Human Embryos In Medical Research Essay

Abstract

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

Key words: cell therapy/cloning/embryos/ethics/stem cells

Introduction

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

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

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

What are (embryonic) stem cells?

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

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

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

Potential applications of hES cells and state‐of‐the‐art

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

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

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

Ethical exploration

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

The status of hES cells

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

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

Instrumental use of embryos

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

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

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

Ethics of using surplus IVF embryos as a source of hES cells

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

Proportionality

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

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

Slippery slope

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

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

Subsidiarity

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

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

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

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

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

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

(iii) Analysis of the developmental potential of adult stem cells is a rapidly evolving field of research, particularly in animal model systems. Experiments carried out within the last two years have demonstrated, for example, that bone marrow cells can give rise to nerve cells in mouse brain (Mezey et al., 2000), neural cells from mouse brain can turn into blood and muscle (Bjornson et al., 1999; Galli et al., 2000), and even participate in the development of chimeric mouse embryos up to mid‐gestation (Clarke et al., 2000). Although apparently spectacular in demonstrating that neural stem cells from mice can form most cell types under the appropriate conditions, it is still unclear whether true plasticity in terms of function has been demonstrated or whether the cells simply ‘piggy‐back’ with normal cells during development. Published evidence of ‘plasticity’ in adult human stem cells is more limited, but recent evidence suggests that the MAPCs from bone marrow may represent a breakthrough (Jiang et al., 2002; Schwartz et al., 2002;). They are accessible. Collection is relatively non‐destructive for surrounding tissue compared, for example, with the collection of neural stem cells from adult brain, although their numbers are low: 1 in 108 of these cells exhibit the ability to form populations of nerve, muscle and a number of other cell types and they only become evident after several months of careful culture. Clonal analysis has provided rigorous proof of plasticity: a single haematopoietic stem cell can populate a variety of tissues when injected into lethally irradiated mice (Krause et al., 2001) or into blastocyst stage embryos to generate chimeric embryos (Jiang et al., 2002). Nonetheless, there are potential hazards to using cells that have been cultured for long periods for transplantation and although MAPCs seem to have normal chromosomes, it is important to establish that the pathways governing cell proliferation are unperturbed. This is also true for hES cells. However, the powerful performance of mES cells in restoring function in a rat model for Parkinson’s disease (Kim et al., 2002), has not yet been matched by MAPCs. Bone marrow stem cells have been shown very recently to restore function to some extent in a mouse heart damaged by coronary ligation, an experiment that mimics the conditions of the human heart soon after infarction (Orlic et al., 2001). Although clinical restoration of function in a damaged organ is usually sought rather longer after the original injury than in these experiments, which were performed before scar tissue had formed, this approach will certainly be worth pursuing. An alternative, non‐invasive, haematopoietic stem cell source is umbilical cord blood. This is used clinically for transplantation as an alternative to bone marrow in patients for whom no bone marrow match is available. Cord blood contains precursors of a number of lineages but its pluripotency, or even multipotency, is far from proven. Nevertheless, the prospect of autologous transplantation of haematopoietic stem cells of bone marrow in the long term makes this an important research area in terms of alternatives to therapeutic cloning (see below).

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

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

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

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

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

Therapeutic cloning

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

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

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

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

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

Abstract

Stem cell research offers great promise for understanding basic mechanisms of human development and differentiation, as well as the hope for new treatments for diseases such as diabetes, spinal cord injury, Parkinson’s disease, and myocardial infarction. However, human stem cell (hSC) research also raises sharp ethical and political controversies. The derivation of pluripotent stem cell lines from oocytes and embryos is fraught with disputes about the onset of human personhood. The reprogramming of somatic cells to produce induced pluripotent stem cells avoids the ethical problems specific to embryonic stem cell research. In any hSC research, however, difficult dilemmas arise regarding sensitive downstream research, consent to donate materials for hSC research, early clinical trials of hSC therapies, and oversight of hSC research. These ethical and policy issues need to be discussed along with scientific challenges to ensure that stem cell research is carried out in an ethically appropriate manner. This article provides a critical analysis of these issues and how they are addressed in current policies.

I. Introduction

STEM CELL RESEARCH offers great promise for understanding basic mechanisms of human development and differentiation, as well as the hope for new treatments for diseases such as diabetes, spinal cord injury, Parkinson’s disease, and myocardial infarction (1). Pluripotent stem cells perpetuate themselves in culture and can differentiate into all types of specialized cells. Scientists plan to differentiate pluripotent cells into specialized cells that could be used for transplantation.

However, human stem cell (hSC) research also raises sharp ethical and political controversies. The derivation of pluripotent stem cell lines from oocytes and embryos is fraught with disputes regarding the onset of human personhood and human reproduction. Several other methods of deriving stem cells raise fewer ethical concerns. The reprogramming of somatic cells to produce induced pluripotent stem cells (iPS cells) avoids the ethical problems specific to embryonic stem cells. With any hSC research, however, there are difficult dilemmas, including consent to donate materials for hSC research, early clinical trials of hSC therapies, and oversight of hSC research (2). Table 1​ summarizes the ethical issues that arise at different phases of stem cell research.

Table 1

Ethical issues at different phases of stem cell research

II. Multipotent Stem Cells

Adult stem cells and cord blood stem cells do not raise special ethical concerns and are widely used in research and clinical care. However, these cells cannot be expanded in vitro and have not been definitively shown to be pluripotent.

A. Cord blood stem cells

Hematopoietic stem cells from cord blood can be banked and are widely used for allogenic and autologous stem cell transplantation in pediatric hematological diseases as an alternative to bone marrow transplantation.

B. Adult blood stem cells

Adult stem cells occur in many tissues and can differentiate into specialized cells in their tissue of origin and also transdifferentiate into specialized cells characteristic of other tissues. For example, hematopoietic stem cells can differentiate into all three blood cell types as well as into neural stem cells, cardiomyocytes, and liver cells.

Adult stem cells can be isolated through plasmapheresis. They are already used to treat hematological malignancies and to modify the side effects of cancer chemotherapy. Furthermore, autologous stem cells are being used in clinical trials in patients who have suffered myocardial infarction. Their use in several other conditions has not been validated or is experimental, despite some claims to the contrary (3).

III. Embryonic Stem Cell Research

Pluripotent stem cell lines can be derived from the inner cell mass of the 5- to 7-d-old blastocyst. However, human embryonic stem cell (hESC) research is ethically and politically controversial because it involves the destruction of human embryos. In the United States, the question of when human life begins has been highly controversial and closely linked to debates over abortion. It is not disputed that embryos have the potential to become human beings; if implanted into a woman’s uterus at the appropriate hormonal phase, an embryo could implant, develop into a fetus, and become a live-born child.

Some people, however, believe that an embryo is a person with the same moral status as an adult or a live-born child. As a matter of religious faith and moral conviction, they believe that “human life begins at conception” and that an embryo is therefore a person. According to this view, an embryo has interests and rights that must be respected. From this perspective, taking a blastocyst and removing the inner cell mass to derive an embryonic stem cell line is tantamount to murder (4).

Many other people have a different view of the moral status of the embryo, for example that the embryo becomes a person in a moral sense at a later stage of development than fertilization. Few people, however, believe that the embryo or blastocyst is just a clump of cells that can be used for research without restriction. Many hold a middle ground that the early embryo deserves special respect as a potential human being but that it is acceptable to use it for certain types of research provided there is good scientific justification, careful oversight, and informed consent from the woman or couple for donating the embryo for research (5).

Opposition to hESC research is often associated with opposition to abortion and with the “pro-life” movement. However, such opposition to stem cell research is not monolithic. A number of pro-life leaders support stem cell research using frozen embryos that remain after a woman or couple has completed infertility treatment and that they have decided not to give to another couple. This view is held, for example, by former First Lady Nancy Reagan and by U.S. Senator Orrin Hatch.

On his Senate website, Sen. Hatch states: “The support of embryonic stem cell research is consistent with pro-life, pro-family values.

“I believe that human life begins in the womb, not a Petri dish or refrigerator … . To me, the morality of the situation dictates that these embryos, which are routinely discarded, be used to improve and save lives. The tragedy would be in not using these embryos to save lives when the alternative is that they would be discarded” (6).

A. Existing embryonic stem cell lines

In 2001, President Bush, who holds strong pro-life views, allowed federal National Institutes of Health (NIH) funding for stem cell research using embryonic stem cell lines already in existence at the time, while prohibiting NIH funding for the derivation or use of additional embryonic stem cell lines. This policy was a response to a growing sense that hESC research held great promise for understanding and treating degenerative diseases, while still opposing further destruction of human embryos. NIH funding was viewed by many researchers as essential for attracting scientists to make a long-term commitment to study the basic biology of stem cells; without a strong basic science platform, therapeutic breakthroughs would be less likely.

President Bush’s rationale for this policy was that the embryos from which these lines were produced had already been destroyed. Allowing research to be carried out on the stem cell lines might allow some good to come out of their destruction. However, using only existing embryonic stem cell lines is scientifically problematic. Originally, the NIH announced that over 60 hESC lines would be acceptable for NIH funding. However, the majority of these lines were not suitable for research; for example, they were not truly pluripotent, had become contaminated, or were not available for shipping. As of January 2009, 22 hESC lines are eligible for NIH funding. However, these lines may not be safe for transplantation into humans, and long-standing lines have been shown to accumulate mutations, including several known to predispose to cancer. In addition, concerns have been raised about the consent process for the derivation of some of these NIH-approved lines (7). The vast majority of scientific experts, including the Director of the NIH under President Bush, believe that a lack of access to new embryonic stem cell lines hinders progress toward stem cell-based transplantation (8). For example, lines from a wider range of donors would allow more patients to receive human leukocyte agent matched stem cell transplants (9).

Currently, federal funds may not be used to derive new embryonic stem cell lines or to work with hESC lines not on the approved NIH list. NIH-funded equipment and laboratory space may not be used for research on nonapproved hESC lines. Both the derivation of new hESC lines and research with hESC lines not approved by NIH may be carried out under nonfederal funding. Because of these restrictions on NIH funding, a number of states have established programs to fund stem cell research, including the derivation of new embryonic stem cell lines. California, for example, has allocated $3 billion over 10 yr to stem cell research.

Under President Obama, it is expected that federal funding will be made available to carry out research with hESC lines not on the NIH list and to derive new hESC lines from frozen embryos donated for research after a woman or couple using in vitro fertilization (IVF) has determined they are no longer needed for reproductive purposes. However, federal funding may not be permitted for creation of embryos expressly for research or for derivation of stem cell lines using somatic cell nuclear transfer (SCNT) (10,11).

B. New embryonic stem cell lines from frozen embryos

Women and couples who undergo infertility treatment often have frozen embryos remaining after they complete their infertility treatment. The disposition of these frozen embryos is often a difficult decision for them to make (12). Some choose to donate these remaining embryos to research rather than giving them to another couple for reproductive purposes or destroying them. Several ethical concerns come into play when a frozen embryo is donated, including informed consent from the woman or couple donating the embryo, consent from gamete donors involved in the creation of the embryo, and the confidentiality of donor information.

1. Informed consent for donation of materials for stem cell research.

Since the Nuremburg Code, informed consent has been regarded as a basic requirement for research with human subjects. Consent is particularly important in research with human embryos (13). Members of the public and potential donors of embryos for research hold strong and diverse opinions on the matter. Some consider all embryo research to be unacceptable; others only support some forms of research. For instance, a person might consider infertility research acceptable but object to research to derive stem cell lines or research that might lead to patents or commercial products (14). Obtaining informed consent for potential future uses of the donated embryo respects this diversity of views. Additionally, people commonly place special emotional and moral significance on their reproductive materials, compared with other tissues (15).

2. Waiver of consent.

In the United States, federal regulations on research permit a waiver of informed consent for the research use of deidentified biological materials that cannot be linked to donors (16). Thus, logistically it would be possible to carry out embryo and stem cell research on deidentified materials without consent. For example, during IVF procedures, oocytes that fail to fertilize or embryos that fail to develop sufficiently to be implanted are ordinarily discarded. These materials could be deidentified and then used by researchers. Furthermore, if infertility patients have frozen embryos remaining after they complete treatment, they are routinely contacted by the IVF program to decide whether they want to continue to store the embryos (and to pay freezer storage fees), to donate them to another infertile woman or couple, or to discard them. If a patient chooses to discard the embryos, it would be possible to instead remove identifiers and use them for research. Still another possibility involves frozen embryos from patients who do not respond to requests to make a decision regarding the disposition of frozen embryos. Some IVF practices have a policy to discard such embryos and inform patients of this policy when they give consent for the IVF procedures. Again, rather than discard such frozen embryos, it is logistically feasible to deidentify them and give them to researchers.

However, the ethical justifications for allowing deidentified biological materials to be used for research without consent do not always hold for embryo research (13). For example, one rationale for allowing the use of deidentified materials is that the ethical risks are very low; there can be no breach of confidentiality, which is the main concern in this type of research. A second rationale is that people would not object to having their materials used in such a manner if they were asked. However, this assumption does not necessarily hold in the context of embryo research. A 2007 study found that 49% of women with frozen embryos would be willing to donate them for research (12). Such donors might be offended or feel wronged if their frozen embryos were used for research that they did not consent to. Deidentifying the materials would not address their concerns.

3. Consent from gamete donors.

Frozen embryos may be created with sperm or oocytes from donors who do not participate any further in assisted reproduction or childrearing. Some people argue that consent from gamete donors is not required for embryo research because they have ceded their right to direct further usage of their gametes to the artificial reproductive technology (ART) patients. However, gamete donors who are willing to help women and couples bear children may object to the use of their genetic materials for research. In one study, 25% of women who donated oocytes for infertility treatment did not want the embryos created to be used for research (17). This percentage is not unexpected because reproductive materials have special significance, and many people in the United States oppose embryo research. Little is known about the wishes of sperm donors concerning research.

There are substantial practical differences between obtaining consent for embryo research from oocyte donors and from sperm donors. ART clinics can readily discuss donation for research with oocyte donors during visits for oocyte stimulation and retrieval. However, most ART clinics obtain donor sperm from sperm banks and generally have no direct contact with the donors. Furthermore, sperm is often donated anonymously to sperm banks, with strict confidentiality provisions.

As a matter of respect for gamete donors, their wishes regarding stem cell derivation should be determined and respected (13). Gamete donors who are willing to help women and couples bear children may object to the use of their genetic materials for research. Specific consent for stem cell research from both embryo and gamete donors was recommended by the National Academy of Sciences 2005 Guidelines for Human Embryonic Stem Cell Research and has been adopted by the California Institute for Regenerative Medicine (CIRM), the state agency funding stem cell research (18,19). This consent requirement need not imply that embryos are people or that gametes or embryos are research subjects.

4. Confidentiality of donor information.

Confidentiality must be carefully protected in embryo and hESC research because breaches of confidentiality might subject donors to unwanted publicity or even harassment by opponents of hESC research (20). Although identifying information about donors must be retained in case of audits by the Food and Drug Administration as part of the approval process for new therapies, concerns about confidentiality may deter some donors from agreeing to be recontacted.

Recently, confidentiality of personal health care information has been violated through deliberate breaches by staff, through break-ins by computer hackers, and through loss or theft of laptop computers. Files containing the identities of persons whose gametes or embryos were used to derive hESC lines should be protected through heightened security measures (20). Any computer storing such files should be locked in a secure room and password-protected, with access limited to a minimum number of individuals on a strict “need-to-know” basis. Entry to the computer storage room should also be restricted by means of a card-key, or equivalent system, that records each entry. Audit trails of access to the information should be routinely monitored for inappropriate access. The files with identifiers should be copy-protected and double encrypted, with one of the keys held by a high-ranking institutional official who is not involved in stem cell research. The computer storing these data should not be connected to the Internet. To protect information from subpoena, investigators should obtain a federal Certificate of Confidentiality. Human factors in breaches of confidentiality should also be considered. Personnel who have access to these identifiers might receive additional background checks, interviews, and training. The personnel responsible for maintaining this confidential database and contacting any donor should not be part of any research team.

hESC research using fresh oocytes donated for research raises several additional ethical concerns as well, as we next discuss (21).

C. Ethical concerns about oocyte donation for research

Concerns about oocyte donation specifically for research are particularly serious in the wake of the Hwang scandal in South Korea, in which widely hailed claims of deriving human SCNT lines were fabricated. In addition to scientific fraud, the scandal involved inappropriate payments to oocyte donors, serious deficiencies in the informed consent process, undue influence on staff and junior scientists to serve as donors, and an unacceptably high incidence of medical complications from oocyte donation (22,23,24). In California, some legislators and members of the public have charged that infertility clinics downplay the risks of oocyte donation (19). CIRM has put in place several protections for women donating oocytes in state-funded stem cell research.

1. Medical risks of oocyte retrieval.

The medical risks of oocyte retrieval include ovarian hyperstimulation syndrome, bleeding, infection, and complications of anesthesia (25). These risks may be minimized by the exclusion of donors at high-risk for these complications, careful monitoring of the number of developing follicles, and adjusting the dose of human chorionic gonadotropin administered to induce ovulation or canceling the cycle (25).

Because severe hyperovulation syndrome may require hospitalization or surgery, women donating oocytes for research should be protected against the costs of complications of hormonal stimulation and oocyte retrieval (19). The United States does not have universal health insurance. As a matter of fairness, women who undergo an invasive procedure for the benefit of science and who are not receiving payment beyond expenses should not bear any costs for the treatment of complications. Even if a woman has health insurance, copayments and deductibles might be substantial, and if she later applied for individual-rated health insurance, her premiums might be prohibitive. Compensation for research injuries has been recommended by several U.S. panels (26) but has not been adopted because of difficulties calculating long-term actuarial risk and assessing intervening factors that could contribute to or cause adverse events.

Requiring free care for short-term complications of oocyte donation is feasible. In California, research institutions must ensure free treatment to oocyte donors for direct and proximate medical complications of oocyte retrieval in state-funded research. The term “direct and proximate” is a legal concept to determine how closely an injury needs to be connected to an event or condition to assign responsibility for the injury to the person who carried out the event or created the condition. Commercial insurance policies are available to cover short-term complications of oocyte retrieval. CIRM allows state stem cell grants to cover the cost of such insurance. The rationale for making research institutions responsible for treatment is that they are in a better position than individual researchers to identify insurance policies and would have an incentive to consider extending such coverage to other research injuries.

2. Protecting the reproductive interests of women in infertility treatment.

If women in infertility treatment share oocytes with researchers—either their own oocytes or those from an oocyte donor—their prospect of reproductive success may be compromised because fewer oocytes are available for reproductive purposes (21). In this situation, the physician carrying out oocyte retrieval and infertility care should give priority to the reproductive needs of the patient in IVF. The highest quality oocytes should be used for reproductive purposes (21).

As discussed in Section B. 2, in IVF programs some oocytes fail to fertilize, and some embryos fail to develop sufficiently to be implanted. Such materials may be donated to researchers. To protect the reproductive interests of donors, several safeguards should be in place (20). For the donation of fresh embryos for research, the determination by the embryologist that an embryo is not suitable for implantation and therefore should be discarded is a matter of judgment. Similarly, the determination that an oocyte has failed to fertilize and thus cannot be used for reproduction is a judgment call. To avoid any conflict of interest, the embryologist should not know whether a woman has agreed to research donation and also should receive no funding from grants associated with the research. Furthermore, the treating infertility physicians should not know whether or not their patients agree to donate materials for research.

3. Payment to oocyte donors.

Many jurisdictions have conflicting policies about payment to oocyte donors. Reimbursement to oocyte donors for out-of-pocket expenses presents no ethical problems because donors gain no financial advantage from participating in research. However, payment to oocyte donors in excess of reasonable out-of-pocket expenses is controversial, and jurisdictions have conflicting policies that may also be internally inconsistent (27,28).

Good arguments can be made both for and against paying donors of research oocytes more than their expenses (29). On the one hand, some object that such payments induce women to undertake excessive risks, particularly poorly educated women who have limited options for employment, as occurred in the Hwang scandal. Such concerns about undue influence, however, may be addressed without banning payment. For example, participants could be asked questions to ensure that they understood key features of the study and that they felt they had a choice regarding participation (19). Also, careful monitoring and adjustment of hormone doses can minimize the risks associated with oocyte donation (25). A further objection is that paying women who provide research oocytes undermines human dignity because human biological materials and intimate relationships are devalued if these materials are bought and sold like commodities (14,30).

On the other hand, some contend that it is unfair to ban payments to donors of research oocytes, while allowing women to receive thousands of U.S. dollars to undergo the same procedures to provide oocytes for infertility treatment (29). Moreover, healthy volunteers, both men and women, are paid to undergo other invasive research procedures, such as liver biopsy, for research purposes. Furthermore, bans on payment for oocyte donation for research have been criticized as paternalistic, denying women the authority to make decisions for themselves (31). On a pragmatic level, without such payment, it is very difficult to recruit oocyte donors for research.

4. Informed consent for oocyte donation.

In California, CIRM has instituted heightened requirements for informed consent for oocyte donation for research (19). The CIRM regulations go beyond requirements for disclosure of information to oocyte donors (19). The major ethical issue is whether donors appreciate key information about oocyte donation, not simply whether the information has been disclosed to them or not. As discussed previously, in other research settings, research participants often fail to understand the information in detailed consent forms (32). CIRM thus reasons that disclosure, while necessary, is not sufficient to guarantee informed consent. In CIRM-funded research, oocyte donors must be asked questions to ensure that they comprehend the key features of the research (19). Evaluating comprehension is feasible because it has been carried out in other research contexts, such as in HIV prevention trials in the developing world (33). According to testimony presented to CIRM, evaluation of comprehension has also been carried out with respect to oocyte donation for clinical infertility services.

IV. Somatic Cell Nuclear Transfer (SCNT)

Pluripotent stem cell lines whose nuclear DNA matches a specific person have several scientific advantages. Stem cell lines matched to persons with specific diseases can serve as in vitro models of diseases, elucidate the pathophysiology of diseases, and screen potential new therapies. Lines matched to specific individuals also offer the promise of personalized autologous stem cell transplantation.

One approach to creating such lines is through SCNT, the technique that produced Dolly the sheep. In SCNT, reprogramming is achieved after transferring nuclear DNA from a donor cell into an oocyte from which the nucleus has been removed. However, creating human SCNT stem cell lines has not only been scientifically impossible to date but is also ethically controversial (34,35).

A. Ethical concerns about SCNT

1. Objections to creating embryos specifically for research.

Some people who object to SCNT believe that creating embryos with the intention of using them for research and destroying them in that process violates respect for nascent human life. Even those who support deriving stem cell lines from frozen embryos that would otherwise be discarded sometimes reject the intentional creation of embryos for research. In rebuttal, however, some argue that pluripotent entities created through SCNT are biologically and ethically distinct from embryos (36).

2. Objections to human reproduction using SCNT.

There are several compelling objections to using SCNT for human reproduction. First, because of errors during reprogramming of genetic material, cloned animal embryos fail to activate key embryonic genes, and newborn clones misexpress hundreds of genes (37,38). The risk of severe congenital defects would be prohibitively high in humans. Second, even if SCNT could be carried out safely in humans, some object that it violates human dignity and undermines traditional, fundamental moral, religious, and cultural values (34). A cloned child would have only one genetic parent and would be the genetic twin of that parent. In this view, cloning would lead children to be regarded more as “products of a designed manufacturing process than ‘gifts’ whom their parents are prepared to accept as they are.” Furthermore, cloning would violate “the natural boundaries between generations” (34). For these reasons, cloning for reproductive purposes is widely considered morally wrong and is illegal in a number of states. Moreover, some people argue that because the technique of SCNT can be used for reproduction, its development and use for basic research should be banned.

3. Use of animal oocytes to create SCNT lines using human DNA.

Because of the shortage of human oocytes for SCNT research, some scientists wish to use nonhuman oocytes to derive lines using human nuclear DNA. These so-called “cytoplasmic hybrid embryos” raise a number of ethical concerns. Some opponents fear the creation of chimeras—mythical beasts that appear part human and part animal and have characteristics of both humans and animals (39). Opponents may feel deep moral unease or repugnance, without articulating their concerns in more specific terms. Some people view such hybrid embryos as contrary to a moral order embodied in the natural world and in natural law. In this view, each species has a particular moral purpose or goal, which mankind should not try to change. Others view such research as an inappropriate crossing of species barriers, which should be an immutable part of natural design. Finally, some are concerned that there may be attempts to implant these embryos for reproductive purposes.

In rebuttal, supporters of such research point out that the biological definitions of species are not natural and immutable but empirical and pragmatic (40,41,42). Animal-animal hybrids of various sorts, such as the mule, exist and are not considered morally objectionable. Moreover, in medical research, human cells are commonly injected into nonhuman animals and incorporated into their functioning tissue. Indeed, this is widely done in research with all types of stem cells to demonstrate that cells are pluripotent or have differentiated into the desired type of cell. In addition, some concerns can be addressed through strict oversight (40), for example prohibiting reproductive uses of these embryos and limiting in vitro development to 14 d or the development of the primitive streak, limits that are widely accepted for other hESC research. Finally, some people regard repugnance per se an unconvincing guide to ethical judgments. People disagree over what is repugnant, and their views might change over time. Blood transfusion and cadaveric organ transplantation were originally viewed as repugnant but are now widely accepted practices. Furthermore, after public discussion and education, many people overcome their initial concerns.

V. Fetal Stem Cells

Pluripotent stem cells can be derived from fetal tissue after abortion. However, use of fetal tissue is ethically controversial because it is associated with abortion, which many people object to. Under federal regulations, research with fetal tissue is permitted provided that the donation of tissue for research is considered only after the decision to terminate pregnancy has been made. This requirement minimizes the possibility that a woman’s decision to terminate pregnancy might be influenced by the prospect of contributing tissue to research. Currently there is a phase 1 clinical trial in Batten’s disease, a lethal degenerative disease affecting children, using neural stem cells derived from fetal tissue (43,44).

VI. Induced Pluripotent Stem Cells (iPS Cells)

Somatic cells can be reprogrammed to form pluripotent stem cells (45,46), called induced pluripotential stem cells (iPS cells). These iPS cell lines will have DNA matching that of the somatic cell donors and will be useful as disease models and potentially for allogenic transplantation.

Early iPS cell lines were derived by inserting genes encoding for transcription factors, using retroviral vectors. Researchers have been trying to eliminate safety concerns about inserting oncogenes and insertional mutagenesis. Reprogramming has been successfully accomplished without known oncogenes and using adenovirus vectors rather than retrovirus vectors. A further step was the recent demonstration that human embryonic fibroblasts can be reprogrammed to a pluripotent state using a plasmid with a peptide-linked reprogramming cassette (47,48). Not only was reprogramming accomplished without using a virus, but the transgene can be removed after reprogramming is accomplished. The ultimate goal is to induce pluripotentiality without genetic manipulation. Because of unresolved problems with iPS cells, which currently preclude their use for cell-based therapies, most scientists urge continued research with hESC (49).

iPS cells avoid the heated debates over the ethics of embryonic stem cell research because embryos or oocytes are not used. Furthermore, because a skin biopsy to obtain somatic cells is relatively noninvasive, there are fewer concerns about risks to donors compared with oocyte donation. The President’s Council on Bioethics called iPS cells “ethically unproblematic and acceptable for use in humans” (39). Neither the donation of materials to derive iPS cells nor their derivation raises special ethical issues.

A. Downstream research

Some potential downstream uses of iPS cell derivatives may be so sensitive as to call into question whether the original somatic cell donors would have agreed to such uses (50). iPS cells will be shared widely among researchers who will carry out a variety of studies with iPS cells and derivatives, using common and well-accepted scientific practices, such as:

  • Genetic modifications of cells

  • Injection of derived cells into nonhuman animals to demonstrate their function, including the injection into the brains of nonhuman animals.

  • Large-scale genome sequencing

  • Sharing cell lines with other researchers, with appropriate confidentiality protections, and

  • Patenting scientific discoveries and developing commercial tests and therapies, with no sharing of royalties with donors (51).

These standard research techniques are widely used in other types of basic research, including research with stem cells from other sources. Generally, donors of biological materials are not explicitly informed of these research procedures, although such disclosure is now proposed for whole genome sequencing (52,53).

Such studies are of fundamental importance in stem cell biology, for example to characterize the lines and to demonstrate that they are pluripotent. Large-scale genome sequencing will yield insights about the pathogenesis of disease and identify new targets for therapy. Injection of human stem cells into the brains of nonhuman animals will be required for preclinical testing of cell-based therapies for many conditions, such as Parkinson’s disease, Alzheimer’s disease, and stroke.

However, some downstream research could also raise ethical concerns. For example, large-scale genome sequencing may evoke concerns about privacy and confidentiality. Donors might consider it a violation of privacy if scientists know their future susceptibility to many genetic diseases. Furthermore, it may be possible to reidentify the donor of a deidentified large-scale genome sequence using information in forensic DNA databases or at an Internet company offering personal genomic testing (54,55). Other donors may object to their cells being injected into animals. For example, they may oppose all animal research, or they may have religious objections to the mixing of human and animal species. The injection of human neural progenitor cells into nonhuman animals has raised ethical concerns about animals developing characteristics considered uniquely human (56,57). Still other donors may not want cell lines derived from their biological materials to be patented as a step toward developing new tests and therapies. People are unlikely to drop such objections even if the cell lines were deidentified or even if many years had passed since the original donation. Thus there may be a tension between respecting the autonomy of donors and obtaining scientific benefit from research, which can be resolved during the process of obtaining consent for the original donation of materials.

It would be unfortunate if iPS cell lines that turned out to be extremely useful scientifically (for example because of robust growth in tissue culture) could not be used in additional research because the somatic cell donor objected. One approach to avoid this is to preferentially use somatic cells from donors who are willing to allow all such basic stem cell research and to be contacted for future sensitive research that cannot be anticipated at the time of consent (50). Donors could also be offered the option of consenting to additional specific types of sensitive but not fundamental downstream research, such as allogenic transplantation into other humans and reproductive research involving the creation of totipotent entities.

Because these concerns about consent for sensitive downstream research also apply to other types of stem cells, it would be prudent to put in place similar standards for consent to donate materials for derivation of other types of stem cells. However, these concerns are particularly salient for iPS cells because of the widespread perception that these cells raise no serious ethical problems and because they are likely to play an increasing role in stem cell research.

VII. Stem Cell Clinical Trials

Transplantation of cells derived from pluripotent stem cells offers the promise of effective new treatments. However, such transplantation also involves great uncertainty and the possibility of serious risks. Some stem cell therapies have been shown to be effective and safe, for example hematopoietic stem cell transplants for leukemia and epithelial stem cell-based treatments for burns and corneal disorders (58). However, “there are some clinics around the world already exploiting patients’ hopes by purporting to offer effective stem cell therapies for seriously ill patients, typically for large sums of money, but without credible scientific rationale, transparency, oversight, or patient protections” (58). Although supporting medical innovation under very limited circumstances, the International Society for Stem Cell Research has decried such use of unproven hSC transplantation.

These clinical trials should follow ethical principles that guide all clinical research, including appropriate balance of risks and benefits and informed, voluntary consent. Additional ethical requirements are also warranted to strengthen trial design, coordinate scientific and ethics review, verify that participants understand key features of the trial, and ensure publication of negative findings (59). These measures are appropriate because of the highly innovative nature of the intervention, limited experience in humans, and the high hopes of patients who have no effective treatments.

A. Risks and prospective benefits in stem cell clinical trials

The risks of innovative stem cell-based interventions include “tumor formation, immunological reactions, unexpected behavior of the cells, and unknown long-term health effects” (58). Evidence of safety and proof of principle should be established through appropriate preclinical studies in relevant animal models or through human studies of similar cell-based interventions. Requirements for proof of principle and safety should be higher if cells have been manipulated extensively in vitro or have been derived from pluripotent stem cells (58).

Even with these safeguards, however, because of the highly innovative nature of the intervention and limited experience in humans, unanticipated serious adverse events may occur. In older clinical trials of transplantation of fetal dopaminergic neurons into persons with Parkinson’s disease, transplanted cells failed to improve clinical outcomes (60,61). Indeed, about 15% of subjects receiving transplantation late developed disabling dyskinesias, with some needing ablative surgery to relieve these adverse events (60,61). Although the transplanted cells localized to the target areas of the brain, engrafted, and functioned to produce the intended neurotransmitters, appropriately regulated physiological function was not achieved. Participants in phase I trials may not thoroughly understand the possibility that hESC transplantation might make their condition worse.

B. Informed consent in early stem cell clinical trials

Problems with informed consent are well documented in phase I clinical trials. Participants in cancer clinical trials commonly expect that they will benefit personally from the trial, although the primary purpose of phase I trials is to test safety rather than efficacy (62). This tendency to view clinical research as providing personal benefit has been termed the “therapeutic misconception” (32,63). Analyses of cancer clinical trials reveal that the information in consent forms generally is adequate. However, in early phase I gene transfer clinical trials, researchers’ descriptions of the direct benefit to participants commonly were vague, ambiguous, and indeterminate (64).

Participants in phase I stem cell-based clinical trials might overestimate their benefits and underestimate the risks. The scientific rationale for hSC transplantation and preclinical results may seem compelling. In addition, highly optimistic press coverage might reinforce unrealistic hopes.

Several measures may enhance informed consent in early stem cell-based clinical trials (59). First, researchers should describe the risks and prospective benefits in a realistic manner. Researchers need to communicate the distinction between the long-term hope for effective treatments and the uncertainty inherent in any phase I trial. Participants in phase I studies need to understand that the intervention has never been tried before in humans for the specific condition, that researchers do not know whether it will work as hoped, and that the great majority of participants in phase I studies do not receive a direct benefit.

Second, investigators in hESC clinical trials should discuss a broader range of information with potential participants than in other clinical trials. The doctrine of informed consent requires researchers to discuss with potential participants information that is pertinent to their decision to volunteer for the clinical trial (65). Generally, the relevant information concerns the nature of the intervention being studied and the risks and prospective benefits. However, in hESC transplantation, nonmedical issues may be prominent or even decisive for some participants. Individuals who regard the embryo as having the moral status of a person would likely have strong objections to receiving hESC transplants. Although this intervention might benefit them medically, such individuals might regard it as complicit with an immoral action. Thus researchers in clinical trials of hESC transplantation should inform eligible participants that transplanted materials originated from human embryos.

Third, and most important, researchers should verify that participants have a realistic understanding of the clinical trial (59). The crucial ethical issue about informed consent is not what researchers disclose in consent forms or discussions, but rather what the participants in clinical trials understand. In other contexts, some researchers have ensured that participants understand the key features of the trial by assessing their comprehension. In HIV clinical trials in developing countries, where it has been alleged that participants did not understand the trial, many researchers are now testing each participant to be sure he or she understands the essential features of the research (33). Such direct assessment of participants’ understanding of the study has been recommended more broadly in contexts in which misunderstandings are likely (26). We urge that such tests of comprehension be carried out in phase I trials of hSC transplantation (58,59).

Careful attention to consent in highly innovative clinical trials might prevent controversies later. In early clinical trials of organ transplantation, the implantable totally artificial heart, and gene transfer, the occurrence of serious adverse events led to allegations that study participants had not truly understood the nature of the research (66,67,68). The resulting ethical controversies brought about negative publicity and delays in subsequent clinical trials.

VIII. Institutional Oversight of Stem Cell Research

Human stem cell research raises some ethical issues that are beyond the mission of institutional review boards (IRBs) to protect human subjects, as well as the expertise of IRB members. There should be a sound scientific justification for using human oocytes and embryos to derive new human stem cell lines. However, IRBs usually do not carry out in-depth scientific review. Some ethical issues in hESC research do not involve human subjects’ protection, for example the concern that transplanting human stem cells into nonhuman animals might result in characteristics that are regarded as uniquely human.

A. The stem cell research oversight committee (SCRO)

An institutional SCRO with appropriate scientific and ethical expertise, as well as public members, should be convened at each institution to review, approve, and oversee stem cell research (18,69,70). The SCRO will need to work closely with the IRB and, in cases of animal research, with the Institutional Animal Care and Use Committee. Because of the sensitive nature of hSC research, the SCRO should include nonaffiliated and lay members who can ensure that public concerns are taken into account.

B. Use of stem cell lines derived at another institution

Sharing stem cells across institutions facilitates scientific progress and minimizes the number of oocytes, embryos, and somatic cells used. However, ethical concerns arise if researchers work with lines that were derived in other jurisdictions under conditions that would not be permitted at their home institution. Researchers and SCROs need to distinguish core ethical standards that are accepted by international consensus—informed consent and an acceptable balance of benefits and risks—from standards that vary across jurisdictions and cultures. Using lines whose derivation violated core standards would erode ethical conduct of research by providing incentives to others to violate those standards.

The review process should focus on those types of hSC derivation that raise heightened levels of ethical concern (71). hSC lines derived using fresh oocytes and embryos require in-depth review because of concerns about the medical risks of oocyte donation, undue influence, and setbacks to the reproductive goals of a woman undergoing infertility treatment.

Dilemmas occur when donors of research oocytes receive payments in excess of their expenses and such payments are not permitted in the jurisdiction where the hSC cells will be used. For example, the United Kingdom enacted an explicit policy to allow such payment after public consultation and debate and provided reasons to justify its decision (72,73,74,75). Jurisdictions that ban payments should accept such carefully considered policies as a reasonable difference of opinion on a complex issue. Concerns about payment should be less if lines were derived from frozen embryos remaining after IVF treatment and donors were paid in the reproductive context. Such payments, which were carried out before donation for research was actually considered, are not an inducement for hESC research (71).

Other dilemmas arise with hESC lines derived from embryos using gamete donors. As previously discussed, explicit consent for the use of reproductive materials in stem cell research should be obtained from any gamete donors as well as embryo donors (13,76). An exception may be made to “grandparent” older lines derived from frozen embryos created before such explicit consent became the standard of care, for example before the 2005 National Academy of Sciences guidelines (76). Use of such older lines is appropriate because it would be unreasonable to expect physicians to comply with standards that had not yet been developed (71). It would also be acceptable to grandparent lines if gamete donors agreed to unspecified future research or gave dispositional control of frozen embryos to the woman or couple in IVF. However, the derivation should be consistent with the ethical and legal standards in place at the time the line was derived.

In summary, hSC research offers exciting opportunities for scientific advances and new therapies, but also raises some complex ethical and policy issues. These issues need to be discussed along with scientific challenges to ensure that stem cell research is carried out in an ethically appropriate manner.

Footnotes

This work was supported by National Institutes of Health (NIH) Grant 1 UL1 RR024131-01 from the National Center for Research Resources (NCRR) and NIH Roadmap for Medical Research and by the Greenwall Foundation. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH.

B.L. is co-chair of the California Institute for Regenerative Medicine Scientific and Medical Accountability Standards Working Group.

Disclosure Summary: The authors have no conflicts of interest to declare.

First Published Online April 14, 2009

Abbreviations: ART, Artificial reproductive technology; hESC, human embryonic stem cell; hSC, human stem cell; iPS cells, induced pluripotent stem cells; IRB, institutional review board; IVF, in vitro fertilization; SCNT, somatic cell nuclear transfer.

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