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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: 12 May 2020

Ethical challenges regarding the use of stem cells: interviews with researchers from Saudi Arabia

• Ghiath Alahmad   ORCID: orcid.org/0000-0002-3331-4378 1 ,
• Sarah Aljohani 1 &
• Muath Fahmi Najjar 1  

BMC Medical Ethics volume  21 , Article number:  35 ( 2020 ) Cite this article

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With the huge number of patients who suffer from chronic and incurable diseases, medical scientists continue to search for new curative methods for patients in dire need of treatment. Interest in stem cells is growing, generating high expectations in terms of the possible benefits that could be derived from stem cell research and therapy. However, regardless of the hope of stem cells changing and improving lives, there are many ethical, religious, and political challenges and controversies that affect the research, and mandated to establish ethical guidelines and regulations. In Saudi Arabia, key stakeholders play an active role in discussing the ethics of stem cell research and therapy. The focus of the study was to explore professionals’ perceptions related to the ethical challenges of using stem cells in research and treatment in Saudi Arabia.

A qualitative research study was conducted to explore and describe the perceptions of 25 professionals employed at different tertiary hospitals in the various regions of Saudi. A thematic analysis was performed to search for and identify the most significant perceptions shared by the participants. Four themes were generated based on the ethical challenges of four areas related to stem cell use, including (1) forbidden and permitted sources of stem cells, (2) informed consent, (3) beneficence, and (4) ethical regulations and guidelines.

The study identified that there is a growing need to advance the knowledge, education, and awareness related to stem cell research and treatment in Saudi Arabia.

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Literature highlights the significance of understanding stem cell therapy and research to support the development of regenerative medicine [ 1 , 2 , 3 ]. McLaren reported that there are millions of individuals suffering from and succumbing to “incurable degenerative diseases of the nervous system, heart, liver, pancreas, and other organs” annually [ 3 ]. Similarly, Lovell-Badge discussed the fact that stem cells offer great hope for patients with enervating illnesses such as “diabetes, Parkinson’s, and Huntington’s diseases” [ 4 ]. In this context, medical practitioners consider stem cells as the hope and light for many patients who are suffering and in dire need of a cure [ 1 ]. However, as indicated by several authors, the use of stem cells, present many ethical, political, and even religious challenges, either related to resources, use, or rights of donors [ 5 , 6 ]. Bharadwaj mentioned the increasing movements of social and government concerns regarding stem cell research and clinical medication in countries such as the United States, United Kingdom, and Japan. More recently, emerging countries also incorporated stem cell therapies in their practices [ 7 ].

Lo and Parham provided a classification of the different ethical issues based on the four phases of stem cell research. The first phase is the “donation of biological material,” highlighting the problem of “informed and voluntary consent” [ 2 ]. The second phase, research with human embryonic stem cells, creates several ethical issues. These issues include the “destruction of embryos and the creation of embryos for research purposes” as well as financial compensation to oocyte donors, medical hazards related to the retrieval of the oocyte, and the need to protect the reproductive interests of women undergoing infertility treatment [ 2 ]. The third phase of the research is using stem cell lines obtained from other institutions leading to the issue of adverse legal and ethical principles [ 2 ]. The fourth and last step is the use of stem cells in clinical trials, encompassing both the advantages and disadvantages of the trial and informed consent [ 2 ].

Stem cell research in Saudi Arabia

Many Arabic countries conduct research with stem cells, as evidenced by the hundreds of scientific papers published in this field. Saudi Arabia is ahead in stem cell research as many universities, such as King Saud University and King Faisal Specialized Hospital and Research Center, started stem cell research more than 20 years ago [ 8 ]. In addition, many other research institutions, established later, play a leading role in this field such as King Abdullah International Medical Research Center with a specialized stem cell research department, including a stem cell registry containing more than 10,000 donors and the Cord Blood Bank [ 9 ].

From an ethical perspective, Saudi Arabia was the first country in the region to have ethical regulations related to the use of and research with stem cells. The Research Ethics Law promulgated in 2010 and its implementing regulation in 2012 includes all ethical guidelines to control stem cell research [ 10 ]. This was followed in 2014 by Jordan where a specific law about stem cell is announced [ 11 ]. In addition to these national laws, many research centers have institutional guidelines, for example King Faisal Specialized Hospital and Research Center and King Abdullah International Medical Research Center.

Though there is an abundance of stem cell research, the ethical component has not been researched in depth. There is no literature related to the views of physicians and researchers about the ethical challenges of using stem cells. It is important to explore this important issue to enhance the ethical component and maintaining the progress of stem cell research through finding appropriate solutions of all ethical challenges and obstacles.

Research design

A qualitative research design was used to explore and describe the perceptions and experiences of participants regarding the ethical challenges of using stem cells in a “subjective and reflexive manner” [ 12 ]. The aim was to gather, explore, analyze, and extract the most meaningful perceptions of the sample using interviews. The qualitative approach was deemed appropriate for the study to emphasize the content of the data to explore a specific phenomenon.

Data collection

We collected data from professionals employed at tertiary hospitals from various regions in Saudi Arabia where stem cell research have been conducted or are being conducted. The target population included physicians from any medical specialty or non-physician researchers doing stem cell research. We visited the potential hospitals and presented the objectives and purpose of the study. We collected contact information of potential participants with the permission from the gatekeepers of the hospitals and other pertinent representatives. We used a snowball sampling technique, defined by Clark and Creswell as the sampling of individuals based on the recommendations and suggestions of others [ 12 ]. Once a participant agreed to participate, we actively inquired from the participant to identify other possible candidates for the study. The technique allowed us to recruit 25 participants. The demographic characteristics of the sample are displayed in Table  1 .

We conducted individual semi-structured interviews with open-ended questions and audiotaped the interviews. Before conducting the interviews, written informed consent was obtained. The consent form highlighted voluntary participation, no monetary reward or promise. The privacy and confidentiality clauses were explained thoroughly. The interviews were held in a private room at the preferred time and date of the participants. Each interview lasted between 40 and 60 min.

Data analysis

After completing the 25 interview transcripts, data analysis commenced. The analysis involved identifying, analyzing, and reporting the most frequent and meaningful patterns or themes [ 12 ]. The analysis followed Braun and Clarke’s six-step process [ 13 ]. First, we familiarized ourselves with the interviews and actively read and reread the transcripts and generated initial codes as the second step. In the third step, we searched for themes across the data and the initial codes were categorized in the themes. We were mindful of the three objectives and purposes of the study to identify the most important points and concepts. The fourth step entailed the constant review of the themes, with the original data or the interviews. In the fifth step, the themes were named. Finally, the last step is the creation of the report as presented in the next section. We used the NVivo12 by QSR software to assist in the management and systematic tabulation of the themes.

A thematic analysis was performed to search for the most significant and meaningful responses from the sample. The thematic analysis resulted in four themes to address the three key objectives of the study. From the participant perspective, some sources are forbidden due to ethical issues. In addition, researchers and professionals must obtain an informed consent at all times (following the IRB) and follow the international regulations regarding stem cell research. The participants expressed the need to clarify the purpose of the research and storage procedures. Table  2 displays the themes in response to the study objectives.

Theme I: an exploration of the sample’s views regarding forbidden and permitted sources of stem cells

The participants’ position regarding the sources of stem cells can be classified in two categories: permitted and forbidden resources. The majority felt that some sources of stem cells should be forbidden because they may lead to serious religious issues, but some sources were considered safe and acceptable.

Adult stem cells as a source was considered safe providing the extraction is done within the prescribed processes and guidelines. An interviewee said, “S ources which are like skin liver heart these are allowed… Adult stem cells- allowed.” A second participant added, “Adult stem cells [are] approved for clinical use.”

Pluripotent stem cells are becoming an acceptable resource of stem cells, due to their positive and safe characteristics. An interviewee shared that the use of pluripotent stem cells is continuously advancing with the hope of curing different diseases, saying: “ Why not? It’s a new science, and the people are trying to use pluripotent stem cells in another type of... a different kind of disease, and there is a lot of clinical intervention a lot of clinical trials still under investigation there is no clear answer.” Another participant indicated that pluripotent stem cells are similar to adult stem cells and can easily be replicated, saying: “Pluripotent stem cells it’s actually an adult cell you reprogramed the genetic and you move it back so you can do anything with it.”

According to our interviewees, the umbilical cord is a safe and promising stem cell source. A participant commented, “umbilical cord is one of the best sources of stem cells.”

The participants also indicated that the placenta is a permitted source, and they experienced no issues as the placenta was used previously to extract stem cells. A participant stated that using the placenta is not harmful, saying, “We used to collect stem cells from the placenta. It is not invasive.”

Obtaining stem cells from fetuses were perceived differently. One group clearly and completely forbids any use of stem cells from any fetus, either intentionally aborted or accidently miscarried, regardless of the age of fetus. One of the interviewees responded that the use is strictly prohibited, stating, “This is forbidden” and a second indicated clearly and strongly, “Miscarried fetuses before reaching [120 days] the same, the same, forbidden.” This group of professionals stated that the aborted fetus is rejected as the institutions and stakeholders are aware that the use of such a source may lead to ethical dilemmas. As one of the participants expressed, “there may be ethical issues that go along with the use of an aborted fetus.” In addition, the use of embryonic stem cells may lead to more serious and critical religious issues. A participant stated, “That they must adhere to the religious teaching that one must not touch or alter the fetus.”

However, some of the participant accepted fetuses aborted for therapeutic reasons, but forbid stem cells obtained from fetuses aborted for non-therapeutic reasons. An interviewee said, “However, these source of stem cells that we’re using is probably less chaotic, and hence should be utilized or the regulations should be applied like any other biological materials.” Spontaneously miscarried fetuses can be accepted as a resource of stem cells, if they are less than 120 days of age. One interviewee said, “If the fetus is less than 120 days old, it is not considered a human, and we can use its stem cells.”

Theme II: an exploration of professionals’ opinions regarding the ethical challenges of securing informed consent, with IRB approval

The second thematic category explored the sample’s perceptions concerning the challenges related to obtaining informed consent for stem cell research. The participants emphasized the importance of informed consent to guarantee the voluntary participation of donors. One of the interviewees said, “We do have consent actually, we never collect stem cells without taking a consent from the patient. Sure, sure yeah, we take the permission before we start collecting the cells.” However, for umbilical cord blood, consent is obtained from parents, usually during the routine visits to clinics during the pregnancy, as expressed by one interviewee.

According to the participants, the consent should explain and clearly describe the purpose of the research. A participant said: “I think that the donor should be informed what exactly we are doing with tissue that he has that we take it from him.” Another said, “The scope of the research should be properly presented. Such practice will protect both parties, the researcher and donor, from future issues.”

All donor rights should be mentioned in the informed consent. One of the interviewees said, “Donors’ rights musts be clarified and explained to them, including, but not limited to, withdrawal right.”

The explanation should be in understandable, clear language and the terms and conditions of the forms should be simplified. The communication must be sufficient to ensure the donor understand fully. A participant narrated, “The researchers must take the time to orient and explain the content of the informed consent to the volunteers.” The informed consent documents should have been reviewed and approved by an ethics committee. A participant discussed the process of procuring the form, as follows: We submit the consent to the research office as a part of the submitted research proposal and then you will get IRB approval for all proposals including the informed consent.”

Theme III: an exploration of the professionals’ perceptions regarding the ethical challenges related to the benefit resulting from the stem cell research

The participants described the potential value of the sources of stem cells in the field of medicine and research. According to the majority, any use of stem cells should be beneficial, either to the donors or to the public. A participant said, “Even if there is no direct benefit to the donors themselves, but at least stem cells research should have some potential benefits to others.” A second opinion was “There are different applications and uses of the umbilical cord and it can save many patients today.” When using stem cells in treatment, the approved procedures should be followed meticulously, as explained by one of the interviewees, “Not following approved methods may lead to serious consequences.”

The sample emphasized the responsibility of being transparent when informing and communicating with the patient about any potential benefit. “It is very important not give the patients false hope about treatment by stem cells,” as expressed by one of the interviewees. A second participant was concerned about false hopes based on wrong assumptions, “I am very sad to see hopeless people spend all their earnings and energy in trying something that can never be a success.”

Theme IV: an exploration of stem cell research regulations

Four subthemes were developed related to the regulations related to stem cell research theme, including the importance of following international regulations, the need to use international guidelines based on Islamic laws (fatwas) and beliefs, no national law related to stem cells, and the need to increase the researchers’ knowledge about the ethical guidelines of stem cells.

The majority of the sample considered following regulations and guidelines consistently every time stem cells are used as an important issue. A participant explained, “ We have to follow the set procedures by regulators and the law because it involves safety of patients.” Our findings indicate that our researchers are using international regulations in their current practice and research with stem cells. One researcher said, “ Actually we are already use international guidelines. We used to follow that when I was getting my training in the west, and we here continue do the same.” Another researcher justified why international regulations should be followed, “Following the international regulations on stem cell research is needed for two reasons: the ethical principles are the same, and we are in many cases part of international multicenter research.” However, when applying these international regulations, Islamic law and fatwas should be taken in account. One of the participants explained, “Nothing that contradicts Sariah is acceptable, and this is true when it comes to stem cells, especially when it comes to the permitted or forbidden resources.”

The participants also indicated a lack of standardization in the local setting. A participant narrated that currently, they follow only the international regulations for their clinical trials and research. The participant described the increasing need for a targeted local policy related to stem cells, saying: “There is no national standardization as far as I know.” According to a second participant, the main issue in Saudi is the actual lack of a national law related to stem cell research and therapy, he commented, “Ethics must be a priority in Saudi to be able to create laws that would be in line with the local religious or spiritual beliefs.” Another participant also expressed the need to create local guidelines, which should match the international guidelines and not contradict the Islamic law. A last perspective was as follows: “Definitely, it’s good to have a supporting in fatwa for our patients satisfaction. This is because patients and the community rely on the fatwa more than the IRB. They don’t know about the IRB. So, I think that’s why the need the fatwa. I think we would reassure our patients about that.”

Many participants admitted that researchers lack adequate knowledge and information regarding ethical considerations and guidelines about stem cells research. One of the participants said, “The researchers themselves need to be trained or oriented in a formal setting to become aware about the ethical guidelines of using stem cells. ”

Though researchers are doing research in the stem cell field, they realize the ethical challenges they are facing in their research. Having spent a significant part of their scientific life in Western countries, they are aware of ethical issues; however at the same time, their cultural and religious background plays a role in their perceptions regarding the ethical challenges and how to deal with them.

The first point to manage appropriately is the source of stem cells, classified in permitted and forbidden sources. While the sample accepts adult stem cells in general, they have a different point of view regarding embryonic stem cells. These stem cells are affected by ethical, legal, and religious considerations, especially regarding the method of obtaining the cells and more specifically, when it results in destroying embryos who may have a degree of dignity and humanity, similar to other researchers, societies and universities in the west [ 14 ]. A particular concern is if the fetus is more than 120 days old, the time of soul installment according to Islamic law [ 15 ], which is in the middle between the two opposing opinions: the first sees embryos less than complete and conscious persons, while the second sees them equal to all human beings and should not be treated differently. The sensitivity related to using stem cells from embryonic sources resulted in a significant increase in the interest of adult stem cells in medical research, even though the lesser importance they have.

The researchers’ points of view about permitted and forbidden sources, as stated in the Saudi law of ethics of research on living creatures and its implementing regulations [ 10 ], match almost completely except for limiting the use of pluripotent stem cells to laboratories only. The researchers did not mention extra fetuses (extra fertilized eggs) which, as prescribed in the Saudi law, are not permitted as a source of stem cells. The reason may be because it is neither a common practice nor legal to use this source. Researchers where satisfied with the available sources, namely cord blood and imported cell lines.

The source of stem cells was not the only point discussed by the sample. They highlighted several factors to be considered to ensure stem cell research is ethical. The points are a component of the general rules related to conducting ethical medical research, locally and internationally [ 16 ]. It was expected that the sample would mention obtaining informed consent prior to any stem cell donation, adult or embryonic, before use. Informed consent should also be obtained from donors of adult stem cells. However, for embryonic stem cells, consent should be obtained from the parents. It is noteworthy that the researchers highlighted the importance of clarifying the purpose of stem cell donation to the potential donors to avoid any possibility of employing practices that may invalidate the consent. Mandating review and approval of an ethics committee of the informed consent form protect the donors who may miss understanding some points in the informed consent documents. Although there is no direct benefit to the donors from stem cell research, the altruism principle is an important motivation to donate stem cells, which is supported by studies in other regions [ 17 ]. The participants mentioned the importance that research should not be futile but have a direct or indirect benefit. The researchers recognize that stem cells have the potential of future success and many people, especially patients with chronic diseases and difficult to treat diseases, have placed their hope on stem cells. So, it is understandable that the sample mentioned repeatedly that patients should be warned against false hope and they emphasized the importance of transparency in stem cell treatment or research; the idea that is highlighted by other researchers [ 18 ].

The awareness of researchers about the importance of respecting and complying to international guidelines can be understood in the context of receiving tertiary education abroad where they internalized the international guidelines and conducted research according to these guidelines. Frequently, the current research in Saudi Arabia is a continuation of their previous research during their training. The second reason which explains the importance of following international guidelines is that the majority of research is multi-center international studies and following the same principles is essential for success.

The harmonization of ethical and legal rules related to stem cell research with the Islamic point of view is important due to two reasons. Firstly, the acceptance or willing participation of potential donors will significantly increase if they are informed that the research is in line with Islamic law, and secondly, the Research Ethics Law in Saudi Arabia mandates that all practices in stem cell research should be in line with Islamic rules to be allowed and legitimate. However, the sample where not sufficiently aware of the regulation related to stem cell research mentioned in the Saudi Law of Research Ethics [ 10 ]. This caveat reflects a lack of responsibility about keeping themselves updated, as the law is readily available on the website of the National Committee of Bioethics www.kacst.edu.sa . From another perspective, the offices responsible in the National Committee of Bioethics should promote the law efficiently to raise awareness in researchers and donors.

In conclusion, the participants of the study indicate various ethical challenges regarding the use of stem cells in research. For the majority of the participants, specific stem cell sources are forbidden in Saudi. Particularly, embryonic stem cells as the use may result in serious religious issues. The participants also reject aborted or (some) miscarried fetuses as a source. In response to the second objective, the ethical principles and challenges related to stem cell research were identified. The sample emphasized the importance of always securing IRB approval of the informed consent documents. Informed consent should include an explanation of the scope of the research and the participants’ rights, in simple understandable language to ensure complete understanding.

The majority of the participants reported that they already follow the international regulations related to stem cell research, which they had been exposed to during their studies and training, mostly in Western countries. However, surprisingly, they are not necessarily aware of existing national local laws, which reflects a critical need of research ethics education in general and in stem cell ethics in particular, through courses, conferences, and university programs-which are currently lacking in Saudi. Also, conducting analytic and comparative studies about stem cells in Saudi research ethics law may help to increase awareness among researchers. Additional in-depth research to include different categories with different levels will be very important at the next stage.

Availability of data and materials

The datasets generated during the study are available from the corresponding author on reasonable request.

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Acknowledgements

We would like to thank the experts involved in stem cell research who agreed to participate in our study.

This study was funded by King Abdullah International Medical Research Center. There was no role of the funding body in the study design, collection, analysis, interpretation of data and in the manuscript writing.

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(GA) designed, directed, analyzed and interpreted the study interviewee data and he was the major contributor in writing the manuscript. (MN) carried out the interviews with study subjects and he helped in drafting the manuscript. (SA) helped in interviewing, drafting, and reviewing the final manuscript. All authors read and approved the final manuscript.

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Alahmad, G., Aljohani, S. & Najjar, M.F. Ethical challenges regarding the use of stem cells: interviews with researchers from Saudi Arabia. BMC Med Ethics 21 , 35 (2020). https://doi.org/10.1186/s12910-020-00482-6

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• Volume 34, Issue 12
• The ethics of stem cell research: can the disagreements be resolved?
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• Jan Helge Solbakk 1 ,
• Søren Holm 2
• 1 Section for Medical Ethics, University of Oslo, Norway
• 2 Cardiff Law School, UK, and Section for Medical Ethics, University of Oslo, Norway
• Søren Holm, Cardiff Law School, Museum Avenue, Cardiff CF10 3AX, UK; holms{at}cardiff.ac.uk

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It is now 10 years ago that human embryonic stem cell research appeared as a major topic of societal concern following significant scientific breakthroughs. 1 2 During these 10 years it has become obvious that stem cell research is embedded in a narrative characterised by hope and hype and that it has created heated moral and political debate. Although it would be tempting to try to deconstruct the importance attributed to hope in this story or to unmask the different instigators active in promoting hype, 3 – 5 the main aim of this editorial is to briefly review the controversies underlying the debate and propose some possible answers to a set of inter-related questions:

What are the main disagreements in the stem cell debate?

Is there any hope that we can resolve these main disagreements?

Has the debate been a fruitful model for future debates about ethically contentious issues in biomedicine, or has it been characterised more by rhetoric than by argument?

What kind of ethical debates are most efficient as models for future debates?

WHAT KIND OF ETHICAL DEBATE IS MOST EFFICIENT AS A MODEL FOR FUTURE DEBATES?

Could it be the case that ethical debates that are characterised by overselling of the potential of the technology are more efficient as models for future debates about ethically contentious issues in biomedicine than more sober and “neutral” debates? The narratives of stem cell research are full of examples of overselling and underselling, and we will suggest that it is precisely for this reason that there is a lot to learn morally from reviewing the narratives. The two main forms of overselling are

therapeutic overselling (when considering the time required to achieve therapeutic breakthroughs as well as the potential of stem cell therapy); and

ethical overselling (ie, claiming that there exist possibilities of developing “clean” forms of stem cell therapy, that is, forms of stem cell therapy that are not contaminated with moral evil).

That overselling is a major component of the debate entails that the debate is a complicated mix of rhetorical arguments and more sound and reasoned arguments.

Is this a problem or a strength?

In the view of the protagonist of rhetoric, there are no possibilities of moral discourse without the use of such devices, because every form of discourse is disguised in some sort of rhetorical clothing. Furthermore, in moral discourse, at least three different forms of rhetoric are in play: first, a rhetoric aimed at manipulation (the contested form); second, rhetoric aimed at knowledge-based persuasion (the idealised form); and third, rhetoric aimed at creating moral visions (the underestimated form). All these forms of rhetoric may serve as means for making future debates about ethically contentious issues in biomedicine more fruitful, and it is unclear that we could ever agree on the precise borders between manipulation, persuasion and the language of the visionary. Besides, in ethical deliberation we learn more from previous mistakes than from exemplary reasoning—that is, morally speaking there is more to gain from negative models than from discourse about ethical forms of infallibility. Moral reasoning is characterised by a logic of a lesser purity than the logic of logic; it does not deal only with issues of logical consistency or the lack of it in people’s minds; it engages appetites, beliefs and desires as well, and it deals with emotions such as pity and fear. 6 7 Furthermore, it deals with coherence or the lack of coherence in people’s lives, not only in their arguments; and, finally, it deals with meaning and narrative. 8

WHAT ARE THE POSSIBILITIES OF RESOLVING THE DISAGREEMENTS IN THE STEM CELL DEBATE?

Having briefly addressed the role of over-selling and rhetoric in the stem cell debate, we shall now move to the questions directly addressing the possibilities of resolving the different controversies. Basically, it is possible to distinguish between two different types of disagreement in the stem cell debate. The first is disagreement about empirical findings and the interpretation of them. That is, researchers may disagree about the appropriate way of interpreting some of these findings and they may disagree about their scientific and medical implications, especially in the long run. These empirical disagreements will eventually become settled by the evidence. In 50 years’ time it will be possible to look back and say how important embryonic stem cell research has been for the development of therapy and for increasing basic knowledge about cell biology and embryology.

The second kind of disagreement comprises ontological and ethical disagreements about the moral status of human embryos and the moral status of cells derived from such entities. These disagreements reignite and transpose old conflicts from the abortion and embryo research debates to the stem cell arena 9 . The three main questions in play here are whether it is ever permissible 1) to use embryos for destructive research (the “moral status” issue); 2) to create embryos for destructive research (the “embryos as means” issue); and 3) to produce human–animal mixed embryos (the “are humans special” issue). A particular kind of stem cell research can actualise one or more of these issues. Can these disagreements also be resolved? Probably not by philosophical argument, or even by manipulative or persuasive rhetoric. There are no signs that the two heavily polarised sides in the debate are getting closer to agreement or compromise, and this is, furthermore, one of those debates in which those who advocate moderate positions are immediately attacked from both sides. This also makes a true compromise unlikely, because neither side is likely to be willing to give up key features of its position.

But maybe some other form of resolution is possible. Maybe society and its members do not need cast-iron moral certainty before reaching an accommodation. The absence of agreement or true compromise does not necessarily commit us to paralysis or crass Schumpeterian majority rule.

There are at least three reasonably realistic scenarios with regard to the future role of embryonic stem cells in the unfolding stem cell narrative:

The use of such cells will eventually become completely redundant owing to advances in adult or induced pluripotent stem cell research and therapies.

The use of such cells will continue to be important for research, but their use in therapies will be minimal.

The use of a large number of such cell lines will be a central component in future stem cell therapies—for instance, because the therapies will be personalised through somatic cell nuclear replacement technologies.

All three scenarios are built on the assumption that in a not too distant future, stem cell research will lead to therapeutic breakthroughs in some important therapeutic area, and we believe that that is fairly realistic.

If the first scenario becomes reality, human embryonic stem cells will be used only in an interim period, that is, only in the basic research phase and before the implementation of efficient stem cell therapies that do not involve such cells. In this scenario the issue of destruction of human embryos will therefore eventually disappear and the moral problem will be solved, although there will still be a lingering problem regarding whether the fact that research with human embryos was necessary to develop the therapies somehow taints the therapies morally. If, furthermore, the success is due to success in inducing somatic cells to pluripotency, 10 we create a new problem, since it may also, in a not too distant future, be possible to make human embryos from such cells! 11 Contrary to resolving the moral quandaries of stem cell research, this seems to resuscitate the potentiality argument—thus adding heat to the bonfire instead of extinguishing it. It is, however, beyond the scope of this editorial to analyse whether a possibility to make human embryos from any cell of the human body entails every cell having a potentiality to become an embryo. 12 13

The second scenario involves a continued use of human embryos in research but only limited use in therapies. As a matter of social development, it is likely that many societies would be willing to live with such a situation, while maintaining some official claim that human embryos deserve specific respect. This would be very similar to the present situation in assisted reproduction, where the sacrifice of a limited number of human embryos is accepted in order to get the therapeutic benefits for the childless.

What, then, about the third and last scenario? This is the scenario in which it is least likely that the ethical disagreements can be resolved, partly because the rhetoric of respecting the embryo while destroying it is most strained in this scenario.

It therefore seems that in two of the three scenarios it is likely that the controversies surrounding human embryonic stem cell research will be resolved. In scenario 1 they will truly disappear, whereas in scenario 2 the resolution will be achieved through a societal accommodation that may not be philosophically appealing but that is likely to work and be reasonably stable over time. This raises the interesting question of which of the three scenarios is the most likely.

Based on our discussions with stem cell scientists of many persuasions, we believe that it is the second scenario and that there is therefore a chance that the stem cell controversies will eventually recede from the societal scene to the pages of ethics journals. Whether this will happen, only time can tell.

Acknowledgments

The research underlying this editorial has been supported by the Norwegian Research Council (Going to the Roots of the Stem Cell Controversy project) and the Leverhulme Trust (International Stem Cell Ethics Network grant).

• Thomson JA ,
• Itskovitz-Eldor J ,
• Shapiro SS ,
• Schnieke AE ,
• Takahashi K ,

Competing interests: None declared.

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The Ethics of Human Cloning and Stem Cell Research

• Markkula Center for Applied Ethics
• Focus Areas
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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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Stem Cell Research as Innovation: Expanding the Ethical and Policy Conversation

Rebecca dresser.

Daniel Noyes Kirby Professor of Law and Professor of Ethics in Medicine at Washington University in St. Louis.

In 1998, researchers established the first human embryonic stem cell line. Their scientific triumph triggered an ethics and policy argument that persists today. Bioethicists, religious leaders, government officials, patient advocates, and scientists continue to debate whether this research poses a promise, a threat, or a mixed ethical picture for society.

Scientists are understandably excited about the knowledge that could come from studying human embryonic stem cells. Most of them believe these cells offer a precious opportunity to learn more about why diseases develop and how they might be prevented or attacked. In their quest to gain support for stem cell research, scientists and others have claimed that the research could generate cures and treatment for everything from heart disease to cancer.

Although most people are now familiar with claims about the diverse medical benefits stem cell research might deliver, they are less familiar with the diverse ethical issues relevant to the research. Most of the ethics debate focuses on the morality of destroying human embryos for the benefit of others. This is an important issue, but stem cell research raises other important ethical issues — issues that have received relatively little attention in the public arena. After more than a decade of narrowly focused analysis, it is time to expand the discussion.

The debate over embryonic stem cell research should consider a diversity of ethical and policy issues. Many of the ethical and policy issues that stem cell research presents apply to biomedical research in general, such as questions about appropriate research priorities and allocation of limited resources for research and health care. In this sense, the debate over stem cell research offers an opportunity to examine a variety of ethical and policy issues raised by biomedical innovation.

In this article, I place stem cell research in a broader ethics and policy context by describing three considerations that merit more attention in the debate. These include the following: (1) truth-telling and scientific integrity; (2) priorities in resource allocation for research and health care; and (3) responsibilities in civic discourse about bioethical controversies.

Truth-Telling and Scientific Integrity

New breakthroughs in biomedical science are often hailed as potential cures for the diseases that plague modern society. In many cases, however, the breakthroughs fall short of initial expectations. Innovations such as the artificial heart, fetal tissue transplantation, and gene therapy proved disappointing when they were tested in humans.

A similar result could occur with stem cell research. The excitement over stem cell research is unprecedented, and this creates fertile ground for exaggeration. Researchers, patient advocates, and politicians promise stem cell remedies for nearly every major health problem in the United States. And the promises come from both supporters and opponents of embryonic stem cell research. Supporters stress the advances possible through embryonic stem cells, while opponents emphasize potential therapeutic benefits from adult stem cells and other alternative sources. 1

The predictions on both sides violate the ethical responsibility to be accurate in describing the state of scientific exploration. Although there are a few established therapies that employ adult stem cells, most of the claims about stem cell therapies lack a solid evidentiary foundation. Much of the existing data comes from laboratory and animal studies. The first human trial of an embryonic stem cell intervention did not begin until 2009. 2 It will be many years before researchers can gather the human data necessary to determine whether stem cells will live up to their promise.

Much remains to be learned about the therapeutic abilities of stem cells. The cells’ treatment potential lies in their capacity to develop into different types of specialized human cells. The hope is that they could replace cells damaged through illness or injury. For this to work, however, scientists must understand more about how transplanted cells behave in the human body. They must also develop the power to control how the cells develop. Without this power, the cells could cause cancer or other harm to the recipient.

Because the immune system rejects foreign tissue, immune rejection is another possible barrier to effective therapies. 3 In theory, the problem could be solved by using stem cells created from a cloned embryo made with an individual patient’s somatic cell, but this procedure appears to present significant scientific challenges. 4 Moreover, economic and practical difficulties could impede efforts to devise therapies using stem cells from cloned embryos. 5 More work is also needed to determine whether induced pluripotent cells, the latest potential substitute for embryonic stem cells, could be safe and effective sources of replacement tissue. Novel uses of other kinds of adult stem cells also need further investigation to determine their clinical utility. 6

These and other scientific uncertainties make unqualified or barely qualified claims about therapies and cures from stem cell research ethically suspect. Ordinary people, including patients and their families, may be misled by such claims. They may develop unfounded hope for relief in a matter of months or years, rather than a more realistic understanding. They will be sorely disappointed once they become aware of the “significant technical hurdles… that will only be overcome through years of intensive research.” 7

Inflated promises about stem cell benefits can harm vulnerable people and can harm the research endeavor, as well. When members of the public realize that much work remains before effective therapies can be devised, their support for stem cell studies may diminish. They may become less willing to urge government support for the research, and less willing to contribute to nonprofit organizations supporting stem cell research.

The hype about stem cell research threatens scientific integrity, too. The field was undermined when the world learned of the fraud committed by South Korean researchers who claimed they had created stem cell lines from cloned human embryos. Besides dismay at the research team’s failure to observe basic standards of scientific integrity, there was speculation that editors and peer reviewers at Science , the journal that published the research, were too eager to publish the cloning reports. Some wondered whether scientists’ enthusiasm for the stem cell field led them to be less demanding than they should have been in their scrutiny of the research claims. 8

Other threats to scientific integrity arise when stem cell research becomes the basis for exaggerated claims by interest group lobbyists. Scientific organizations have claimed that limits on government funding for embryonic stem cell research could damage U.S. scientific preeminence. In the funding controversy’s early years, critics predicted a huge “brain drain” as U.S. scientists migrated to other nations offering generous support for the research. 9 Yet few scientists actually left this country to engage in stem cell research. 10 Several states stepped in to offer substantial funding, and nonprofit and private-sector support became available, too. 11 Even before the Obama administration revised the federal funding policy, U.S. researchers had many opportunities to pursue embryonic stem cell research.

Stem cell research has become a hot-button political issue, and this development could tarnish the public’s respect for and trust in science. Traditionally, science has enjoyed bipartisan support in the U.S., and in many respects, it still does. The debate over government funding for embryonic stem cell research does not divide along party lines. At the same time, however, politicians and their supporters have used the stem cell cause to advance partisan objectives. As one observer reported in 2006, “Politicians from both major parties are trying to use such research as a ‘wedge issue’ to woo voters.” 12

During the past decade, stem cell research became enmeshed in partisan politics from the national to the local level. Senator John Kerry made his support for federal funding of embryonic stem cell research a major theme in his 2004 campaign for the presidency. 13 For his part, former president Bush used his opposition to embryo destruction for research as a means to advance his campaign. 14 In the 2008 presidential election, both candidates claimed to support expanded federal funding for embryonic stem cell research, but the issue became politicized when research advocates warned that Senator John McCain’s position might change if he were elected. 15 Stem cells have also taken center stage in some state elections. In my own state of Missouri, where an initiative about stem cell research was on the November 2006 ballot, U.S. Senate and even county council candidates made stem cell research central to their election efforts. 16 The topic was a major issue in the 2006 New York governor’s race as well. 17

Stem cell research has joined abortion as a controversial matter on which politicians are expected to take a stand. It has become impossible to insulate this type of research from political debate. If stem cell research becomes identified with a particular political party or with specific candidates, then its fate could be determined more by politics than by substantive results in the laboratory. 18

There is one positive development in the public discussion about stem cell research. Many stem cell research supporters have begun to convey more realistic messages about the prospects for stem cell therapies. 19 In an ironic twist, one of the cautionary voices is James Wilson, who led the gene transfer trial in which Jesse Gelsinger died. Recounting the problems that came from the hype and haste surrounding clinical trials of gene transfer interventions, Wilson wrote in 2009, “I am concerned that expectations for the timeline and scope of clinical utility of [human embryonic stem cells] have outpaced the field’s actual state of development and threaten to undermine its success.” 20 He called on stem cell researchers and professional organizations, like the International Society for Stem Cell Research, to “steadfastly discourage” the exaggeration characterizing many claims about medical benefits from stem cell research. 21

Like Wilson, more experts and journalists express caution about the potential for stem cell therapies and focus instead on the value of stem cells as basic science tools that could help researchers understand how and why diseases develop. 22 But it is still easy to find examples of hype about stem cell therapies, such as in the publicity surrounding the first human trial of an embryonic stem cell intervention. 23

Like the Human Genome Project, stem cell research is most likely a form of scientific inquiry whose benefits will emerge slowly and incrementally. (Indeed, the Human Genome Project is now criticized as a costly research effort that to date has produced few actual medical benefits. 24 ) Rather than presenting stem cell research as a short-term answer for today’s patients, supporters should portray it as a promising scientific development that might, after many years of investigation, contribute to new medical interventions. 25 Just as physicians should be honest in disclosing a poor prognosis to a patient, scientists and advocacy groups should be honest about the lack of certainty that stem cell research will produce cures and effective therapies.

Social Justice and Allocation of Limited Resources

Stem cell research raises general questions about the appropriate allocation of government and private resources in biomedicine. One set of allocation questions addresses priority setting in biomedical research. The other set of allocation questions concerns the relative priority of research versus health care in funding decisions. These are questions that apply to biomedical research in general, but stem cell research nicely illustrates the relationship between research funding choices and social justice considerations.

Stem cell research is just one form of promising research. The National Institutes of Health (NIH), the largest public funder of biomedical science, supports many kinds of research offering opportunities to advance knowledge. The research portfolios of industry and nonprofit organizations also reveal an array of promising research areas. But neither the public nor the private sector can support every promising research project. Every research funding source has limited resources. As a result, these entities face hard choices about where to invest their limited dollars. How should funding agencies, nonprofit organizations, and private companies decide where to channel their resources?

According to NIH officials, five considerations play a role in the agency’s spending choices: (1) public health needs; (2) scientific merit of specific study proposals; (3) potential for advances in a particular area; (4) distribution across diverse research areas (because it is impossible to predict exactly where advances will occur); and (5) national training and infrastructure needs. The first criterion, public health needs, is determined by the following factors: (1) number of people with a specific disease; (2) number of deaths a specific disease causes; (3) degree of disability a specific disease produces; (4) how much a specific disease shortens the average lifespan; (5) a specific disease’s financial and social costs; and (6) the threat posed to others by contagious disease. According to the NIH, all of these considerations play a role in allocating research resources; none is rated as more important than another. 26

In the private sector, industry tends to allocate funds to research on conditions and products offering the greatest potential for financial reward. Many nonprofit organizations represent a single disease or demographic group and use their limited funds to support research that could benefit their specific constituencies.

The choices these entities make about research funding allocation raise social justice issues. As a publicly funded agency, the NIH has a duty to distribute its resources in a just manner. People disagree about whether private organizations have justice-based obligations, but a growing literature on corporate responsibility contends that even for-profit entities have a duty to consider the public good in their decision making. 27

What qualifies as a just approach to allocation of resources for research? The NIH priority-setting criteria incorporate justice-based considerations, but they are quite general. Moreover, officials have been unwilling to rank the criteria in order of importance. This means that the agency takes no position on the relative importance of, for example, research aimed at conditions that shorten the average lifespan and research aimed at conditions affecting the most people. In reality, critics say, the priority-setting criteria are so loose that congressional politics often determines where NIH dollars are directed. 28

The NIH criteria also leave open a significant social justice question, which is whether the U.S. has obligations to support research primarily aimed at helping people in poor nations. Some would contend that research funded by the U.S. government should address only domestic health concerns, but for many years, NIH has funded some international health research. There has been little public discussion of whether this approach is appropriate, however, and if it is appropriate, what portion of the NIH budget should be devoted to the health problems of people in other countries. 29

Although the proper approach to research priority setting is contested, the NIH criteria offer a framework for evaluating stem cell research. Much stem cell research is aimed at understanding and treating chronic diseases of aging, such as heart disease and neurological diseases. Indeed, some advocates proclaim that stem cell research will pave the way to “regenerative medicine,” in which the tissues and organs that deteriorate with age will be replaced with new ones created from stem cells. According to this group, interventions developed through stem cell research will substantially extend the human life span. 30

Not only are these predictions inconsistent with the duty to acknowledge the uncertainties accompanying early-stage research, they also raise resource allocation questions. Should extending the average U.S. life span be a high priority in research funding decisions? Would it be more defensible to give conditions that cause premature death a higher priority? Should strategies targeting prevention rather than treatment have a higher priority? 31

Another factor is the costs of the treatments that might emerge though stem cell research. Although basic science studies involving stem cells might help researchers develop new drugs and other relatively affordable medical interventions, the stem cell therapies that regenerative medicine enthusiasts describe could be relatively costly. As one group considering justice issues raised by stem cell research observed, “It seems inevitable, and of serious moral concern, that there will be significant economic barriers to access to new therapies utilizing stem cells or other cell-based preparations.” 32 If stem cell research produces expensive treatments, how many people will be able to benefit from the research investment? 33

Even more dramatic social justice questions arise when one considers biomedical research in an international context. Research is concentrated in wealthy nations and much of it focuses on the health problems of people fortunate enough to live in those nations. 34 Stem cell research is a prime example of this phenomenon, since much of the research (although not all of it) targets conditions arising later in life. But does justice require that prosperous nations devote more of their research funds to conditions that cause premature death in poor countries? 35

Questioning the justice of research funding allocation decisions may seem sacrilegious, given how popular biomedical science is in this country. But bioethicist Daniel Callahan presents the following thought experiment:

[C]onsider — as an imaginative exercise — what we would get if there was no progress at all from this point forward, and medicine remained restricted to what is now available. The rich countries would remain rich. Most of their citizens would make it to old age in reasonably good health. There would continue to be incremental gains in mortality and morbidity, the fruits of improved social, economic, and educational conditions, and improvements in the evaluation and use of present therapies. No prosperous country would sink from the lack of medical advances. 36

Another startling take on research priorities comes from neuroscientist Floyd Bloom. In his 2003 presidential address to the American Association for the Advancement of Science, Bloom declared that the quest for improved health care should focus more on health outcomes research than on the genomics research so often portrayed as a vehicle to medical advances. 37 These points provide a basis for considering stem cell research in a broader research context. Although stem cell research might eventually deliver benefits to some patients, benefits could also be achieved by investing resources in other kinds of research.

The social justice inquiry is relevant to many areas of biomedical research, not just stem cell research. Indeed, such an inquiry might support research on some conditions that are the focus on stem cell research, such as juvenile diabetes and spinal cord injury, which affect many young people. Nevertheless, it is important to see stem cell research as simply one of many scientific opportunities that could deliver health benefits. Investments in stem cell research will reduce the funds available for other types of biomedical research. In stem cell research, as in other research areas, the relative value and likely cost of any potential therapeutic benefits should be part of the decision making about research priorities.

A second matter of social justice concerns the relative priority of research needs and health care needs. Is it more important to conduct research aimed at improving care for future patients, or to provide better health care to today’s patients? In the U.S., as Daniel Callahan observes, “[T]he research drive has received an awful lot of money and great attention, but we have done less well with the delivery of health care….” 38 Because millions of people lack health insurance coverage and millions more have inadequate coverage, many patients are unable to benefit from the clinical interventions developed through past research efforts. 39 Is it ethical to devote large sums of money to research while so many people lack access to medical care that could give them longer and better lives?

Supporters contend that stem cell research is needed to aid patients with conditions that cannot be treated with existing therapies. From this perspective, there is a social justice basis for channeling limited resources to stem cell research. But those defending a moral duty to conduct stem cell research should consider another social justice perspective. Expanding access to health care would assist a currently disadvantaged group of people. Most standard health care interventions have been studied and found to be reasonably effective. Many are also relatively affordable. For these reasons, directing limited resources to health care delivery might achieve social justice objectives more efficiently than directing resources to stem cell research. This argument has even more force in the international context. Lack of access to basic health care, clean water, and other public health services produces high death rates in poor countries. 40 In this situation, small amounts of money can make huge contributions to improving and extending human lives.

What justifies our nation’s substantial investment in biomedical innovation, when millions of people here and abroad are denied access to proven medical interventions? 41 Once again, the stem cell controversy opens a window to a larger moral problem. The social justice inquiry raises questions about the priority that stem cell and other basic science studies should have in the competition for limited resources. If government officials and health advocates want to help patients, meaningful help would also come from a system that supplied adequate health care to more people, both across the nation and worldwide.

Responsibilities in Civic Discourse

People have passionate views on stem cell research. Their passion has had two detrimental effects on the public debate. One is the exaggeration about therapeutic benefits I referred to earlier. The other is disrespect for people with opposing positions. Too often, people caught up in the debate portray those with different positions inaccurately and unfairly.

Opponents of embryonic stem cell research use the slippery slope to cast aspersions on the morality of research supporters. According to some opponents, research supporters will accept almost anything to advance science and human health. Thus, for example, those who would allow the creation and destruction of human embryos to advance knowledge will also accept a world in which human beings are “grown for spare body parts.” 42 And any move to allow early embryos to be destroyed in research “will provide the leverage to thrust the research door open for Franken-steinian experimentation on the most vulnerable of our species.” 43

On the other hand, people supporting embryonic stem cell research belittle those assigning a high moral status to early human embryos. Underlying this attitude is disdain for anyone who would let religious and other moral beliefs influence their positions on science policy. Some scientists and advocates recognize that scientific considerations alone cannot determine appropriate state policy on embryonic stem cell research. 44 Others, however, seem to assume that morality has no place in the debate, or alternatively, that no rational individual could assign a high moral status to the early human embryo. As a columnist who supports embryonic stem cell research put it, “Only Bush bitter-enders and the pope are in the perverse position of valuing the life of an ailing human being less than that of a tiny clump of cells no bigger than the period at the end of this sentence.” 45

Misleading terminology also characterizes the stem cell debate. For example, many embryonic stem cell research supporters deny that they endorse human cloning. 46 Implicit in this claim is a narrow definition of human cloning that covers only the creation of a child through cloning. But the initial process of creating the cloned embryo (which research supporters prefer to call somatic cell nuclear transfer) is the same in research cloning and cloning to have children. 47 People who believe that the early human embryo has a high moral status do not differentiate between the two activities. Yet speakers often fail to clarify which definition of cloning they adopt, which leads to confusion in the public debate.

Also misleading is the term “therapeutic cloning,” which suggests to the layperson that this is a procedure with proven clinical benefit, rather than one that remains theoretical at this point. And in yet another form of terminology manipulation, embryonic stem cell research supporters characterize their proposals for liberal federal funding policies as efforts “to promote all ethical forms of stem cell research.” 48 This characterization avoids what is at the heart of the policy controversy, which is the question of whether or not research requiring embryo destruction is ethical. Such language games fail to give due regard to the moral disagreements underlying the policy disputes over stem cell research.

Decisions about U.S. stem cell research — whether to prohibit, regulate, permit, or financially support it — occur in the democratic context. The ongoing debates over stem cell research ought to reflect a better deliberative process than we have seen so far. In their work on deliberative democracy, political scientists Amy Gutmann and Dennis Thompson offer guidance for improving the deliberations over stem cell research. Below I describe their general framework for deliberative democratic policymaking and then apply it to stem cell policy formation.

Gutmann and Thompson describe four deliberative democracy characteristics relevant to stem cell research policy. First, policy arguments and choices must be supported by reasons. The requirement for reason-giving rests on a moral principle that underlies democracy: the principle that citizens should be regarded as agents participating in their society’s decisions. To participate in a democracy, citizens must understand why certain choices are made. Learning the basis for official actions allows people to challenge decisions that rest on false or misleading reasons. The reason-giving requirement also demonstrates respect for all citizens, no matter what their economic or political power happens to be. All are entitled to an explanation for the policies their officials impose. 49

Gutmann and Thompson describe a second feature of deliberative democracy, which is that the reasons underlying a policy must be accessible to all affected by that policy. Accessible reasons are understandable not only to those agreeing with the policy, but also to those opposing it. To fulfill this requirement, decision makers must publicly articulate their reasons for a specific policy choice and those reasons must have an acceptable public content. This means that reasons should rest on facts, rather than false information. Members of the public should also be able to evaluate the beliefs supporting a policy choice: “It would not be acceptable, for example, to appeal only to the authority of revelation, whether divine or secular in nature.” 50 In a deliberative democracy, Thompson and Gutmann maintain, individuals can disagree with a policy and at the same time conclude that the policy has a legitimate basis.

Deliberative democracy’s third characteristic addresses the status of policies over time. Deliberations are aimed at a specific policy decisions, and at some point those decisions must be made. Policies then become binding on citizens. But deliberative democracy requires that policies remain open to revision. If new facts are discovered that undercut the initial policy choice, officials should reassess their original choice. If emerging discoveries or events provoke people to new value judgments affecting their policy views, officials should take these changes into account. People should be free to challenge existing policies, and officials should make revisions when they are justified. As Thompson and Gutmann observe, those disagreeing with a policy choice will be more likely to accept it if they know they can in the future work to alter that choice. 51

Thompson and Gutmann discuss a fourth dimension of deliberative democracy with special relevance to the stem cell research debate. Participants in deliberations should aim for what Thompson and Gutmann call “economy of moral disagreement.” 52 This concept comes from the deliberative directive to respect those with values and positions that differ from our own. The concept “does not ask us to compromise our moral understandings in the interest of agreement, but rather to search for significant points of convergence between our own understandings and those of citizens whose positions, taken in their more comprehensive forms, we must reject.” 53 Deliberative democracy asks parties in disagreement to seek common ground, sometimes forgoing their ideal policies for ones that elicit greater agreement. 54

Policy debates about stem cell research should incorporate these features. Proponents of different policies should offer accessible reasons for their positions. For example, research supporters should go beyond simplistic slogans linking stem cell research with lifesaving cures. They should supply clear and accurate information about potential clinical results, tempering the promises of effective therapies with realistic accounts of what must be achieved before therapies become available. In turn, people promoting alternatives to embryonic stem cell research should supply clear and accurate information about adult stem cells, induced pluripotent cells, and other alternative sources that avoid embryo destruction. They too should speak of therapies as possibilities that remain uncertain and probably many years away. Both groups should emphasize that most stem cell work remains in the laboratory and that no one can say whether or when medical applications will emerge from that work.

Both advocates and opponents of embryonic stem cell research should also do a better job of confronting the moral questions raised by their positions. Those whose views reflect religious beliefs about the moral status of early human embryos should offer reasons for their positions that can be accepted by people who fail to share those beliefs. Those who claim to see the human embryo as an entity owed special respect should explain why embryo destruction is consistent with this moral status position. People worried about risks to women providing eggs to create embryos for stem cell research should explain why the usual human subject protections are inadequate in this situation. And those who think the risks to women are justified should consider how they will respond if women experience harm from the egg production process.

Adversaries in the stem cell debate should aim for an economy of moral disagreement as well, seeking to develop policies that individuals with differing positions could accept. For example, if people on both sides agree that the goal of improved health care justifies government funding for stem cell research, federal officials could decide to pursue that goal in a manner that demonstrates respect for those opposed to embryo destruction. Officials could for a limited time period fund only stem cell research using cells from alternative sources. If suitable alternatives failed to emerge during that time, government support could be redirected to research involving stem cells from destroyed embryos. A similar policy approach could be taken to research cloning, with support initially directed to research aimed at developing patient-matched stem cells through methods that avoid the need for donated eggs.

Policies incorporating the reverse presumptions might also be devised. Such policies would authorize financial support for embryonic stem cell research from IVF and cloned embryos for a limited period, but would cease such support once alternative sources became available. 55 Policies like these would demonstrate respect for those holding different positions on the ethics of creating and destroying embryos for research. And these options are not the only possibilities. A deliberative commitment in policy development could yield a variety of options that accommodate to some degree the different moral positions on stem cell research.

How does the latest development in federal policy look through the lens of deliberative democracy? In the 2009 revision of the federal funding policy for stem cell research, some features of deliberate democracy were evident, but there were deliberative shortcomings as well. In announcing his plans to liberalize the policy, President Obama cautioned against exaggerating the possibility of medical benefits from the research. At the same time, he characterized the research as a step toward the “day when words like ‘terminal’ and ‘incurable’ are potentially retired from our vocabulary.” 56 He recognized the moral opposition of “thoughtful and decent people” to embryonic stem cell research and spoke of avoiding the “perils” the research presents through “proper guidelines and strict oversight.” 57 But he neither defined those perils nor explained how guidelines and oversight would avoid them. Thus, the president gave a nod to the moral dispute and the importance of supplying accessible reasons for the position he endorsed, but the deliberative effort was relatively superficial.

The final NIH Guidelines on Human Stem Cell Research 58 also exhibit deliberative strengths and weaknesses. The guidelines permit federal funding for research on stem cell lines created from embryos donated by couples who have completed their infertility treatment. But the guidelines rule out funding for research using lines created from embryos produced purely for research. In published commentary on the guidelines, NIH officials said there was “broad public support” for funding research using stem cells from donated embryos, but that “a similar consensus has not emerged” on the ethics of creating stem cells through procedures like cloning, in part because they require women to provide eggs at some risk to their health. 59 In this respect, we can see an effort to provide accessible reasons for the decision and, possibly, to economize moral disagreement by allowing only limited expansion of the funding rules.

But another aspect of the guidelines failed to conform to deliberative ideals. In a telephone press briefing on the final guidelines, Acting NIH Director Dr. Raynard Kington said the agency had received thousands of comments opposing government funding of any research using stem cell lines created through embryo destruction. The official commentary on the guidelines neither mentions those comments nor explains why they did not prevail. In the telephone briefing, Dr. Kington said that agency officials deemed the comments “nonresponsive” to their request for comments on the guidelines they had proposed earlier in the year. 60 A robust deliberative approach would have acknowledged the high number of opposing comments and devoted at least a few sentences to explaining why the agency’s position differed from that taken in the comments. 61

Stem cell research could generate knowledge that would allow certain individuals to live longer and better lives. It would be a happy event if in the future stem cell research produced relief for at least some individuals with illnesses or injuries not curable at present. Yet there are no guarantees that this happy future will materialize. Although we may support and admire the scientists devoted to developing a better understanding of human health and disease, we should also be aware that no one can ensure that effective treatments will emerge.

The therapeutic benefits of stem cell research are possible, but uncertain. And many other areas of biomedical science fit this description. Stem cell research is not the only field in which exciting discoveries are occurring and future patients may benefit from investments in these areas, too. This is not a reason to deny support to stem cell research, but it is a reason to consider it in a larger context. Advocates weaken their case when they portray stem cell research as if it were the only promising research around. 62 More government support for stem cell research could help patients in the future, but so could support for research in other biomedical fields.

Participants in the stem cell debate should also recognize deficiencies in the health system denying patients the benefits of past research. Advocacy for stem cell research should include advocacy for a better health system. Without improvements in this system, any therapeutic benefits developed through stem cell research will be unjustly limited to patients fortunate enough to have access to the best health care. 63

Moreover, the stem cell controversy should press us to reexamine existing research and health care priorities. Should officials devote more funds to research aimed at translating laboratory discoveries into actual clinical benefits? 64 Should they channel more funds to studies that could have a significant public health impact? And what level of investment should the U.S. make in programs aimed at developing and delivering affordable care to disadvantaged people in this nation and around the world? These are ethical questions with immense significance, but they are often overlooked amid the excitement over specific research discoveries like those involving stem cell research.

Last, ethical considerations sometimes justify setting limits on scientific innovation. For example, there is nearly universal agreement that people should not be forced to participate in research, even though a coercive research policy could generate extremely valuable knowledge. Some people believe there should also be severe limits on research involving early human embryos, while others disagree. These are not disputes that science can settle. They are instead value conflicts to be expected in a pluralistic society like ours. In struggling with these conflicts, we should maintain respect for those holding differing views, and we should look for policies that are consistent with as many of those views as possible.

Advocates often portray stem cell research as presenting a choice between ending human life and saving human life. 65 But the choices are much more complicated than that. Many ethical considerations are relevant to policy choices about stem cell research, but they often go unmentioned. Instead, the sound bite approach to stem cell research has produced a shrill and divisive policy climate. Fewer sound bites and an expanded ethical conversation could produce more defensible policy decisions about stem cell research.

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Study uncovers multiple lineages of stem cells contributing to neuron production

by Elena Garrido, Miguel Hernandez University of Elche

The development of the cerebral cortex largely depends on the stem cells responsible for generating neurons, known as radial glial cells. Until now, it was believed that these stem cells generated neurons following a simple process, that is, a single cell lineage.

However, a study led by the Neurogenesis and cortical expansion laboratory, headed by researcher Víctor Borrell at the Institute for Neurosciences (IN), a joint center of the Spanish National Research Council (CSIC) and the Miguel Hernández University (UMH) of Elche, has discovered not only that there are many more types of radial glial cells than previously thought, but also that there are at least three different processes of neurogenesis that occur in parallel in the same brain areas and at the same moment of development.

The results of this work, published in the journal Science Advances , reveal the complexity of neurogenesis through the involvement of parallel lineages. "We have discovered that there are several alternative routes to generate neurons and that all the routes work at the same time, although we have also seen that the final result is always a neuron with similar characteristics and functions at that stage of development," explains Borrell.

Furthermore, researchers find evidence that the existence of parallel lineages is related to the folding of the cerebral cortex. "A fundamental aspect in this sense is that the 'routes' to form neurons work at the same time and in the same place, but not in the same quantity throughout the cortex, being different between gyrus and sulcus," says the article's first author, Lucía del Valle Antón.

To understand this link, researchers have studied the formation of neurons in regions that will undoubtedly give rise to a gyrus and a sulcus in the ferret brain, while, by using public databases, they have also been able to analyze it in human and mouse brains.

During the development of the study, in which the researcher Juan Antonio Moreno Bravo, who directs the Development, Wiring, and Function of Cerebellar Circuits laboratory, also participated, the experts observed that, although the three lineages are functioning in both gyrus and sulcus zones, different processes predominate depending on the location.

"At first, the cortex is smooth, but there is an area that will grow a lot, and as it grows, it will end up forming a gyrus. Meanwhile, next to it, other areas will grow less and will remain sunken, forming a sulcus," says Borrell. "The first difference between a gyrus and a sulcus is how much it grows, and this is related to how many neurons will be born in that place. For example, in the sulcus, what we find is that of these three 'routes,' the one that generates fewer neurons predominates, while in the gyrus, the opposite will happen."

Understanding the existence of these new types of stem cells , which possess a high capacity for division, along with the various mechanisms for generating neurons in parallel, enables us to comprehend the processes that lead to the enlargement of the human cerebral cortex compared to other species.

This research has allowed scientists to explore, with unprecedented detail, the genes expressed by neurons in both the gyrus and the sulcus. Borrell explains, "We aimed to observe which of all the cells we investigated express genes known to be mutated in human malformations. We verified that not all these cells express the genes responsible for these brain malformations. We observed that they are mainly expressed by the newborn neurons, rather than the progenitors."

Along these lines, the researcher highlights that, despite having the same functions at a global level, the neurons that are born in the gyrus express genes that are essential for the human cortex to have gyri. This indicates that, when patients have malformations because their brain lacks gyri, the defects occur specifically in the neurons of the gyrus and not in those of the sulcus.

International collaboration

In this study, which involved collaboration with researchers from the ISF Stem Cell Research Institute (Helmholtz Zentrum) and the Max Planck Institute for Biological Intelligence, both located in Munich (Germany), the researchers based their results on the sequencing of individual cells at the transcriptomics level, a technique that enables us to identify all the genes that are expressed in each of the cells.

Scientists analyzed thousands of cells using informatics tools to determine the genetic trajectory of these cells and their respective lineages. Upon investigating and validating the lineage data across the three species, they observed that in the human brain, these three parallel lineages also occur, similar to what is observed in ferrets.

However, in the case of mice, analyses conducted have observed only a single predominant route in the creation of neurons. Future research will be necessary to determine whether mice lost these lineages due to evolution or if, on the contrary, these "routes" are still present but in such small proportions that they are undetectable with current tools.

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• Published: December 1999

Stem cell politics, ethics and medical progress

• George J. Annas 1 ,
• Arthur Caplan 2 &
• Sherman Elias 3  

Nature Medicine volume  5 ,  pages 1339–1341 ( 1999 ) Cite this article

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Tremendous controversy has surrounded efforts to undertake research on totipotent human stem cells. To date public policy in the United States has attempted to skirt the ethical and social questions raised by this research. Annas et al. argue that research using human embryos as a source of totipotent stem cells can secure broad public support if there is an open and public discussion about the ethical justification for undertaking such research and the assurance of adequate federal regulation and oversight.

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Thomson, J.A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282 , 1145–1147 (1998).

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• Published: 26 April 2023

Regeneration of the heart: from molecular mechanisms to clinical therapeutics

• Qian-Yun Guo 1 ,
• Jia-Qi Yang 1 ,
• Xun-Xun Feng 1 &
• Yu-Jie Zhou 1  

Military Medical Research volume  10 , Article number:  18 ( 2023 ) Cite this article

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Heart injury such as myocardial infarction leads to cardiomyocyte loss, fibrotic tissue deposition, and scar formation. These changes reduce cardiac contractility, resulting in heart failure, which causes a huge public health burden. Military personnel, compared with civilians, is exposed to more stress, a risk factor for heart diseases, making cardiovascular health management and treatment innovation an important topic for military medicine. So far, medical intervention can slow down cardiovascular disease progression, but not yet induce heart regeneration. In the past decades, studies have focused on mechanisms underlying the regenerative capability of the heart and applicable approaches to reverse heart injury. Insights have emerged from studies in animal models and early clinical trials. Clinical interventions show the potential to reduce scar formation and enhance cardiomyocyte proliferation that counteracts the pathogenesis of heart disease. In this review, we discuss the signaling events controlling the regeneration of heart tissue and summarize current therapeutic approaches to promote heart regeneration after injury.

Cardiovascular disease is the leading cause of death and accounts for approximately 32% of global deaths, resulting in the losses of 17.9 million lives each year [ 1 , 2 ]. Military personnel is significantly more likely to report higher work-related stress than civilians [ 3 , 4 ], contributing to the long-term development of cardiovascular diseases and acute triggering of heart failure [ 5 ]. Cardiovascular disease represents the cause of more than 10% of military pilots’ groundings [ 6 ]. The rate of heart failure among hospitalized veterans reaches as high as 0.5% [ 7 ]. These studies highlight the importance of cardiovascular research in military medicine. Despite tremendous efforts and advances in cardiovascular research and therapies, heart failure continues to maintain high mortality and morbidity rates [ 1 , 8 ]. Taking longer life expectancy, higher rates of obesity, diabetes, and modern lifestyle into consideration, epidemiologic studies predicted a 46% increase in heart failure patients by 2030 [ 9 , 10 ]. Figure  1 illustrates the standard of care for managing heart failure. Currently, pharmacological treatment can slow down heart failure progression, but it still needs a breakthrough.

Standard of care for heart failure. Pharmacological treatment and medical devices are currently being used to manage the progression of diseases. β-blocker, ACEi, MRA, and SGLT2i are usually used for all patients with heart failure in order to reduce mortality. For selected patients, diuretic, ivabradine, and digoxin might be used. For advanced stage patients, device and surgery would be recommended. ACEi angiotensin-converting enzyme inhibitor, ARNi angiotensin receptor neprilysin inhibitor, ARB angiotensin receptor blocker, MRA aldosterone receptor antagonists, SGL2i sodium glucose cotransporter 2 inhibitor, HR heart rate, CRT-P cardiac resynchronization therapy-pacemakers, CRT-D cardiac resynchronization therapy-defibrillators, ICD implantable cardioverter defibrillator, MCS mechanical circulatory support

Potential approaches for cardiac regeneration have been tested, including strategies based on in situ cellular reprogramming and de novo tissue engineering methods. Although promising data have been accumulated, each of these approaches faces challenges. Cardiomyocytes of the adult human heart are terminally differentiated and have virtually no regenerative capacity, making it hard to reboot the proliferation of cardiomyocytes after injuries [ 11 ]. Although tissue engineering approaches have developed rapidly owing to the improvement of biomaterials and 3D printing, creating a functional heart in vitro remains a great challenge [ 12 ]. Stem cell-based therapies attempt to promote heart regeneration by injecting stem cells into patients. However, the survival, anchor, differentiation, and maturation of stem cells at the injured site are hard to control, and thus require further optimization before being ready for clinical practice [ 13 , 14 ]. Recent studies suggest that the substances secreted by stem cells may promote heart regeneration [ 15 , 16 ], initiating the search for drugs that target the molecular signaling pathways induced by these substances. Therefore, further understanding the molecular mechanism controlling heart regeneration will help to facilitate the emergence of new therapies that could restore cardiac function. This review summarizes the molecular signaling pathways for heart regeneration and discusses the progress and challenges of approaches for heart regeneration.

Role of molecular signalings in heart regeneration

Notch and notch intracellular domain (nicd) promote cardiomyocyte proliferation and inhibit immune cell infiltration.

Heart regeneration was first described in zebrafish 20 years ago by Poss et al. [ 17 ]. Since this milestone study, the underlying signaling pathways have been extensively studied, as summarized in Fig.  2 , first, showing that Notch mediates heart generation [ 18 ]. Since then, efforts have been made to understand the signaling events boosting cardiomyocyte proliferation, with the hope of aiding human heart regeneration. Notch signaling plays an important role in regulating endocardium maturation via serpine1. Inhibiting or activating Notch both result in impairment of heart regeneration, indicating a dynamic change of Notch activity is crucial [ 19 ]. In addition, Notch signaling in the endocardium interacts with cardiomyocytes as an antagonist for Wnt signaling and promotes cardiomyocyte proliferation [ 20 ]. Following the initial inflammatory response, the endocardium and epicardium regenerate first to provide the right environment for cardiomyocyte proliferation. For example, the endocardium and epicardium secrete retinoic acid, and the epicardium produces fibronectin of extracellular matrix (ECM) [ 21 , 22 ]. The newly-formed heart muscle is found to populate via cardiomyocyte dedifferentiation and proliferation [ 23 ]. A study by Gemberling et al. [ 24 ] demonstrated that neuregulin 1 (Nrg1) is up-regulated after heart injury and serves as a potent inducer of cardiomyocyte proliferation. Notch signaling is also involved in this process, and a remarkable increase in Notch1b and DeltaC expression has been observed [ 18 ]. Interestingly, both Notch inhibition and Notch overexpression have been found to inhibit cardiomyocyte proliferation and heart regeneration, suggesting a delicate balance of this pathway is required [ 25 ]. Further studies by Pfefferli et al. [ 26 ] and Gupta et al. [ 27 ] have distinguished the contribution of different layers of cardiomyocytes during regeneration. Fate mapping with careg:EGFP has shown that the primordial cardiac layer incompletely regenerates after cryoinjury and grow restrictively by lateral expansion, while cortical and trabecular layers are primarily responsible for myocardium growth. When overexpressed specifically in cardiomyocytes, Notch also improves cardiac function by reducing the formation of scars [ 28 ]. Notch signaling pathway as a potential target for therapeutic approaches has been recently discussed [ 29 ]. Functional screening of congenital heart disease risk loci shows that maml3 mutants can decrease cardiomyocyte proliferation through inhibition of Notch signaling [ 30 ], indicating that overexpression of maml3 may induce cardiomyocyte proliferation by activating Notch.

Signaling pathways in heart repair and regeneration. Hippo-YAP, Notch and Nrg-ErbB signaling pathways are the major players in regulating heart repair and regeneration after injuries. Hippo-Yap regulates cardiomyocyte proliferation, migration, and apoptosis, thus affecting scar formation after injury. Notch signaling controls cardiomyocyte proliferation, as well as immune cell infiltration and endocardial cell maturation. Nrg-ErbB signaling affects cardiomyocyte dedifferentiation, division, and survival. FAT4 FAT atypical cadherin 4, MST macrophage stimulating, SAV1 salvador family domain-containing protein 1, LATS large tumor suppressor kinase, MOB1 MOB kinase activator 1, YAP Yes-associated protein, TAZ tafazzin, phospholipid-lysophospholipid transacylase, TEAD TEA domain family, ADAM ADAM metallopeptidase domain, NICD Notch intracellular domain, MAM mastermind, CSL citrate synthase like, ErbB2 Erb-B2 receptor tyrosine kinase, RAF v-raf-leukemia viral oncogene, PI3K phosphatidylinositol 3-kinase, MEK1 mitogen-activated protein kinase kinase 1, ERK extracellular signal-regulated kinase, Akt protein kinase B, mTOR mechanistic target of rapamycin kinase, JUN Jun proto-oncogene, ETS ETS transcription factor family, FOS FBJ osteosarcoma oncogene, LRP LDL receptor related protein, GSK-3β glycogen synthase kinase-3 beta, TCF T-cell factor, LEF lymphoid enhancer factor

Hippo and Yes-associated protein (YAP) regulate cardiomyocyte proliferation and scar formation

The Hippo-YAP pathway is highly conserved and plays a pivotal role in cardiomyocyte cell cycle re-entry. Hippo deficiency enhances cardiomyocyte regeneration and heart functional recovery while reducing scar formation after myocardial infarction in adult mice [ 31 , 32 ]. The Hippo-deficient cardiomyocytes express higher levels of proliferative and stress response genes, such as Park2 [ 32 ]. YAP, the inactivated downstream effector of Hippo, is abundant in neonatal heart tissue but not in adult heart tissue. Recent studies found YAP to be a key regulator for cardiac development and regeneration in mice [ 33 , 34 , 35 ]. Similar to inhibiting Hippo, activation of YAP results in less scar formation and improved heart function after myocardial infarction at postnatal days 7 and 28 as well as adult stages [ 35 , 36 ]. In Erb-B2 receptor tyrosine kinase (ErbB2)-overexpressed mice, YAP mediated a robust epithelial-mesenchymal transition (EMT)-like regeneration by interacting with the cytoskeleton and altering the mechanical characteristics of the cell [ 33 ]. In addition, non-coding RNAs make up a major part of the complex regulatory signaling network. Eulalio et al. [ 37 ] found that miR-199a and miR-590 can effectively induce cell cycle re-entry of cardiomyocytes in vitro as well as in neonatal and adult mice. In murine myocardial infarction models, overexpression of miR-199a and miR-590 via single-dose injection of synthetic RNA promotes cardiac regeneration and recovery of cardiac function [ 37 , 38 ]. Recently, Gabisonia et al. [ 39 ] found that, using infarcted pig hearts, miR-199a was shown to facilitate cardiac repair and increase muscle mass and contractility. Follow-up studies on miR-199a have identified potential downstream signaling, such as CD151 [ 40 ], mechanistic target of rapamycin (mTOR) [ 41 ] and Wnt2 [ 42 ]. Cardiac-specific overexpression of miR-128 in neonatal mice attenuates cardiomyocyte proliferation and functional recovery after myocardial infarction. miR-128 regulates cardiomyocyte cell cycle re-entry via SUZ12, a chromatin modifier that targets p27, cyclin E, and CK2 [ 43 ]. Overexpression of miR-195 (a member of miR-15) leads to reduced proliferation and hypertrophy of cardiomyocytes, while inhibition of the miR-15 family increases cardiomyocyte proliferation after myocardial infarction in adult mice. The downstream target of miR-195 includes cell cycle genes, mitochondrial genes, and inflammatory genes [ 44 ]. Similarly, miR-1/-133a is also a negative regulator of cardiomyocyte cell cycle re-entry in the adult heart. Short-term deletion of miR-1/-133a protects against myocardial infarction. However, long-term deficiency leads to heart failure [ 45 ]. circNfix, a circular RNA, is up-regulated in the adult hearts of humans and mice. Knocking down circNfix releases suppression on downstream cyclinA2 and cyclinB1 and increases miR-214 activity, leading to enhanced cardiomyocyte proliferation and recovery after injury [ 46 ]. miR-152 has been found to be a target of Toll-like receptor 3 (TLR3) and induces cardiomyocyte proliferation by regulating cell cycle proteins downstream of YAP1 [ 47 ]. Recent study shows that FAM122A, an endogenous inhibitor of protein phosphatase 2A, is a novel regulator in the mesendodermal specification and cardiac differentiation via Hippo and Wnt signaling pathways [ 48 ]. In the first step, RNA-binding protein LIN28a stimulates the formation of new cardiomyocytes and prevents cardiomyocyte apoptosis [ 49 ]. Activation of YAP promotes progenitor regeneration by triggering LIN28a transcription [ 50 ].

To date, little is understood about the removal of the scar and the functional integration of regenerated cardiomyocytes. The collagenolytic activity was detected in the injured region between day 14 to 30. In the same period, expressions of matrix metalloproteins (MMPs), such as MMP-2 and MMP-14a, are up-regulated, suggesting a potential role for them in scar removal [ 51 ]. Expression of miR-101a is inhibited after the onset of injury but up-regulated between days 7 to 14. Suppression of miR-101a promotes cardiomyocyte proliferation but inhibits scar removal. Depletion of the downstream target gene Fosab rescued the scar-clearing defect of miR-101a inhibition, demonstrating that miR-101a regulates scar removal via Fosab [ 52 ]. Scar formation is regulated by YAP signaling, and macrophages directly produce collagen to make up the scar [ 53 , 54 ]. Deletion of YAP from zebrafish does not affect the proliferation of cardiomyocytes but leads to larger injuries, showing that initial scar formation is important to control the damage [ 53 ]. In zebrafish, fibrosis does not preclude scar-free regeneration [ 55 , 56 ].

ErbB/PI3K/ERK and Wnt/β-catenin control cardiomyocyte proliferation, dedifferentiation, and inflammation

The Nrg1/ErbB has been recognized as a potential signaling pathway involved in the heart regeneration program. Nrg1 was initially proposed for its potential relevance to mitogenic effects in mammalian cardiomyocytes and further was proved in the post-injured zebrafish heart by Gemberling et al. [ 24 ], which provided the foundation for mouse experiments and clinical trials. In adult mice, injection of Nrg1 induces cell cycle re-entry and cardiomyocyte division. Inactivation of the tyrosine receptor ErbB4 for Nrg1 reduces cardiomyocyte proliferation, while stimulation of ErbB4 enhances it [ 57 ]. The deletion of another co-receptor for Nrg1, ErbB2, also shows its importance for cardiomyocyte proliferation in neonatal mice. Constitutive activation of ErbB2 in both neonatal and adult mice leads to cardiomyocyte proliferation and dedifferentiation via extracellular signal-regulated kinase (ERK), protein kinase B (Akt) and glycogen synthase kinase-3 beta (GSK-3β)/β-catenin downstream signaling. Notably, transient activation of ErbB2 promotes regeneration after myocardial infarction in mice [ 58 ].

The initial inflammatory response is required for complete regenerative capacity. Anti-inflammatory treatment reduces cardiomyocyte proliferation and impairs the vascularization of newly-formed tissue, resulting in an inability to clear the fibrotic deposition [ 59 ]. In contrast, the immune cell is not required for cardiomyocyte mitotic activity under normal conditions [ 59 ]. Fang et al. [ 60 ] have found that inflammatory cytokines promote cardiomyocyte proliferation via activating JAK1/STAT3 signaling. Inhibiting this signaling by expressing a dominant negative form of STAT3 leads to a reduction in cardiomyocyte proliferation. MAPK/ERK acts as a critical signaling for vertebrate tissue regeneration; its potential roles in tissue engineering and regenerative medicine have been emphasized [ 61 ]. Kynurenine stimulates cardiomyocyte proliferation by activating the cytoplasmic aryl hydrocarbon receptor-SRC-YAP/ERK pathway; it also stimulates cardiac angiogenesis by facilitating aryl hydrocarbon receptor nuclear translocation and increasing vascular endothelial growth factor A (VEGF-A) expression [ 62 ]. Dual-specificity phosphatase 6 (DUSP6), which can dephosphorylate ERK1/2, is a regenerative repressor during zebrafish heart regeneration [ 63 ]. Deletion of Dusp6 in mice improves cardiac outcomes by reducing neutrophil-mediated myocardial damage induced by myocardial infarction-caused inflammation [ 64 ]. Furthermore, a DUSP6 inhibitor has been tested in myocardial infarction rats, showing that it improves heart function and suppresses inflammatory cardiac remodeling [ 65 ]. In addition, the cardiac-derived ECM may provide an ideal scaffold for heart tissue engineering [ 66 ], and nuclear pore numbers are decreased during cardiomyocyte maturation, and this reduces nuclear responses to activation of MAPK induced by extracellular signals [ 67 ]. Activation of Nrf1, a stress-responsive transcription factor is seen in regenerating cardiomyocytes. Nrf1 overexpression can protect the heart from ischemic injury, while deletion inhibits neonatal heart regeneration by affecting proteasome and redox balance [ 28 ]. The role of Wnt in promoting cardiomyocyte differentiation has been further investigated, showing that it may provide a powerful tool for stem cell-based regeneration therapy [ 68 ]. These studies suggest that the molecular events initiated by extracellular signals may have therapeutic benefits for heart regeneration.

Approaches and challenges for heart regeneration

The fate mapping experiments in mice have shown that new cardiomyocytes originate from pre-existing ones, during homeostasis [ 69 ], after injury in adults [ 69 , 70 ], and during neonatal heart regeneration [ 71 ]. In addition, using a transgenic line of hypoxia-inducible factor-1α (HIF-1α), Kimura et al. [ 70 ] showed that hypoxic cardiomyocytes exhibit characteristics of neonatal heart cells and contribute mostly to cardiomyocyte formation in adults. Despite these results, many efforts have been focused on the c-Kit + progenitor cells from the bone marrow [ 72 ], which were later shown to play a negligible role in heart regeneration [ 73 ]. Using the Cre/lox system and a reporter line, endogenous c-Kit + cells are found to generate cardiomyocytes at a percentage less than 0.03. Although c-Kit + cells contribute to the revascularization of cardiac endothelial cells, their role in myocardium regeneration is insignificant.

In order to develop new therapies, recent studies have worked on understanding the regulatory role of non-muscle cells, such as immune cells, endothelial cells, and cardiac fibroblasts. In neonatal mice, CD4 + regulatory T cells (Tregs) are necessary for cardiac regeneration. Depletion of Tregs inhibits cardiomyocyte proliferation and induces fibrosis, whereas adoptive transfer of Tregs rescues this phenotype [ 74 ]. Interestingly, ablation of CD4 + Tregs in mice at postnatal day 8 promotes heart regeneration after resection [ 75 ], suggesting the role of immune cells might differ by stages. Endothelial cells support heart regeneration by reassembling arteries, which serve as a scaffold for cardiomyocyte repopulation and also reperfuse the ischemic tissues [ 76 , 77 ]. Endothelial cell migration is induced by the CXCL12-CXCR4 signaling pathway. Genetic inhibition of this signaling leads to formation of larger scars and the reduction of cardiomyocyte proliferation after myocardial infarction [ 76 ]. Consistent with this, inhibition of revascularization in zebrafish with dominant negative VEGF-A also hindered regeneration, suggesting that endothelial cells are actively engaged in cardiomyocyte proliferation [ 78 ]. Cardiac fibroblasts deposit ECM and their number increases during development and diseases, such as heart failure [ 79 ]. Transcriptomic analysis showed different gene expression profiles between fetal and adult fibroblasts of humans, suggesting fibroblasts might be potential contributors to embryonic heart regeneration [ 80 ]. However, ablating activated fibroblasts in mice has a protective effect after acute injuries [ 81 ], which contradicts its vital function in promoting heart regeneration of zebrafish [ 82 ]. This could potentially be explained by the existence of different sub-clusters of fibroblasts in the heart, but further studies are still needed [ 83 ]. In summary, modulating immune cells, endothelial cells, and fibroblasts after injury may promote cardiac regeneration and lead to further mitigation of disease.

The regenerative ability of the mammalian heart is lost during development. In humans, the scar-free repair of the heart is feasible, but only at early developmental stages [ 84 , 85 ]. A case report of a newborn child by Haubner et al. [ 86 ] showed strong regeneration ability after severe myocardial infarction and tissue damage. The cardiac function of this 1-year-old child recovered a few weeks after the initial injury. Similar responses have been seen in other cases by Cesna et al. [ 87 ], Deutsch et al. [ 88 ], and Farooqi et al. [ 89 ], leading to the hope of repairing a damaged adult heart by reactivating regenerative processes that are present during the neonatal stage. Similar to humans, mice lose the capacity for heart regeneration during the early postnatal stage between postnatal days 1 to 7 [ 84 ]. A well-designed study by Drenckhahn et al. [ 90 ] showed that embryonic cardiomyocytes are able to re-enter the cell cycle and proliferate to form heart muscles. In this study, the X-linked gene Hccs was deleted specifically in the heart muscle; this deletion is lethal for the cell. In heterozygous females (half of the cardiomyocytes were normal due to random X inactivation), the mutant cells contributed to less than 10% of tissue volume, showing that the normal cardiomyocytes are able to regenerate about 50% loss of cardiomyocytes at embryonic stage [ 90 ]. By removing 10% of the ventricle from mice at various ages, the time windows of regeneration are characterized [ 71 ]. The murine heart can regenerate at postnatal day 1 after surgical resection with minimal scar or hypertrophy [ 91 ]. This regenerative ability is continuously lost until it ceases at postnatal day 7. In support of this conclusion, similar results have been observed in many other injury models by Haubner et al. [ 92 ] and Porrello et al. [ 44 ] although the collagen scar has been observed when resecting a larger part (20%) of the ventricle [ 93 ]. A study by Porrello et al. [ 44 ] using left anterior descending artery (LAD) ligation-induced injury showed that the heart regenerates within 3 weeks after extensive necrosis. This study compared changes in gene expression after injury between postnatal days 1, 3, and 10. Many genes regulating mitosis, cell division, cell cycle, and ECM synthesis have been identified, including NPPA (atrial natriuretic factor), Nanog (stem cell marker), and HIF3A (hypoxia-inducible factor-3α gene) [ 92 ]. Further study by Darehzereshki et al. [ 91 ] with cryoinjury models has revealed different modes of repair after different types of injury. Neonatal hearts are able to regenerate after non-transmural cryoinjury but not after transmural injury and differential plasminogen activator inhibitor 1 (PAI-1) expression could be a potential explanation. Konfino et al. [ 94 ] found that both neonatal and adult mice respond differently to LAD-induced myocardial infarction and resection. The adult heart forms a thin scar after myocardial infarction, whereas apical resection leads to the occurrence of a hemorrhagic scar. Together, these findings suggest that different treatments should be developed to administer to specific injuries.

The limitation of this model is the lack of cell death, inflammation, and debris clearance steps during the healing process [ 95 ]. Cryoinjury is one of the most commonly used methods, in which a precooled metal is used to freeze part of the ventricle [ 55 , 56 ]. Although cardiac tissue loss is similar to the resection model, it takes much longer, around 130 d, to regenerate the heart after cryoinjury [ 56 ]. Genetic models of cardiomyocyte death have also been used to study heart regeneration in zebrafish. Wang et al. [ 96 ] ablated cardiomyocyte with the expression of cytotoxic diphtheria toxin A chain, induced by cell-specific cyclization recombination enzyme (Cre). This method induces around 60% loss of cardiomyocytes while leaving the endocardium and epicardium intact, which resembles cardiomyopathy in human patients [ 97 ]. Heart function and tissue are restored in around 30 d, which could be attributed to the importance of epicardium in heart regeneration [ 98 ].

Using these injury models, the cellular processes of heart regeneration have been better characterized and a signaling network of genes was identified to be crucial for scar-free regeneration. The regenerative process can be separated into four major stages: 1) the acute reaction to injury, including recruitment of immune cells and deposition of fibrotic tissues; 2) the endocardium and epicardium regenerate in order to support the myocardium; 3) the myocardium is regenerated via proliferation, and 4) the functional integration of newly generated cardiomyocytes, scar removal, and inflammation resolution [ 95 ].

Transplantation of progenitor-derived cells and stem cells

Cell transplantation to repair the injured heart has been started for more than a decade. Intracoronary administration of bone marrow-derived progenitor cells can improve the recovery of left ventricular contractile function in patients with acute myocardial infarction [ 99 ]. However, studies with double-blind randomized designs show that injection of bone marrow mononuclear cells fails to improve the left ventricular contractile function [ 100 , 101 , 102 ]. The randomized placebo-controlled study of myoblast transplantation also shows that myoblast injections are unable to improve echocardiographic heart function [ 103 ]. Adverse effects such as arrhythmias are always problematic, as skeletal myoblasts are not able to conduct electromechanical signals as cardiomyocytes [ 104 ]. Therefore, efficient treatment may be cell-specific and achieved by transplantation of progenitor-derived cells. Recent studies have graded mesoderm assembly controls cell fate and morphogenesis of the early mammalian heart [ 105 ].

Another approach is to induce the differentiation of cardiomyocytes in vitro using embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs). Both cell types are able to succeed in vitro to produce cardiomyocyte-like cells [ 106 , 107 ]. Convincing evidence shows that transplantation of ESC-derived cardiomyocytes improves heart function by integrating with pre-existing cardiomyocytes to transduce electromechanical signals [ 108 , 109 ]. Although transplantation of human ESC-derived cardiomyocytes can regenerate the infarcted pig heart, it induces ventricular tachyarrhythmias [ 110 ]. There have been few clinical trials in humans given the ethical challenges of ESCs as well as concerns about side effects. One trial shows some positive results, but with an overall low engraft rate and lack of careful characterization of the control group [ 111 ]. Similarly, another trial shows that transplantation of iPSC-derived cardiomyocytes improves ventricular contractility and promotes heart regeneration, but has low engraftment and survival rate of cardiomyocytes, and induces complications such as tachycardia [ 112 , 113 ].

The POSEIDON study shows that bone marrow-derived mesenchymal stem cells (MSCs) may have cardiogenic potential and improve the functional capacity of the heart [ 114 ]. However, the conclusion is hindered by the lack of a placebo control group and a small patient cohort of 30. However, a randomized double-blind trial shows that bone marrow-derived mesenchymal stromal cells produce a moderate improvement in left ventricular ejection fraction (LVEF) and stroke volume of ischemic heart [ 115 ]. Similar results have been reported in trials using MSCs derived from different sources, such as the umbilical cord-mesenchymal stem cell (UC-MSC) [ 116 ]. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial demonstrated that MSC injection is overall safe [ 117 ] and has long-term benefits in patients with significant left ventricular enlargement [ 118 , 119 ]. The recent CONCERT-HF trial shows that MSC in combination with c-Kit positive cells (CPCs) can significantly reduce heart failure-related major adverse cardiac events (HF-MACE). However, no improvement in left ventricular function or reduction of scar size can be achieved, requiring further elucidation of the underlying mechanism [ 120 , 121 ]. Other clinical trials show that MSC injection fails to produce functional improvement of the heart [ 122 , 123 ]. Although MSCs can differentiate into cardiomyocytes in vitro [ 124 ], MSC-derived endothelial cells are the main contributor to heart regeneration in animal model [ 125 ]. A randomized double-blind multi-center trial TEAM-AMI shows that the efficacy of MSC injection is highly dependent on the microenvironment [ 126 ], supporting that the clinical benefits are mainly mediated by indirect effects instead of by generating new cardiomyocytes [ 123 ]. Vagnozzi et al. [ 127 ] showed that intracardiac injection of killed stem cells or use of chemical inducers for immune response produced similar results as live adult stem cell. All these treatments induce a regional accumulation of CCR2 + and CX3CR1 + macrophages, which affect fibroblasts and the ECM at the injury site. A series of animal studies by Bolli et al. [ 128 ] demonstrated that transplanted cells cannot engraft into the myocardium nor differentiate to cardiomyocytes, although improved cardiac function was observed. This dissociation of therapeutic improvement with engrafting rate has been seen among MSCs, ESCs, and CPCs treatment, independent of delivery method and preconditions [ 129 ]. These new findings suggest that the benefits from stem cell injection are mainly due to secreted factors instead of cell replenishment. Therefore, understanding the molecular signaling induced by factors secreted by stem cells becomes more important for treatment of heart injury. Recent studies show that endoderm-derived islet1-expressing cells can differentiate into endothelial cells to function as hematopoietic stem and progenitor cells [ 130 ], which may serve as an alternative approach for stem cell transplant; in addition, human- or animal-derived decellularized heart patches have been used in vivo and in vitro studies to promote the regeneration of heart tissue [ 131 ]. However, due to the complexity of cardiac tissue engineering, significant hard work must be done before the approaches can be clinically used.

Currently, a growing number of clinical trials [ 130 ] (see Bolli et al. [ 129 ] for a comprehensive list of trials) and Meta-analyses [ 132 ] have greatly expanded the knowledge and potential choices of cell sources and interventions for heart disease, such as IMMNC-HF with bone marrow mononuclear cell [ 133 ]; LAPiS (NCT04945018), HEAL-CHF (NCT03763136) and NCT05223894 with human iPSC derived cardiomyocytes; NCT05147766 with UC-MSCs; NCT03797092 with adipose-derived stromal cell; and BioVAT-HF (NCT04396899) with engineered human myocardium. DREAM-HF, a phase III clinical trial, recruited 565 patients and upon completion will provide evidence in analyzing the efficiency of MSC injection as a heart failure treatment [ 14 , 134 , 135 ]. Recent studies show that human mesenchymal stromal cells and endothelial colony-forming cells reduce cardiomyocyte apoptosis, scar size, and adverse cardiac remodeling, compared to vehicle, in a pre-clinical model of acute myocardial infarction [ 136 ]. Human ESC-derived endothelial cells also attenuate cardiac remodeling in a mouse myocardial infarction model [ 137 ]. Besides cardiomyocytes, cardiac interstitial cells also play crucial roles during cardiac regeneration [ 138 ], which opens another avenue to improve heart regeneration. These studies provide useful information for cell therapy approach to treat cardiac injury in the future.

Inducing proliferation of existing cardiomyocytes

The safest and least immunogenic option for cardiac regeneration is using pre-existing cardiomyocytes, although human cardiomyocytes are well-known for being non-proliferative [ 85 ]. There is evidence supporting that cardiomyocytes self-renew at a slow but steady speed [ 69 ], and previous mechanistic studies in mice and zebrafish have provided clues for potential therapeutic targets. Combined expression of cell cycle-related genes, Cdk1 , Ccnb , Cdk4, and Ccnd induces post-mitotic cell proliferation and improves ventricular function after myocardial infarction [ 139 ]. As discussed earlier, the Hippo-YAP pathway is a promising target for promoting cardiomyocyte proliferation. Adeno-associated virus (AAV)-based genetic knockdown of Hippo pathway gene Sav in pig models has been shown to increase the renewal rate of cardiomyocytes after myocardial infarction and improve LVEF [ 140 ]. No arrythmia, tumor formation, or mortality has occurred after treatment, making this a promising approach to advancing clinical trials.

Another potential target is Myc, a transcription factor involved in cell replication, differentiation, metabolism, and apoptosis [ 141 ]. Four-hour acute activation of Myc signaling in juvenile mice leads to a marked proliferative response in vivo [ 142 ]. Mechanistically, this effect is mediated by positive transcription elongation factor b (P-TEFb), which consists of CDK9 and cyclinT1. Furthermore, a transient cardiomyocyte-specific expression of Myc, SRY-box transcription factor 2 (SOX2), OCT4 (named POU5F1; POU domain, class 5, transcription factor 1), and KLF transcription factor 4 (KLF4) can induce dedifferentiation of adult cardiomyocytes characterized by a gene expression profile resembling that of fetal cells. This allows the reprogrammed cardiomyocytes to re-enter the cell cycle and divide into more cardiomyocytes, leading to improved cardiac function after myocardial infarction [ 143 ]. Prolonged expression of these four factors resulted in tumor formation and lethality in mice, however, urging the need for more in-depth studies to avoid potential safety issues.

The Nrg1 has shown its mitogenic effect in pre-existing cardiomyocytes (mentioned in section “ErbB/PI3K/ERK and Wnt/β-catenin control cardiomyocyte proliferation, dedifferentiation, and inflammation”). Furthermore, Polizzotti et al. [ 144 ] show that recombinant neuregulin 1 (rNRG1) induces the proliferation of cardiomyocytes both in mice and in isolated human myocardium, which opened the therapeutic window and prompted clinical trials. A double-blind, placebo-controlled clinical trial of neuregulin 1β3 (cimaglermin alfa) shows sustained improvements in LVEF [ 145 ]. Another clinical trial shows that recombinant human neuregulin 1 (rhNRG1) can increase LVEF and decrease end-diastolic volume (EDV) and end-systolic volume (ESV) in chronic heart failure patients. However, these results were statistically indistinguishable from the placebo, and it remains unclear if this treatment improves heart function by inducing regeneration [ 146 ]. Overall, there is active research underway to develop and optimize therapies using identified gene targets and to explore new targets, i.e. , Hoxb13 by Nguyen et al. [ 147 ], Meis1 by Mahmoud et al. [ 148 ], and miR-199a by Eulalio et al. [ 37 ] and Gabisonia et al. [ 39 ].

Reprogramming non-muscle cells into cardiomyocytes

Reprogramming other cells of the heart, such as fibroblasts, into cardiomyocytes, is another way to achieve the challenging task of repairing the heart. As a large cell population of the heart [ 149 ], fibroblasts are the first responders after cardiac injuries, thus making them an ideal source of cardiomyocytes. Forced expression of cardiac transcription factor combinations, such as GATA binding protein 4 (GATA4), myocyte enhancer factor 2C (MEF2C), and T-box transcription factor 5 (TBX5) (GMT cocktail) [ 150 ]; or GATA4, heart and neural crest derivatives expressed transcript 2 (HAND2), MEF2C and TBX5 (GHMT) [ 151 ], can successfully transform fibroblasts into cardiomyocytes in vitro. Bypassing the iPSC stage, this approach reprograms fibroblasts directly into contractile cardiomyocytes that express typical cardiomyocyte markers. In vivo expression of GHMT using retroviral infection in mice showed that reprogramed cells can form cardiomyocytes and conduct electromechanical signals after myocardial infarction induced by LAD ligation [ 151 ]. Many genes and signaling pathways involved in heart regeneration also modulate reprogramming of fibroblast into cardiomyocytes, including Notch signaling [ 152 ], zinc finger transcription factor 281 (ZNF281; regulating inflammation) [ 153 ], fibroblast growth factor (FGF) and VEGF [ 154 ], Akt1/protein kinase B [ 155 ], Bmi1 (epigenetic factor) [ 156 ], and chemical factors [ 157 ]. Recently, Wang et al. [ 158 ] found that autophagic factor Beclin1 negatively regulates fibroblast reprogramming in an autophagy-independent manner, and that Beclin1 haploinsufficiency in mice promotes reprogramming and reduces scar size after myocardial infarction. In addition, a combination of miRNAs, miR-1, -133, -208, and -499 have also been found to induce cardiomyocytes from fibroblasts both in vitro and in vivo [ 159 , 160 ], providing alternative targets for fibroblast reprogramming. Alternatively, Lalit et al. [ 161 ] showed that mesoderm posterior bHLH transcription factor 1 (MESP1), GATA4, TBX5, NK2 homeobox 5 (NKX2-5), and BAF60C (SMARCD3, SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily D, member 3) expressed in fibroblasts produce a progenitor population that gives rise to cardiomyocytes, endothelial cells, and mural cells in myocardial infarction mice models. Recent study also suggests that the cardiac gene TBX20 (T-box transcription factor 20) enhances myocardial reprogramming induced by the MGT133 reprogramming cocktail (MEF2C, GATA4, TBX5, and miR-133) [ 162 ]. In summary, transcription factor combinations play an important role in transforming fibroblasts into cardiomyocytes in mice.

Despite the success in mice, human fibroblasts are more resistant to both the transcription factor and miRNA combination-induced reprogramming and have shown overall inadequate efficacy to produce cardiomyocytes. Furthermore, the induced cardiomyocytes mostly lack contractility [ 163 , 164 ]. Follow-up studies discovered that the reprogramming process of human fibroblasts requires the addition of other factors, such as MESP1 and myocardin (MYOCD) [ 165 , 166 ], ZFPM2 (zinc finger protein, FOG family member 2) [ 166 ], V-Ets erythroblastosis virus E26 oncogene homolog 2 (ETS2) and MESP1 [ 167 ]. More efforts are still needed to understand the molecular mechanism and the heterogeneity [ 168 ] of induced cardiomyocytes and improve the efficacy of this approach before clinical application. Nevertheless, studies using mouse models have reached a new level by using a novel Tcf21iCre/reporter/MGTH2A transgenic mouse system showing that cardiac reprogramming can repair myocardial infarction [ 169 ]. However, whether it is safe and efficacy for patients remains to be validated.

Non-cell-based approaches

Although still in the early stages, approaches that are not based on cells have the great potential as they bypass the difficulties related to low engraft rates, unclear mechanism, and ethical and safety problems. Study by Puente et al. [ 170 ] in postnatal mice found that oxidative stress induces cell cycle arrest, thus contributing to the loss of heart regenerative ability. Based on this finding, Nakada et al. [ 171 ] designed experiments where mice were exposed to hypoxia for a week after myocardial infarction. This treatment triggers a robust regenerative response and improves left ventricular systolic response. Fate-mapping showed that pre-existing cardiomyocytes proliferate to form myocardium, making it an intriguing idea to treat patients with gradual systemic hypoxia.

Secreted factors, such as growth factors VEGF-A, FGF-2, Nrg1, and thymosin b4, protect against myocardial injuries in animal models [ 172 , 173 ]. However, this effect has not been seen in clinical trials with both VEGF-A and FGF-2 [ 174 , 175 ]. One explanation for this might be that the delivery method cannot ensure a high bioavailability, as a better recovery is achieved by using synthetic mRNA to express VEGF-A in mice [ 176 ]. Recent studies show that VEGF-A-induced angiogenic sprouting can be attenuated by siRNA knockdown or CRISPR/Cas9 knockout of LINC00607 [ 177 ]. VEGF mRNA has been administrated to patients via direct intramyocardial injection, showing that it may be safe for introducing genetic material to the cardiac muscle [ 178 ]. Nrg1 sustains the epicardial-mediated cardiac regeneration capacity of neonatal heart explants [ 179 ]. Oxytocin also activates epicardial cells and promotes heart regeneration after cardiac injury [ 180 ]. Daily administration of thymosin β4, a peptide known to restore vascularization of the epicardium [ 181 ], gives mice the capability of producing new cardiomyocytes and improves recovery after myocardial infarction [ 182 , 183 ]. These studies have been confirmed by a recent report showing that thymosin β4 and also prothymosin α promote cardiac regeneration in mice [ 184 ]. Exosomes are small extracellular vesicles containing different cargoes like protein, RNA and lipids [ 185 ]. Exosomes secreted by iPSC or cardiac progenitor populations promote cardiac functional recovery in animal models [ 186 , 187 ]. Furthermore, mechanistic studies by Cai et al. [ 188 ] and Zhou et al. [ 189 ] showed that the epicardium, similar to stromal stem cell, plays an important role in heart regeneration by both serving as a source for cardiomyocytes, and most importantly, by providing the required paracrine factors [ 190 ]. A proteomic study by Arrell et al. [ 191 ] comparing chronic infarction models with and without human stem cell treatment identified 283 and 450 altered proteins, respectively. This finding could provide a roadmap to future therapeutics using secreted factors. Owing to the advancement of the biomedical engineering field, new methods are being developed to efficiently deliver these factors, including exosomes [ 192 ], cardiac patches [ 193 ], and bioactive hydrogel [ 194 ]. For example, a recent report shows that cardiac tissue regeneration can be induced by the delivery of miR-126 and miR-146a via exosomes [ 195 ]. Recent studies show that cardiogel-loaded chitosan patches or injectable hydrogels containing anti-apoptotic, anti-inflammatory, and pro-angiogenic agents may have therapeutic benefits for heart injury [ 196 , 197 ]. Together, the precise delivery of factors promoting myocardial proliferation and inhibiting apoptosis and inflammation has the potential to enable heart regeneration in situ.

Together, these findings provide exciting new directions for regenerative therapeutics for human heart disease. Notably, there are several barriers that need to be removed before translating these findings to clinical practice, such as the variability between species and the insufficient reproduction of results [ 198 ]. By using quantitative measurement, human-animal chimeras [ 199 ], large-animal models and platforms, i.e., CIBERCV Cardioprotection Large Animal Platform (CIBER-CLAP) [ 198 , 200 ], standardized protocols and quality-control infrastructure [ 201 ], future preclinical studies are anticipated to yield positive clinical results.

Conclusions and perspectives

In summary, active research in the field has revealed common molecular mechanisms for heart regeneration and potential new targets for therapies. These potential gene targets function to regulate immune response, cardiac fibroblast activation, epicardium recovery, and cardiomyocyte proliferation after injuries. Inspired by these findings, current trials focus on inducing heart regenerative ability by cell-based approaches, including progenitor cell transplantation, inducing cardiomyocyte proliferation, and direct reprogramming. Other ongoing therapeutic explorations involve non-cell-based approaches, such as secreted factors and exosomes. In addition, the contribution of non-cardiomyocytes, such as endothelial cells and the epicardium has been actively studied. Figure  3 illustrates current approaches for heart regeneration. With studies for genetics and genomics developed gradually, gene editing technology, especially CRISPR/Cas9, has made continuous breakthroughs, which opens up a new way to manipulate the genome in vitro and in vivo, and also provides an unprecedented opportunity to explore the application of gene editing in cardiovascular diseases [ 202 , 203 ]. iPSCs are increasingly being used as substitutes or supplements for animal models of cardiovascular disease [ 204 ]. Jiang et al. [ 205 ] have found that fibroblasts could be reprogrammed into cardiovascular progenitor cells using transgenic methods, which are called CRISPR-induced cardiovascular progenitor cells (ciCPCs). The implanted ciCPCs differentiate into cardiovascular cells in vivo, which significantly improve myocardial systolic function and the formation of scars, and provide a new source of cells for myocardial regeneration. With the development of artificial intelligence, Theodoris et al. [ 206 ] recently developed a machine learning approach to identify small molecules, which correct gene networks dysregulated in iPSC broadly. This approach could prevent and treat specific cardiovascular diseases in a mouse model. This study points to human–machine learning, network analysis, and iPSC technology to make this strategy feasible and potentially represent an effective path for drug discovery [ 206 ]. In addition, Lin et al. [ 207 ] demonstrated that multiplexed CRISPRi screening combined with machine learning confers functional robustness to gene expression. The prediction of synergistic enhancers by machine learning provides an effective strategy for identifying pairs of noncoding variants associated with disease-causing genes beyond the analysis of genome-wide association studies [ 207 ]. There’s a reasonable prospect that gene editing and artificial intelligence will also bring breakthroughs in heart regeneration in the future. These attempts generated promising results and could be further optimized and then tested in larger populations. Cre recombinase microinjection will help researchers identify the cell progenitors and gene networks involved in organ development [ 208 ]. A variety of tissues and organs including hearts have been produced via 3D bio-printing, which serves as in vitro models for pharmacokinetics and drug screening [ 209 ]. Although it is not promised, 3D bio-printing may be used for repairing, or even replacing, an injured heart in the future. We believe that the endeavors in fighting against heart injury will finally lead to a breakthrough for adult heart regeneration.

Current approaches for heart regeneration. Current attempts at heart regenerative therapies include cell based and non-cell based approaches. Each of these approaches has its own advantages and faces different challenges. iPSC induced pluripotent stem cell, BMC bone marrow cell, MSC mesenchymal stem cell, Cdk1 cyclin-dependent kinase 1, Ccnb cyclin B, SOX2 SRY-box transcription factor 2, OCT4 POU domain, class 5, transcription factor 1, KLF4 KLF transcription factor 4, YAP Yes-associated protein, Nrg neuregulin, FGF fibroblast growth factor, VEGF vascular endothelial growth factor, GATA4 GATA binding protein 4, HAND2 heart and neural crest derivatives expressed transcript 2, MEF2C Myocyte enhancer factor 2C, TBX5 T-box transcription factor 5

Availability of data and materials

Not applicable.

Abbreviations

Adeno-associated virus

Protein kinase B

SMARCD3, SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily d, member 3

Bone marrow cells

Congestive Heart Failure Cardiopoietic Regenerative Therapy

CIBERCV Cardioprotection Large Animal Platform

CRISPR-induced cardiovascular progenitor cells

C-Kit positive cells

Extracellular matrix

End-diastolic volume

Epithelial-mesenchymal transition

Erb-B2 receptor tyrosine kinase

Extracellular signal-regulated kinase

Embryonic stem cells

End-systolic volume

Fibroblast growth factor

GATA binding protein 4

Glycogen synthase kinase-3 beta

Heart and neural crest derivatives expressed transcript 2

Heart failure-related major adverse cardiac events

Hypoxia-inducible factor 3α gene

Hypoxia-inducible factor-1α

Induced pluripotent stem cells

KLF transcription factor 4

Left anterior descending artery

Left ventricular ejection fraction

Myocyte enhancer factor 2C

Mesoderm posterior bHLH transcription factor 1

Mesenchymal stem cell

Mechanistic target of rapamycin kinase

Notch intracellular domain

NK2 homeobox 5

Neuregulin 1

POU domain, class 5, transcription factor 1

Positive transcription elongation factor b

Recombinant human neuregulin 1

Recombinant neuregulin 1

SRY-box transcription factor 2

T-box transcription factor 5

Regulatory T cells

Toll-like receptor 3

Umbilical cord-mesenchymal stem cell

Vascular endothelial growth factor A

Yes-associated protein

Zinc finger protein, FOG family member 2

Zinc finger transcription factor 281

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Acknowledgements

We want to thank Michael Simons from Yale Cardiovascular Center for providing the learning opportunity for Qian-Yun Guo. In addition, we thank the biorender.com for providing platform of creating research graphics.

This work was supported by the Natural Science Foundation of Beijing, China (7214223, 7212027), the Beijing Hospitals Authority Youth Programme (QML20210601), the Chinese Scholarship Council (CSC) scholarship (201706210415), the National Key Research and Development Program of China (2017YFC0908800), the Beijing Municipal Health Commission (PXM2020_026272_000002, PXM2020_026272_000014), and the National Natural Science Foundation of China (82070293).

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Guo, QY., Yang, JQ., Feng, XX. et al. Regeneration of the heart: from molecular mechanisms to clinical therapeutics. Military Med Res 10 , 18 (2023). https://doi.org/10.1186/s40779-023-00452-0

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ORIGINAL RESEARCH article

Eltrombopag can promote platelet implantation after allogeneic hematopoietic stem cell transplantation as safely and similarly to thrombopoietin.

• 1 Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
• 2 Department of Hematology, The Affiliated Hospital of Shandong University of Traditional Chinese Medical, Jinan, Shandong, China
• 3 Department of Hematology, The Affiliated Taian City Centeral Hospital of Qingdao University, Taian, Shandong, China
• 4 Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
• 5 Branch of National Clinical Research Center for Hematologic Diseases, Jinan, Shandong, China
• 6 National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou, China

Background: Eltrombopag has demonstrated efficacy in treating low platelet (PLT) levels, but it remains unclear whether eltrombopag can promote PLT engraftment after hematopoietic stem cell transplantation (HSCT).

Methods: Forty-one HSCT patients received eltrombopag 50 mg/d from +1 day until PLT >50 × 10 9 /L or 1 month after HSCT. Fifty-one patients in the same period received thrombopoietin (TPO) to promote PLT graft after HSCT and served as a control group.

Results: A total of 51 patients who applied TPO during the same period were treated as a control. In the eltrombopag group, the median time to white blood cells (WBC) graft was 12 days (range, 10-17 days) and the PLT graft was 15 days (range, 10-30 days), whereas for the patients in the TPO group, the median time to WBC and PLT graft was 12 days (range, 9-23 days) and 15.5 days (range, 9-41 days), respectively. In the first month after HSCT, the median WBC count in the eltrombopag group was 4.41 × 10 9 /L (range, 0.87-40.01 × 10 9 /L) and the median PLT was 89x10 9 /L (range, 30-401 × 10 9 /L); the median WBC and PLT \counts in the TPO group were 4.65 × 10 9 /L (range, 0.99-23.63 × 10 9 /L) and 86 × 10 9 /L (range, 5-512 × 10 9 /L), respectively. Patients in the TPO or eltrombopag group did not experience serious side effects after drug administration, and the difference in side effects on liver and kidney function between the two groups was not statistically significant.

Conclusion: Eltrombopag is safe and similarly promotes platelet engraftment to thrombopoietin after allogeneic HSCT.

1 Introduction

Hematopoietic stem cell transplantation (HSCT) is an effective curative measure for many hematologic malignancies and some nonmalignant diseases. Neutrophil and platelet (PLT) implantation after HSCT is essential for optimal results ( 1 ). Prolonged isolated thrombocytopenia (PT) is a very common complication for all patients with HSCT. PT patients are usually faced with uniformly poor outcomes ( 2 , 3 ). Thus, how to reduce the incidence of PT and successfully manage thrombocytopenia after HSCT remains a major challenge.

Thrombopoietin (TPO) is a cytokine, and previous studies have shown that TPO is the main physiological cytokine that stimulates platelet production ( 4 , 5 ). A prospective randomized controlled study has shown that recombinant human TPO (rhTPO) promotes platelet engraftment in patients after HSCT ( 6 ). The safety of rhTPO has been demonstrated in many previous trials ( 6 , 7 ).

Eltrombopag is a small molecule non-peptide oral formulation that is an agonist of the thrombopoietin receptor, and it can increase PLT counts in patients with thrombocytopenia. Although initially used to improve thrombocytopenia in chronic immune thrombocytopenia (ITP), it was later found to be effective in other causes of thrombocytopenia ( 8 ). Since thrombopoietin receptors are expressed on both megakaryocytes and hematopoietic stem cells, hematopoietic stem cell can be stimulated by eltrombopag ( 9 – 11 ). More recently, eltrombopag has been used for the treatment of thrombocytopenia and graft failure after HSCT ( 12 ).

The effects of eltrombopag on poor graft function of HSCT patients have been studied and were shown to be effective ( 13 , 14 ). However, it remains unclear whether eltrombopag can promote PLT engraftment after HSCT.

Herein, we conducted a retrospective, single-arm clinical trial to evaluate the effect of eltrombopag on platelet engraftment in patients after transplantation and the safety of clinical use of eltrombopag.

2 Materials and methods

2.1 study design.

We enrolled a total of 94 patients diagnosed with hematological malignancies who underwent HSCT from three hospitals from 21 January 2019 to 10 November 2021. The three hospitals both used TPO or eltrombopag after transplantation as standard treatment. These patients were divided into two groups. Patients were administered 50 mg (qd) from +1 day until PLT >50 × 10 9 /L or 1 month after HSCT were classified as the eltrombopag group, and patients who used TPO only during the same period were divided into the TPO Group. We verified ANC and PLT counts daily for post-transplant patients. Additionally, we monitored kidney and liver function every three days. We compared the implantation of white blood cells (WBC) and PLT of the two groups after HSCT. We also analyzed the side effects of both drugs on patients’ liver function, kidney injury, and outcomes. This study was approved by the institutional ethics board of Shandong Provincial Hospital Affiliated to Shandong First Medical University, the Affiliated Hospital of Shandong University of Traditional Chinese Medicine and Taian City Central Hospital. This study was performed in accordance with the Helsinki Declaration of 1975 and was approved by the institutional ethics board of Shandong Provincial Hospital (Jinan, China), the Affiliated Hospital of Shandong University of Traditional Chinese Medicine (Jinan, China), the Affiliated Taian City Center Hospital of Qingdao University (Taian, China). Informed consent.

2.2 Conditioning regimen and prophylaxis of GVHD

All patients received myeloablative conditioning regimens including busulfan + cyclophosphamide (busulfan 0.8 mg/kg in 9 doses, cyclophosphamide 50 g/kg/day, days -3, -2), busulfan + fludarabine (busulfan 0.8 mg/kg in 9 doses, fludarabine 30mg/kg/day, from day -6 to day-2),or total body irradiation + cyclophosphamide (total body irradiation 3Gy/day, from day -6 to day-4, cyclophosphamide 50 g/kg/day, days -3, -2)-based regimens. To prevent GVHD, cyclosporine A, mycophenolate, and short-term methotrexate were administered in all patients. Patients who underwent matched HSCT from sibling donors did not receive ATG, and the other patients received ATG (2.5 mg/kg/day, from day -5 to day -2).

2.3 Stem cell mobilization and infusion

Granulocyte colony-stimulating factor (5-10 μg/kg/day) was used to mobilize hematopoietic stem cells into the peripheral blood. Peripheral blood stem cells were collected on the fifth day after mobilization. The ideal infused mononuclear cells were more than 5 × 10 8 /kg, and CD34 + cells should were more than 2 × 10 6 /kg.

2.4 Indicators and definitions

WBC engraftment after HSCT was defined as neutrophil granulocyte count greater than 0.5 × 10 9 /L for three consecutive days. PLT engraftment was defined as a PLT count exceeding 20 × 10 9 /L for three consecutive days without transfusion support. We also compared the time achieved for the WBC count>0.2 after HSCT and the number of WBC and PLT at 1 and 3 months after HSCT between the two groups. Liver function was assessed by analyzing the levels of glutamic oxaloacetic transaminase (AST), glutamic-pyruvic transaminase(ALT), alkaline phosphatase (ALP) and total bilirubin (TBIL). Kidney injury was assessed by measuring urinary protein levels (Upro), blood urea nitrogen (BUN), and creatinine (CREA). The grade of liver and kidney injury was determined according to the World Health Organization (WHO) classification system. Parallelly, we collected the number of MKCs in the bone marrow of patients one month after HSCT. Acute GVHD (aGVHD) was accessed according to the Glucksberg criteria ( 15 ) and cGvHD was graded based on the revised Seattle criteria ( 16 ). Overall survival (OS) was defined as the time between HSCT and death. Progression-free survival (PFS) was defined as the time between HSCT and disease recurrence or death.

2.5 Statistical analysis

The T test was used to compare continuous variables and the chi-square test was used to compare categorical variables. The Kaplan-Meier method and Cox proportional hazard model were used to estimate leukocyte and PLT engraftment, OS, PFS, and GVHD. SPSS v.25.0 was used for data analysis. P<0.05 based on the 2-sided hypothesis tests were considered statistically significant.

3.1 Patients’ characteristics

This study involved 94 consecutive patients. A total of 43 patients received eltrombopag after HSCT, among whom 2 individuals experienced severe nausea and vomiting, making oral medication intolerable. Subsequently, they switched to treatment with thrombopoietin (TPO). As these two patients underwent cross-over treatment with two different medications, they were not included in a specific treatment group for analysis. A total of 41 patients finally enrolled in the eltrombopag group. A total of 51 patients used TPO and were enrolled in the TPO group. The patient characteristics are summarized in Table 1 . There was a significant difference in follow-up time between the eltrombopag group and the TPO group. There were no significant differences in sex, recipient’s sex, patient’s age, pre-HSCT CR, donor-recipient HLA and other indexes between the two groups ( Table 1 ).

Table 1 Characteristics of the patients.

3.2 Engraftment

All patients achieved engraftment, and none displayed primary graft rejection. The median time to recovery from WBC was 12 days (range, 10-17 days) in the eltrombopag group and 12 days (range, 9-23 days) in the TPO group (P = 0.174, HR = 1.344, 95%CI: 0.877-2.059) ( Figure 1A ). Two patients had poor engraftment of PLT in the TPO group. The median time to PLT engraftment was 15 days (range, 10-30 days) in the eltrombopag and 15.5 days (range, 9-41 days) in the TPO group (P = 0.299, HR = 1.249, 95%CI: 0.821-1.901) ( Figure 1B ).

Figure 1 (A) WBC engraftment after HSCT. (B) PLT engraftment after HSCT. (C) Time course of WBC counts >0.2 × 10 9 /L after HSCT.

We compared the time to WBC counts >0.2 × 10 9 /L in both groups. In the eltrombopag and TPO groups, the median time to WBC >0.2 × 10 9 /L was 11 days (range, 9-16 days) and 11 days (range, 9-22 days), respectively (eltrombopag vs TPO: P = 0.545, HR = 1.138, 95%CI: 0.749-1.729) ( Figure 1C ). We collected the = WBC and PLT counts at 1 and 3 months after HSCT. At the first month after HSCT, the median WBC count was 4.41 × 10 9 /L (range, 0.87-40.01 × 10 9 /L) in the eltrombopag group and 4.65 × 10 9 /L (range, 0.99-23.63 × 10 9 /L) in the TPO group, respectively (P = 0.720, HR = 1.079, 95%CI: 0.711-1.637), and 3.96 × 10 9 /L (range, 2.19-21.69 × 10 9 /L) and 4.21 × 10 9 /L (range, 1.59-10.41 × 10 9 /L) at the third month after HSCT, respectively (P = 0.371, HR = 0.819, 95%CI: 0.529-1.268). While for PLT it was 89 × 10 9 /L (range, 30-401 × 10 9 /L) and 86 × 10 9 /L (range, 5-512 × 10 9 /L) in the TPO and eltrombopag group at the 1st month, respectively (eltrombopag vs. TPO: P = 0.198, HR = 0.761, 95%CI: 0.503-1153). The median PLT count was 91 × 10 9 /L (range, 3-299 × 10 9 /L) and 90 × 10 9 /L (range, 9-261 × 10 9 /L) in the two groups at the third month, respectively (Eltrombopag vs TPO: P = 0.625, HR = 0.897, 95%CI: 0.581-1.387).

One month after HSCT, all patients in the eltrombopag group had PLT >25 × 10 9 /L, while in the TPO group 89% of the patients had PLT >25. Overall, 89% of the patients in the eltrombopag group had PLT >25 × 10 9 /L, while in the TPO group, 89% patients had PLT >25 × 10 9 /L. Approximately, 89% of patients in the eltrombopag group had PLT >50 × 10 9 /L, while 58% patients in the TPO group had PLT >50 × 10 9 /L. In the eltrombopag group, the PLT counts of 51% patients were over 100 × 10 9 /L, and in the TPO group 42% patients had counts greater than 100. Three months after HSCT, in the eltrombopag group, 90% patients had PLT >25 × 10 9 /L, compared with 89% patients in the TPO group, whereas 77% of the patients in the eltrombopag group had PLT >50 × 10 9 /L, and 71% of patients in the TPO group had PLT >50 × 10 9 /L. There were 52% patients in the eltrombopag group with PLT >100 × 10 9 /L, whereas 49% patients of the TPO group.

The MKCs in the bone marrow were assayed 1 month after HSCT. No MKCs were found in the bone marrow of 3 patients in the Eltrombopag group and 3 patients in the TPO group. The median level of MKC was 44 (range, 2-345) and 58 (range, 2-788) in the eltrombopag and TPO group, respectively (P = 0.425).

3.3 Graft-versus-host disease

Sixteen patients developed grade II-IV aGVHD in the eltrombopag group, while 17 developed grade II-IV aGVHD in the TPO group. At 100 days after HSCT, no significant differences were observed in cumulative aGVHD in the eltrombopag (39%, 95% CI: 23%-54%) vs TPO groups (33.3%, 95% CI: 19%-46%) (P = 0.734, HR = 1.125, 95%CI: 0.569-2.228) ( Figure 2A ). One (2%, 95% CI: 1%-7%) patient developed grade II-IV cGVHD in the eltrombopag group and 9 (17%, 95% CI: 6%-28%) developed grade II-IV cGVHD in the TPO group. The number of patients developing cGVHD in the Eltrombopag and TPO group was not significantly different (P = 0.188, HR = 0.246, 95%CI: 0.030-1.988) ( Figure 2B ).

Figure 2 (A) Cumulative incidence of grade II to IV aGVHD. (B) Cumulative incidence of grade II to IV cGVHD. (C) Overall survival (OS). (D) Progressive-free survival (PFS).

3.4 Survival

Survival analysis revealed no statistical difference (eltrombopag vs. TPO: P = 0.467, HR = 1.490, 95%CI: 0.509-4.364) in the 2-year OS in the eltrombopag (85%, 95% CI 74%-96%) vs TPO groups (78%, 95% CI 66%-90%) ( Figure 2C ). The two-year PFS was similar in the eltrombopag group and in the TPO group (80%, 95CI: 67%-93% vs 78%, 95CI: 66%-90%, P = 0.305, HR = 1.664, 95%CI: 0.629-4.403, Figure 2D ). Six (17%) and 11 (24%) patients died in the Eltrombopag and TPO group, respectively (P = 0.394).

We also compared the adverse effects on the liver and kidney in the eltrombopag and TPO groups after HSCT. We evaluated liver and kidney function throughout the treatment period after transplantation. Based on TBIL levels, 37 patients in the eltrombopag group were assessed as having grade 0 liver injury, 4 patients had grade I liver injury. Forty-two patients were evaluated as having grade 0 liver injury and 7 patients had grade I liver injury in the TPO group, respectively (P = 0.514). According to ALP levels, all patients in the eltrombopag group had a grade 0 liver injury, 44 patients had a grade 0 liver injury, and 5 patients had a grade I liver injury in the TPO group, respectively (P = 0.060). Based on BUN levels, there were 39 patients with grade 0 kidney injury and 2 patients with grade I injury in the eltrombopag group, whereas 45 patients with grade 0 kidney injury and 4 patients with grade I in the TPO group TPO (P = 0.685). Based on CREA levels, all patients had grade 0 kidney injury in the eltrombopag group, 48 of the patients had grade 0 kidney injury, and I patient had grade 1 in the TPO group (P > 0.999). Depending on Upro levels, 24 of the patients had grade 0 kidney injury and 17 patients had grade I in the eltrombopag group. Twenty-four patients had grade 0 kidney injury and 25 patients had grade I in the TPO group TPO (P = 0.365).

4 Discussion

HSCT is the only curable treatment for many hematological malignant diseases and some non-malignant diseases, but according to the literature, approximately 5%-44% of patients will experience thrombocytopenia after HSCT ( 17 – 19 ). Long-term thrombocytopenia after transplantation is also a risk factor for a poor prognosis ( 20 ). Currently, there is no standard treatment for thrombocytopenia after transplantation. Gamma globulin, androgen, and recombinant human thrombocytopenia (rhTPO) are commonly used in clinical treatment of thrombocytopenia after transplantation. Eltrombopag is an oral small molecule agonist for the thrombopoietin receptor. As early as 2008, eltrombopag was approved by the US FDA for the treatment of primary immune thrombocytopenia (ITP) ( 21 ), and effective rates were reported to be 59% to 85% ( 22 ). Eltrombopag has been shown to have promising results in patients with ITP and refractory severe aplastic anemia (rSAA), with almost 80% of patients with ITP and 40% of rSAA showing platelet recovery after treatment ( 23 – 25 ). In addition, eltrombopag has recently been used for the treatment of thrombocytopenia after HSCT and showed high effectiveness ( 13 , 26 – 30 ). However, it is not clear whether Eltrombopag can promote platelet implantation after HSCT.

TPO is a key regulator of thrombogenesis, which promotes proliferation and multiploidy of megakaryocytes by stimulating stem cells to differentiate into megakaryocytes, thus promoting thrombogenesis ( 5 , 31 , 32 ). Sun et al. ( 33 ) treated 24 patients with chronic isolated thrombocytopenia (PT) after HSCT with rhTPO, and the study showed that 45.8% of the patients responded to rhTPO treatment and eventually achieved platelet implantation. Delayed platelet implantation (DPE) is also a common complication after allo-HSCT, Kanda ( 34 ) showed that 5-37% of patients who received allo-HSCT developed DPE ( 19 ), while Wang et al. ( 35 ) demonstrated that rhTPOT could promote platelet transplantation after HSC. IFN-γ, a key pro-inflammatory cytokine, was reported to be involved in the destruction of HSPC by inhibiting TPO signaling, while eltrombopag can bypass this inhibition in vitro by activating c-MPL signaling ( 36 , 37 ). Since the thrombopoietin receptor is expressed in both megakaryocytes and hematopoietic stem cells, eltrombopag can promote the formation and maturation of megakaryocytes to release platelets and promote stem cell generation ( 38 , 39 ). It has also been reported that not only PLT, but also hemoglobin and WBCs increased significantly with eltrombopag treatment after allogeneic HSCT ( 25 , 40 , 41 ). These studies suggest that eltrombopag may play a better role in promoting hematopoietic stem cell graft.

In our study, there were 2 cases of poor platelet implantation after transplantation among patients with TPO. Except for these 2 cases of poor platelet implantation, the remaining 51 patients in the TPO group and the 41 patients in the Eltrombopag group were successfully implanted with white blood cells and platelets after transplantation. The median leucocyte and platelet grafting time after transplantation were the same in both groups. Furthermore, we found that the patients with the highest leukocyte or platelet implantation after transplantation were both in the TPO group. We also analyzed the number of WBCs and PLTs in both groups at 1 and 3 months after transplantation. WBCs were higher in the TPO group at 1 and 3 months after transplantation, whereas PLT counts were higher in the eltrombopag group at 1 month after transplantation. The number of MKC in the bone marrow 1 month after transplantation was similar between the two groups and there are no statistical differences. From our study, it can be seen that eltrombopag can promote PLT implantation after HSCT, which is the same as confirms findings from a previous study that found that eltrombopag could be used to treat graft dysfunction after transplantation ( 42 , 43 ).

Early treatment with TPO and Eltrombopag after HSCT had tolerable side effects and high safety ( 44 – 47 ). Han et al. ( 6 ) conducted a study including 120 patients with HSCT and found that there was no difference in adverse events involving liver function, kidney function, coagulation function and GVHD between rhTPO group and the control group, and the probability of OS was similar. Another study involved 38 patients who received eltrombopag for thrombocytopenia after HSCT and found that all patients were well tolerated. Twenty-three patients developed aGVHD, but all of these patients recovered without discontinuing eltrombopag. Other serious adverse reactions such as severe liver injury and thrombosis were not observed ( 48 ). In our study, only two patients who used TPO developed III-IV aGVHD, none of the patients in the two groups had grade III-IV aGVHD, the liver injury and kidney injury were mild, and none of the patients had other serious adverse reactions. Additionally, patients treated with eltrombopag and TPO had similar OS and PFS. Our study showed the tolerance and safety of TPO and eltrombopag was in accordance with other previously published data ( 7 , 49 ).

It should be noted that due to the retrospective nature of this study, we cannot determine to what extent platelet recovery after transplantation is affected by TPO or Eltrombopag. Furthermore, this study is limited by the small sample size of patients, which can cause data bias. More prospective randomized controlled large-sample clinical studies are needed to confirm the exact efficacy of early application of Eltrombopag after transplantation.

However, this study has confirmed that eltrombopag can be used to promote platelet implantation in patients early after transplantation, its efficacy is not inferior to that of TPO in promoting platelet implantation, and its side effects can be tolerated and are safe.

Data availability statement

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.

Ethics statement

The studies involving humans were approved by the institutional ethic board of Shandong Provincial Hospital Affiliated to Shandong First Medical University, the Affiliated Hospital of Shandong University of TCM and Taian City Central Hospital and followed the Helsinki Declaration of 1975. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements.

Author contributions

YL: Data curation, Software, Writing – original draft. FK: Supervision, Writing – review & editing. GB: Supervision, Writing – review & editing. YJ: Data curation, Methodology, Writing – review & editing. WZ: Software, Writing – review & editing. XS: Methodology, Writing – review & editing. XHS: Methodology, Writing – review & editing. YL: Resources, Writing – review & editing. MD: Resources, Writing – review & editing. DY: Software, Writing – review & editing. XW: Supervision, Writing – review & editing. XF: Supervision, Writing – review & editing.

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Technology Projects of Jinan (No. 202019044); 2021 Shandong Medical Association Clinical Research Fund—Qilu Special Project; and Young scholars research of the Chinese medical association hematology—Sansheng Pharmaceutical Project.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Keywords: eltrombopag, thrombopoietin, safety, prognosis, allogeneic hematopoietic stem cell transplantation, platelet engraftment

Citation: Li Y, Kong F, Bai G, Jiang Y, Zhang W, Sun X, Sui X, Li Y, Ding M, Yuan D, Wang X and Fang X (2024) Eltrombopag can promote platelet implantation after allogeneic hematopoietic stem cell transplantation as safely and similarly to thrombopoietin. Front. Immunol. 15:1340908. doi: 10.3389/fimmu.2024.1340908

Received: 19 November 2023; Accepted: 25 March 2024; Published: 08 April 2024.

Reviewed by:

Copyright © 2024 Li, Kong, Bai, Jiang, Zhang, Sun, Sui, Li, Ding, Yuan, Wang and Fang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Xiaosheng Fang, [email protected] ; Xin Wang, [email protected]

† These authors have contributed equally to this work

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.