One of the most promising routes toward enabling researchers to gain access to the tools they need to make progress in the science of regenerative medicine is the proposal to remove embryonic stem cells from deceased human embryos.1 This approach, defended most notably by Donald Landry, M.D., Chair of the Department of Medicine at the University of Columbia, will remain important even if the recently reported discoveries concerning induced pluripotent stem cells prove to be as promising as they initially appear to be.
The retrieval of cells from deceased human embryos would enable scientists to obtain genuine embryonic stem cells for use in their efforts to cure various diseases that they believe could be alleviated if wider access to these cells were made available. Most importantly, harvesting cells from deceased human embryos overcomes the central moral objection to this line of research, namely, that it requires the destruction of living human embryos.
Under this proposal, the death of the human embryo would be determined under the universal concept of death for an organism, a concept applied daily to developed humans, namely, the irreversible loss of integrated organic function. The irreversible loss of integrated function in the embryo would be defined as the cessation of cell division within the organism as a whole. This conforms to the generally accepted concept of death that is currently in use within the medical community today, and thus would move the discussion from the presence or absence of moral dismay over the destruction of living embryos to a discussion concerning the appropriate means of donating embryonic stem cells following death.2
The aim of this paper is to defend both the moral acceptability of retrieving embryonic stem cells from deceased human embryos and to explain and defend the appropriateness of the proposed criterion.
Under the proposal outlined here, scientists would have access to an abundant supply of embryonic stem cells following the natural death of human embryos. The only difference in current practice would be a delay in retrieving these cells to allow the embryos to die without human interference. As such, adoption of this proposal would open the door to protective legislation for embryos that now lie abandoned in IVF clinics. Presently, no laws govern the disposition of these embryos. Consequently, they are not treated with the respect that is due to them as living human beings, and their remains are not treated with the respect that is due to them following their death.3 Every human being has the right to die a natural and dignified death, one that does not result from an intentional act of destruction carried out by others. The proposal to retrieve embryonic stem cells from deceased human embryos would also justify a legislative ban on the creation of human embryos for the sole purpose of destroying them in research.4
Retrieving stem cells from deceased human embryos depends on formulating a sound definition of death at embryonic stages. Currently, there is no accepted standard for the determination of death in embryonic human beings. The situation is similar to that which existed prior to the Uniform Determination of Death Act, which provided model legislation for state enactments concerning the proper definition of death in clinical settings, and which invoked both the standard cardiopulmonary criteria and the more recent brain-death criteria.5 The cardiopulmonary criteria had long been in use, but the Uniform Determination of Death Act added brain-based criteria for those cases in which the cardiopulmonary criteria were inadequate to clinical experience. Advances in medical technology had enabled cardiopulmonary function to continue artificially in the absence of all brain function, despite the obvious death of the individual.
Similarly, desiccation and autolysis are obvious indications of death in the human embryo, but these common-sense criteria may overlook a prior sign of death that occurs when the embryo suffers the irreversible cessation of cell cleavage. If the cessation of cell cleavage can be confirmed as an appropriate indicator that embryonic death has indeed occurred, then we will have a universal standard for the determination of death in the embryo, not simply for the purpose of determining when its cells may be retrieved for research, but also to ensure that the embryo is treated as a living human being until the moment of death. Preliminary research has shown that, just as some of the organs and tissues of a dead body continue to live after the death of the organism as a whole, some cells in the deceased human embryo continue to live following the arrest of cell cleavage.6 These cells, like the organs of a brain-dead body, are suitable candidates for retrieval for the purposes of biomedical research and medical therapy. Cells obtained in this way have already shown themselves to be capable of producing an embryonic stem cell line.7
These facts point to the need for model legislation, similar to the Uniform Determination of Death Act, that will provide language that can be enacted by the federal government or the states to ensure that the death of the embryo is properly determined according to accepted standards of medical knowledge, and that no embryonic stem cells are harvested prior to a proper determination of death. The definition of death in a human embryo that we defend below is the irreversible arrest of cell cleavage. By "irreversible" we mean that point after which no human embryo returns to spontaneous cell division. By "cell cleavage" we mean the active process of cell division that marks the organic unity of the embryo as a whole. We discuss below the types of additional experiments and observations that would be necessary to confirm that arrest of embryonic development is indeed irreversible in a particular embryo, and also explain why the cessation of development in the early stages of embryonic development is synonymous with the death of the embryo.
In order to evaluate this proposal, both morally and scientifically, it is necessary to briefly review this new field of research. In the political sphere, efforts have been underway for many years among liberal-leaning legislators to promote government funding of destructive human embryo research. The public generally does not realize that it is perfectly legal to clone a human being in the United States, although no one successfully done so yet. Scientists are also free to create and destroy human embryos solely for research purposes (without federal funding). Embryos that lie abandoned in IVF clinics are commonly destroyed by researchers in order to obtain their embryonic stem cells, with many political leaders arguing that human embryos should have no standing whatsoever under law.
As of now, all of the success in the area of regenerative medicine has come from adult stem cells. For example, adult stem cells taken from the patient's own body, such as mesenchymal cells found in bone marrow, have been transformed into cardiac cells and used to repair damaged heart tissue following myocardial infarction. Currently there are no FDA-approved clinical trials using human embryonic stem cells, but many scientists think that these cells nonetheless hold great promise for future cures of seriously debilitating diseases. We will only know their therapeutic potential through experimentation and clinical trial, but given the widespread controversy over their sources, that research is not likely to move forward without continuing to generate significant political resistance from those who find treating embryos as research materials morally repugnant.
Typically, embryonic stem cells are obtained from living human embryos around the fourth or fifth day of development, when the embryo has reached the blastocyst stage. The blastocyst is a ball of cells with an internal cavity. Inside that cavity is the "inner cell mass" that is the source of embryonic stem cells. To obtain homogeneous cultures of cells derived from the inner cell mass (i.e., embryonic stem cell "lines"), the entire embryo is typically placed into culture under conditions in which the structural integrity of the embryo breaks down. The highly motile cells of the embryo's outer layer migrate away, and the inner cell mass remains as an intact cluster that is removed and cultured separately to establish an embryonic stem cell line.
Embryonic stem cells have both a longevity and a developmental flexibility that may make them especially useful for therapies that will regenerate damaged human tissues. In terms of their standing in nature, however, it is clear that embryonic stem cells are the early cells of a developing human being that must be destroyed in order to obtain these cells. Therefore, the use of these cells to establish stem cell lines, and the downstream use of any products or therapies that follow from the use of these lines, is morally problematic.
The cells of the inner cell mass are pluripotent, indicating their capacity to become any of many different types of differentiated cells of the organism, and should not be confused with the totipotent cells of the early embryo. The cells of a two-celled embryo, if separated, each retain the ability to become a complete new organism. When this happens in nature, it is called twinning, but the same separation of the early embryo can also be done artificially in a laboratory. The individual cells of the eight-celled or later-stage embryo no longer have the property of totipotency. Hence, if they could be obtained independently of embryo destruction, their use in research therapies would not pose any further moral difficulties - at least not as severe as those currently expressed over the destruction of embryos. Embryonic stem cells are clearly not embryos, and therefore their use does not involve the destruction of human life.
The most promising methods of obtaining pluripotent stem cells without destroying human life were outlined by the President's Council on Bioethics in its white paper Alternative Sources of Human Pluripotent Stem Cells.8 This report represents an important effort to find sources of stem cells that will be widely acceptable to the American public. Any products or therapies issuing from stem cell research that have their origins in the destruction of human embryos close themselves off from a significant segment of the population. Members of the scientific community often do not seem to appreciate the seriousness of this concern.9 Many citizens believe that to gain any personal advantage from the destruction of human embryos, even if it means cures for their own serious diseases, is wrong. Methods of obtaining pluripotent stem cells that are not compromised in this way would be of benefit to everyone: individual patients, scientific researchers, and pharmaceutical and product manufacturers. Four such methods were outlined in the Council's white paper. The advantages of the deceased embryo approach can be seen by a comparison with these other methods.
The first proposal for obtaining embryonic stem cells without destroying human embryos is embryo biopsy. Here one derives an embryonic stem cell line from a single cell plucked from an embryo.10 The procedure is typically used in pre-implantation genetic diagnosis (PGD). At the eight-cell stage, one of the cells, called a blastomere, is removed and tested for genetic defects. If any is found, the embryo is not transferred to the uterus, but is set aside and allowed to die or is destroyed. The procedure is clearly eugenic. The parents select some offspring over others on the basis of genetic information. Data from the European Society for Human Reproduction and Embryology (ESHRE) suggest that PGD significantly reduces embryo viability compared to non-biopsied embryos.11 The PDG embryo typically survives the extraction, but the removal of one-eighth of its matter is likely to have long-range consequences that are as of yet unknown.
Embryo biopsy faces an even more serious hurdle. The removal of a cell from an embryo involves more than a minimal risk to a non-consenting subject. Under standard research protocols governing the treatment of human subjects, research cannot pose more than a minimal risk of harm when it is of no therapeutic benefit. Removing a "starter-cell" from an embryo for the sole purpose of starting an embryonic stem cell line is clearly of no benefit to the embryo, but is done solely for the benefit of others, namely, for those who might be helped by the establishment of a stem cell line and any therapies that it may produce. The embryo itself is viewed as nothing more than a utilitarian source of therapeutic cells. The argument that the biopsied embryo might potentially benefit, at some point in the future, from the stem cell line established from it is not persuasive. Standard research protocols require that the research intervention be of direct benefit to the subject; future possible benefits do not justify more than minimal risk.12 Among the four proposals set before the President's Council on Bioethics, this one was greeted with the greatest degree of skepticism.13 Although variations of this method have been proposed, all proposals of this type face similar difficulties.14
A second proposal is to create "biological artifacts" that would not be human embryos, but teratomas or some other nonhuman entity. Various proposals have been worked out, but a typical model is a variation on cloning or somatic cell nuclear transfer. The nucleus of an adult somatic (body) cell is fused with an enucleated ovum, but before fusion takes place, genetic changes are introduced into the nucleus and the ovum that alter the epigenetic development of the cell resulting from the fusion, and thus prevent the formation of a human embryo. Because the changes are made prior to fusion, no embryo would exist from the very beginning of development. What is produced is therefore not an embryo or a human organism, but merely a useful human cell type that is capable of generating pluripotent stem cells.15
The common objection to this method is that we do not have a clear criterion by which to distinguish between embryos and non-embryos. How can we be certain that what is produced through altered nuclear transfer is not an embryo, although a very defective one? Or perhaps the entity passes through a momentary period of human existence before it self-destructs because of the various genetic manipulations imposed on it. Although it is easy enough to distinguish between a growth such as a hydatidiform mole and an embryo, it may not be quite so easy to distinguish between a "biological artifact" and an embryo, especially if that artifact results from the suppression of only one or two genetic factors. Given what is at stake, we would need a high degree of certitude that what is produced is not just a defective embryo. This approach would first have to be perfected in animals before it could be tried on human oocytes.
Third, there is the proposal for "dedifferentiation." Here one begins with an adult cell and manipulates it so that it returns to an earlier state, thus producing a pluripotent stem cell out of an adult cell. The recent research of Shinya Yamanaka, Rudolf Jaenisch, and Konrad Hochedlinger, showing that adult somatic cells can be reprogrammed to produce pluripotent stem cells (induced pluripotent stem, or iPS, cells), represents a very important advance in this area.16 If this method proves successful in human beings, as is expected, the procedure would not only be a critical breakthrough in embryonic stem cell research, but would also resolve the same key moral concern as would the harvesting of cells from deceased embryos. The discovery involves reprogramming a somatic cell through the introduction of genes that return it to an earlier pluripotent state, which can then be used in regenerative medicine to provide possible cures that are tailor-made for a particular patient.
This is a considerably simpler method for obtaining patient-specific stem cells than the currently favored "therapeutic cloning," a procedure that has not yet been accomplished in humans. If researchers can produce a pluripotent stem cell line simply by taking one of the patient's own cells and reprogramming it, then it is not necessary to go through the elaborate procedure of creating a clone of the patient, growing that cloned human being in vitro for several days, and then killing it in order to retrieve embryonic stem cells for use in regenerative medicine.
Nonetheless, this approach still faces significant obstacles before it will see any practical application. The key scientific challenges are discussed by Nicanor Austriaco, O.P., elsewhere in this journal.17 As he reports, the procedure has been carried out only in mice, involves the use of retroviruses that can potentially produce tumors, and depends on one specific gene that is associated with some forms of cancer in humans. These obstacles are not insurmountable, but the fact that induced pluripotent stem cells are not genuine embryonic stem cells makes it unlikely that this method will completely supplant the desire for embryonic stem cells that currently exists among researchers.
An adult cell that is reprogrammed so that is becomes pluripotent is obviously not identical to a cell that is removed from an early-stage embryo, despite the ability of such reprogrammed cells to stand in as functional equivalents of embryonic stem cells. Authentic stem cells from embryos are the only cells relevant to the study of human development. Should induced pluripotent stem cells be successful in treating human diseases, the demand for true embryonic stem cells would be greatly reduced, but not eliminated. We can expect researchers to continue to clamor for "discarded" embryos that they can use to obtain embryonic stem cells for the study of human development, if not for therapeutic purposes. The proposal to remove genuine embryonic stem cells from deceased embryos would suit this need, and thus provide researchers with the full range of cells that they need in regenerative medicine, and for basic scientific investigations without the destruction of human embryos.
The fourth proposal considered by the President's Council on Bioethics was developed by Dr. Donald Landry. Although establishing proper criteria for the determination of death in the human embryo is not without its own problems, both scientific and moral, this proposal lends itself to the kind of regulatory oversight that would immediately improve the condition and treatment of human embryos and their remains. Under this proposal, rather than being the cause of the embryo's demise, the researcher would delay removing embryonic stem cells until after death had been verified by a medically recognized standard. Rather than asking parents for permission to destroy embryos left in IVF laboratories, researchers would ask for permission to retrieve embryonic stem cells following the natural death of embryos. This is not to say that embryonic death poses no serious moral problems, but it is obviously better if parents give permission for the harvesting of cells from dead embryos than if they give permission for the actual killing of their embryos.18
Embryos that would be candidates for cell donation under the deceased embryo proposal are a subset of those that are deemed "nonviable" by laboratory technicians following a typical IVF cycle. Because of poor growth or cell formation, such nonviable embryos are set aside and not transferred to the uterus. On day five, some of these embryos are already dead and some are in the process of dying. It is a situation not unlike that found in any hospital setting, where the loved ones of those who suffer from terminal illnesses are approached concerning the possibility of organ donation following death. Obviously, we would never allow a fellow human being to be put to death so that his organs might be harvested, even if permission were given by the next of kin. Similarly, in the case of dying embryos, we should not allow them to be put to death so that their cells might be harvested for research, despite permission from couples who have undergone infertility treatment. Human embryos should be properly diagnosed as dead prior to any donation of their cells.
Most religious organizations recognize that it falls to the medical community to provide a proper criterion for the determination of death.19 The Catholic Church holds that death is a separation of the soul from the body, and thus a spiritual event that can never be directly observed by the instruments of medical science. Nonetheless, the Church recognizes that determining the signs of death is the work of the physician, who can verify, through the application of diagnostic techniques and medical technology, not the exact moment of death per se, but the fact that death has already occurred in a particular individual.20 Almost everyone agrees that the only person qualified to certify the fact of death is the physician. The determination of death in the embryo should likewise fall to the considered judgment of the medical community in the light of the findings of science. Inevitably, physicians will arrive at such criteria, just as they have for determining death in non-embryonic human beings.
The most important advantage of establishing criteria for death at embryonic stages and requiring a legal certification of death prior to donation of cells for research is that it would ensure that all human embryos produced in IVF laboratories are treated with an appropriate level of respect. First and foremost, that respect would prohibit their direct killing, but second, it would also guarantee that the bodies of deceased human embryos would be treated as those of any other human being. In particular, the practice of dumping the bodies of human embryos down a laboratory sink or incinerating them with common medical waste would be ended. These restrictions could be codified in law as a requirement for the disbursement of federal and state funds. Although this may seem unlikely at a time when there are virtually no limits whatsoever on the actions of laboratory researchers, the fact is that today there is no established law concerning the disposition of abandoned embryos. The first laws enacted in this area should favor embryonic life, and political efforts to do so would not encounter any countervailing laws.
The production of human beings in IVF laboratories has been condemned by various religious organizations, including the Catholic Church, as a violation of the inherent dignity of human life.21 The IVF industry is responsible for the generation of the hundreds of thousands of human lives that now lie abandoned in fertility laboratories throughout the United States. To produce human life in such a callous way is contrary to the right of children to be conceived and born within the natural bonds of marriage.22 This raises a serious concern. Would acceptance of the proposed criterion for determining death in the embryo lead to immoral association with those who produce human life in vitro? The routine wastage of human life in IVF clinics is a strong reason to avoid any association with this technique of artificial reproduction.
Under this proposal, however, the donation of cells from deceased human embryos would occur only after the wrongs associated with IVF have already been done. Researchers would merely be picking up the pieces, as it were, and trying to bring some good out of an otherwise tragic situation. The donation of cells from deceased embryos is certainly not going to increase the number of embryos produced by IVF laboratories. The highly lucrative practice of IVF relies entirely on the growing problem of infertility among the general population and, specifically, on the willingness of the wealthy to continue to spend vast amounts of money to overcome this problem. We should be willing to support any law that would limit the number of embryos produced in IVF laboratories or require all embryos produced to be transferred to their mother's uterus and brought to term. Quite frankly, we do not think that such legislation is even remotely possible in the United States. The IVF industry will continue to use "quality control" methods of embryo production better suited to animal husbandry regardless of the acceptance of any scientifically rigorous standard for the declaration of death in embryos, and regardless of any decision on the part of couples to donate stem cells from deceased embryos.
Human embryos are entitled to the same declaration of death as are any other human beings. To deprive them of this declaration simply because they are produced in vitro constitutes an injustice against them. A declaration of death represents an official and public recognition that a human life has come to an end and that the remains of that human being must now be treated with due respect. Currently, human embryos are not declared dead at all, but are treated as so much biological waste. Model legislation that codified the determination of death in the embryo would not result in any increase in the use of IVF, which is driven by independent considerations, but would instead bring a strong measure of legal protection to embryos who have the misfortune to be produced in this way.
If such legislation were enacted, the process of obtaining embryonic stem cells from deceased embryos would have to be kept distinct from the laboratory work of those who operate the IVF laboratory and from those who declare the death of the embryo. In keeping with standard protocols regarding organ donation, the physician who determines death in the embryo must not be the same person who seeks permission from the parents for cell donation. Nor can he be the one who removes organs or cells from the deceased. This effectively places a bar between the actions of those who carry out the IVF procedures and those who arrive after the fact of embryo death and remove donated cells.
The death of the embryo represents a significant dividing point between the wrongs committed by the parents and the IVF technicians, and the actions of researchers who follow. No further harm can come to the embryo following death. Those who oppose the destruction of human life in the IVF process, and those who oppose IVF in principle as an immoral means of achieving pregnancy, would be able to retrieve these cells without immorally cooperating in the wrongdoing of those who have brought about this tragic situation.
In any donation of cells, organs, or tissues following death there must be someone who has authority over the remains to give consent. But in the present case, the moral standing of the parents is questionable. If it is wrong for them to engender embryonic human beings in a laboratory, and wrong to leave them to die there, how can these same parents have the authority to give permission to researchers to extract cells from them? By their refusal to transfer the embryos to the uterus and so care for their own offspring, have they not surrendered all responsibility over them? Have they not shown, by the manner in which they produced these embryos, that they are unworthy of making decisions with regard to the disposition of their remains?23
The response to this question must begin with a statement of the correct course of action in the disposition of human embryos. First, producing offspring in IVF laboratories, and selecting which ones will be transferred to the womb, is eugenic and ought to be prohibited by law. As already noted, we do not think such legislation is likely to be enacted in the near future. But if parents have already used IVF, and embryos remain, their first duty is to transfer as many of their offspring as they can and so attempt to bring them to term.
Some ethicists argue that embryos should never be frozen, but should be allowed to die a natural death.24 Others argue that they should be cryopreserved and made available either for later transfer or even for adoption by other couples.25 If there is no one who is willing to receive the abandoned embryos, then at some point, after it is evident that decay has set in, we would argue that human embryos should be allowed to die a natural death on the grounds that further storage constitutes an extraordinary means of preserving life. This is a tragic situation, but it is difficult to see what else can be done. Certainly, endless freezing in liquid nitrogen is not a solution.
Little of the above reasoning, however, applies directly to the case at hand, for the embryos that are set aside because of some question about their viability will not even be frozen for later possible transfer, but will simply be allowed to die in the laboratory. Again, we do not approve of this practice, but simply note that this is currently what is done. It is preferable, in our view, that some legal oversight be put in place to secure a measure of respect for the embryos that are derived from a morally unacceptable practice that is already well entrenched in the United States and throughout the world. A proper determination of death would bring some measure of recognition of the inherent dignity of these embryonic human beings and would allow procedures to be put in place for the subsequent retrieval of embryonic stem cells for use in research.
In the United States, consent is not presumed when someone dies. In many parts of Europe, the victim of a traffic accident must have a card that indicates his opposition to the use of his remains for organ transplantation. Such a presumption has never been acceptable to the American people, who rightly hold that the disposition of human remains falls to the decision-making authority of immediate family members. Only they can properly give consent to any request from medical personnel to extract organs for possible use in transplantation.
The moral standing of the parents who create embryos through IVF is less than ideal, but as a sheer factual matter, there is no other qualified agent who can act in this capacity. Certainly, the current practice, in which the laboratory technicians have the responsibility for disposing of unwanted embryos, is completely unacceptable. The reason why these embryos fail to be accorded the respect due to them is because final decisions about their treatment fall to those who are not personal relations and who have no personal concern for them. The parents, though we may fault them for their choices, are the only ones who are in a position to show proper concern for their offspring. Those parents who do not care about their own embryos should nonetheless be obliged under law to make decisions that will be appropriate to the responsibilities they have assumed. The laws that currently exist in this area give the parents the option of donating their living embryos for research. This freedom should be restricted so that they may donate the cells only of their embryos that have died.
Those who find parental control in this matter unacceptable could ask that the law forbid parents from donating the cells of deceased embryos, but this seems unwise for two reasons. First, as the embryos are dead, no harm can come to them from the decision to donate their cells. Second, it seems arbitrary to restrict the range of parental choice in this way. Either the parents are responsible for the disposition of their own embryos or they are not - and if they are responsible, they should have the freedom to dispose of the remains in any way that is respectful. The law should not try to limit the role of the parents unless what they seek to do is clearly immoral. But it clearly is not immoral to donate cells and tissues of loved ones after death.
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3. Can We Distinguish between Living and Dead Embryos?
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