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Ethics of Stem Cell Research

Human embryonic stem cell (HESC) research offers much hope for alleviating the human suffering brought on by the ravages of disease and injury. HESCs are characterized by their capacity for self-renewal and their ability to differentiate into all types of cells of the body. The main goal of HESC research is to identify the mechanisms that govern cell differentiation and to turn HESCs into specific cell types that can be used for treating debilitating and life-threatening diseases and injuries.

Despite the tremendous therapeutic promise of HESC research, the research has met with heated opposition because the harvesting of HESCs involves the destruction of the human embryo. HESCs are derived in vitro around the fifth day of the embryo’s development (Thomson et al . 1998). A typical day-5 human embryo consists of 200–250 cells, most of which comprise the trophoblast, which is the outermost layer of the blastocyst. HESCs are harvested from the inner cell mass of the blastocyst, which consists of 30–34 cells. The derivation of HESC cultures requires the removal of the trophoblast. This process of disaggregating the blastocyst’s cells eliminates its potential for further development. Opponents of HESC research argue that the research is morally impermissible because it involves the unjust killing of innocent human beings.

Scientists recently succeeded in converting adult human skin cells into cells that appear to have the properties of HESCs by activating four genes in the adult cells (Takahashi et al . 2007; Yu et al . 2007). The reprogrammed cells—“induced pluripotent stem cells” (iPSCs)—could ultimately eliminate the need for HESCs. However, at present, the consensus in the scientific community is that both HESC and iPSC research should be pursued, as we do not yet know whether iPSCs have the same potential as HESCs or whether it is safe to transplant them into humans. Thus, the controversies around HESC research will continue, at least in the near-term.

While the principal source of the controversy surrounding HESC research lies in competing views about the value of human embryonic life, the scope of ethical issues in HESC research is broader than the question of the ethics of destroying human embryos. It also encompasses questions about, among other things, whether researchers who use but do not derive HESCs are complicit in the destruction of embryos, whether there is a moral distinction between creating embryos for research purposes and creating them for reproductive ends, the permissibility of cloning human embryos to harvest HESCs, and the ethics of creating human/non-human chimeras. This entry provides an overview of all but the last two issues just listed; cloning and human-non-human chimeras are addressed in separate entries.

1.1 When does a human being begin to exist?

1.2 the moral status of human embryos, 1.3 the case of “doomed embryos”, 2. the ethics of using human embryonic stem cells in research, 3. the ethics of creating embryos for stem cell research and therapy, 4. stem cell-derived gametes, 5. stem cell-derived organoids, gastruloids, and synthetic embryos, cited resources, other resources, related entries, 1. the ethics of destroying human embryos for research.

The potential therapeutic benefits of HESC research provide strong grounds in favor of the research. If looked at from a strictly consequentialist perspective, it’s almost certainly the case that the potential health benefits from the research outweigh the loss of embryos involved and whatever suffering results from that loss for persons who want to protect embryos. However, most of those who oppose the research argue that the constraints against killing innocent persons to promote social utility apply to human embryos. Thus, as long as we accept non-consequentialist constraints on killing persons, those supporting HESC research must respond to the claim that those constraints apply to human embryos.

In its most basic form, the central argument supporting the claim that it is unethical to destroy human embryos goes as follows: It is morally impermissible to intentionally kill innocent human beings; the human embryo is an innocent human being; therefore it is morally impermissible to intentionally kill the human embryo. It is worth noting that this argument, if sound, would not suffice to show that all or even most HESC research is impermissible, since most investigators engaged in HESC research do not participate in the derivation of HESCs but instead use cell lines that researchers who performed the derivation have made available. To show that researchers who use but do not derive HESCs participate in an immoral activity, one would further need to establish their complicity in the destruction of embryos. We will consider this issue in section 2. But for the moment, let us address the argument that it is unethical to destroy human embryos.

A premise of the argument against killing embryos is that human embryos are human beings. The issue of when a human being begins to exist is, however, a contested one. The standard view of those who oppose HESC research is that a human being begins to exist with the emergence of the one-cell zygote at fertilization. At this stage, human embryos are said to be “whole living member[s] of the species homo sapiens … [which] possess the epigenetic primordia for self-directed growth into adulthood, with their determinateness and identity fully intact” (George & Gomez-Lobo 2002, 258). This view is sometimes challenged on the grounds that monozygotic twinning is possible until around days 14–15 of an embryo’s development (Smith & Brogaard 2003). An individual who is an identical twin cannot be numerically identical to the one-cell zygote, since both twins bear the same relationship to the zygote, and numerical identity must satisfy transitivity. That is, if the zygote, A, divides into two genetically identical cell groups that give rise to identical twins B and C, B and C cannot be the same individual as A because they are not numerically identical with each other. This shows that not all persons can correctly assert that they began their life as a zygote. However, it does not follow that the zygote is not a human being, or that it has not individuated. This would follow only if one held that a condition of an entity’s status as an individual human being is that it be impossible for it to cease to exist by dividing into two or more entities. But this seems implausible. Consider cases in which we imagine adult humans undergoing fission (for example, along the lines of Parfit’s thought experiments, where each half of the brain is implanted into a different body) (Parfit 1984). The prospect of our going out of existence through fission does not pose a threat to our current status as distinct human persons. Likewise, one might argue, the fact that a zygote may divide does not create problems for the view that the zygote is a distinct human being.

There are, however, other grounds on which some have sought to reject that the early human embryo is a human being. According to one view, the cells that comprise the early embryo are a bundle of homogeneous cells that exist in the same membrane but do not form a human organism because the cells do not function in a coordinated way to regulate and preserve a single life (Smith & Brogaard 2003, McMahan 2002). While each of the cells is alive, they only become parts of a human organism when there is substantial cell differentiation and coordination, which occurs around day-16 after fertilization. Thus, on this account, disaggregating the cells of the 5-day embryo to derive HESCs does not entail the destruction of a human being.

This account is subject to dispute on empirical grounds. That there is some intercellular coordination in the zygote is revealed by the fact that the development of the early embryo requires that some cells become part of the trophoblast while others become part of the inner cell mass. Without some coordination between the cells, there would be nothing to prevent all cells from differentiating in the same direction (Damschen, Gomez-Lobo and Schonecker 2006). The question remains, though, whether this degree of cellular interaction is sufficient to render the early human embryo a human being. Just how much intercellular coordination must exist for a group of cells to constitute a human organism cannot be resolved by scientific facts about the embryo, but is instead an open metaphysical question (McMahan 2007a).

Suppose that the 5-day human embryo is a human being. On the standard argument against HESC research, membership in the species Homo sapiens confers on the embryo a right not to be killed. This view is grounded in the assumption that human beings have the same moral status (at least with respect to possessing this right) at all stages of their lives.

Some accept that the human embryo is a human being but argue that the human embryo does not have the moral status requisite for a right to life. There is reason to think that species membership is not the property that determines a being’s moral status. We have all been presented with the relevant thought experiments, courtesy of Disney, Orwell, Kafka, and countless science fiction works. The results seem clear: we regard mice, pigs, insects, aliens, and so on, as having the moral status of persons in those possible worlds in which they exhibit the psychological and cognitive traits that we normally associate with mature human beings. This suggests that it is some higher-order mental capacity (or capacities) that grounds the right to life. While there is no consensus about the capacities that are necessary for the right to life, some of the capacities that have been proposed include reasoning, self-awareness, and agency (Kuhse & Singer 1992, Tooley 1983, Warren 1973).

The main difficulty for those who appeal to such mental capacities as the touchstone for the right to life is that early human infants lack these capacities, and do so to a greater degree than many of the nonhuman animals that most deem it acceptable to kill (Marquis 2002). This presents a challenge for those who hold that the non-consequentialist constraints on killing human children and adults apply to early human infants. Some reject that these constraints apply to infants, and allow that there may be circumstances where it is permissible to sacrifice infants for the greater good (McMahan 2007b). Others argue that, while infants do not have the intrinsic properties that ground a right to life, we should nonetheless treat them as if they have a right to life in order to promote love and concern towards them, as these attitudes have good consequences for the persons they will become (Benn 1973, Strong 1997).

Some claim that we can reconcile the ascription of a right to life to all humans with the view that higher order mental capacities ground the right to life by distinguishing between two senses of mental capacities: “immediately exercisable” capacities and “basic natural” capacities. (George and Gomez-Lobo 2002, 260). According to this view, an individual’s immediately exercisable capacity for higher mental functions is the actualization of natural capacities for higher mental functions that exist at the embryonic stage of life. Human embryos have a “rational nature,” but that nature is not fully realized until individuals are able to exercise their capacity to reason. The difference between these types of capacity is said to be a difference between degrees of development along a continuum. There is merely a quantitative difference between the mental capacities of embryos, fetuses, infants, children, and adults (as well as among infants, children, and adults). And this difference, so the argument runs, cannot justify treating some of these individuals with moral respect while denying it to others.

Given that a human embryo cannot reason at all, the claim that it has a rational nature has struck some as tantamount to asserting that it has the potential to become an individual that can engage in reasoning (Sagan & Singer 2007). But an entity’s having this potential does not logically entail that it has the same status as beings that have realized some or all of their potential (Feinberg 1986). Moreover, with the advent of cloning technologies, the range of entities that we can now identify as potential persons arguably creates problems for those who place great moral weight on the embryo’s potential. A single somatic cell or HESC can in principle (though not yet in practice) develop into a mature human being under the right conditions—that is, where the cell’s nucleus is transferred into an enucleated egg, the new egg is electrically stimulated to create an embryo, and the embryo is transferred to a woman’s uterus and brought to term. If the basis for protecting embryos is that they have the potential to become reasoning beings, then, some argue, we have reason to ascribe a high moral status to the trillions of cells that share this potential and to assist as many of these cells as we reasonably can to realize their potential (Sagan & Singer 2007, Savulescu 1999). Because this is a stance that we can expect nearly everyone to reject, it’s not clear that opponents of HESC research can effectively ground their position in the human embryo’s potential.

One response to this line of argument has been to claim that embryos possess a kind of potential that somatic cells and HESCs lack. An embryo has potential in the sense of having an “active disposition” and “intrinsic power” to develop into a mature human being (Lee & George 2006). An embryo can mature on its own in the absence of interference with its development. A somatic cell, on the other hand, does not have the inherent capacity or disposition to grow into a mature human being. However, some question whether this distinction is viable, especially in the HESC research context. While it is true that somatic cells can realize their potential only with the assistance of outside interventions, an embryo’s development also requires that numerous conditions external to it are satisfied. In the case of embryos that are naturally conceived, they must implant, receive nourishment, and avoid exposure to dangerous substances in utero . In the case of spare embryos created through in vitro fertilization—which are presently the source of HESCs for research—the embryos must be thawed and transferred to a willing woman’s uterus. Given the role that external factors—including technological interventions—play in an embryo’s realizing its potential, one can question whether there is a morally relevant distinction between an embryo’s and somatic cell’s potential and thus raise doubts about potentiality as a foundation for the right to life (Devolder & Harris 2007).

Some grant that human embryos lack the properties essential to a right to life, but hold that they possess an intrinsic value that calls for a measure of respect and places at least some moral constraints on their use: “The life of a single human organism commands respect and protection … no matter in what form or shape, because of the complex creative investment it represents and because of our wonder at the divine or evolutionary processes that produce new lives from old ones.” (Dworkin l992, 84). There are, however, divergent views about the level of respect embryos command and what limits exist on their use. Some opponents of HESC research hold that the treatment of human embryos as mere research tools always fails to manifest proper respect for them. Other opponents take a less absolutist view. Some, for example, deem embryos less valuable than more mature human beings but argue that the benefits of HESC research are too speculative to warrant the destruction of embryos, and that the benefits might, in any case, be achieved through the use of noncontroversial sources of stem cells (e.g., adult stem cells) (Holm 2003).

Many, if not most, who support the use of human embryos for HESC research would likely agree with opponents of the research that there are some circumstances where the use of human embryos would display a lack of appropriate respect for human life, for example, were they to be offered for consumption to contestants in a reality TV competition or destroyed for the production of cosmetics. But proponents of the research hold that the value of human embryos is not great enough to constrain the pursuit of research that may yield significant therapeutic benefits. Supporters of the research also frequently question whether most opponents of the research are consistent in their ascription of a high value to human embryos, as opponents generally display little concern about the fact that many embryos created for fertility treatment are discarded.

When spare embryos exist after fertility treatment, the individuals for whom the embryos were created typically have the option of storing for them for future reproductive use, donating them to other infertile couples, donating them to research, or discarding them. Some argue that as long as the decision to donate embryos for research is made after the decision to discard them, it is morally permissible to use them in HESC research even if we assume that they have the moral status of persons. The claim takes two different forms. One is that it is morally permissible to kill an individual who is about to be killed by someone else where killing that individual will help others (Curzer, H. 2004). The other is that researchers who derive HESCs from embryos that were slated for destruction do not cause their death. Instead, the decision to discard the embryos causes their death; research just causes the manner of their death (Green 2002).

Both versions of the argument presume that the decision to discard spare embryos prior to the decision to donate them to research entails that donated embryos are doomed to destruction when researchers receive them. There are two arguments one might marshal against this presumption. First, one who wants to donate embryos to research might first elect to discard them only because doing so is a precondition for donating them. There could be cases in which one who chooses the discard option would have donated the embryos to other couples were the research donation option not available. The fact that a decision to discard embryos is made prior to the decision to donate the embryos thus does not establish that the embryos were doomed to destruction before the decision to donate them to research was made. Second, a researcher who receives embryos could choose to rescue them, whether by continuing to store them or by donating them to infertile couples. While this would violate the law, the fact that it is within a researcher’s power to prevent the destruction of the embryos he or she receives poses problems for the claim that the decision to discard the embryos dooms them or causes their destruction.

Assume for the sake of argument that it is morally impermissible to destroy human embryos. It does not follow that all research with HESCs is impermissible, as it is sometimes permissible to benefit from moral wrongs. For example, there is nothing objectionable about transplant surgeons and patients benefiting from the organs of murder and drunken driving victims (Robertson 1988). If there are conditions under which a researcher may use HESCs without being complicit in the destruction of embryos, then those who oppose the destruction of embryos could support research with HESCs under certain circumstances.

Researchers using HESCs are clearly implicated in the destruction of embryos where they derive the cells themselves or enlist others to derive the cells. However, most investigators who conduct research with HESCs obtain them from an existing pool of cell lines and play no role in their derivation. One view is that we cannot assign causal or moral responsibility to investigators for the destruction of embryos from which the HESCs they use are derived where their “research plans had no effect on whether the original immoral derivation occurred.” (Robertson 1999). This view requires qualification. There may be cases in which HESCs are derived for the express purpose of making them widely available to HESC investigators. In such instances, it may be that no individual researcher’s plans motivated the derivation of the cells. Nonetheless, one might argue that investigators who use these cells are complicit in the destruction of the embryos from which the cells were derived because they are participants in a research enterprise that creates a demand for HESCs. For these investigators to avoid the charge of complicity in the destruction of embryos, it must be the case that the researchers who derived the HESCs would have performed the derivation in the absence of external demand for the cells (Siegel 2004).

The issue about complicity goes beyond the question of an HESC researcher’s role in the destruction of the particular human embryo(s) from which the cells he or she uses are derived. There is a further concern that research with existing HESCs will result in the future destruction of embryos: “[I]f this research leads to possible treatments, private investment in such efforts will increase greatly and the demand for many thousands of cell lines with different genetic profiles will be difficult to resist.” (U.S. Conference of Catholic Bishops 2001). This objection faces two difficulties. First, it appears to be too sweeping: research with adult stem cells and non-human animal stem cells, as well as general research in genetics, embryology, and cell biology could be implicated, since all of this research might advance our understanding of HESCs and result in increased demand for them. Yet, no one, including those who oppose HESC research, argues that we should not support these areas of research. Second, the claim about future demand for HESCs is speculative. Indeed, current HESC research could ultimately reduce or eliminate demand for the cells by providing insights into cell biology that enable the use of alternative sources of cells (Siegel 2004).

While it might thus be possible for a researcher to use HESCs without being morally responsible for the destruction of human embryos, that does not end the inquiry into complicity. Some argue that agents can be complicit in wrongful acts for which they are not morally responsible. One such form of complicity arises from an association with wrongdoing that symbolizes acquiescence in the wrongdoing (Burtchaell 1989). The failure to take appropriate measures to distance oneself from moral wrongs may give rise to “metaphysical guilt,” which produces a moral taint and for which shame is the appropriate response (May 1992). The following question thus arises: Assuming it is morally wrongful to destroy human embryos, are HESC researchers who are not morally responsible for the destruction of embryos complicit in the sense of symbolically aligning themselves with a wrongful act?

One response is that a researcher who benefits from the destruction of embryos need not sanction the act any more than the transplant surgeon who uses the organs of a murder or drunken driving victim sanctions the homicidal act (Curzer 2004). But this response is unlikely to be satisfactory to opponents of HESC research. There is arguably an important difference between the transplant case and HESC research insofar as the moral wrong associated with the latter (a) systematically devalues a particular class of human beings and (b) is largely socially accepted and legally permitted. Opponents of HESC research might suggest that the HESC research case is more analogous to the following kind of case: Imagine a society in which the practice of killing members of a particular racial or ethnic group is legally permitted and generally accepted. Suppose that biological materials obtained from these individuals subsequent to their deaths are made available for research uses. Could researchers use these materials while appropriately distancing themselves from the wrongful practice? Arguably, they could not. There is a heightened need to protest moral wrongs where those wrongs are socially and legally accepted. Attempts to benefit from the moral wrong in these circumstances may be incompatible with mounting a proper protest (Siegel 2003).

But even if we assume that HESC researchers cannot avoid the taint of metaphysical guilt, it is not clear that researchers who bear no moral responsibility for the destruction of embryos are morally obligated not to use HESCs. One might argue that there is a prima facie duty to avoid moral taint, but that this duty may be overridden for the sake of a noble cause.

Most HESCs are derived from embryos that were created for infertility treatment but that were in excess of what the infertile individual(s) ultimately needed to achieve a pregnancy. The HESCs derived from these leftover embryos offer investigators a powerful tool for understanding the mechanisms controlling cell differentiation. However, there are scientific and therapeutic reasons not to rely entirely on leftover embryos. From a research standpoint, creating embryos through cloning technologies with cells that are known to have particular genetic mutations would allow researchers to study the underpinnings of genetic diseases in vitro . From a therapeutic standpoint, the HESCs obtained from leftover IVF embryos are not genetically diverse enough to address the problem of immune rejection by recipients of stem cell transplants. (Induced pluripotent stem cells may ultimately prove sufficient for these research and therapeutic ends, since the cells can (a) be selected for specific genetic mutations and (b) provide an exact genetic match for stem cell recipients.) At present, the best way to address the therapeutic problem is through the creation of a public stem cell bank that represents a genetically diverse pool of stem cell lines (Faden et al . 2003, Lott & Savulescu 2007). This kind of stem cell bank would require the creation of embryos from gamete donors who share the same HLA-types (i.e., similar versions of the genes that mediate immune recognition and rejection).

Each of these enterprises has its own set of ethical issues. In the case of research cloning, some raise concerns, for example, that the perfection of cloning techniques for research purposes will enable the pursuit of reproductive cloning, and that efforts to obtain the thousands of eggs required for the production of cloned embryos will result in the exploitation of women who provide the eggs (President’s Council on Bioethics 2002, Norsigian 2005). With respect to stem cell banks, it is not practically possible to create a bank of HESCs that will provide a close immunological match for all recipients. This gives rise to the challenge of determining who will have biological access to stem cell therapies. We might construct the bank so that it provides matches for the greatest number of people in the population, gives everyone an equal chance of finding a match, or ensures that all ancestral/ethnic groups are fairly represented in the bank (Faden et al . 2003, Bok, Schill, & Faden 2004, Greene 2006).

There are, however, more general challenges to the creation of embryos for research and therapeutic purposes. Some argue that the creation of embryos for non-reproductive ends is morally problematic, regardless of whether they are created through cloning or in vitro fertilization. There are two related arguments that have been advanced to morally distinguish the creation of embryos for reproductive purposes from the creation of embryos for research and therapeutic purposes. First, each embryo created for procreative purposes is originally viewed as a potential child in the sense that each is a candidate for implantation and development into a mature human. In contrast, embryos created for research or therapies are viewed as mere tools from the outset (Annas, Caplan & Elias 1996, President’s Council on Bioethics 2002). Second, while embryos created for research and therapy are produced with the intent to destroy them, the destruction of embryos created for reproduction is a foreseeable but unintended consequence of their creation (FitzPatrick 2003).

One response to the first argument has been to suggest that we could, under certain conditions, view all research embryos as potential children in the relevant sense. If all research embryos were included in a lottery in which some of them were donated to individuals for reproductive purposes, all research embryos would have a chance at developing into mature humans (Devander 2005). Since those who oppose creating embryos for research would likely maintain their opposition in the research embryo lottery case, it is arguably irrelevant whether embryos are viewed as potential children when they are created. Of course, research embryos in the lottery case would be viewed as both potential children and potential research tools. But this is also true in the case of embryos created for reproductive purposes where patients are open to donating spare embryos to research.

As to the second argument, the distinction between intending and merely foreseeing harms is one to which many people attach moral significance, and it is central to the Doctrine of Double Effect. But even if one holds that this is a morally significant distinction, it is not clear that it is felicitous to characterize the destruction of spare embryos as an unintended but foreseeable side-effect of creating embryos for fertility treatment. Fertility clinics do not merely foresee that some embryos will be destroyed, as they choose to offer patients the option of discarding embryos and carry out the disposal of embryos when patients request it. Patients who elect that their embryos be discarded also do not merely foresee the embryos’ destruction; their election of that option manifests their intention that the embryos be destroyed. There is thus reason to doubt that there is a moral distinction between creating embryos for research and creating them for reproductive purposes, at least given current fertility clinic practices.

Recent scientific work suggests it is possible to derive gametes from human pluripotent stem cells. Researchers have generated sperm and eggs from mouse ESCs and iPSCs and have used these stem cell-derived gametes to produce offspring (Hayashi 2011; Hayashi 2012). While it may take several years before researchers succeed in deriving gametes from human stem cells, the research holds much promise for basic science and clinical application. For example, the research could provide important insights into the fundamental processes of gamete biology, assist in the understanding of genetic disorders, and provide otherwise infertile individuals a means of creating genetically related children. The ability to derive gametes from human stem cells could also reduce or eliminate the need for egg donors and thus help overcome concerns about exploitation of donors and the risks involved in egg retrieval. Nonetheless, the research gives rise to some controversial issues related to embryos, genetics, and assisted reproductive technologies (D. Mathews et al . 2009).

One issue arises from the fact that some research on stem cell-derived gametes requires the creation of embryos, regardless of whether one is using ESCs or iPSCs. To establish that a particular technique for deriving human gametes from stem cells produces functional sperm and eggs, it is necessary to demonstrate that the cells can produce an embryo. This entails the creation of embryos through in vitro fertilization. Since it would not be safe to implant embryos created during the early stages of the research, the likely disposition of the embryos is that they would be destroyed. In such instances, the research would implicate all of the moral issues surrounding the creation and destruction of embryos for research. However, the creation of embryos for research in this situation would not necessitate the destruction of the embryos, as it does when embryos are created to derive stem cell lines. One could in principle store them indefinitely rather than destroy them. This would still leave one subject to the objection that life is being created for instrumental purposes. But the force of the objection is questionable since it is not clear that this instrumental use is any more objectionable than the routine and widely accepted practice of creating excess IVF embryos in the reproductive context to increase the probability of generating a sufficient number of viable ones to produce a pregnancy.

Further issues emerge with the prospect of being able to produce large quantities of eggs from stem cells. As the capacity to identify disease and non-disease related alleles through preimplantation genetic diagnosis (PGD) expands, the ability to create large numbers of embryos would substantially increase the chances of finding an embryo that possesses most or all of the traits one wishes to select. This would be beneficial in preventing the birth of children with genetic diseases. But matters would become morally contentious if it were possible to select for non-disease characteristics, such as sexual orientation, height, superior intelligence, memory, and musical ability. One common argument against using PGD in this way is that it could devalue the lives of those who do not exhibit the chosen characteristics. Another concern is that employing PGD to select for non-disease traits would fail to acknowledge the “giftedness of life” by treating children as “objects of our design or products of our will or instruments of our ambition” rather accepting them as they are given to us (Sandel 2004, 56). There is additionally a concern about advances in genetics heightening inequalities where certain traits confer social and economic advantages and only the well-off have the resources to access the technology (Buchanan 1995). Of course, one can question whether the selection of non-disease traits would in fact lead to devaluing other characteristics, whether it would alter the nature of parental love, or whether it is distinct enough from currently permitted methods of gaining social and economic advantage to justify regulating the practice. Nonetheless, the capacity to produce human stem cell-derived gametes would make these issues more pressing.

There have been a number of recent scientific studies in which stem cells have, under certain in vitro culture conditions, self-organized into three-dimensional structures that resemble and recapitulate some of the functions of human organs (Lancaster & Knoblich 2014; Clevers 2016). These “organoids” have been established with human stem cells for a variety of organs, including, among others, the kidney, liver, gut, pancreas, retina, and brain. In addition to organoids, stem cells have been shown to self-organize into embryo-like structures in vitro . Human embryonic stem cells have formed structures – referred to as “gastruloids” – that bear some resemblance to embryos during gastrulation, which is the stage several days after implantation where the body plan and some tissues tissue types, including the central nervous system, start to develop (Warmflash et al. 2014; Deglincerti et al . 2016; Shahbazi 2016). Researchers have also combined mouse embryonic stem cells and trophoblast stem cells to create “synthetic embryos,” which have a structure akin to pre-implantation embryos (Rivron et al . 2018). Synthetic embryos have been shown to implant into the mouse uterus, though their potential to develop to term has not been demonstrated.

While these scientific advances offer promising avenues for better understanding human development and disease, they also raise some novel and challenging ethical issues. In the case of organoids, cerebral organoids raise the most vexing issues. Researchers have produced cerebral organoids with a degree of development similar to that of a few-months-old embryo, and have already used them to study how the Zika virus causes microcephaly in fetuses (Garcez et al . 2016). At present, there is some evidence that cerebral organoids may be able to receive afferent stimulations that produce simple sensations (Quadrato et al . 2017). However, they currently lack the kind of mature neural networks and sensory inputs and outputs essential to the development of cognition. If, through bioengineering, human cerebral organoids were to develop the capacity for cognition, that would provide grounds for ascribing an elevated moral status to them, and it would raise concomitant issues about our moral obligations towards them. In the nearer term, it is more likely that cerebral organoids will develop some degree of consciousness Assuming we have a shared understanding of consciousness (e.g., phenomenal consciousness), one challenge is to identify means of measuring the presence of consciousness, since a cerebral organoid cannot communicate its internal states (Lavazza & Massimini 2018). But even if we can verify that an organoid is conscious, there remains the question of the moral significance of consciousness (Shepherd 2018). There is debate over whether consciousness has intrinsic value (Lee 2018), and whether in some cases it is better for a conscious being to not possess it (Kahane & Savulescu 2009). Those who reject the intrinsic value and moral significance of consciousness might find the case of a conscious entity that has led a solely disembodied existence, emerges and persists in the absence of any social or cultural nexus, and lacks beliefs and desires, to be a paradigmatic case where the value of consciousness is doubtful.

With respect to gastruloids and synthetic embryos (if the latter are successfully produced with human stem cells), the central question is whether these entities are sufficiently like human embryos in their structure and functions to give rise to moral concerns about their use in research. Gastruloids do not possess all the characteristics of an embryo, as they do not form all of the embryonic tissues (e.g., they do not have the trophectoderm, which mediates the attachment to the uterus). At the same time, gastruloids may, with extra-embryonic tissues, achieve a developmental stage in which they manifest a whole body plan. Recall that one argument (discussed in Section 1.1 above) for rejecting that human embryos are human beings is that the cells that comprise the early embryo do not function in a coordinated way to regulate and preserve a single organism. Gastruloids can in principle operate with this higher level of coordination. While one may still reject that this characteristic of gastruloids confers human rights on them, their more advanced stage of development might ground reasonable claims for according them greater respect than embryos at an earlier stage. In the case of both gastruloids and human synthetic embryos, the possibility that they ultimately lack the potential to develop into mature human beings may be of significance in morally distinguishing them from normal human embryos. As noted previously (in section 1.2 above), one argument for ascribing a high moral status to human embryos and for distinguishing the potential of human embryos from the potential of somatic cells and embryonic stem cells is that embryos have an “active disposition” and “intrinsic power” to develop into mature humans on their own. If synthetic embryos and gastruloids do not possess this disposition and power, then those who oppose some forms of human embryo research might not object to the creation and use of human gastruloids and synthetic embryos for research.

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• Published: 04 August 2008

Plenary Session 6

Ethical issues in stem cell research and treatment

• Jeremy Sugarman 1   na1  

Cell Research volume  18 ,  page S176 ( 2008 ) Cite this article

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The incredible promise of stem cell research to at minimum advance scientific understanding and perhaps ultimately to treat persons with devastating diseases gives moral force to efforts to conduct this research. However, stem cell research has been riddled with ethical questions, in part because the predominant methods being used to derive or attempt to derive human embryonic stem cells require destruction of the embryo. Nevertheless, the ethical debates surrounding human embryonic stem cell research have not been solely related to those associated with the embryo. For instance, the creation of chimeras in some stem cell research has elicited concerns. Oocyte harvesting, which is essential to the creation of human embryonic stem cells raises concerns related to safety of the donor. Other important ethical issues relate to informed consent of both donors of gametes and embryos as well as recipients of stem cells and stem cell products. Further, there has been some concern related to the commercialization of the process, justice, and the responsible conduct of research. In addressing the ethical issues associated with human embryonic stem cell research, it is important to note that they are being deliberated in a setting where scientific excitement is high, there are extraordinarily powerful arguments for access to investigational treatments, and the financial, moral and political stakes are great. In an attempt to minimize the ethical issues associated with human embryonic stem cell research so important research can proceed, professional groups have issued guidelines for the ethical conduct of this research and its oversight. Systematic data regarding these efforts should be collected in order to enhance the likelihood that they meet their ethical goals.

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Jeremy Sugarman: Jeremy Sugarman, MD, MPH, MA is the Harvey M. Meyerhoff Professor of Bioethics and Medicine, Professor of Medicine, Professor of Health Policy and Management, and Deputy Director for Medicine of the Berman Institute of Bioethics at the Johns Hopkins University. Dr Sugarman served as Senior Policy and Research Analyst for the White House Advisory Committee on Human Radiation Experiments. Dr Sugarman continues to conduct both theoretical and empirical research in medical ethics, concentrating on informed consent, research ethics, and the ethical issues associated with emerging technologies. Dr Sugarman serves on the Scientific and Research Advisory Board for the Canadian Blood Service and the Maryland Stem Cell Research Commission. He is currently Chair for the Ethics Working Group of the HIV Prevention Trials Network, the Ethics Officer for the Resuscitation Outcomes Consortium, Co-Chair of the Johns Hopkins' Embryonic Stem Cell Oversight Committee, and a member of ISSCR Task Force on Clinical Trials.

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• Published: 07 July 2014

Ethical issues in stem cell research and therapy

• Nancy MP King 1 &
• Jacob Perrin 2  

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Rapid progress in biotechnology has introduced a host of pressing ethical and policy issues pertaining to stem cell research. In this review, we provide an overview of the most significant issues with which the stem cell research community should be familiar. We draw on a sample of the bioethics and scientific literatures to address issues that are specific to stem cell research and therapy, as well as issues that are important for stem cell research and therapy but also for translational research in related fields, and issues that apply to all clinical research and therapy. Although debate about the moral status of the embryo in human embryonic stem cell research continues to have relevance, the discovery of other highly multipotent stem cell types and alternative methods of isolating and creating highly multipotent stem cells has raised new questions and concerns. Induced pluripotent stem cells hold great promise, but care is needed to ensure their safety in translational clinical trials, despite the temptation to move quickly from bench to bedside. A variety of highly multipotent stem cells - such as mesenchymal stem/stromal cells and stem cells derived from amniotic fluid, umbilical cord blood, adipose tissue, or urine - present the opportunity for widespread biobanking and increased access. With these increased opportunities, however, come pressing policy issues of consent, control, and justice. The imperatives to minimize risks of harm, obtain informed consent, reduce the likelihood of the therapeutic misconception, and facilitate sound translation from bench to bedside are not unique to stem cell research; their application to stem cell research and therapy nonetheless merits particular attention. Because stem cell research is both scientifically promising and ethically challenging, both the application of existing ethical frameworks and careful consideration of new ethical implications are necessary as this broad and diverse field moves forward.

Introduction

As every reader of this journal knows, ‘stem cell research’ is a category of enormous breadth and complexity. Current and potential therapeutic applications for stem cells are numerous. Stem cell researchers may be engaged in many different endeavors, including but not limited to seeking new sources of highly multipotent stem cells and methods of perpetuating them; creating induced pluripotent stem cell (iPSC) lines to study genetic disorders or explore pharmacogenomics; conducting animal or early-phase human studies of experimental stem cell interventions; or working with stem cells and biomaterials to develop organoids and other products for use in regenerative medicine, to name only a few possibilities.

In this review of selected major ethical issues in stem cell research and therapy, we briefly describe and discuss the most significant ethical implications of this wide-ranging and fast-moving field. Our discussion addresses research oversight in the historical context of human embryonic stem cell (hESC) research; clinical translation and uncertainty; the profound tension between the desire for clinical progress and the need for scientific caution; and issues of consent, control, commercialization, and justice arising from stem cell banking, disease modeling, and drug discovery. We seek to make stem cell scientists more aware of the need for clarity of discussion and to improve professional and public understanding of the ethical and policy issues affecting this important but early research. A review this brief is necessarily general; our hope is that researchers can use this discussion as a starting point for more in-depth identification and analysis of issues pertinent to specific translational research projects [ 1 – 3 ].

Stem cell research: oversight and clinical translation

The basic system of regulation and review of research involving humans and animals as subjects [ 4 , 5 ] is familiar to investigators. Recently, however, the term ‘translational’ has come to describe a line of research inquiry intended to stretch from bench to bedside and beyond. This has helped to emphasize that thinking about ethical issues should begin at the earliest stages of preclinical research. Ethics in both research and clinical settings is most effective when it is preventive.

In this respect, stem cell research is not unique; stem cell researchers should ask themselves the same questions about the trajectory of their translational research as would any other biomedical researcher [ 6 ]. Oversight of cell-based interventions does, however, include additional features that, while adding complexity to the regulatory process, also make it easier to take a long view, by requiring attention to the use of stem cells at all research stages. Increasing pressures for the rapid clinical translation and commercialization of stem cell products underscore the value of this long view [ 7 – 14 ].

The ethical issues that all researchers face during clinical translation begin with the need to ask a meaningful question, the answer to which has both scientific and social value and can be reached by the study as designed when properly conducted [ 6 , 15 ]. The risks of harm and the potential benefits to society from the development of generalizable knowledge (and, sometimes, potential direct benefit to patient-subjects) must be weighed and balanced at each stage of the research. Sound justification is necessary to support moving from the laboratory into animal studies, and from animals into human subjects, as well as through relevant phases of research with humans [ 15 – 18 ]. Minimizing the risks of harm, selecting and recruiting appropriate patient-subjects, facilitating informed decision making through the consent form and process, and avoiding the ‘therapeutic misconception’, whereby unduly high expectations affect all interested parties to a clinical trial, are all significant research ethics considerations, especially in first-in-human and other early-phase studies [ 19 – 26 ]. To many researchers, these considerations are simply requirements of sound and responsible study design, as exemplified, for example, in US Food and Drug Administration (FDA) guidance documents and investigational new drug requirements [ 27 ]. It should come as no surprise, however, that research design and research ethics are closely intertwined [ 1 , 6 , 15 ].

Stem cell research may give rise to heightened concern in several of these areas. One such concern is clarity of language. The term ‘stem cell’ by itself is broad and non-specific enough to be confusing; it can refer to hESCs, to iPSCs, to other types of multipotent and highly multipotent stem cells (including but not limited to stem cells derived from amniotic fluid, umbilical cord blood, adipose tissue, or urine), or to determined or adult stem cells like hematopoietic stem cells (HSCs), which have long been used in standard therapies. Patients, science reporters, and the public, on hearing the term ‘stem cell’, may thus find it difficult to distinguish between experimental stem cell interventions and proven stem cell therapies of long standing, such as treatments involving autologous or allogeneic HSC transplantation. The commercial availability worldwide of unproven ‘stem cell therapies’ that have not been studied in translational research adds to this confusion [ 12 , 14 , 24 – 26 , 28 , 29 ].

Human embryonic stem cells and embryonic stem cell research oversight committees

Hopes that the ethical controversy surrounding hESCs would become irrelevant when new sources of highly multipotent stem cells became available have proven somewhat premature. hESCs remain scientifically promising and continue to have important uses, even as research with iPSCs and other highly multipotent stem cells gains momentum [ 30 – 32 ]. A brief discussion thus seems warranted.

The first hESC line was derived in 1998, ushering in one of the most public, spirited, and intractable debates in research ethics: the moral status of the embryo from which hESCs are derived. To harvest hESCs, it is first necessary to destroy the 5-day-old preimplantation embryo. Opponents of hESC research argue that because the embryo is capable of developing into a human being, it has significant moral standing; therefore, its destruction is unethical. Some proponents of hESC research deny that the embryo has any moral status; others grant it limited moral status but argue that the value of this limited status is far outweighed by the potential benefits that can result from hESC research [ 24 , 33 ].

The ethical implications of hESC research in the US have been reflected in federal funding policy and in research oversight. In 2003, the National Academy of Sciences (NAS) established a committee to develop guidelines for institutions and investigators conducting hESC research [ 9 ]. The NAS Guidelines for Human Embryonic Stem Cell Research , most recently amended in 2010 [ 34 ], comprehensively address permissible and impermissible categories of hESC research and recommend the establishment of embryonic stem cell research oversight committees (ESCROs) to assist in research review. They also incorporate National Institutes of Health guidelines promulgated after a 2009 federal funding expansion, recommend oversight of research with human pluripotent stem cells, and address questions of consent from all donors of biomaterials, creation and use of embryos for research purposes, and animal-human chimeras.

Many research institutions have created ESCROs or ‘SCROs’ to review hESC and iPSC research; others rely on their institutional review boards or their animal care and use committees or both. As stem cell research diversifies, its ethical oversight also becomes more diverse, and questions have been raised regarding the ongoing need for specialized committees like ESCROs and SCROs [ 9 , 10 ]. The NAS Guidelines are nonetheless likely to continue providing guidance for a variety of oversight bodies reviewing stem cell research [ 9 , 10 , 32 ].

Induced pluripotent stem cells on the translational pathway

Controversy about the derivation and use of hESCs led investigators to seek less ethically fraught but maximally useful types of stem cells [ 31 ]. The history of iPSCs is one of seeking efficient ways to induce pluripotency that minimize the risk of teratoma development [ 35 ]. Although the rapidly developing science has reduced risks of harm and has increased the efficiency of pluripotent cell line creation to some extent, safety and efficacy concerns remain [ 36 ]. Indeed, the most recent advance in inducing pluripotency - stimulus-triggered acquisition of pluripotency, or STAP [ 37 ] - was widely heralded [ 38 ] but has since been called into question [ 39 ]. Obokata and colleagues [ 37 ] presented data suggesting that subjecting somatic cells to various stresses could quickly and safely produce iPSCs, but their results have not proven reproducible.

In research with iPSCs as well as with other types of stem cells, it is essential that preclinical studies in animal models and other media be sufficient to justify the progression to clinical trials. Toxicity and the risk of tumorigenicity must be assessed for all stem cell-based products, especially when genetically modified, in order to minimize the risks of harm as far as feasible before moving to humans [ 11 , 12 , 16 , 17 , 26 , 40 ].

Concern about the research use of animals - especially non-human primates - in preclinical research, including iPSC research, is growing and must be addressed; at the same time, researchers are increasingly aware that good animal models are often unavailable or inadequate to predict effects in humans. Thus, considerable uncertainty continues to surround first-in-human trials and other early-phase studies using stem cells, even as the rapid pace and apparently improving safety of iPSC creation tempt the field to move rapidly into clinical research and even therapeutic applications [ 5 , 25 , 41 ].

Clinical trials: uncertainty and human subjects

Clinical trials of iPSCs and other highly pluripotent stem cell interventions generally enroll patients as subjects at all trial stages, as using healthy volunteers may raise safety concerns or compromise the value of the data. All clinical trials must, of course, be carefully designed, rigorously justified, and properly conducted in order to protect the rights, interests, and welfare of trial subjects and contribute to generalizable knowledge [ 11 , 12 , 15 – 17 , 25 , 26 , 35 , 40 ]. Stem cell researchers can and should benefit from the lessons learned by gene transfer researchers: rapid transition to clinical applications without sufficient understanding of the mechanisms of effect is both inefficient and unwise [ 11 , 12 , 25 , 42 ].

The Geron trial provides just one instructive example. In late January 2009, the FDA approved the first clinical trial of an hESC-based experimental intervention for spinal cord injury. The product, oligodendrocyte progenitor cells (OPCs), is thought to remyelinate spinal cord axons. The trial was to enroll a small number of patient-subjects with recent serious spinal cord lesions. It was placed on hold once by the FDA to ensure the purity and safety of the OPCs and ultimately was halted by the sponsor, Geron Corporation (Menlo Park, CA, USA), for reasons of cost, after only four patient-subjects had received the intervention.

Both the trial’s design and its ultimate discontinuation were controversial. Its design caused controversy because the subjects were enrolled very soon after a serious injury, making understanding and consent challenging in this first-in-human trial and in addition making it potentially difficult to distinguish between spontaneous recovery of function and remyelination attributable to the intervention. Patients with older lesions, though very probably in a better position to make decisions about trial participation, have scar tissue that makes remyelination unlikely or impossible. The sponsor’s premature discontinuation of the trial was problematic because data insufficiency renders worthless not only its own investment but also those made by patient-subjects and investigators. The outcome had the potential to discourage pioneering stem cell research in the future [ 25 , 43 , 44 ]. Nonetheless, identifying the optimal time for post-injury intervention, both to maximize the potential for assessing effects on remyelination and to promote an optimal decision-making process by patient-subjects, is of ongoing concern to spinal cord injury researchers studying cell-based interventions [ 45 ]. More recently, discussions of ethical and design issues in particular stem cell trials (for example, macular degeneration [ 2 ] and cardiovascular disease [ 3 ]) highlight the difficult balance between the imperatives of caution and progress for first-in-human trials in high-profile areas like stem cell intervention research.

Disclosure and discussion of uncertainty with potential subjects in stem cell trials are essential in order to reduce the incidence of therapeutic misconception, whereby research subjects and also investigators and oversight bodies view research as a treatment modality or significantly overestimate the likelihood of direct benefit or both [ 19 – 22 , 41 ]. This information transparency also helps protect the integrity of the research process and the safety of patients in the face of increasing global availability of unapproved and unproven stem cell ‘treatments’ [ 11 , 12 , 16 , 24 – 26 ].

Many types of multipotent and highly multipotent stem cells have been identified as potentially suitable for clinical applications. Some of the most significant challenges faced in clinical application include how quickly to move forward in the face of great promise, great uncertainty, and great clinical need; how to regard research with investigational interventions that are difficult to standardize and impossible to undo; and how to define and describe these uncertainties in the consent process. A growing number of prestigious academics from both science and bioethics are calling attention to these challenges [ 2 , 24 , 26 , 42 ].

One prominent scientist commentator compares the current state of stem cell research with the histories of HSC transplantation and gene transfer research, citing several principles: risks of harm should be commensurate with the severity of the condition under study, preclinical animal models remain critically important, and gaining insight into therapeutic mechanisms is essential to the success of a line of clinical research. He advocates ‘a conservative approach to clinical translation of stem cell therapies’ at present, not because of risks of harm, ‘but rather because our understanding of the mechanisms by which stem cells might prove useful, and in which diseases, remains primitive’ [ 25 ]. Similarly, in an international survey of stem cell scientists and scholars of ethical issues in stem cell research, a prolific bioethics research group has identified increasing concerns arising from pressures for clinical translation, commercialization, and oversight of new stem cell technologies [ 14 ].

Highly multipotent stem cells: biobanking, disease modeling, and drug discovery

Some applications of stem cell research, such as disease modeling, drug discovery and testing, cell line banking, and commercialization of stem cell therapies, also give rise to ethical considerations specific to the field [ 11 , 12 , 14 , 16 , 24 – 26 , 28 , 29 ]. iPSCs and other highly multipotent stem cells have many additional important uses outside the typical clinical research trajectory. The creation and use of disease-specific iPSC lines, both alone and in combination with regenerative medicine products (for example, to produce ex vivo organoids), are essential components of disease modeling and drug discovery. ‘Body-on-a-chip’ types of three-dimensional organoid arrays hold great promise for improving drug development, disease modeling, and pharmacogenomic research, by lowering costs, speeding results, and increasing the safety and potential efficacy signaling of first-in-human trials, and considerable research is under way [ 46 ]. That promise is as yet unrealized, but questions of consent and control arise even at the bench. Because iPSC lines are derived from the somatic cells of identifiable individuals, disclosing to those individuals the planned and envisioned uses of iPSCs derived from the cells they have donated and obtaining consent from them are critical for the creation and sharing of cell line research libraries and the future uses of biomaterials derived from previously donated biospecimens [ 24 , 26 , 47 – 50 ].

As potentially therapeutic applications proliferate for different highly multipotent stem cell types and as technical barriers to the collection and perpetuation of cell lines continue to fall, proposed research and treatment uses abound for both autologous and allogeneic stem cells. In particular, the development of public and other broadly accessible biobanking models for stem cells derived from umbilical cord blood, amniotic fluid and placental tissue, urine, and adipose tissue holds promise for easy collection of good allograft matches for a large percentage of the population but also requires attention to ethical and policy issues [ 26 , 51 ].

Justice in stem cell research and treatment

Justice is a necessary but neglected consideration in all scientific research. Like many novel biotechnologies, gene- and cell-based and regenerative medicine interventions and products can be extraordinarily costly and time- and labor-intensive to develop and use. Justice thus requires attention to the costs of developing stem cell therapies and making them available, with the goal of reducing unfair disparities in access. Cost is a standard distributive justice concern. Less commonly discussed is the effect of research funding decisions on health disparities - both priority-setting within research and priority between research funding and funding for medical care, public health, and other public goods [ 19 – 21 ].

Justice considerations are addressed in stem cell research and therapy in several ways. The first is biobanking policy and practice. The rationale for public stem cell banking is to provide a resource for transplantation of blood-forming HSCs to virtually anyone. Ideally, large-scale banking efforts could store enough different lines of broadly multipotent and pluripotent stem cells, suitable for use in regenerative medicine applications, to provide good matches for nearly the entire population of the US. Comprehensive systems for the collection, storage, and use of stem cells of different types are, however, still in the early stages of technological and policy development. Scientific, practical, and ethical challenges include ensuring broad availability of matches for those in need, determining access for both research and therapy, refining consent forms and processes, and protecting confidentiality in labeling and information linkage [ 11 , 12 , 16 , 26 , 51 , 52 ]. Thus, large-scale biobanking of stem cell lines holds the potential to greatly increase access to stem cell therapies and reduce costs, but because available allogeneic matches may not be perfect, balancing the harms and benefits of biobanking remains critical.

The second justice-promoting feature of stem cell research and therapy has some similarities. Attempts to standardize and streamline production are more prevalent in stem cell-related research than elsewhere - especially in development of cell-based products and in regenerative medicine. In other new technologies like gene transfer, standardization, the development of platform technologies, and attempts at large-scale, cost-reducing production are in their infancy. This production perspective is an important step in reducing time, labor, and costs and thus increasing access, but it could also have interesting ethical implications. Autologous or individually ‘compounded’ cell-based interventions will certainly be more costly and less readily available - and will take more time to produce - than allogeneic and other ‘mass-produced’ cell-based interventions, which may provide a less-than-perfect match or fit for a given patient. Such differences could have efficacy implications that must be monitored and balanced against cost savings and access gains [ 51 ].

A final justice consideration that is heightened in the stem cell context is the simple reality that important work dedicated to improving the health of the public takes place in a market system with its attendant pressures of competition and commercialization. The attempt to ensure that hope does not become hype and that hype does not become fraud is a matter of justice. Thus, sound practice in clinical translation, careful discussion in the media, and even seeking balance between scientific transparency and data-sharing and the intellectual property interests of industry all have important justice implications [ 13 , 16 , 24 – 29 , 42 , 53 ]. As research funding shrinks and competitive pressures grow, it may become increasingly difficult to move deliberately toward clinical translation and to allocate research resources wisely. This is especially likely as more is learned about how to reduce the risks of harm from the creation and use of iPSCs and as the costs of careful progress continue to increase. The fewer resources we have, the more important it is to allocate funds to maximize the likelihood of knowledge development in areas of greatest promise and clinical need [ 14 , 21 ].

Individual researchers may at first regard justice considerations as somewhat removed from their daily work at bench or bedside. The goals of advancing knowledge and, ultimately, improving human health are nonetheless social goals, not merely scientific goals. Researchers make vital contributions to societal views about the value of - and best directions for - scientific progress. For this reason alone, it is worthwhile for researchers to keep in mind the population-level applications of stem cell research as well as the effects of stem cell therapy on individual health.

Summary and conclusions

As our discussion has shown, many of the ethical and policy issues that are most significant for stem cell research and therapy are similar to those arising in other novel biotechnologies. Consideration of these issues in both scientific and bioethics literatures addresses many common themes: the minimization of risks of harm; the importance of information disclosure and informed consent; the potential for overpromising, overexpectations, and the therapeutic misconception; and the pressure from disease constituencies and commercial entities to move quickly into the clinic, too often at the expense of understanding basic mechanisms. In the realm of clinical translation, trial-specific examinations of ethical issues continue to provide important guidance, not only with regard to the trials specifically considered but also as models for investigators starting down new translational pathways.

Although the creation and use of hESCs have long been the unique focus of stem cell ethics, more current controversies include the creation, for research use, of human embryos, human-animal chimeras, and gametes. Yet these marquee controversies are, in the long run, less important for the field as a whole than are more mundane, justice-oriented concerns like the creation and use of stem cell banks for research and therapy, facilitation of ‘off-the-shelf’ stem cell applications that could be less costly though perhaps less than perfect, and questions of consent, provenance, and policy. Finally, moving forward with the right blend of creativity and caution is essential, in the interest of both science and patients. In all areas of stem cell research and therapy, nuanced consideration and discussion of the best translational pathways, as viewed by ethics as well as science, will play a vital role in balancing hope and hype now and in the future, as the field continues its rapid progress.

Abbreviations

embryonic stem cell research oversight (committee)

US Food and Drug Administration

human embryonic stem cell

hematopoietic stem cell

induced pluripotent stem cell

National Academy of Sciences

oligodendrocyte progenitor cell

stem cell research oversight (committee).

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King, N.M., Perrin, J. Ethical issues in stem cell research and therapy. Stem Cell Res Ther 5 , 85 (2014). https://doi.org/10.1186/scrt474

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The Ethics of Human Cloning and Stem Cell Research

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Report from a conference on state regulation of cloning and stem cell research.

"California Cloning: A Dialogue on State Regulation" was convened October 12, 2001, by the Markkula Center for Applied Ethics at Santa Clara University. Its purpose was to bring together experts from the fields of science, religion, ethics, and law to discuss how the state of California should proceed in regulating human cloning and stem cell research.

A framework for discussing the issue was provided by Center Director of Biotechnology and Health Care Ethics Margaret McLean, who also serves on the California State Advisory Committee on Human Cloning. In 1997, the California legislature declared a "five year moratorium on cloning of an entire human being" and requested that "a panel of representatives from the fields of medicine, religion, biotechnology, genetics, law, bioethics and the general public" be established to evaluate the "medical, ethical and social implications" of human cloning (SB 1344). This 12-member Advisory Committee on Human Cloning convened five public meetings, each focusing on a particular aspect of human cloning: e.g., reproductive cloning, and cloning technology and stem cells. The committee is drafting a report to the legislature that is due on December 31, 2001. The report will discuss the science of cloning, and the ethical and legal considerations of applications of cloning technology. It will also set out recommendations to the legislature regarding regulation of human cloning. The legislature plans to take up this discussion after January. The moratorium expires the end of 2002.

What should the state do at that point? More than 80 invited guests came to SCU for "California Cloning" to engage in a dialogue on that question. These included scientists, theologians, businesspeople from the biotechnology industry, bioethicists, legal scholars, representatives of non-profits, and SCU faculty. Keynote Speaker Ursula Goodenough, professor of biology at Washington University and author of Genetics , set the issues in context with her talk, "A Religious Naturalist Thinks About Bioethics." Four panels addressed the specific scientific, religious, ethical, and legal implications of human reproductive cloning and stem cell research. This document gives a brief summary of the issues as they were raised by the four panels.

Science and Biotechnology Perspectives

Thomas Okarma, CEO of Geron Corp., launched this panel with an overview of regenerative medicine and distinguished between reproductive cloning and human embryonic stem cell research. He helped the audience understand the science behind the medical potential of embryonic stem cell research, with an explanation of the procedures for creating stem cell lines and the relationship of this field to telomere biology and genetics. No brief summary could do justice to the science. The reader is referred to the report of the National Bioethics Advisory Committee (http://bioethics.georgetown.edu/nbac/stemcell.pdf) for a good introduction.

Responding to Okarma, were J. William Langston, president of the Parkinson’s Institute, and Phyllis Gardner, associate professor of medicine and former dean for medical education at Stanford University. Both discussed the implications of the president’s recent restrictions on stem cell research for the non-profit sector. Langston compared the current regulatory environment to the Reagan era ban on fetal cell research, which he believed was a serious setback for Parkinson’s research. He also pointed out that stem cell research was only being proposed using the thousands of embryos that were already being created in the process of fertility treatments. These would ultimately be disposed of in any event, he said, arguing that it would be better to allow them to serve some function rather than be destroyed. President Bush has confined federally-funded research to the 64 existing stem cell lines, far too few in Langston’s view. In addition, Langston opposed bans on government funding for stem cell research because of the opportunities for public review afforded by the process of securing government grants.

Gardner talked about the differences between academic and commercial research, suggesting that both were important for the advancement of science and its application. Since most of the current stem cell lines are in the commercial sector and the president has banned the creation of new lines, she worried that universities would not continue to be centers of research in this important area. That, she argued, would cut out the more serendipitous and sometimes more altruistic approaches of academic research. Also, it might lead to more of the brain drain represented by the recent move of prominent UCSF stem cell researcher Roger Pedersen to Britain. Gardner expressed a hope that the United States would continue to be the "flagship" in stem cell research. Her concerns were echoed later by moderator Allen Hammond, SCU law professor, who urged the state, which has been at the forefront of stem cell research to consider the economic impact of banning such activity. All three panelists commended the decision of the state advisory committee to deal separately with the issues of human cloning and stem cell research.

Religious Perspectives

Two religion panelists, Suzanne Holland and Laurie Zoloth, are co editors of The Human Embryonic Stem Cell Debate: Science, Ethics and Public Policy (MIT Press, 2001). Holland, assistant professor of Religious and Social Ethics at the University of Puget Sound, began the panel with a discussion of Protestant ideas about the sin of pride and respect for persons and how these apply to human reproductive cloning. Given current safety concerns about cloning, she was in favor of a continuing ban. But ultimately, she argued, cloning should be regulated rather than banned outright. In fact, she suggested, the entire fertility industry requires more regulation. As a basis for such regulation, she proposed assessing the motivation of those who want to use the technology. Those whose motives arise from benevolence--for example, those who want to raise a child but have no other means of bearing a genetically related baby--should be allowed to undergo a cloning procedure. Those whose motives arise more from narcissistic considerations -- people who want immortality or novelty -- should be prohibited from using the technology. She proposed mandatory counseling and a waiting period as a means of assessing motivation.

Zoloth reached a different conclusion about reproductive cloning based on her reading of Jewish sources. She argued that the availability of such technology would make human life too easily commodified, putting the emphasis more on achieving a copy of the self than on the crucial parental act of creating "a stranger to whom you would give your life." She put the cloning issue in the context of a system where foster children cannot find homes and where universal health care is not available for babies who have already been born. While Zoloth reported that Jewish ethicists vary considerably in their views about reproductive cloning, there is fairly broad agreement that stem cell research is justified. Among the Jewish traditions she cited were:

The embryo does not have the status of a human person.

There is a commandment to heal.

Great latitude is permitted for learning.

The world is uncompleted and requires human participation to become whole.

Catholic bioethicist Albert Jonsen, one of the deans of the field, gave a historical perspective on the cloning debate, citing a paper by Joshua Lederburg in the 1960s, which challenged his colleagues to look at the implications of the then-remote possibility. He also traced the development of Catholic views on other new medical technologies. When organ transplantation was first introduced, it was opposed as a violation of the principal, "First, do no harm" and as a mutilation of the human body. Later, the issue was reconceived in terms of charity and concern for others. One of the key questions, Jonsen suggested, is What can we, as a society that promotes religious pluralism, do when we must make public policy on issues where religious traditions may disagree. He argued that beneath the particular teachings of each religion are certain broad themes they share, which might provide a framework for the debate. These include human finitude, human fallibility, human dignity, and compassion.

Ethics Perspectives

Lawrence Nelson, adjunct associate professor of philosophy at SCU, opened the ethics panel with a discussion of the moral status of the human embryo. Confining his remarks to viable, extracorporeal embryos (embryos created for fertility treatments that were never implanted), Nelson argued that these beings do have some moral status--albeit it weak--because they are alive and because they are valued to varying degrees by other moral agents. This status does entitle the embryo to some protection. In Nelson’s view, the gamete sources whose egg and sperm created these embryos have a unique connection to them and should have exclusive control over their disposition. If the gamete sources agree, Nelson believes the embryos can be used for research if they are treated respectfully. Some manifestations of respect might be:

They are used only if the goal of the research cannot be obtained by other methods.

The embryos have not reached gastrulation (prior to 14 to 18 days of development).

Those who use them avoid considering or treating them as property.

Their destruction is accompanied by some sense of loss or sorrow.

Philosophy Professor Barbara MacKinnon (University of San Francisco), editor of Human Cloning: Science, Ethics, and Public Policy , began by discussing the distinction between reproductive and therapeutic cloning and the slippery slope argument. She distinguished three different forms of this argument and showed that for each, pursuing stem cell research will not inevitably lead to human reproductive cloning. MacKinnon favored a continuing ban on the latter, citing safety concerns. Regarding therapeutic cloning and stem cell research, she criticized consequentialist views such as that anything can be done to reduce human suffering and that certain embryos would perish anyway. However, she noted that non-consequentialist concerns must also be addressed for therapeutic cloning, among them the question of the moral status of the early embryo. She also made a distinction between morality and the law, arguing that not everything that is immoral ought to be prohibited by law, and showed how this position relates to human cloning.

Paul Billings, co-founder of GeneSage, has been involved in crafting an international treaty to ban human reproductive cloning and germ-line genetic engineering. As arguments against human cloning he cited:

There is no right to have a genetically related child.

Cloning is not safe.

Cloning is not medically necessary.

Cloning could not be delivered in an equitable manner.

Billings also believes that the benefits of stem cell therapies have been "wildly oversold." Currently, he argues, there are no effective treatments coming from this research. He is also concerned about how developing abilities in nuclear transfer technology may have applications in germ-line genetic engineering that we do not want to encourage. As a result, he favors the current go-slow approach of banning the creation of new cell lines until some therapies have been proven effective. At the same time, he believes we must work to better the situation of the poor and marginalized so their access to all therapies is improved.

Legal Perspectives

Member of the State Advisory Committee on Human Cloning Henry "Hank" Greely addressed some of the difficulties in creating a workable regulatory system for human reproductive cloning. First he addressed safety, which, considering the 5 to 10 times greater likelihood of spontaneous abortion in cloned sheep, he argued clearly justifies regulation. The FDA has currently claimed jurisdiction over this technology, but Greely doubted whether the courts would uphold this claim. Given these facts, Greely saw three alternatives for the state of California:

Do nothing; let the federal government take care of it.

Create an FDA equivalent to regulate the safety of the process, an alternative he pointed out for which the state has no experience.

Continue the current ban on the grounds of safety until such time as the procedure is adjudged safe. Next Greely responded to suggestions that the state might regulate by distinguishing between prospective cloners on the basis of their motivation, for example, denying a request to clone a person to provide heart tissue for another person but okaying a request if cloning were the only opportunity a couple might have to conceive a child. Greely found the idea of the state deciding on such basis deeply troubling because it would necessitate "peering into someone’s soul" in a manner that government is not adept at doing.

The impact of regulation on universities was the focus of Debra Zumwalt’s presentation. As Stanford University general counsel, Zumwalt talked about the necessity of creating regulations that are clear and simple. Currently, federal regulations on stem cells are unclear, she argued, making it difficult for universities and other institutions to tell if they are in compliance. She believes that regulations should be based on science and good public policy rather than on politics. As a result, she favored overall policy being set by the legislature but details being worked out at the administrative level by regulatory agencies with expertise. Whatever regulations California develops should not be more restrictive than the federal regulations, she warned, or research would be driven out of the state. Like several other speakers, Zumwalt was concerned about federal regulations restricting stem cell research to existing cell lines. That, she feared, would drive all research into private hands. "We must continue to have a public knowledge base," she said. Also, she praised the inherent safeguards in academic research including peer review, ethics panels, and institutional review boards.

SCU Presidential Professor of Ethics and the Common Good June Carbone looked at the role of California cloning decisions in contributing to the governance of biotechnology. California, she suggested, cannot address these issues alone, and thus might make the most useful contribution by helping to forge a new international moral consensus through public debate. Taking a lesson from U.S. response to recent terrorist attacks, she argued for international consensus based on the alliance of principle and self-interest. Such consensus would need to be enforced both by carrot and stick and should, she said, include a public-private partnership to deal with ethical issues. Applying these ideas to reproductive cloning, she suggested that we think about which alliances would be necessary to prevent or limit the practice. Preventing routine use might be accomplished by establishing a clear ethical and professional line prohibiting reproductive cloning. Preventing exceptional use (a determined person with sufficient money to find a willing doctor) might not be possible. As far as stem cell research is concerned, Carbone argued that the larger the investment in such research, the bigger the carrot--the more the funder would be able to regulate the process. That, she suggested, argues for a government role in the funding. If the professional community does not respect the ethical line drawn by politicians, and alternative funding is available from either public sources abroad or private sources at home, the U.S. political debate runs the risk of becoming irrelevant.

"California Cloning" was organized by the Markkula Center for Applied Ethics and co-sponsored by the Bannan Center for Jesuit Education and Christian Values; the Center for Science, Technology, and Society; the SCU School of Law; the High Tech Law Institute; the Howard Hughes Medical Institute Community of Science Scholars Initiative; and the law firm of Latham & Watkins.

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Article Contents

Introduction, what are (embryonic) stem cells, potential applications of hes cells and state‐of‐the‐art, ethical exploration, the status of hes cells, instrumental use of embryos, ethics of using surplus ivf embryos as a source of hes cells, therapeutic cloning, conclusions and recommendations, acknowledgements.

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Human embryonic stem cells: research, ethics and policy

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Guido de Wert, Christine Mummery, Human embryonic stem cells: research, ethics and policy, Human Reproduction , Volume 18, Issue 4, April 2003, Pages 672–682, https://doi.org/10.1093/humrep/deg143

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The use of human embryos for research on embryonic stem (ES) cells is currently high on the ethical and political agenda in many countries. Despite the potential benefit of using human ES cells in the treatment of disease, their use remains controversial because of their derivation from early embryos. Here, we address some of the ethical issues surrounding the use of human embryos and human ES cells in the context of state‐of‐the‐art research on the development of stem cell based transplantation therapy.

Human embryonic stem cells (hES cells) are currently discussed not only by the biologists by whom they were discovered but also by the medical profession, media, ethicists, governments and politicians. There are several reasons for this. On the one hand, these ‘super cells’ have a major clinical potential in tissue repair, with their proponents believing that they represent the future relief or cure of a wide range of common disabilities; replacement of defective cells in a patient by transplantation of hES cell‐derived equivalents would restore normal function. On the other hand, the use of hES cells is highly controversial because they are derived from human pre‐implantation embryos. To date, most embryos used for the establishment of hES cell lines have been spare embryos from IVF, but the creation of embryos specifically for deriving hES cells is also under discussion. The most controversial variant of this is the transfer of a somatic cell‐nucleus from a patient to an enucleated oocyte (unfertilized egg) in order to produce hES cells genetically identical to that patient for ‘autologous’ transplantation (so‐called ‘therapeutic’ cloning); this may prevent tissue rejection.

The question ‘Can these cells be isolated and used and, if so, under what conditions and restrictions’ is presently high on the political and ethical agenda, with policies and legislation being formulated in many countries to regulate their derivation. The UK has been the first to pass a law governing the use of human embryos for stem cell research. The European Science Foundation has established a committee to make an inventory of the positions taken by governments of countries within Europe on this issue ( European Science Foundation, 2001 ).

In order to discuss the moral aspects of the isolation and use of hES cells, which is the aim of the present article, it is first essential to understand exactly what these cells are, where they come from, their intended applications and to define the ethical questions to be addressed.

‘Stem cells’ are primitive cells with the capacity to divide and give rise to more identical stem cells or to specialize and form specific cells of somatic tissues. Broadly speaking, two types of stem cell can be distinguished: embryonic stem (ES) cells which can only be derived from pre‐implantation embryos and have a proven ability to form cells of all tissues of the adult organism (termed ‘pluripotent’), and ‘adult’ stem cells, which are found in a variety of tissues in the fetus and after birth and are, under normal conditions, more specialized (‘multipotent’) with an important function in tissue replacement and repair.

hES cells are derived from the so‐called ‘inner cell mass’ of blastocyst stage embryos that develop in culture within 5 days of fertilization of the oocyte ( Thomson et al ., 1998 ; Reubinoff et al ., 2000 ). Although hES cells can form all somatic tissues, they cannot form all of the other ‘extraembryonic’ tissues necessary for complete development, such as the placenta and membranes, so that they cannot give rise to a complete new individual. They are therefore distinct from the ‘totipotent’ fertilized oocyte and blastomere cells deriving from the first cleavage divisions. hES cells are also immortal, expressing high levels of a gene called telomerase, the protein product of which ensures that the telomere ends of the chromosomes are retained at each cell division and the cells do not undergo senescence. The only other cells with proven pluripotency similar to that of ES cells are embryonic germ (EG) cells, which as their name implies, have been derived from ‘primordial germ cells’ that would ultimately form the gametes if the fetus had not been aborted. In humans, hEG cells were first established in culture in 1998, shortly after the first hES cells, from tissue derived from an aborted fetus ( Shamblott et al ., 1998 ). Biologically, hEG cells have many properties in common with hES cells ( Shamblott et al ., 2001 ).

In the adult individual, a variety of tissues have also been found to harbour stem cell populations. Examples include the brain, skeletal muscle, bone marrow and umbilical cord blood, although the heart, by contrast, contains no stem cells after birth (reviewed in McKay 1997 ; Fuchs and Segre, 2000 ; Watt and Hogan, 2000 ; Weissman et al ., 2000 ; Blau et al ., 2001 ; Spradling et al ., 2001 ). These adult stem cells have generally been regarded as having the capacity to form only the cell types of the organ in which they are found, but recently they have been shown to exhibit an unexpected versatility ( Ferrari et al ., 1998 ; Bjornson et al ., 1999 ; Petersen et al ., 1999 ; Pittenger et al ., 1999 ; Brazelton et al ., 2000 ; Clarke et al ., 2000 ; Galli et al ., 2000 ; Lagasse et al ., 2000 ; Mezey et al ., 2000 ; Sanchez‐Ramos et al ., 2000 ; Anderson et al ., 2001 ; Jackson et al ., 2001 ; Orlic et al ., 2001 ). Evidence is strongest in animal experiments, but is increasing in humans, that adult stem cells originating in one germ layer can form a variety of other derivatives of the same germ layer (e.g. bone marrow‐to‐muscle within the mesodermal lineage), as well as transdifferentiate to derivatives of other germ layers (e.g. bone marrow‐to‐brain between the mesodermal and ectodermal lineages). To what extent transdifferentiated cells are immortal or acquire appropriate function in host tissue remains largely to be established but advances in this area are rapid, particularly for multipotent adult progenitor cells (MAPCs) of bone marrow ( Reyes and Verfaillie, 2001 ). Answers to these questions with respect to MAPCs, in particular whether they represent biological equivalents to hES and can likewise be expanded indefinitely whilst retaining their differentiation potential, are currently being addressed ( Jiang et al . 2002 ; Schwartz et al ., 2002 ; Verfaillie, 2002 ; Zhao et al ., 2002 ). For other adult stem cell types, such as those from brain, skin or intestine ( Fuchs and Segre, 2000 ), this may remain unclear for the immediate future. Although the discussion here concerns hES cells and the use of embryos, the scientific state‐of‐the‐art on other types of stem cell is important in the context of the ‘subsidiarity principle’ (see below).

In theory, hES cells could be used for many different purposes ( Keller and Snodgrass, 1999 ). Examples in fundamental research on early human development are the causes of early pregnancy loss, aspects of embryonic ageing and the failure of pregnancy in older women (where genetic defects in the oocyte appear to be important). A second category might be toxicology, more specifically research on possible toxic effects of new drugs on early embryonic cells which are often more sensitive than adult cells (drug screening). The most important potential use of hES cells is, however, clinically in transplantation medicine, where they could be used to develop cell replacement therapies. This, according to most researchers in the field represents the real ‘home run’ and it is the ethics of using embryos in this aspect of medicine that will be discussed here. Examples of diseases caused by the loss, or loss of function, of only one or a limited number of cell types and which could benefit from hES cell‐based therapies include diabetes, Parkinson’s disease, stroke, arthritis, multiple sclerosis, heart failure and spinal cord lesions. Although it is known that hES cells are capable of generating neural, cardiac, skeletal muscle, pancreas and liver cells in teratocarcinomas in vivo in immunodeficient mice as well as in tissue culture, it would be an illusion to consider that cell‐therapies will have widespread application in the short term (i.e. within a couple of years). It is unfortunate that sensational treatment in the media, which implied the generation of whole organs from hES cells, initially left this impression so that the more realistic view emerging is already a disappointment to some patient groups. Nonetheless, a proper scientific evaluation of the therapeutic potential is being carried out in countries that allow the isolation and/or use of existing hES cells. The ethical questions here then also include whether the establishment of new hES cell lines can be justified, in the realisation that eventual therapies, based on either hES or adult stem cells are long‐term perspectives.

There are, at least in theory, various sources of hES cells. In most cases to date, these have been spare IVF embryos, although IVF embryos have been specifically created for the purpose of stem cell isolation ( Lanzendorf et al ., 2001 ). In one variant of ‘embryo creation’, it has even been reported that normally organized blastocysts develop from chimeras of two morphologically non‐viable embryos ( Alikani and Willadsen, 2002 ). The most revolutionary option would be the creation of embryos specifically for the purpose of isolating stem cells via ‘nuclear transfer’ (‘therapeutic cloning’). This option is purported to be the optimal medical use of hES technology since the nuclear DNA of the cells is derived from a somatic cell of a patient to receive the transplant, reducing the chances of tissue rejection (see Barrientos et al ., 1998 ; 2000). It is of note that the oocyte in this case is not fertilized, but receives maternal and paternal genomes from the donor cell nucleus. Since by some definitions an embryo is the result of fertilization of an oocyte by sperm, there is no absolute consensus that nuclear transfer gives rise to an embryo (see below).

The establishment of embryonic cell lines is becoming increasingly efficient, with up to 50% of spare IVF embryos that develop into blastocysts after thawing at the 8‐cell stage reported to yield cell lines. There are reports of efficiencies much lower than 50%, however, the quality of the donated embryos being an important determinant of success. Growth of the cell lines over extended periods and in some cases under defined conditions ( Xu et al ., 2001 ) has also been reported, but the controlled expansion and differentiation to specific cell types is an area where considerable research will be required before cell transplantation becomes clinical practice (for review, see Passier and Mummery, 2003 ). In addition, research will be required on how to deliver cells to the appropriate site in the patient to ensure that they survive, integrate in the host tissue and adopt appropriate function. These are the current scientific challenges that will have to be overcome before cell therapy becomes clinical practice; the problems are common to both hES and adult stem cells. The efficiency of establishing embryonic stem cell lines from nuclear transfer embryos is currently unknown, but expected to be lower than from IVF embryos.

In the following section, the status of hES cells is first considered. The questions of whether it is acceptable to use pre‐implantation embryos as a source of ES cells for research on cell transplantation therapy and if so, whether embryo use should be limited to spare embryos or may also include the creation of embryos via nuclear transfer (‘therapeutic cloning’), are then addressed.

What is the ontological status of hES cells? Should they be considered equivalent to embryos or not? Let us first consider the status of the ‘naked’, isolated inner cell mass (ICM; the source for deriving hES cell lines). The ICM is as it were the ‘essence’ of the pre‐implantation embryo, the precursor of the ‘embryo proper’. The isolated ICM, however, no longer has the potential to develop into a fetus and child, as trophoblast cells, necessary for implantation and nourishment of the embryo, and extra‐embryonic endoderm, are absent. It does not necessarily follow, though, that the isolated ICM is no longer an embryo—we suggest that the whole, isolated ICM could best be qualified as a disabled, ‘non‐viable’ embryo (even though it might, at least in theory, be ‘rescued’ by enveloping the ICM with sufficient trophoblast cells).

What, then, is the status of the individual cells from the ICM once isolated, and the embryonic stem cell lines derived from them? Should we consider these cells/cell lines to be non‐viable embryos too? We would argue that when the cells of the ICM begin to spread and grow in culture, the ICM disintegrates and the non‐viable embryo perishes. Some might argue that hES cells are embryos, because, although hES cells in themselves cannot develop into a human being, they might if they were ‘built into’ a cellular background able to make extra‐embryonic tissues necessary for implantation and nutrition of the embryo. At present this is only possible by ‘embryo reconstruction’ in which the ICM of an existing embryo is replaced by ES cells ( Nagy et al ., 1993 ). Commentators who, against this background, regard hES cells as equivalent to embryos, apparently take recourse to the opinion that any cell from which a human being could in principle be created, even when high technology (micromanipulation) would be required to achieve this, should be regarded as an embryo. An absurd implication of this ‘inclusive’ definition of an embryo is that one should then also regard all somatic cells as equivalent to embryos—after all, a somatic nucleus may become an embryo after nuclear transplantation in an enucleated oocyte. It is therefore unreasonable to regard hES cells as equivalent to embryos.

Research into the development of cell‐replacement therapy requires the instrumental use of pre‐implantation embryos from which hES cells are derived since current technology requires lysis of the trophectoderm and culture of the ICM; the embryo disintegrates and is thus destroyed. As has already been discussed extensively in the embryo‐research debate, considerable differences of opinion exist with regard to the ontological and moral status of the pre‐implantation embryo ( Hursthouse, 1987 ). On one side of the spectrum are the ‘conceptionalist’ view (‘the embryo is a person’) and the ‘strong’ version of the potentiality‐argument (‘because of the potential of the embryo to develop into a person, it ought to be considered as a person’). On the other side of the spectrum we find the view that the embryo (and even the fetus) as a ‘non‐person’ ought not to be attributed any moral status at all. Between these extremes are various intermediates. Here, there is a kind of ‘overlapping consensus’: the embryo has a real, but relatively low moral value. The most important arguments are the moderate version of the potentiality argument (‘the embryo deserves some protection because of its potential to become a person’) and the argument concerning the symbolic value of the embryo (the embryo deserves to be treated with respect because it represents the beginning of human life). Differences of opinion exist on the weight of these arguments (how much protection does the embryo deserve?) and their extent (do they apply to pre‐implantation embryos?). In view of the fact that up to 14 days of development, before the primitive streak develops and three germ layers appear, embryos can split and give rise to twins or two embryos may fuse into one, it may reasonably be argued that at these early stages there is in principle no ontological individuality; this limits the moral value of an embryo.

Pre‐implantation embryos are generally regarded from the ethical point of view as representing a single class, whereas in fact ∼50–60% of these embryos are aneuploid and mostly non‐viable. For non‐viable embryos, the argument of potentiality does not of course apply. Their moral status is thus only based on their symbolic value, which is already low in ‘pre‐individualized’ pre‐implantation embryos. The precise implications of this moral difference for the regulation of the instrumental use of embryos is, however, beyond the scope of the present article.

The view that research with pre‐implantation embryos should be categorically forbidden is based on shaky premises and would be difficult to reconcile with the wide social acceptance of contraceptive intrauterine devices. The dominant view in ethics is that the instrumental use of pre‐implantation embryos, in the light of their relative moral value, can be justified under certain conditions. The international debate focuses on defining these conditions.

Possible objections are connected to the principle of proportionality, the slippery slope argument, and the principle of subsidiarity.

Proportionality

It is generally agreed that research involving embryos should be related to an important goal, sometimes formulated as ‘an important health interest’ (the principle of proportionality). Opinions differ on how this should be interpreted and made operational. In a number of countries, research on pre‐implantation embryos is permitted provided it is related to human reproduction. Internationally, however, such a limitation is being increasingly regarded as too restrictive ( De Wert et al ., 2002 ). The isolation of hES cells for research into cell‐replacement therapies operates as a catalyst for this discussion. It is difficult to argue that research into hES cells is disproportional. If embryos may be used for research into the causes or treatment of infertility, then it is inconsistent to reject research into the possible treatment of serious invalidating diseases as being not sufficiently important. The British Nuffield Council on Bioethics ( Nuffield Council on Bioethics, 2000 ) also saw no reason for making a moral distinction between research into diagnostic methods or reproduction and research into potential cell therapies.

Even if one argued that there is a difference between the two types of research, research on cell therapy would, if anything, be more defensible than research on reproduction. One (in our opinion somewhat dubious) argument is to be found in McGee and Caplan (1999 ); here the suggestion is made that in using embryos for cell therapy, no embryos are actually sacrificed: ‘In the case of embryos already slated to be discarded after IVF, the use of stem cells may actually lend permanence to the embryo. Our point here is that the sacrifice of an early human embryo, whether it involves a human person or not, is not the same as the sacrifice of an adult because life of a 100‐cell embryo is contained in its cells nuclear DNA.’ In other words, the unique characteristic of an embryo is its DNA; by transplanting cells containing this DNA to a new individual, the DNA is preserved and the embryo therefore not sacrificed—a ‘win–win’ situation for both the embryo and cell transplant recipient. The implication is thus that the use of embryos for cell transplantation purposes is ethically preferable to disposing of them or using them in other (‘truly destructive’) types of research. This extreme genetic ‘reductionism’ is highly disputable and not convincing: the fact that embryos are actually sacrificed in research into cell therapy is masked. A second, more convincing, argument, that the instrumental use of embryos is in principle easier to justify for isolation of hES cells than, for example, research directed towards improving IVF, is that it has potentially far wider clinical implications. It therefore, unquestionably meets the proportionality requirement.

Slippery slope

The slippery slope argument can be considered as having two variants, one empirical and the other logical. The empirical version involves a prediction of the future: ‘Acceptance of practice X will inevitably lead to acceptance of (undesirable) practice Y. To prevent Y, X must be banned’. The logical version concerns the presumed logical implications resulting from the moral justification of X: ‘Justification of X automatically implies acceptance of (undesirable) practice Y’. In this context the problem often lies in the lack of precise definition of X: ‘The difficulty in making a conceptual distinction between X and Y that is sharp enough to justify X without at the same time justifying Y, is a reason to disallow X.’ Both versions of the argument play a role in the debate about the isolation of hES cells for research into cell replacement therapy. An example of the logical version is that acceptance of hES cells for the development of stem cell therapy for the treatment of serious disease automatically means there is no argument against acceptance of use, for example, for cosmetic rejuvenation (Nuffield Council on Bioethics, 2000). The main difficulty is, according to these critics, the ‘grey area’ between these two extremes. One answer to this objection is to consider each case individually rather than reject all cases out of hand. One could use the same objection for example against surgery, which can equally be used for serious as well as trivial treatments.

An example of the empirical version of the slippery slope argument is that the use of hES cells for the development of cell therapy would inevitably lead to applications in germ‐line gene therapy and in therapeutic cloning, then ultimately reproductive cloning. This version of the argument is unconvincing too; even if germ line gene therapy and therapeutic cloning would be categorically unacceptable, which is not self‐evident, it does not necessarily follow from this that the use of hES cells for cell‐therapy is unacceptable. The presumed automatism in the empirical version of the slippery slope argument is disputable.

Subsidiarity

A further condition for the instrumental use of embryos is that no suitable alternatives exist that may serve the same goals of the research. This is termed ‘the principle of subsidiarity’. Critics of the use of hES cells claim that at least three such alternatives exist, which have in common that they do not require the instrumental use of embryos: (i) xenotransplantation; (ii) human embryonic germ cells (hEG cells), and (iii) adult stem cells.

The question is not whether these possible alternatives require further research (this is, at least for the latter two, largely undisputed), but whether only these alternatives should be the subject of research. Is a moratorium for isolating hES cells required, or is it preferable to carry out research on the different options, including the use of hES cells, in parallel?

The answer to this question depends on how the principle of subsidiarity ought to be applied. Although the principle of subsidiarity is meant to express concern for the (albeit limited) moral value of the embryo, it is a sign of ethical one‐dimensionality to present every alternative, which does not use embryos, as a priori superior. For the comparative ethical analysis of hES cells from pre‐implantation embryos on the one hand, and the possible alternatives mentioned on the other, a number of relevant aspects should be taken into account. These include: the burdens and/or risks of the different options for the patient and his or her environment; the chance that the alternative options have the same (probably broad) applicability as hES cells from pre‐implantation embryos; and the time‐scale in which clinically useful applications are to be expected.

A basis for initiating a comparative ethical analysis is set out below:

(i) Xenotransplantation is viewed at present as carrying a risk, albeit limited, of cross‐species infections and an accompanying threat to public health. This risk is, at least for the time being, an ethical and safety threshold for clinical trials. Apart from that, the question may be raised from a perspective of animal ethics whether it is reasonable to breed and kill animals in order to produce transplants, when at the same time spare human embryos are available which would otherwise be discarded;

(ii) In principle, the use of hEG cells from primordial germ cells of dead fetuses seems from a moral perspective to be more acceptable than the instrumental use of living pre‐implantation embryos, provided that the decision to abort was not motivated by the use of fetal material for transplantation purposes. To date, however, hEG cells have been difficult to isolate and culture, with only one research group reporting success ( Shamblott et al ., 1998 ; 2001). In addition, research in mice suggests abnormal reprogramming of these cells in culture: chimeric mice generated between mouse (m)EG cells and pre‐implantation embryos develop abnormally while chimeras using mouse (m)ES cells develop as normally as non‐chimeric mice ( Steghaus‐Kovac, 1999 ; Surani, 2001 ). This makes the outcome of eventual clinical application of these cells difficult to predict in terms of health risks for the recipient.

(iii) Analysis of the developmental potential of adult stem cells is a rapidly evolving field of research, particularly in animal model systems. Experiments carried out within the last two years have demonstrated, for example, that bone marrow cells can give rise to nerve cells in mouse brain ( Mezey et al ., 2000 ), neural cells from mouse brain can turn into blood and muscle ( Bjornson et al ., 1999 ; Galli et al ., 2000 ), and even participate in the development of chimeric mouse embryos up to mid‐gestation ( Clarke et al ., 2000 ). Although apparently spectacular in demonstrating that neural stem cells from mice can form most cell types under the appropriate conditions, it is still unclear whether true plasticity in terms of function has been demonstrated or whether the cells simply ‘piggy‐back’ with normal cells during development. Published evidence of ‘plasticity’ in adult human stem cells is more limited, but recent evidence suggests that the MAPCs from bone marrow may represent a breakthrough ( Jiang et al ., 2002 ; Schwartz et al ., 2002 ;). They are accessible. Collection is relatively non‐destructive for surrounding tissue compared, for example, with the collection of neural stem cells from adult brain, although their numbers are low: 1 in 10 8 of these cells exhibit the ability to form populations of nerve, muscle and a number of other cell types and they only become evident after several months of careful culture. Clonal analysis has provided rigorous proof of plasticity: a single haematopoietic stem cell can populate a variety of tissues when injected into lethally irradiated mice ( Krause et al ., 2001 ) or into blastocyst stage embryos to generate chimeric embryos ( Jiang et al ., 2002 ). Nonetheless, there are potential hazards to using cells that have been cultured for long periods for transplantation and although MAPCs seem to have normal chromosomes, it is important to establish that the pathways governing cell proliferation are unperturbed. This is also true for hES cells. However, the powerful performance of mES cells in restoring function in a rat model for Parkinson’s disease ( Kim et al ., 2002 ), has not yet been matched by MAPCs. Bone marrow stem cells have been shown very recently to restore function to some extent in a mouse heart damaged by coronary ligation, an experiment that mimics the conditions of the human heart soon after infarction ( Orlic et al ., 2001 ). Although clinical restoration of function in a damaged organ is usually sought rather longer after the original injury than in these experiments, which were performed before scar tissue had formed, this approach will certainly be worth pursuing. An alternative, non‐invasive, haematopoietic stem cell source is umbilical cord blood. This is used clinically for transplantation as an alternative to bone marrow in patients for whom no bone marrow match is available. Cord blood contains precursors of a number of lineages but its pluripotency, or even multipotency, is far from proven. Nevertheless, the prospect of autologous transplantation of haematopoietic stem cells of bone marrow in the long term makes this an important research area in terms of alternatives to therapeutic cloning (see below).

Although studies with adult stem cells so far have been encouraging, Galli (2000 ), author of the first adult neural stem studies and much cited by advocates of the view that adult stem cells have a proven developmental potency equal to that of ES cells, himself disagrees entirely with this viewpoint (see Editorial, 2000 ). It has even been suggested that the results from adult stem cell research are being misinterpreted for political motives and ‘hints of the versatility of the adult cells have been over interpreted, overplayed and over hyped’ ( Vastag, 2001 ). Opponents of ES cell research are now heralding Verfaillie’s adult stem cells as proof that work on hES cells is no longer needed. However the stem cell research community and Verfaillie herself ( Vastag, 2002 ) have called for more research on both adult and embryonic stem cells. ES cells that can perform as powerfully as those described by Kim et al . (2002 ) in the rat Parkinson model make it far too early in the game for them to be discounted ( Editorial, 2002 ).

The question remains, however, should a moratorium be imposed on isolating hES cells for research in cell therapy in the light of the indisputably promising results from adult stem cell research? The lack of consensus arises largely from disagreement on interpretation of the subsidiarity principle. Against the restrictive viewpoint that research on hES cells may only take place if there is proof that adult stem cells are not optimally useful, there is the more permissive viewpoint that hES cell research may, and indeed should, take place so long it is unclear whether adult stem cells are complete or even partial alternatives.

On the basis of the following arguments, a less restrictive interpretation of the subsidiarity principle is morally justified. ( Stem Cell Research, 2000 ) To begin with, the most optimistic expectation is that only in the long run will adult stem cells prove to have equal plasticity and developmental potential as hES cells (and be as broadly applicable in the clinic), and there is a reasonable chance that this will never turn out to be the case. If hES cells from pre‐implantation embryos have more potential clinical applications in the short term, then the risk of a moratorium is that patients will be deprived of benefit. This in itself is a reason to forgo a moratorium—assuming that the health interests of patients overrule the relative moral value of pre‐implantation embryos. Secondly, the simultaneous development of different research strategies is preferable, considering that research on hES cells will probably contribute to speeding up and optimising clinical applications of adult stem cells. In particular, the stimuli to drive cells in particular directions of differentiation may be common to both cell types, while methods of delivery to damaged tissue are as likely to be common as complementary. A moratorium on hES cell research would remove the driving force behind adult stem cell research.

A final variant on adult stem cell sources concerns the use of embryonal carcinoma (EC) cells, a stem cell population found in tumours (teratocarcinomas) of young adult patients. These cells have properties very similar to hES cells. The results of a phase I (safety) trial using these cells in 11 stroke victims in the USA have recently been published and permission granted by the Food and Drug Administration (FDA) for a phase II trial (effectivity) ( Kondziolka et al ., 2000 ). The patients received neural cells derived from retinoic acid (vitamin A) treatment of teratocarcinoma stem cells. Although the scientific and ethical consensus is that these trials were premature in terms of potential risk of teratocarcinoma development at the transplant site, all patients survived with no obvious detrimental effects, no tumour formation and in two cases a small improvement in symptoms. After two years, the transplanted cells were still detectable by scanning ( Kondziolka et al ., 2000 ). Despite its controversial nature, this trial has nevertheless probably set a precedent for similar trials using neural derivatives of hES, the best controlled differentiation pathway of hES cells at the present time ( Reubinoff et al ., 2001 ; Zhang et al ., 2001 ). Proponents believe that such trials would be feasible even in the short term ( McKay, 1997 ). Neural differentiation of hEC cells is fairly easy to induce reproducibly but most other forms of differentiation are not; even if ultimately regarded as ‘safe’, hEC cells will not replace hES cells in terms of developmental potential and are therefore not regarded as an alternative.

In view of both the only relative moral value of pre‐implantation embryos and the uncertainties and risks of the potential alternative sources for the development of cell therapy, a moratorium for isolating human embryonic stem cells is unjustified.

Before discussing the ethical issues around ‘therapeutic cloning’, the term itself requires consideration. To avoid confusion, it has been proposed that the term ‘cloning’ be reserved for reproductive cloning and that ‘Nuclear transplantation to produce stem cells’ would be better terminology for therapeutic cloning ( NAS report, 2002 ; Vogelstein et al ., 2002 ). Others have pointed out the disadvantage of this alternative term, namely that it masks the fact that an embryo is created for instrumental use. More important in our opinion however, is that the use of the adverb ‘therapeutic’ suggests that hES cell therapy is already a reality: strictu sensu there can only be a question of therapeutic applications once clinical trials have started. In the phase before clinical trials, it is only reasonable to refer to research on nuclear transfer as ‘research cloning’ or ‘nuclear transplantation for fundamental scientific research’, aimed at future applications of therapeutic cloning.

Some consider this technology to be ethically neutral; they claim that the ‘construct’ produced is not a (pre‐implantation) embryo. Qualifications suggested for these constructs include: activated oocyte, ovasome, transnuclear oocyte cell, etc. ( Kiessling, 2001 ; Hansen, 2002 ) However, to restrict the definition of ‘embryo’ to the product of fertilization in the post‐Dolly era is a misleading anachronism. Although the purpose of therapeutic cloning is not the creation of a new individual and it is unlikely that the viability of the constructed product is equivalent to that of an embryo derived from sexual reproduction, it is not correct to say that an embryo has not been created.

The core of the problem is that here human embryos are created solely for instrumental use. Whether or not this can be morally justified—and if so, under what conditions—has already been an issue of debate for years in the context of the development of ‘assisted reproductive technologies’ (ART). Is it acceptable to create embryos for research, and if so, is therapeutic cloning morally acceptable too?

A preliminary question: is it justified to create embryos for research?

Article 18 of the European Convention on Human Rights and Biomedicine forbids the creation of embryos for all research purposes ( Council of Europe, 1996 ). However, this does not close the ethical and political debates in individual EU member states.

In the ‘classical’ normative debate on embryo research, two perspectives can be distinguished: a ‘fetalist’ perspective (focusing on the moral value of the embryo), and a ‘feminist’ perspective (with the interests of women, particularly candidate oocyte donors, playing a central role) ( Raymond, 1987 ). Both perspectives have a different outlook on the question of whether or not there is a decisive moral distinction between research with spare IVF embryos on the one hand, and creating embryos for research on the other. In other words: is the difference between these practices such that the former can be acceptable under specific conditions, and the latter absolutely not?

Fetalist perspective

Instrumentalization of the embryo is sometimes regarded as far greater and fundamentally different when it involves the creation of embryos for research purposes rather than the use of spare embryos. This difference, however, is just gradual. Not only is the embryo used completely instrumentally in both cases, the moral status is also identical. The difference is in the intention at fertilization, which, although a real difference, is relative. It is a misconception to think that in the context of regular IVF treatment every embryo is created as a ‘goal in itself’: the goal is the solution of involuntary childlessness and the loss of some embryos is a calculated risk beforehand.

Feminist perspective

From a feminist perspective, the creation of embryos for research should be evaluated critically in as far as it may require hormone treatment of a woman to obtain oocytes for research purposes: can this be morally justified when it requires unpleasant treatment of the donor with no benefit at all, or even a detrimental outcome, for her own state of health? A first objection is that women themselves become objects of instrumental use. Here, however, an analogy can be made with recruiting healthy research subjects. Relevant considerations concern whether or not the research serves an important goal, whether the burdens and risks to the subjects are proportional, and whether valid informed consent of the research subject/donor is given. The second objection is that the health risks to the women themselves are too high and the degree of discomfort disproportional. Difference of opinion exists, however, also among women, about the disproportionality of hormone treatment. There are, furthermore, several potential alternatives that do not require hormone treatment of healthy women. One involves the in‐vitro maturation (IVM) of immature oocytes after their isolation from dead donors or donors having ovaries removed for other reasons. IVM is successful in cattle and sheep (efficiency ∼40%), although it is, for the moment, much lower in humans.

In conclusion, from both a fetalist and a feminist perspective there is no overriding categorical objection against bringing pre‐implantation embryos into existence for instrumental use. If the research cannot be conducted using spare embryos and its importance for human health is beyond doubt, we believe the creation of embryos specifically for research is morally justified subject to the required oocytes being obtained in a morally sound way.

Ethics of therapeutic cloning

Can therapeutic cloning be morally acceptable? The principle of proportionality, the slippery slope, and the principle of subsidiarity enter the debate again, but in a slightly different way.

It is doubtful whether the principle of proportionality provides a convincing a‐priori objection against therapeutic cloning. If it is considered acceptable to create embryos for research aimed at improving ART (freezing of oocytes; IVM of oocytes, etc…), then it is inconsistent to reject therapeutic cloning beforehand as being disproportional. Maybe even some opponents of creating embryos for the improvement of ART can conditionally accept therapeutic cloning because of the important health interests of patients.

Slippery‐slope

A consequentialist objection (fashioned as a ‘slippery‐slope’ argument) is that therapeutic cloning will inevitably lead to reproductive cloning. This objection is not convincing; if reproductive cloning is categorically unacceptable (the debate on this issue is still ongoing), it is reasonable to prohibit this specific technology, and not to ban other, non‐reproductive, applications of cloning. A second objection that could be raised in this context is that the creation of embryos through cloning for the isolation of stem cells could in the long term be used to justify the initiation of pregnancy from these embryos and their use simply as a vehicle for generating sufficient cells of the required type for transplantation; the pregnancy would be interrupted the moment the appropriate developmental stage was reached ( Lanza et al ., 2002 ). Relevant questions here are: is this a realistic scenario in the human (or just science fiction), would it be unacceptable, and is it unavoidable?

In terms of being a realistic means of generating genetically identical (fetal) tissue for transplantation, it could theoretically be an option, but whether it would actually be useful would depend on the alternatives available at the time transplantation techniques themselves have been perfected to clinical applicability (see below).

In terms of moral acceptability, most people would consider pregnancy‐and‐abortion‐for‐transplantation to be far more difficult to justify than the creation of pre‐implantation embryos for instrumental use in vitro , firstly because of the higher moral status/symbolic value of the fetus, and secondly because of the significantly greater burden of pregnancy‐and‐abortion‐for‐transplantation for women. ( De Wert et al ., 2002 ) Even though many countries do forbid pregnancy‐for‐transplantation, it has been argued that it could be morally justified as a last resort, on the basis that sacrificing a fetus (a potential person) may be justified in order to rescue the life of a person.

Finally, in scrutinising the slippery slope argument, it is important to assess whether instrumental use of pre‐implantation embryos makes pregnancy‐for‐abortion unavoidable. Again, the apparent automatism is disputable: if we reject pregnancy‐for‐abortion as being unacceptable, we can continue its prohibition.

Taking these points for and against together, the slippery slope argument does not provide a convincing basis for banning therapeutic cloning.

Therapeutic cloning can only be morally acceptable if there are no good alternatives. It is important to note that therapeutic cloning strictu sensu is not likely to be short‐term prospect. Apart from unsolved technical difficulties with nuclear transfer itself in human oocytes ( Cibelli et al ., 2002 ), much basic research is still needed to determine whether the differentiation of hES cells can be controlled and sufficient cell numbers generated to be a useful therapy. This research can be done with spare IVF embryos. In this light, creation of embryos for therapeutic cloning is, in our opinion, premature. Although critics of this point of view could use our own argument that delay in the development of research cloning could, just as a moratorium on hES cell isolation and research, have negative consequences for patients, the evidence suggests that further optimization of the technology as such could take place in animals. We believe that the duration of any ‘delay’ in offering therapy to patients would not then be of real significance.

At the same time, research on potential alternatives for therapeutic cloning, which likewise avoid (or at least reduce) the problem of rejection but which do not involve the creation of human embryos for instrumental use, should be stimulated. For the comparative ethical analysis, it is again important to avoid the pitfall of one‐dimensionality. Possible alternative options include: (i) the use of adult cells, both stem cells and differentiated cells; (ii) making optimal use of spare embryos: embryo‐banks and immuno‐tolerance and (iii) the use of entities with an undetermined status: ‘hybrids’ and ‘parthenotes’.

Adult cells

Adult tissue is a potential source of two alternatives: stem cells, which may be induced to transdifferentiate by extracellular signals, and somatic cells (nuclei) which require direct reprogramming signals, for example from an oocyte after nuclear transfer, to adopt a new fate. Both sources will, however, require substantial research to become realistic alternatives. Until it has been shown that adult stem cells at some point re‐express ES cell markers we will never know if transdifferentiation or direct reprogramming are the same or not.

For direct reprogramming of somatic nuclei, new methods may be developed which do not require nuclear transfer to oocyte cytoplasm. Examples of current work in this area include the study of cellular hybrids derived from the fusion of (embryonic) stem cells with somatic or adult stem cells ( Surani, 2001 ; Terada et al ., 2002; Ying et al ., 2002 ). An understanding of the basic mechanisms underlying reprogramming is already being undertaken in mice, cattle and sheep and indeed, the creation of ‘Dolly’ re‐initiated a wave of research in nuclear reprogramming in mammals. The ultimate aim of this research in the context of cell transplantation therapy would be chemically‐induced nuclear re‐programming in the test‐tube to derive the required cell type, obviating the necessity for therapeutic cloning altogether. First evidence that this might be feasible demonstrated direct reprogramming of fibroblasts to neural cells and T‐cells in culture by temporary permeabilization of the fibroblasts to allow them to take up extracts of neural and T‐cells, respectively ( Hakelien et al ., 2002 ). In this sense, therapeutic cloning may be regarded, perhaps, as a temporary option; in the long term it will be replaced by a direct reprogramming alternative.

Research on direct reprogramming of adult somatic nuclei may ultimately require the creation of human embryos for instrumental use. In view of the importance of this research, both in terms of the contribution to the development of cell therapy and the potential ultimately to reduce the instrumental use of human embryos by developing an alternative for therapeutic cloning, this research would no doubt also meet the principle of proportionality.

Optimal use of spare embryos

Various strategies should be considered. Firstly, the generation of a bank of hES cell lines from a wide spectrum of genotypes is required to be able to offer a reasonable tissue match for every patient requiring a cellular transplant. Estimates of the number of independent cell lines that would actually be required for this vary greatly, from a few hundred to several thousand. Such a bank is already being discussed in the UK but could ultimately be established as a European resource. However, even very good tissue matches between donor and recipient require some degree of immunosuppressive therapy, which has long term negative side‐effects for patients, including increased risk of tumorigenesis

Secondly, there should be further development and application of ‘immunotolerance’ methodology. This may be particularly useful in combination with matching from an hES cell bank. The observation that patients receiving bone marrow transplants are more immunotolerant to other tissue transplantation from the same donor have led to the suggestion that immunotolerance may also be induced by initial injection of hES‐derived haematopoietic cells followed by the cell type of interest derived from the same hES cell line ( Kaufman et al ., 2001 ). The transplant may then be tolerated without being genetically identical, and lower doses or no immunosuppressives required. The combination of ‘near match’ with immunotolerance is probably a promising option.

For certain genetically based diseases, autologous transplantation may not always be appropriate since the transplanted tissue will bear the same genetic defect. Immunotolerance hES cell strategies may then be a particularly attractive or the only option. Should the success rates be very high, then attempts to create genetically identical transplantable tissue may become superfluous, not only for these, but for all patients. If, however, it works imperfectly or only for some patients, then therapeutic cloning may well remain an important option for the majority of all other patients.

Creating entities with an undefined status

Various alternative options raise classification problems, as the entities created to obtain cells have an undefined status. Firstly, transplanting the somatic nucleus of a patient into an enucleated animal oocyte. The logic behind this variant of therapeutic cloning is twofold: one, assuming that the ‘units’ thus created are not human embryos because only their nuclear but not mitochondrial DNA is human, advocates of this strategy argue that it circumvents the controversial issue of the instrumental use of human embryos. Two, a technical advantage of this approach would be that plenty of animal oocytes would be available; the feminist objection to creating human embryos for research would, of course, not apply.

It is not yet known whether this is a scientifically realistic option (whether hES cells can be effectively obtained following this approach). Animal research has so far been limited and not generally successful ( Barrientos et al ., 1998 ; 2001); polymorphic interspecies differences in mitochondrial DNA are thought to make such reconstructed zygotes non‐viable or prone to major developmental abnormalities. There are however, unvalidated reports of successful applications of the technique in China. The Donaldson Committee advocated a ban on this approach, but without any argumentation (Stem Cell Research, 2000). However, if this were a realistic option scientifically, then we believe that the issues involved deserve further ethical discussion. The major questions that should be addressed include: is the risk acceptable? As for xenotransplantation, there is also here the risk of cross‐species infection, although this may be extremely small, because the nuclear DNA of the animal, which may harbour viruses, is removed from the oocyte. Is it reasonable to argue that this ‘artificial combination’ should not be considered equivalent to a human embryo? Since the entire nuclear DNA is human, the reconstructed combination should, we think, be regarded as a human embryo. The procedure should thus not be presented as an ‘embryo saving’ variant of therapeutic cloning. However, only further in‐utero research with reconstructed animal embryos, for example embryos created by transplanting the somatic nucleus of a rat into an enucleated mouse oocyte, will provide a more definitive answer. Finally: in‐vitro research may well show that embryos obtained by transplanting a human somatic nucleus into an enucleated animal oocyte are non‐viable (like parthenotes, see below). The moral status of non‐viable pre‐implantation embryos, and more particularly, the question as to whether the conditions for research using non‐viable embryos may be more permissive than the conditions for using viable embryos, needs further debate (see earlier).

A second option may be the generation of parthenogenetic embryos for the isolation of hES cell lines. Here, an unfertilized (haploid) oocyte is treated chemically such that it becomes diploid, with two identical sets of the maternal chromosomes. These uniparental embryos are by definition gynogenetic and never result in viable offspring, because they fail to generate extra‐embryonic tissues. Nevertheless, in mice (see Boediono et al ., 1999 ) and in apes ( Cibelli et al ., 2002 ), parthenotes have been shown to develop to the blastocyst stage and yield cell lines with properties not distinguishable from ES cells derived from fertilized oocytes. However, in view of the fact that some genes are genomically imprinted, such that they are expressed only if inherited via the male germ line, ES cells derived from parthenotes may well be abnormal. First attempts at parthenogenesis in humans have not yielded hES cell lines ( Cibelli et al ., 2002 ). It is important to realise that such hES cell lines, if developed in humans, would only provide a tissue match for the oocyte donor, i.e. women of reproductive age. Although it has been speculated that two sets of male chromosomes could also be used in parthenotes, there is no evidence that this is a real option.

Cibelli and colleagues have referred to parthenogenesis as cloning. Whether this is correct depends on the timing of parthenogenesis: if initiated before the first complete meiotic division, then the procedure amounts to cloning (the same genotype as the female); if after the first meiotic division (ie recombination and loss of half) then it is not cloning. In this light, the experiments of Cibelli et al . (2002) would not qualify as cloning in the strict sense.

Some will certainly argue that the parthenote is not an embryo; parthenogenesis would then be classified as an ‘embryo‐saving’ strategy. As the parthenote undergoes the first divisions normally and is at these stages not distinguishable from embryos derived by normal fertilization, we would argue that it should be regarded as a non‐viable embryo. In the light of its non‐viability, the potentiality argument is not applicable. The moral status of parthenotes may therefore be regarded as very low, lower even than that of normal viable embryos at the same stage (see earlier). Thus, although not an ‘embryo‐saving alternative’, all other things being equal, parthenogenesis may be regarded as ethically preferable to the generation of viable embryos by fertilization or nuclear transfer (for instrumental use). In addressing the question of whether this research is premature given the current lack of proof that human ES cells are clinically useful as a source of transplantable cells, the lower moral status of parthenotes should be taken into account.

Regarding moral judgements as a ‘quasi stable equilibrium’ is particularly appropriate when applied to the ethics of isolating hES cells for research into cell replacement therapy. Stem cell research is highly dynamic, with many questions and ‘unknowns’. New insights into the effectiveness, risks and usefulness of the various alternatives may have immediate consequences for the ethical evaluation of the isolation of hES cells.

The status of the pre‐implantation embryo is the most sensitive and disputed point in the debate on isolation of hES cells for research. The dominant view in ethics, however, is that the moral status of the pre‐implantation embryo is relatively low and that the instrumental use of these embryos can be morally justified under some conditions.

The moral status of non‐viable pre‐implantation embryos is lower than the moral status of viable pre‐implantation embryos. The precise implications of this difference in moral status for the regulation of the instrumental use of embryos need further ethical scrutiny.

Both the principle of proportionality and a permissive interpretation of the principle of subsidiarity, make a moratorium on the isolation of hES cells unjustified.

Parallel research on alternatives is important and requires major support. Research on hES cells can provide an important impetus in this context.

The moral difference between research on surplus embryos and the creation of embryos for research is only gradual. A complete ban on creating embryos for instrumental use in research is morally unjustified.

A categorical ban on research on human therapeutic cloning is not justified, although the creation of embryos by cloning for the isolation of hES cells is, at the present time, premature. The necessary research can currently be carried out using animal embryos and surplus human IVF embryos.

Research into potential alternatives for therapeutic cloning, which does not require human embryos or which requires only the use of spare embryos, should be stimulated.

Banning the transplantation of a human somatic nucleus to an animal oocyte (as a variant of therapeutic cloning) is premature and morally unjustified.

The question whether therapeutic cloning should be allowed, becomes acute if research with spare embryos suggests that usable transplants can be obtained in vitro from hES cells and if the possible alternatives for therapeutic cloning are less promising or need more time for development than is currently expected. In that case, therapeutic cloning can be morally justified on the basis of both the principle of proportionality and the principle of subsidiarity.

We are grateful to Drs K.Lawson and J.Geraedts for comments on the manuscript.

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Topics: Stem Cell Research

A guide that provides information and resources on teaching responsible conduct of research that focuses on the topic of stem cell research. Part of the Resources for Research Ethics Education collection.

What is Research Ethics

Why Teach Research Ethics

Animal Subjects

Biosecurity

Collaboration

Conflicts of Interest

Data Management

Human Subjects

Peer Review

Publication

Research Misconduct

Social Responsibility

Stem Cell Research

Whistleblowing

Descriptions of educational settings , including in the classroom, and in research contexts.

Case Studies

Other Discussion Tools

Information about the history and authors of the Resources for Research Ethics Collection

• Critically evaluate the decision to conduct research with stem cells Both the spirit of the regulations and good science requires that individuals give thoughtful consideration to what defines an acceptable use of stem cells.  
• Comply with regulations Having made a considered decision to use human stem cells, no use of those cells for the purposes of research, teaching, or testing should commence that is not explicitly part of an approved protocol or specifically waived under relevant regulations.  
• Promote responsible use of stem cells If you are responsible for training others or if you observe indifference to considerations for responsible stem cell research, you should make attempts to initiate discussion, identify relevant regulations, and promote responsibility. If significant violations of regulations are observed, then those observations should be reported to the appropriate people in the institution.

In recent years, biomedical research has been significantly altered by technologies for the derivation of human cell lines capable of differentiation into any of the cells of the human body. Such cells are sometimes called "pluripotent" because they have the power ("potency") to become many ("pluri-") different cells. It has long been known that such cells exist, but it wasn’t until 1981 that stem cells were isolated from mouse embryos (Evans and Kaufman, 1981; Martin, 1981), and only in 1998 that the derivation of human embryonic stem cells was first reported (Thomson et al., 1998). This tool was quickly recognized as an opportunity to better understand normal and pathological human development, to identify and test new pharmacological therapies, and perhaps to even replace diseased tissues or organs. Many scientists viewed this as a potentially revolutionary approach to studying human biology. However, because a necessary first step was to use and destroy human embryos such research raised serious questions for some members of the public, as well as some scientists.

While most hESC scientists view the human embryo as human cells with great biological and scientific potential, there are many members of our society who hold religious beliefs that define the human embryo as equivalent to a human life. By this view, any harm or destruction of the human embryo is tantamount to harm or destruction of a human life. This perspective has become more than a matter of personal opinion. For many years now, under the Dickey amendment (1995), the U.S. Congress has agreed to federal restrictions on any research that would require harm or destruction of the human embryo. This restriction was partially lifted in 2001 by President Bush’s announcement that research with stem cell lines existing as of August 9, 2001, could be eligible for federal funding.

Subsequently, President Obama announced a new approach to approving stem cell lines for federal funding (Obama, 2009). The question now is not whether stem cell lines were created before a particular date, but whether or not those lines meet criteria that have been defined for ethically derived stem cell lines (NIH, 2009). While the result has been an increase in the number of stem cell lines approved for federal funding, it is noteworthy that the number of lines meeting these criteria is limited (NIH Human Embryonic Stem Cell Registry). In fact, many of the lines approved under the Bush policy are not acceptable under the Obama guidelines.

It would be a mistake to assume that religion is the only basis for arguments against hESC research. It is clear that some individuals and groups are motivated more by philosophical, political, or even economic arguments. However, whether based on religion or otherwise, most polls show that opponents to hESC research may represent a minority, but that minority is substantial in size and in impact (e.g., pollingreport.com).

Stem cells can be obtained from embryos, but embryos are only one of many potential sources. In the fetus, and even in an adult, stem cells can be found in many body tissues. The best known of these sources is bone marrow, in which stem cells are produced that are capable of differentiating into different types of blood cells. However, these stem cells are not pluripotent as defined above. Such cells are often called adult or tissue-specific stem cells. These cells have important, but restricted, clinical applications distinct from the wider range of possibilities with human embryonic stem cells (Wood, 2005).

Several sources of pluripotent stem cells have now been identified. One of these sources is based on the technology used to clone “Dolly” the sheep (Campbell et al., 1996), “Snuppy” the dog (Lee et al., 2005), and many other mammalian species. The first step to cloning these animals is a technique called Somatic Cell Nuclear Transfer (SCNT). SCNT in any species begins with an egg of that species from which the genetic material is removed. This egg can then be fused with an adult cell of the individual to be cloned. The result is an egg that now contains a full complement of DNA. Under appropriate laboratory conditions, that egg can be induced to divide as if it were a fertilized egg. If allowed to progress far enough, the resulting embryo can be implanted in the uterus of an individual of the same species, potentially resulting in the birth of a clone. However, it is also possible to allow the “embryo” to develop only for the purpose of harvesting stem cells rather than implantation. This source of stem cells is particularly important for stem cell research as well as potential therapies because of the opportunity to produce stem cells and differentiated cells that are genetically and immunologically matched to the adult donor.

Until 2005, researchers had been frustrated in their attempts to duplicate with human cells the same success achieved with SCNT in many other mammalian species. Some researchers were considering the possibility that SCNT in humans would be for all practical purposes impossible. This view was apparently proven wrong when the laboratory of Dr. Hwang Woo Suk published a report demonstrating the successful derivation of stem cell lines from eleven separate cases of human SCNT (Hwang et al., 2005). Hwang, whose laboratory had cloned the first dog (Lee et al., 2005), was seen as so far ahead with SCNT that other laboratories around the world suspended attempts to achieve human SCNT, choosing instead to collaborate with Hwang’s laboratory. Unfortunately, the story began to unravel in late 2005 and by the next year, it was clear that the results announced in Dr. Hwang’s paper were entirely falsified (Kennedy, 2006). Because researchers throughout the world had chosen to not pursue SCNT, this line of research was set back a year or more. It wasn’t until 2008 that scientists at Stemagen successfully reported human SCNT (French et al., 2008)

Although SCNT has both scientific and therapeutic benefits, it still raises significant ethical questions, particularly because it depends on women who are willing and able to donate some of their eggs. Egg donation is not free of risk and, therefore, many bioethics committees and regulatory bodies have decided to err on the side of caution by prohibiting payment for eggs donated for the purposes of stem cell research. While on the one hand this position might be seen as paternalistic, the case can be made that any significant payment might lead those who are young or poor to overlook the possible risks of donation. The debate about payment is likely to continue, but it is clear that SCNT depends on a resource (human eggs) that is in limited supply and that can be obtained only through a time-consuming and invasive procedure.

An ongoing hope is that pluripotent cells might be found without the need for either human embryos or eggs. A number of reports have suggested that such cells might be found, for example, in amniotic fluid (De Coppi et al., 2007) and testes (Conrad et al., 2008). Another approach, reprogramming of adult cells, has been found to be far easier than expected and provisionally as good as or better than other sources of cells. In brief, cells (e.g., fibroblasts) are obtained from an individual, treated with a viral vector to introduce as few as 4 genes which, effectively, dedifferentiate (reprogram) the cells to become pluripotent stem cells (Takahishi et al., 2007; Yu et al., 2007). These cells are now commonly referred to as induced pluripotent stem (iPS) cells. Although these findings are intriguing, it remains to be seen whether the various alternative sources of pluripotent stem cells will prove to have the same qualities as the stem cells derived from human embryos (Hyun et al., 2007).

Regulations and Guidelines

In just ten years (1998-2008), the field of human embryonic stem cell research evolved rapidly. Almost certainly, because of intense public scrutiny, the landscape for regulations and guidelines has also evolved rapidly. Unfortunately, the regulatory environment for this research varies not only across international borders, but significant differences are found even among the states of the United States. It is neither useful nor possible to describe regulations in each of these jurisdictions both because of extensive variation and because regulatory changes continue to be driven by changing public opinion and rapid advances in the sciences. However, a few examples are useful to illustrate the complex and often conflicting approaches to stem cell research across international and interstate borders.

Internationally, the environment for stem cell research ranges from a virtual prohibition to a near absence of restriction (Isasi and Knoppers, 2006). Several countries, including Austria, Norway, and Poland, have prohibited any human embryo research. Others, such as the U.S. and Germany, prohibit the use of federal funds for hESC research, but in the face of public pressure both countries have adopted national policies that allow the use of federal funds for stem cell lines created before August 2001 and May 2007, respectively. Finally, for all practical purposes, China and Singapore are examples of countries with relatively few restrictions on hESC research.

The variation across international borders in stem cell regulations should not be taken as a sign that the international stem cell community has been silent about the responsible conduct of stem cell research. The International Society for Stem Cell Research (ISSCR), (one of the leading international stem cell research organizations, has established a variety of guidelines that are now widely accepted throughout the stem cell research community (ISSCR, 2006). Key principles of these guidelines are:

• "All experiments pertinent to human embryonic stem cell research that involve pre-implantation stages of human development, human embryos or embryonic cells, or that entail incorporating human totipotent or pluripotent cells into animal chimeras, shall be subject to review, approval and ongoing monitoring by a special oversight mechanism or body equipped to evaluate the unique aspects of the science. Investigators should seek approval through a process of Stem Cell Research Oversight (SCRO)."  
• "Given current scientific and medical safety concerns, attempts at human reproductive cloning should be prohibited."  
• "…privacy and confidentiality of personal information should be protected with the utmost care. Caution must also be taken to ensure that persons are not exploited during the procurement process, especially individuals who are vulnerable due to their dependent status or their compromised ability to offer fully voluntary consent. …there must be a reasonable relationship between those from whom such materials are received and the populations most likely to benefit from the research. Finally, the voluntary nature of the consent process must not be undermined by undue inducements or other undue influences to participate in research."

While the U.S. has significant restrictions on the use of federal funds for stem cell research, such research is still permitted to the extent allowed under state laws. As with international stem cell regulations, tremendous variation can be found among different states (National Conference of State Legislatures, 2008). As of 2008, South Dakota prohibits hESC research, while some states (e.g., California, New York) have been not only permissive of stem cell research, but have approved significant public funding dedicated to hESC research.

The fact that some states are highly permissive of stem cell research does not mean that such research occurs in the absence of either regulations or guidelines. Nationally, guidance that is generally accepted has come from the National Academy of Sciences. Following their initial report (Committee on Guidelines for Human Embryonic Stem Cell Research, 2005), the NAS has published amendments in 2007 and 2008 (Human Embryonic Stem Cell Research Advisory Committee, 2007 and 2008). Two key points in those guidelines are:

• "To provide oversight of all issues related to derivation and use of hES cell lines and to facilitate education of investigators involved in hES cell research, each institution should have activities involving hES cells overseen by an Embryonic Stem Cell Research Oversight (ESCRO) committee."
• "An IRB …should review all new procurements of all gametes, blastocyst, or somatic cells for the purpose of generating new…cell lines."

One of the states that have been most receptive to hESC research is California. In 2004, a significant majority of California voters approved Proposition 71, creating a mechanism for allocating $3 billion for stem cell research over a 10-year period. This voter-approved initiative also put in place a framework to promote scientific, legal, and ethical oversight for stem cell research through the creation of the California Institute for Regenerative Medicine (CIRM). The resulting requirements for CIRM-funded research have generally been extended to all stem cell research in California. Under California law (California Institute for Regenerative Medicine, 2008), key requirements for stem cell research include requirements for review of the research by the equivalent of an ESCRO Committee, criteria for the acceptable derivation of materials that are to be used for research use, and categories of research that are specifically prohibited.

Scientists and clinicians in a private institute (in another country) have reported the birth of a child who is a genetic clone of her mother. Using the same technology as was used to create Dolly the sheep, the scientists had taken the DNA from one of the future mother’s cells, and inserted that DNA into one of her eggs. The resulting cell was stimulated to begin dividing, resulting in a blastocyst (embryo) that could be implanted in the mother’s uterus. Nine months later, the first known human clone was born.  Karl is an assistant professor recently hired at Smalltown University. Karl’s primary research focus is human embryonic stem cells. He is using stem cell lines produced at other research institutions for his own studies to see if he can stimulate those cells to differentiate into nerve cells. Some of his experiments include transplanting those cells into mice to assess the factors that help those cells transform into human neurons integrated into the mouse brain. He is the only faculty member at SU working in stem cell research.  Roxie is a news reporter with the primary news outlet in Smalltown. She is typical of many of the residents of Smalltown, and believes that once an egg is fertilized it is the equivalent of a human life. Roxie has just received the report of the first human clone. Because she believes this story would be of significant interest to her readers, she contacts the press office at SU and asks to speak to a scientist about this report on human cloning. She is introduced to Karl, who is described as an expert in the field of stem cell research.  The questions Roxie brings to the interview are wide-ranging. Some of the initial questions are for background information: How does this technology work? How easy is it? She next asks questions about the cloned human, such as: Is it safe (what are the risks to the mother and child)? Is this legal in this country? Is it ethical to create human life in this way? Later, the interview turns to the work of Karl. Roxie is very concerned about experiments in which human nerve cells will be inserted into the brain of a mouse. She now asks about the possibility that the mouse will have a human brain: Will it be smarter? Will it be able to think like a human? Will it be a human trapped in the body of a mouse? And all of these questions then lead to some fundamental questions: Are scientists playing god when they conduct these kinds of experiments? Who decides which experiments will and won’t be done?  Assuming that Karl has agreed to do this interview, and you had a good idea what type of questions would be asked by Roxie, then how would you advise Karl about the things that he should and should not say and do in the interview?

• Describe three examples of potential benefits from human embryonic stem cell research that are less likely to be achieved by other available approaches.   
• Describe at least one instance in which misconduct or insensitivity to public concerns helped to increase opposition to human embryonic stem cell research. Identify federal or state regulations and guidelines that were apparently direct responses to such abuses.   
• What are the responsibilities of an ESCRO or SCRO Committee?   
• In your institution, what minimal changes (e.g., addition or removal of stem cell lines to be studied) to your protocol require review and approval of the ESCRO or SCRO Committee? What changes are of a magnitude to require submission, review, and approval of a new protocol?   
• If you observed another investigator abusing the privilege of stem cell research, who should be notified?   
• Describe your criteria for the acceptable use of human embryos and stem cells. Consider the importance and likelihood of benefits to be obtained, the source of the material being used (e.g., egg donation for SCNT vs. iPS cells), the nature of the proposed experiments (e.g., in vitro vs. insertion of human cells into a non-human species), and rationale for the proposed research (e.g., basic science, prevention or treatment of disease, or technology that would allow enhancement of an otherwise normal individual).  
• What forums are available in your institution to examine the ethical and/or legal ramifications of stem cell research? What, if anything, can you do to promote such discussion? 

Clearly, from an ethical perspective, stem cell research constitutes one of the most complex of the numerous domains of research. Many considerations might be listed here, but three seem to be particularly noteworthy.

• Public Scrutiny: Stem cell research is likely one of the most watched areas of academic endeavor in the history of academia. This is a direct consequence of two very different public perceptions of this research. Internationally, and certainly within the borders of the U.S., the majority of the public has recognized in this research a potential for a virtual revolution in medicine. It remains to be seen whether this will be the case, but this segment of the population is highly attentive and supportive of all that is happening in stem cell research. In addition, there is a second group, which is very much opposed to human embryonic stem cell research. While most polls and votes indicate that this group is in the minority, it is nonetheless a substantial minority. Among the members of this second group, there is a highly principled belief that harm or destruction of a human embryo is the equivalent of harm or destruction of a human child. For this group, the possible benefits of stem cell research cannot be on the table if those benefits in effect require the taking of human lives. For these reasons, this group is also watching stem cell research closely and seeking alternatives that do not require the use of human embryos. Scrutiny by both supporters and opponents of stem cell research places a higher obligation on stem cell researchers than for other areas of research. In short, mistakes by stem cell researchers are not likely to be overlooked. An ethical lapse, misuse of funds, or violation of regulations will not be merely a matter of individual concern. It is highly likely that such mistakes will reflect at least on the individual’s institution, and also on all of stem cell research, if not science in general.
• Special Respect: A case can be made that the human embryo deserves special respect (Robertson, 1999). At first glance, such a statement may seem unnecessary to supporters of stem cell research and hypocritical to its opponents. Stem cell researchers might argue that since the majority of the public favors such research, and presuming that the researchers are working in a jurisdiction that makes such research legal, then they should no longer have to give any more consideration to human embryos or eggs than they might give any other human cell. Conversely, opponents who view the human embryo as a human life might argue that "special respect" is meaningless if the embryo is still going to be harmed or destroyed. There is, however, a middle ground between these views. As implied by Robertson’s argument (1999), respect does not have to be absolute; it can be in varying degrees. Such respect may not mean that we will abandon human embryonic stem cell research, but we still can and should recognize that it is a privilege to conduct this research. The circumstances under which human eggs or embryos are made available to research are anything but trivial. Under those circumstances, we recognize the precious nature of those human cells. That privilege is one that cannot be taken lightly. In fact, most of us already have internalized a recognition of the differential value we would place on a developing embryo, a fertilized egg, an egg, or sperm. For example, if only some, but not all, of the above could be saved in the face of imminent danger, most of us are likely to put the greatest value on the embryo. In practice, this special value means that we have an obligation to ensure that those cells are put to the best possible use in a project that has been reviewed and approved for ethical, legal, and scientific merit.  
• Origins and Uses: Because much of the debate about human embryonic stem cell research has focused on the embryo, it is easy to overlook that this is not the only ethical challenge requiring consideration. While the origins of stem cells are important and cannot be dismissed, we must also ask about the ethical challenges in the conduct of basic and clinical stem cell research. Many such considerations are characteristic of any research (e.g., standards for recordkeeping, sharing of data, addressing conflicts of interest, or allocating credit), but some issues are specific to stem cell research. Two areas that are of particular note are chimeras and clinical trials. Chimeras:  A chimera is defined in various ways, but the principle is that one organism consists of components that are demonstrably derived from two or more distinct species. The name chimera comes from a monster in Greek mythology that was a combination of different animals (typically a lion, goat, and snake). In biology, chimeras can now be formed either by inserting cells from one species into the adult of another species, or by creating an embryo that begins with cells from two or more species. In principle, it seems that our society already accepts the possibility of saving a child’s life by replacing a defective heart with one that is non-human (e.g., a baboon heart, Altman, 1984), but we are much less comfortable with creating a non-human animal that might have human features (e.g., a human face, ear, or hand). Having the appearance of a human is problematic more because of our discomfort than because it necessarily raises some direct ethical dilemma. However, we have reason to be much more concerned about a human nervous system (i.e., do we have a risk of a non-human animal achieving levels of awareness and understanding that would make it sufficiently human to be deserving of human protections?) or human gametes (i.e., do we have a risk of two non-human animals reproducing with human gametes, thereby producing a human, or largely human, organism?). These questions are very much hypothetical and, if not impossible, highly improbable under the circumstance that the ethical, legal, scientific, and social environment is not one that favors these goals. Nonetheless, responsible science and policy require that one concern for reviewers of stem cell research is to address the potential risks with experiments that involve the mixing of stem cells from two or more species. Clinical Trials:  In the very near future, we are likely to see clinical trials based on reputable, pluripotent stem cell research. We are already seeing numerous stem cell "trials" worldwide that are arguably questionable, and sometimes criminal. By taking advantage of public awareness of and excitement about stem cell research, it is now possible to find groups that will offer to treat or cure almost anything in the context of a clinical "trial" that typically has no control group and for which participants must pay for participation. Payments for such "trials" are often on the order of $10,000 or more. Whether intentional or not, these trials are likely to be scams with little chance of success. Particularly under these circumstances, the stem cell field must meet a higher than average standard before approving the first clinical trials with this very new approach to treating disease. To do otherwise risks a backlash against all of stem cell research if initial trials unexpectedly result in a worsening of disease, serious side effects, or even death. All of these are possible outcomes no matter how much work has been done before the first trials in humans. Therefore to decrease that risk the scientific community can and should set a high bar both for the circumstances under which such a trial should be attempted and for the design of the research study to ensure the highest level of protections for informed consent and the welfare of the research participants.
• Altman LK (1984): Baboon’s Heart Implanted in Infant on Coast. New York Times. October 28, 1984.
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The Resources for Research Ethics Education site was originally developed and maintained by Dr. Michael Kalichman, Director of the Research Ethics Program at the University of California San Diego. The site was transferred to the Online Ethics Center in 2021 with the permission of the author.

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This material is based upon work supported by the National Science Foundation under Award No. 2055332. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation.

Stem Cell Research Ethics Research Paper

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Ethics And Human Embryonic Stem Cell Research

Human embryonic stem cell (hESC) research has been surrounded by considerable controversy in recent years, particularly with regard to the ethical issues associated with such research. The scientific facts are relatively straightforward. Stem cells are undifferentiated, unspecialized cells with the ability both to multiply for long periods and to differentiate into specific kinds of cells after being stimulated by chemical or other signals. This latter property means that stem cells could be transformed into specialized cells with specific functions, such as heart muscle cells, blood cells, or nerve cells. Hence promoters of stem cell research claim that it holds promise for the development of therapeutic interventions for a wide range of diseases in which cells have been damaged or destroyed (e.g., heart disease, diabetes, spinal cord injury, and Parkinson’s disease). Patients with leukemia have been routinely treated with blood adult stem cells (ASCs) from compatible donors since the 1970s, and the success of this therapy is often cited as a precedent for future uses of hESCs. However, other types of stem cell therapies are highly experimental and are currently only used in animal models.

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hESCs can be very difficult to isolate and establish in culture, but a number of stem cell lines have been successfully obtained from the inner cell mass of 4to 6-dayold embryos (blastocysts). Cells are isolated at this early stage because it is thought that in later stages of development, they become more restricted in terms of what types of tissues the stem cells can become. A stem cell line contains cells that continue dividing without differentiating into specialized cells and which remain pluripotent (able to differentiate into any cell type with a few exceptions). Stem cell banks hold cell lines that have been produced under standardized conditions, which have been quality controlled, and provide them to basic and clinical researchers (Faden et al., 2003). The UK Stem Cell Bank is the most prominent of these and is overseeing the International Stem Cell Initiative to track and characterize all stem cell lines worldwide.

Blastocysts used for creating hESCs typically are derived from frozen embryos that were originally created as part of in vitro fertilization (IVF) treatments with the intention of achieving successful pregnancies but that were never implanted. In many countries, there are hundreds of thousands of unused frozen embryos stored in assisted reproductive technology (ART) clinics. In some countries (e.g., Australia, Canada, and the United Kingdom), once couples have finished IVF, they can consent to donation of their surplus stored embryos for research purposes, with some limitations (Isasi and Knoppers, 2006). Elsewhere, excess ART embryos cannot be donated for any type of research (e.g., Italy) or creation of hESCs is explicitly banned (e.g., Germany, which does allow importation of lines created elsewhere for research purposes).

Ethical Debates About The Moral Status Of The Embryo

For many, the main ethical issues associated with hESC research are related to the fact that an embryo must be destroyed to obtain stem cells. Some research is underway regarding accessing stem cells without destroying the embryo, but it has so far been unsuccessful. A central ethical question related to this is: What is the moral status of a human embryo? Beliefs regarding when personhood begins (that is, when a human being has moral status) differ. For instance, some religious traditions hold that personhood begins at conception, and thus hold hESC research (and all other forms of destructive embryo research) to be unethical (Doerflinger, 1999; Meilaender, 2001). We should not use embryos as a means to other ends, they claim, and hence should value them as human beings with moral status and full human rights, perhaps deserving of additional protections because they are especially vulnerable and dependent.

A similar argument can be made without relying on religion: Each of us began life as an embryo. If my life is worthy of respect and hence inviolable by virtue of my humanity, so was my life in earlier stages. Since we cannot define a precise time between conception and birth at which we become a person, we must hold embryos to possess the same inviolability as fully developed human beings (for the problems with this argument, see Sandel, 2004). Opponents of embryo research also argue that allowing such research might create a sort of slippery slope, which will lead to increased social toleration of loss of life for vulnerable persons (such as infants and the disabled), although there is limited empirical evidence about social attitudes to support such a claim.

Other more intermediate views hold that the stage at which embryos would be used for hESC research (less than 6 days old) is so early that the embryo cannot be argued to have moral status and hence ethically can be used for destructive research. The time at which personhood or moral status is said to occur differs, but even many religious traditions would nominate implantation or the formation of the primitive streak at around 14 days. These are said to be markers of an individualized human entity with the inherent potential to become a human person; up until this point, the moral status of the embryo is not that of a person, and its use for certain kinds of research aimed at alleviating illness and suffering can be ethically justifiable (and may in fact be preferable to simple destruction, as research is an acknowledgment of the value of the embryo; see Annas et al., 1999). Nonetheless, the embryo should be given some protections, in recognition of its potential as a human being.

More liberal views claim that to attribute basic and equal human worth to an individual requires more than cells that have the potential to develop into a person (Robertson, 1999). They would cite a much later stage of development as the cut-off point, such as the time at which a termination would no longer be legally allowed under normal circumstances, which is much later than when destruction for hESC research would occur. On this view, there is no moral harm committed when an embryo is destroyed or not transferred into the uterus to attempt pregnancy. Some have argued that embryos have higher and lower moral status, depending on whether they are part of a parental project where there is a desire and intention to bring a pregnancy to term. These arguments typically do not imply that we can do anything we wish with embryos (such as cosmetic testing) as we need to give them special respect because of their source and their symbolic value, but it would allow research aimed at curing serious diseases.

The most liberal view holds that embryos are merely body parts until they can exist independently. Thus they have no independent moral status and belong (as property does) to those persons who donated the parts needed to make them. Therefore, all decision making about disposition of embryos should reside with the couple who contributed the genetic materials, and we must respect these rights as we would any other property rights.

There also is a related debate over intentionality, and in particular whether it is ethically permissible to create embryos explicitly for research purposes (see Davis, 1995; Juengst, 2000; FitzPatrick, 2003), either by using IVF to join a sperm and an egg or via cloning (see the section titled ‘Cloning’ below). Some people who would find it ethically permissible to use already created, stored embryos for research oppose the creation of embryos explicitly for research purposes. Societies that permit or support IVF technologies might be argued to have implicitly endorsed the idea that there will be some wastage of embryos inherent in such procedures, but creating new embryos for research is more morally problematic for many. The Council of Europe’s Oviedo Convention of 1997 prohibits the creation of human embryos for research purposes, but it has yet to be ratified by a majority of its member states. Others argue that the creation of embryos for research purposes is ethically permissible, as such embryos do not have the social significance associated with those created for reproduction and hence have a different moral status.

The term cloning is used to describe a range of processes that involve genetic copying, ranging from copies of sections of DNA (genes) to whole organisms (such as plants). Ethical debates about cloning escalated in 1997 with the birth of Dolly the sheep, a whole organism produced using cloning techniques. Cloning is relevant to debates about hESC research because it has the potential to provide a source of tailored stem cells that might be particularly useful for individualized medical treatments. Human embryo clones could be created using somatic cell nuclear transfer (SCNT), which involves taking an egg cell from a woman in a similar way to how eggs are obtained for in vitro fertilization. The nucleus of the egg is extracted, leaving behind only the cytoplasm. A nucleus is then extracted from a somatic (body) cell of a person (who can be another person or the same woman who donated the original egg) and inserted into the cytoplasm.

Under the correct conditions, the entity created should start to divide as would an embryonic nucleus created naturally (i.e., by the union of egg and sperm). The resulting embryo that is formed has the same genetic material as that of the donor of the somatic cell nucleus, instead of its genome being a blend of the two parents as is usual, and its inner cell mass can be used to obtain stem cells as outlined above. The potential advantage of cloning via SCNT is that if the donor of the somatic cell nucleus is also the potential recipient, the resulting hESCs are less likely to be rejected by the recipient’s immune system when transplanted.

Clones could also be created by splitting an embryo at early stages of cell division; by inserting an embryonic stem cell nucleus into the cytoplasm of an egg; or by stimulation of egg cells such that they become embryos without being fertilized by sperm (parthenogenesis), although many of these techniques are highly experimental and have only been used with animal models.

Ethical Debates On Cloning

In 2005 in a split vote, the United Nations adopted a nonbinding resolution to prohibit all forms of human cloning as they are ‘‘incompatible with human dignity and the protection of human life’’ (United Nations, 2005). However, numerous countries (35 voted against and 37 abstained) did not support the resolution because it failed to distinguish between reproductive and nonreproductive cloning. Typically, ethical responses to cloning split in terms of purposes for which cloning will occur, though many claim that this distinction is difficult to maintain and will be difficult to monitor in practice (Bowring, 2004). Most commentators are opposed to human reproductive cloning, where the intention is to produce a cloned human embryo to implant in a woman in order to produce a pregnancy and eventually a child. There do not seem to be particularly strong rationales for creating this type of human clone, and there are concerns about safety and long-term effects based on animal models; reproductive cloning is explicitly legally prohibited in several countries.

Nonreproductive cloning or SCNT is less controversial for those who are not opposed to hESC research, as the clone is created for research purposes and destroyed at an early stage. This type of cloning is permitted in some countries (e.g., Korea and New Zealand) or is allowed with a license (e.g., the United Kingdom, China, and Australia). Some commentators argue that pursuing cloning research is an ethical imperative, so long as there is appropriate oversight, transparency, and accountability (Devolder and Savulescu, 2006). However, SCNT still requires the donation of eggs, and some ethicists have argued that women who are potential donors might be subject to coercion, including economic or workplace pressures (e.g., for those working in stem cell research labs), or that it would be difficult to foster truly informed consent (see Magnus and Cho, 2005). Many countries do not permit payment beyond reasonable medical expenses for egg donors, hence partially mitigating concerns about economic coercion.

Other Issues Related To hESC Research

Another key issue often raised in relation to hESC research is whether ASC (or somatic stem cell) research, which for many is much less morally problematic, might not be as useful (or more so). ASCs are undifferentiated cells found among differentiated cells in a tissue or organ, although their precise origin is unknown, they can renew themselves and it is thought that they can differentiate to yield the major specialized cell types of the tissue or organ, though perhaps not as many cell types as hESCs. Skeptics claim that ASCs are relatively rare, hard to find with available techniques, and difficult to culture outside of the body. Opponents of hESC research argue that ASC research holds as much if not more promise, and hence should be pursued instead of hESC (though they often conflate their ethical claims with scientific ones). Others would claim that there is no need to put the two types of research in opposition to each other, but that both lines should be pursued so long as there is reasonable evidence and expectation of benefit.

Some critics have argued that ART clinics may put pressure on women and couples to produce more embryos than are needed for IVF treatment in order to allow them to donate for research purposes. Consequently many countries have laws that prohibit donating embryos created after a certain date, which usually reflects when legislation governing hESC research was enacted. However, there seems to be little evidence of such practices occurring, and many safeguards (e.g., cooling-off periods following consent to donation and limits on the number of embryos produced) exist to counter these concerns.

A final set of ethical concerns are associated with the commercialization of these technologies and who will have access to any beneficial therapeutics that might be developed. Some feminist critiques of ART note that these technologies can contribute to oppression; in the case of hESC research, altruistic donation of eggs or embryos could be undermined if these donations are used for commercialized research.

Although many have noted that there is considerable hype associated with the promises held out for stem cell research, there still has not been adequate debate about the broader issues associated with it (Dresser, 2005), including the implications for public health. For instance, as disability advocates among others have noted, it is unclear whether the relatively high costs associated with current research, let alone potential costs associated with any therapies which might be developed, reflect adequate assessment or debate regarding appropriate allocation of health-care resources. As with many areas of medicine, it can be argued that a focus on the prevention of relevant disease conditions might prove more beneficial to a larger number of people. In addition, given that initial costs are likely to be extremely high for stem cell-based treatment options, concerns exist about the possibility for inequities in access. Furthermore, there is no consensus on whether limitations should be placed on commercialized research or how any benefits from such research are likely to reach those who most need care. The patenting of stem cell products might well keep them inaccessible for all but the most advantaged. Stem cell banks which keep resources including stem cell lines in the public domain and accessible to researchers worldwide are one key step in making certain that at least some of the results of research stay in the public domain. hESC research is likely to remain fraught with controversy, and policies about governing it should be made through transparent, democratic processes. The disagreements between opponents and supporters of hESC research are unlikely to be resolved, and hence policy makers face a difficult task of finding ways to accommodate deeply held, conflicting views, particularly when formulating public health policies.

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