintain the developmental potential to form any cell type. These pluripotent, ICM-derived cells are ES cells.

The derivation of ES cell lines from mouse blastocysts was first reported by two independent groups in 1981 (Evans and Kaufman 1981; Martin 1981). The term "ES" cell was introduced to distinguish the origin of these cells from the origin of embryonal carcinoma (EC) cells, which are pluripotent stem cell lines derived from teratocarcinomas. Teratocarcinomas are malignant germ cell tumors that include a mixture of different kinds of differentiated cells. Mouse EC cell lines were used as an in vitro model of mammalian differentiation for years before the derivation of mouse ES cell lines, and the derivation of pluripotent human EC cells was reported in the early 1980s (Andrews et al. 1984; Damjanov and Solter 1976). However, possibly because of their origin in the malignant tumor environment, EC cell lines generally have a much more restricted developmental potential than ES cell lines. Human EC cell lines, for example, have severe chromosomal abnormalities and a fairlv limited developmental potential (Roach et al. 1993). Mouse ES cells injected into an intact preimplantation embryo can intermingle with the host embryo and contribute to normal development, forming a chimera. The ES cells can contribute to any tissue of the chimera, including germ cells, which gives developmental biologists a method to manipulate the germ line of mice. Pluripotent cell lines similar to mouse ES cells have been derived from primordial germ cells, cells that would normally develop into either sperm or egg (Matsui et al. 1992; Resnick et al. 1992). Again, to distinguish their origin, these pluripotent cell lines are referred to as embryonic germ (EG) cell lines. Human EG cell lines were recently derived from human fetal germ cells (Shamblott et al. 1998).

Human ES cell lines were derived from blastocyst-stage preimplantation embryos produced by in vitro fertilization (Thomson et al. 1998). To derive hES cell lines, the ICM of the blastocyst is isolated from the trophectoderm layer and plated on mouse embryonic fibroblasts. After approximately two weeks of culture, ICM-derived cells are dissociated and replated. Undifferentiated hES cells have a characteristic morphology that includes a high nuclear:cytoplasmic ratio and numerous prominent nucleoli (figure 2.2). Human ES cells, human EC, and nonhuman primate ICM cells all express characteristic cell surface markers, including stagespecific embryonic antigen, that differ from those expressed by mouse ES cells (Andrews et al. 1984a,b, 1987; Kannagi et al. 1983; Solter and Knowles 1978; Wenk et al. 1994). The shared pattern of expression of cell surface markers t-y ES cells, human EC cells, and nonhuman primate ES cells, and different pattern of expression by mouse ES cells, reflects fundamental embryologic differences between primates and mice.

Figure 2.2: Human embryonic stem cells on mouse fibroblasts.

The hES cell lines derived to date have a normal complement of chromosomes and are capable of prolonged proliferation. Normal (diploid) human somatic cells proliferate in culture for a characteristic number of tirnes and then stop dividing (replicative senescence). Neoplastic somatic human cells that escape this "mortality" invariably have significant chromosomal changes. Because hES cell lines are derived from very early embryos, they naturally express high levels of the enzyme associated with cellular immortality, telomerase. No hES cell line has been observed to undergo replicative senescence, and one line was cultured continuously for well over a year and maintained a normal karyotype, suggesting that these cell lines are capable of unlimited proliferation. Because proliferation of undifferentiated hES cells appears to be unlimited, it should be possible that unlimited numbers of differentiated derivatives could one day be produced in culture.

When removed from fibroblast feeder layers, hES cells differentiate into a variety of cell types. Leukemia-inhibitory factor, which prevents differentiation of mouse ES cells, fails to prevent differentiation of hES cells in the absence of fibroblasts. Because production of fibroblast feeder layers is labor intensive, the amount of ES cells that can be grown would not yet be therapeutically useful. Thus, identification and purification of factors produced by fibroblast feeder layers that sustain the undifferentiated proliferation of hES cells is a critical research area, because replacing fibroblasts with purified factors would allow routine largescale production of hES cells.

When hES cells are allowed to differentiate in the absence of fibroblasts, they differentiate into a variety of cell types including endoderm, neural cells, and muscle cells. When they are injected into immunocompromised mice, they form teratomas with differentiation of several cell types, including ciliated respiratory epithelium and gut epithelium (endoderm); striated muscle, smooth muscle, cartilage, bone, and connective tissue (mesoderm); neural tissue, skin, and hair (ectoderm); and numerous unidentified types (figure 2.3). Within hES cell teratomas there is abundant evidence of coordinated interactions among cells, and even among cells originating from different embryonic germ layers. For example, development of hair requires coordinated interactions between the overlying ectoderm and underlying mesenchyme.

Because of possible harm to the resulting child, it is not ethically acceptable to manipulate the postimplantation human embryo experimentally, so we are largely ignorant about the mechanisms of early human embryology. Most of what is known about human development, especially in the early postimplantation period, is based on histologic sections of limited numbers of human embryos and on analogy to mouse embryology. However, human and mouse embryos differ significantly, particularly in the formation, structure, and function of fetal membranes and placenta, and formation of an embryonic disk instead of an egg cylinder (Benirschke and Kaufmann 1990; Luckett 1975,1978). For example, the mouse yolk sac is a well-vascularized, robust, extraembryonic organ throughout gestation and has important nutrient exchange functions. In humans, the yolk sac has important early functions, including initiation of hematopoiesis and germ cell migration, but later in gestation it is essentially a vestigial structure. Similarly, dramatic differences exist between mouse and hwnan placentas, both in structure and function. Thus, for understanding developmental events that support the initiation and maintenance of human pregnancy, mice can provide only limited understanding. The hES cell lines provide an important new in vitro model that will improve our understanding of the differentiation of human tissues and thus provide important insights into such processes as infertility, pregnancy loss, and birth defects.

Figure 2.3: Differentiation of human embryonic stem cells in teratomas. (A) gut; (B) striated muscle; (C) bone; (D) neural epithelium.

Implications and Importance of the Research

As developmental biologists become more accomplished at directing hES cells to specific cell types, the differentiated derivatives of the cells should have an important role in developing new therapies. Large, purified populations of hES cell-derived cells, such as heart muscle cells or neurons, could be used to screen for new drugs. Purified, normal human cells would allow accurate screening of candidate drugs, greatly reduce the need for animal testing during the early screening process, and accelerate drug discovery. Differentiated derivatives of hES cells also could be used to test for possible toxic side effects of drugs identified by other methods, and hES cells would be particularly useful for identifying compounds that interfere with normal development.

Finally, differentiated derivatives of hES cells could be applied to transplantation therapies for treatment of a range of human diseases. Because certain diseases result from the death or dysfunction of just one or a few cell types, replacing those cells by transplantation could offer long-term treatment. The hES cells can proliferate indefinitely and differentiate to many, perhaps all, cells of the body. Therefore they have the potential to provide a limitless source of specific cell types for transplantation. Numerous diseases might be treated by this approach, including heart disease, juvenile-onset diabetes, Parkinson's disease, and leukemia. Developmental biology has made dramatic strides in recent years, but it is not yet possible to direct ES cells efficiently to most specific cell types. Significant progress has been made, however, in differentiating the cells to specific lineages, including blood, neural, and muscle cells (Brustle et al. 1999, 1997; Keller 1995; Klug et al. 1996).

Introducing ES cell-derived cells into the body so that they restore useful function to a damaged organ and preventing their rejection are problems likely to prove even more challenging than deriving specific cell types. Cell types whose function require coordinated, three-dimensional integration into host tissue will prove particularly challenging. For example, in a heart attack, part of the heart muscle dies because of a blockage of the blood supply to the muscle. Because an adult has no heart muscle stem cell, if the patient survives, dead heart muscle is permanently replaced by nonfunctional scar tissue. Human ES cells spontaneously differentiate to heart muscle cells in tissue culture, and it should be possible to purify those cells from other cell types. However, getting them back into a damaged heart to replace dead muscle or scar tissue and actually restoring function to the heart will prove challenging. Not only must new muscle integrate ir. a mechanically useful way with surrounding muscle, but new blood vessels will be required to supply the new muscle or it will die. Progress in the field of angiogenesis suggests that inducing new growth of existing vessels to supply transplanted heart muscle may one day be possible, but considerable research is required before this is practical.

After transplanted tissue is successfully integrated, its rejection by the patient's immune system must be prevented. Possible strategies include banks of major histocompatibility complex-typed hES cell lines, genetically modified hES cell lines that are designed to be less immunogenetic, and ES cells genetically identical to a specific patient produced by nuclear transfer. Nuclear transfer technology offers potentially the most effective and most controversial solution. For human medicine, the profound implication of the cloning of Dolly (Wilmut et al. 1997) is that development may be more flexible than once thought, and differentiated cells can be reprogrammed into undifferentiated cells. Dolly was cloned by transplanting the nucleus from a mammary epithelial cell to an enucleated oocyte, and by transferring the resulting nuclear transfer product to a recipient ewe. The same procedure could be performed with a human somatic cell nucleus transferred to an enucleated human oocyte, but instead of transferring the nuclear transfer product to produce a pregnancy, a blastocyst could be produced in vitro and an ES cell line derived. Through this method it might be possible to take a readily accessible cell type such as a skin fibroblast from a biopsy specimen, establish an ES cell line using nuclear transfer from the fibroblast, direct the cell line to heart muscle cells, and transplant those heart muscle cells back to the patient who donated the fibroblast. The heart muscle cells would be genetically identical to the patient's cells for all nuclear-encoded genes. Production of a human embryo by nuclear transfer for therapeutic purposes would be extremely controversial. Reprogramming a differentiated cell nucleus by human oocyte cytoplasm to create an ES cell line has not been demonstrated so it is not even certain that human oocyte cytoplasm has this ability.

Because hES cell-based transplantation therapies are new and unproved, it will be essential to demonstrate their safety and efficacy in an accurate animal model. Rhesus monkey ES cells are very similar to hES cells and rhesus monkeys share a close evolutionary and physiologic relationship with humans (Thomson et al. 1995; Thomson and Marshall 1998). Several important diseases that might be treated by ES cell-based therapies, including Parkinson's disease and diabetes mellitus, have accurate rhesus monkey models (Burns et al. 1983; Jones et al. 1980). Nuclear transfer techniques have been developed in the rhesus monkey (Meng et al. 1997). Elucidating the basic molecular mechanisms by which the oocyte reprograms adult nuclei in this primate species may one day allow the direct reprogramming of human nuclei to produce an ES cell line without having to produce an embryo as an intermediate step. If it becomes possible to derive an ES cell line from a source other than an embryo, ethical controversies surrounding hES cells would greatly diminish.

References

Andrews, P. W., Banting, G., Damjanov, 1., Arnaud, D., and Avner, P. 1984a. Three monoclonal antibodies defining distinct differentiation antigens associated with different high molecular weight polypeptides on the surface of human embryonal carcinoma cells. Hybridoma 3: 347-361.

Andrews, P. W., Damjanov, 1., Simon, D., Banting, G., Carlin, C., Dracopoli, N., and Fogh, J. 1984b. Pluripotent embryonal carcinoma clones derived frrJIll the human teratocarcinoma cell line Tera-2. Laboratory Investigation 50: 147-162. Andrews, P. W., Oosterhuis, J., and Damjanov, 1. 1987. Cell lines from human germ cell tumors. In: Robertson, E., ed. Teratocarcinomas and Embryonic Stem Cells: A Practical Approach. Oxford: 26 IRL Press, pp. 207-246.

Benirschke, K. and Kaufmann, P. 1990. Pathology of the Human Placenta. New York: Springer-Verlag.

Brustle, O., Spiro, A. C., Karran, K., Choudhary, K., O'Kabe, S., and McKay, R. D. G. 1997. In vitro generated neural precursors participate in mammalian brain development. Proceedings of the National Academy of Sciences of the USA 94: 14809-14814.

Brustle, O., Jones, K. N., Learish, R. D., Karram, K., Choudhary, K., Wiestler, 0. D., Duncan, 1. D., and McKay, R. D. G. 1999. Embryonic stem cell-derived glial precursors: A source of myelinating transplants. Science 285(75): 1-753.

Burns, R. S., Chiueh, C. C., Markey, S. P., Ebert, M. H., Jacobowitz, D. M., and Kopin, 1. J. 1983. A primate model of parkinsonism: Selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl4-phenyl-1,2,3,6-tetrahydropyridine. Proceedings of the National Academy of Sciences of tke USA 80: 4546-4550.

Damjanov, 1. and Solter, D. 1976. Animal model of human disease: Teratoma and teratocarcinoma. American Journal of Pathology 83: 241-244.

Evans, M. and Kaufman, M. 1981. Establishment in culture of pluripotential cells from mouse embryos. Nature 292: 154-156.

Jones, C. W., Reynolds, W. A., and Hoganson, G. E. 1980. Streptozotocin diabetes in the monkey: Plasma levels of glucose, insulin, glucagon, and somatostatin, with corresponding morphometric analysis of islet endocrine cells. Diabetes 29: 536-546.

Kannagi, R., Cochran, N. A., Ishigami, F., Hakomori, S., Andrews, P. W., Knowles, B. B., and Solter, D. 1983. Stage-specific embryonic antigens (SSEA-3 and -4) are epitopes of a unique globo-series ganglioside isolated from human teratocarcinoma cells. EMBO Journal 2: 2355-2361.

Keller, G. M. 1995. In vitro differentiation of embryonic stem cells. Current Opinion in Cell Biology 7: 862-869.

Klug, M. G., 8Oonpaa, M. H., Koh, G. Y., and Field, L. J. 1996. Genetically selected cardiomyocytes from differentiating embronic stem cells form stable intracardiac grafts. Journal of Clinical Investigation 98: 216-224.

Luckett, W. P. 1975. The development of primordial and definitive amniotic cavities in early rhesus monkey and human embryos. American Journal of Anatomy 144: 149-168.

Luckett, W. P. 1978. Origin and differentiation of the yolk sac and extraembryonic mesoderm in presomite human and rhesus monkey embryos. American Journal of Anatomy 152: 59-98.

Martin, G. 1981. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proceedings of the National Academy of Sciences of the USA 78: 7634-7638.

Matsui, Y., Zsebo, K., and Hogan, B. L. 1992. Derivation of pluripotential embryonic stem cells from murine primordial germ cells in culture. Cell 70: 841-847.

Meng, L., Ely, J. J., Stouffer, R. L., and Wolf, D. P. 1997. Rhesus monkeys produced by nuclear transfer. Biology of Reproduction 57: 454 459.

Resnick, J. L., Bixler, L. S., Cheng, L., and Donovan, P. J. 1992. Long-term proliferation of mouse primordial germ cells in culture. Nature 359: 550551.

Roach, S., Cooper, S., Bennett, W., and Pera, M. F. 1993. Cultured cell lines from human teratomas: Windows into tumour growth and differentiation and early human development. European Urology 23: 82-88.

Shamblott, M. J., Axelman, J., Wang, S., Bugg, E. M., Littlefield, J. W., Donovan, P. J., Blumenthal, P. D., Huggins, G. R., and Gearhart, J. D. 1998. Derivation of pluripotent stem cells from cultured human primordial germ cells. Proceedings of the National Academy of Sciences of the USA 95: 13726-13731. Solter, D. and Knowles, B. B. 1978. Monoclonal antibody defining a stagespecific mouse embryonic antigen (SSEA-I). Proceedings of the National Academy of Sciences of the USA 75: 5565-5569.

Thomson, J. A., Liskovitz-Eldor, J., Shapiro, S. S., Waknitz, M. A., Swiergiel, J. J., Marshall, V. S., and Jones, J. J. 1998. Embryonic stem cell lines derived from human blastocysts. Science 282: 81145-81147.

Thomson, J. A., Kalishman, J., Gobs, T. G., Durning, M., Harris, C. P., Becker, R. A., and Heam, J. P. 11. 1995. Isolation of a primate embryonic stem cell line. Proceedings of the National Academy of Sciences of the USA 92 7844-7848.

Thomson, J. A. and Marshall, V. S. 1998. Primate embryonic stem cells. Current Topics in DelJelopmental Biology 38: 133-165.

Wenk, J., Andrews, P. W., Casper, 1., Hata, J., Pera, M. F., von Keitz, A., Damjanov, 1., and Fenderson, B. A. 1994. Glycolipids of germ cell tumors: Extended gbobo-series glycolipids are a hallmark of human embryonal carci-noma cells. International Journal of Cancer 58: 108-115.

Wilmut, 1., Schnieke, A. E., McWhir, J., Kind, A. J., and Campbell, K. H. S. 1997. Viable offspring derived from fetal and adult mammalian cells. Nature 385 810-813.



The Human Embryonic Stem Cell Debate: Science, Ethics, and Public Policy
Edited by Suzanne Holland, Karen Lebacqz, and Laurie Zoloth
A Bradford Book The MIT Press Cambridge, Massachusetts London, England
2001



The Stem Cell Debate in Historical Context

John C. Fletcher

On November 14,1998, President Clinton asked the National Bioethics Advisory Commission (NBAC) to provide a thorough review of all issues surrounding human stem cell research, "balancing all ethical and medical considerations." Ten months later, NBAC (1999) submitted its report built on foundations laid by other commissions and advisory panels. One goal of this chapter is to single out the contribution of the first public bioethics body that dealt with controversial issues surrounding use of fetuses and embryos in research. In 1975 the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (National Commission) set an enduring example for how public bioethics can contribute to compassionate compromises on controversial issues. Failure to adhere to that example damages the effectiveness of NBAC's work.

In 1973 the Supreme Court ruled that a fetus is not a person in the context of constitutionally protected rights (Roe v. Wade 410 U.S. 113). The door was opened to freedom of choice in abortion. Members of Congress began to worry about possible exploitation of aborted fetuses.' The National Institutes of Health (NIH) imposed a moratorium on fetal research. In 1974 Congress established the National Commission and charged it with formulating ethical and public policy guidelines for fetal research.

The commission's report (1975), issued some four months later, was a compromise between liberal and conservative views on fetal research. In accord with liberal views, the commission encouraged fetal research because of its many benefits, such as development of polio and rubella vaccines. Yet it also sharply restricted fetal research: where research risks were concerned, fetuses to be aborted had to be treated equally with fetuses to be delivered. This bold specification of a principle of equality of protection honored a conservative viewpoint that contrasted markedly with the utilitarian ethos previously dominating United States research practices.

In coming to this conclusion, the commission drew on the work of several ethicists from conservative traditions. A leading Catholic moral theologian, Richard McCormick, stated that "the fetus is a fellow human being, and ought to be treated ... exactly as one treats a child" (1976). McCormick would permit fetal research provided there was "no discernible risk, no notable pain, no notable inconvenience, and ... promise of considerable benefit" (8). His term "no discernible risk" later evolved into the category of "minimal risk." The meaning of this term continues to be controversial and widely challenged. McCormick's posi tion opened a way conceptually l:or those giving primary rights to the fetus to accept fetal research nonetheless. However, with his position came his restrictive risk standard and, most important, the underlying premise that fetuses ought to be treated equally, as "fellow human beings."

The principle of equal treatment was also picked up by LeRoy Walters, a Protestant ethicist. Walters advised the commission to use a principle of equality of protection whether fetuses were destined for abortion or for delivery. Under this Golden Rule idea, researchers could not impose a higher risk with a fetus to be aborted than they would with a fetus to be delivered (Walters 1976). Although other ethicists also influenced the commission, it WdS the strength of these two positions that led the commission to offer the possibility of research on fetuses to be aborted, provided the risks were minimal and were only what would be accepted for a fetus going to .erm.

Thus, in effect, in spite of Roe v. Wade, the National Commission declared thar societal protection of human subjects ought to be extended to fetuses, even to those slated for abortion. Hence, any in utero fetal research, especially that not designed to benefit the health of the fetus, had to conform to a standard of minimal risk. To make this compromise work, the commission envisioned a continuing ethics advisory board (EAB) as a resource for local institutional review boards (IRBs) and for developing national policy. Some commissioners worried that important fetal research could not be done ethically without selectively assigning higher risks to fetuses to be aborted than to those going to term. The commission invested great hope in a future EAB to make decisions on a case-by-case basis. Its report can be seen as a compromise premised on strong hopes for the work of an EAB that would function like a national IRB.

Regulations for fetal research were promulgated (45 CFR 46) and the moratorium was lifted on July 29, 1975. The regulations distinguish research to meet the health needs of the fetus from research to develop ' important biomedical knowledge which cannot be obtained by other means." Only minimal risk is permitted in the latter category. Minimal risks were defined as "not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests" (45 CFR 46.102i). Application of such a standard to fetuses has never been clarified. Furthermore, the commission envisioned the possibility of occasional waivers approved by an EAB, and indeed one such waiver was granted (Steinfels 1979). However, the charter of the EAB lapsed in 1980 and was not renewed; there has been no EAB since.

After the 1984 election when President Reagan was retained in office, Congress enacted legislation far more protectionist than federal regulations that followed the work of the National Commission. Public law 99-158 effectively nullified the minimal risk standard and ended federal support of fetal research involving any level of risk, including into normal fetal physiology (Fletcher and Schulman 1985). The cost to the nation's health, especially to the health of children, is difficult to calculate but potentially enormous.

Two other laws had a significant impact on the situation in which stem cell research emerged. In 1993 Congress lifted a moratorium on federal funding of in vitro fertilization (IVF) research and nullified the requirement for EAB approval of such research. In 1996 a new Congress banned federal funding for embryo research and dashed NIH hopes to fund improvements of IVF and other projects involving human embryos. The Human Embryo Research Panel had argued in 1994 for federal funding for this research. However, even before the official ban, the threat of strong opposition from Congress toward any embryo research inhibited NIH approval of several clinically relevant projects that had passed NIH scientific review (Charo 1995). After the ban, the NIH received no proposals involving embryo research. Foregoing NIH involvement in arenas such as cancer, genetic research, infertility, and contraceptive research entails large losses to science and costs to human health. These losses ought to arouse moral concern, as obligations of beneficence and utility cannot be met without improvements in maternal and fetal health.

The premise of the federal ban is that embryos, like fetuses, deserve virtually absolute societal protection from destruction or harm in research activities. The language of the ban ("risk of injury or death") is based on earlier federal law restricting funding for fetal research. Congress also prohibited federal funding (with three exceptions) for elective abortions in the Medicaid program.[2] Conservative views of the moral status of the embryo and fetus prevail in the federal sector of science but stop at the border of the private sector.

Private sector research is constrained only by state laws prohibiting embryo research. In states with no laws against it, the research is essentially unregulated. The legality of stem cell research in various states is therefore a complex topic. As Andrews (1999) noted, twenty-four states have no laws specifically addressing research on embryos and fetuses, but in these states legal precedents regarding privacy, informed consent, and commercialization may come into play.

Researchers thus work in a morally bifurcated universe: prohibitive in the public sector and permissive in the private sector. The abortion issue is so explosive that social equilibrium requires such a morally divided universe. In a democracy, the elected majority's beliefs can prevail when Congress denies funding for activities it deems immoral. Federal and state governments may alsc use denial of funding to cool the heat of moral disputes around topics such as abortion.

In this political climate, it is no surprise that NBAC takes conservative moral opinion very seriously. Its chapter on ethical issues begins with a lengthy and thoughtful response to moral objections to using fetal tissue to derive stem cells for human embryonic germ (hEG) cell research. The argument builds on the work of the NIH Human Fetal Tissue Transplantation Panel (1988) but does not assume that the moral case was decided by that panel. Two objections in particular required new response: that providers of fetal tissue for hEG research are morally "complicit" with the preceding abortion, and that researchers are causally responsible for abortions that women can choose with an easier conscience because they believe that others may benefit.

To these objections, NBAC gave three responses. First, no data show that fetal tissue research increases the abortion rate; this weakens the claim that the research contributes to abortion. Second, legal safeguards in effect since 1993 protect against abuses by ensuring that women's consent for abortion must precede any request for consent to fetal tissue research, that women receive no payment for fetal tissue, that no alterations be permitted in the timing or procedures used in performing the abortion, and so on. Third, NBAC maintains that if providers of fetal tissue are to be held causally responsible for abortions, many others would also have to be held causally responsible; for example, those who encourage women to seek education would be responsible if a woman had an abortion in order to continue her education. Since no one holds people causally responsible in such instances, NBAC found that researchers also should not be deemed morally responsible for women's choice to abort.

The case of human embryonic stem (hES) cell research using excess embryos is similar in every respect except for the fact that researchers' actions cause embryos to die. Here, NBAC framed its moral position largely in terms of loyalty to medicine's goals of healing, prevention, and research. These goals were envisioned as "rightly characterized by the principles of beneficence and nonmaleficence"-doing good and avoiding harm. Thus, NBAC drew on widely accepted principles and also on a balance of goods and harms that echoes utilitarian reasoning. A benefit:harms ratio is a familiar tool in ethics to weigh and balance foreseeable consequences of actions. I will return to an analysis of NBAC's position itself in another chapter. What is crucial here is that, by drawing on several modes of reasoning, NBAC may be trying to provide a compromise, following in the footsteps of the National Commission so many years ago. Whether it is as successful in that compromise as was the commission is another question.

At some points, NBAC appears to have worked hard for compromise between liberals and conservatives. It describes clashing views on the question of the moral status of the embryo, and intends to be respectful of all reasonable alternative views. Here is a genuine search for common ground between liberals and conservatives. Noting that conservatives often make room for some instances of abortion, and that this suggests some grounds on which fetal life can be taken, NBAC suggested that such conservatives might willingly cross the gap to permit hES research to save lives or prevent disability, especially if adequate safeguards are in place.

However, in the final analysis, NBAC gave up the search for compromise. When the analogy between permissible abortion and research on hES cells broke down, NBAC turned to urging a benefit:harm ratio. Ultimately, it took the position that embryos are forms of human life but not human subjects of research. Whereas the couple who donate gametes are clearly subjects for purposes of research conducted on their embryos; the embryos themselves are not yet fully subjects. In short, NBAC took a stand on the moral status of the embryo, but simply asserted this stand and did not provide convincing argument for it. The stand is similar to that taken by the EAB in 1979 and by the Human Embryo Research Panel in 1994: an embryo merits respect as a form of human life, but not the same level of respect as would be accorded to persons. This is not a compromise with those who hold that the embryo is a person.

All hope for moral compromise disappeared when NBAC moved to recommend permitting federal funding to derive hES cells from excess embryos. Eight reasons were given to support this position. They ranged from the importance of science to the need for federal support and regulation to avoid industry-driven research, which of necessity operates with some secrecy and limits dissemination of results. These reasons are plausible in themselves; however, the issue is the politics of embryo research. WhGse political interests does the NBAC's stand serve? Here, the position on fedcral funding requires conservatives to compromise their moral beliefs while liberals compromise nothing. This is not a true compromise .

Let us assume for purpose of argument that NBAC is morally right in holding that the ban should be amended to permit federal support for stem cell research. But then let us assume that it is not politically possible to amend the ban now. Congress does not now have a majority who would enact the NBAC position. Hence, what ought to be done cannot be done. In this context, the stage is set for genuine compromise between liberals and conservatives that facilitates the appropriations process for federal funding for embryo research using excess IVF embryos. What might that compromise be?

Given the history of prohibitive policies of Congress and a great need for public education on these issues, one can assume first that Congress and the public will be more easily persuaded to amend the ban if the focus of federal funding is on therapeutic aims rather than on basic research, and second, that arguments such as those made by NBAC regarding the great potential good of this research will become more persuasive as basic research matures and we enter a stage of readiness for clinical trials. A reasonable compromise would be to defer amending the ban untli that point is reached.

This will seem unfair to the liberal mind. However, if one takes the moral opinion of conservatives seriously, as did the NBAC in part of its ethical stance, it follows that federal funding for the derivation of ES cells from excess embryos ought to be a last resort to mount research aimed at saving lives and preventing disability. This may not move the research agenda forward as quickly as liberals would like, but it is a fair compromise with the conservative position that would ban forever all federal support for this research.

The NBAC was charged with balancing medical and ethical considerations. Its work is in fact unbalanced because it did not follow the example of the National Commission and allow the moral logic of compassionate compromise to guide its choices and recommendations on federal funding. Public bioethics is unavoidably political because it aims to influence public policy. In this context, more attention should have been given to the history of congressional actions on fetal and embryo research, the political weight of conservative moral views, and a volatile political context. Public bioethics must be concerned with the politically possible in order to achieve the right balance between competing factors, especially on such a controversial issue. The NBAC's ethical analysis appeals to liberal thought but disappoints pragmatists in ethics and politics. Most unfortunate, it seriously distances this decade's public bioethics body from conservative moral opinion.

1. A very informative political history of events before 1988 is found in Lehrman (1988).

2. First introduced in 1976, the Hyde Amendment, named for its sponsor, Henry Hyde (R.-Il.), restricts all funding of abortion for the federal share of Medicaid except for cases in which two physicians attest that continuation of the pregnancy will result in severe and lasting damage to the woman's physical health, and in cases of reported rape and incest The law took effect after a Supreme Court ruling: Harris v. McRae 448 U.S. 297 (1980).

References

Andrews, L. B. 1999. State regulation of embryo stem cell research. In National Bioethics Advisory Commission. Ethical Issues in Human Stem Cell Research. Vol. Il. Commissioned Papers. Rockville, MD: National Bioethics Advisory Commission .

Charo, R. A. 1995. The hunting of the snark: The moral status of embryos, rightto-lifers, and third world women. Stanford Law and Policy Review 6: 11-27.

Fletcher, J. C. and Schulman, J. D. 1985. Fetal research: The state of the question. Hastings Center Report 15: 6-12.

Human Emhryo Research Panel. 1994. Report of the Human Embryo Research Panel. Washington, DC: National Institutes of I lealth.

Lehrman, D. 1988. Summary: Fetal Research and Fetal Tissue Research. Washington, DC: American Association of Medical Colleges.

McCormick, R. 1976. Experimentation on the fetus: Policy proposals. In Appendix to Report and Recommendations: Research on the Fetus. Washington, DC: National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research.

National Bioethics Advisory Commission. 1999. Ethical Issues in Human Stem Cell Research. Rockville, MD: National Bioethics Advisory Commission.

National Commission for tke Protection of Human Subjects of Biomedical and Behavioral Research. 1975. Report and Recommendations: Research on the Fetus. Washington, DC: U.S. Department of Health, Education, and Welfare.

National Institutes of Health. 1994. Report of the Human Fetal Tissue Transplantation Research Panel. Vol. 1. Bethesda, MD.

Steinfels, M. 1979. At the EAB. Same members, new ethical problems. Hastings Center Report 5: 2.

Walters, L. 1976. Ethical and public policy issues in fetal research. In Appendix to Report and Recommendations: Research on the Fetus. Washington, DC: U.S. Department of Health, Education, and Welfare.



The Human Embryonic Stem Cell Debate: Science, Ethics, and Public Policy
Edited by Suzanne Holland, Karen Lebacqz, and Laurie Zoloth
A Bradford Book The MIT Press Cambridge, Massachusetts London, England
2001