Advanced Search 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.
There are several reasons for this. 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 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, 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? In humans, hEG cells were first established in culture in , shortly after the first hES cells, from tissue derived from an aborted fetus Shamblott et al. 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 ; Fuchs and Segre, ; Watt and Hogan, ; Weissman et al.
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. 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.
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, 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.
For other adult stem cell types, such as those from brain, skin or intestine Fuchs and Segre, , this may remain unclear for the immediate future. 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.
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. 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.
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. 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.
Growth of the cell lines over extended periods and in some cases under defined conditions Xu et al. 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. Should they be considered equivalent to embryos or not?
What, then, is the status of the individual cells from the ICM once isolated, and the embryonic stem cell lines derived from them? 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. It is therefore unreasonable to regard hES cells as equivalent to embryos.
Between these extremes are various intermediates. Differences of opinion exist on the weight of these arguments how much protection does the embryo deserve? 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.
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 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.
Opinions differ on how this should be interpreted and made operational. Internationally, however, such a limitation is being increasingly regarded as too restrictive De Wert et al. Bhaumik and S. Feng, K. Jia, C. Qin et al. Liu, J. Tian, Y. Lu et al. Fluri, P. Tonge, H. Song et al. View at Google Scholar Y. Chen, R. Pelekanos, R. Ellis, R. Horne, E. Wolvetang, and N. View at Google Scholar N. Maherali and K. Bieback, S. Kern, A. Ferlik, and P. S71—S76, Kern, H.
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Fetal stem cells, typically obtained following abortion or miscarriage, are believed to be as pluripotent as their embryonic counterparts, though they occur at a later stage than the true embryonic stem cell. For instance, ReNeuron, Inc. However, it is now clear that certain regions of the brain may have some limited capability to replace damaged or dead cells as a consequence of endogenous stem cells.
Its source could potentially be the same, with the adult stem cell being many generations removed from the original source. If this speculation is true, then one would expect the body to have large numbers of these cells, which it does not.
It has therefore been suggested that halting of replication is the means by which the number of stem cells found in the organs of the body is limited.
In addition, identification of what makes the cells quiescent is of considerable merit. The original belief was that they were not as versatile, healthy, or durable as embryonic stem cells because they appeared to be limited to forming only cells of a similar origin e.
Consequently, these cells became known as multipotent cells. These characteristics meant that adult stem cells would be harder to manipulate or control compared with embryonic cells.
Also, due to their presence in adults, it is likely that the cells could have accumulated abnormalities through continuous exposure of the organism to environmental hazards such as viruses or to replication errors. Some research shows that certain adult stem cells can differentiate into a number of varied cell types, including neurons 37 — 39 of the peripheral and central nervous system.
However, this observation may not be true of all adult stem cells, and more research is required to determine how useful these cells might be for use in treating human disease and injury. Most research on adult stem cells is based on mesenchymal cells, i. These cells include connective tissue and, in particular, bone marrow and muscles. They are multipotent cells and are a relatively homogeneous population of mononuclear progenitor cells that can be made to differentiate into specific cell lines following environmental cues.
Additionally, there are stromal stem cells found in the bone marrow, which are a more heterogeneous population of different cell types with varying degrees of proliferation and differentiation potential.
These specialized cells are discussed below. Embryonic Germ Cells Germ cells are the precursors to the gametes egg and sperm and are therefore found in adult testes and ovaries, and in the areas of the embryo that ultimately differentiate into testes or ovaries.
However, they have been found to differentiate spontaneously, which would suggest that there is less control over their development than with other stem cells. Further research is needed to explore the validity of this hypothesis, though the findings are certainly intriguing and potentially useful. The current belief is that amniotic fluid contains a mixture of embryonic and adult stem cells. It is believed that they are able to differentiate into a variety of cell types, but it is not known whether they are as pluripotent as other types of stem cells.
Some authorities have suggested they could be used as a potential treatment for diabetes. There is a considerable amount of research focusing on umbilical cord blood for the treatment of stroke, myocardial infarction, and a variety of blood-related disorders, with some degree of success. Current evidence suggests that in many cases it is not the stem cells per se that provide the benefit, but rather the growth factors these cells release.
Some research shows that umbilical cord blood cells do seem to have the ability to become neuronal-like cells in vitro, but do not appear to produce neurons of any significant number in animal models of stroke. Although the potential benefit of these cells still remains relatively unexplored, the practice of banking them already has at least one undeniable benefit: providing donors with a source of their own cells, which considerably reduces the chance of rejection if they ever do need them for medical reasons.
Two other recent papers have demonstrated an additional potential source of adult multipotent stem cells: menstrual blood. Current treatments include nuclear radiation exposure and transplantation for the treatment of genetic diseases or cell cancers of the blood and the blood-forming system.
It is important to remember, however, that embryonic stem cell research has never been illegal in the United States; it just cannot be funded from federal sources other than those lines that were approved in August It is also noteworthy that adult stem cells have been researched for three decades, whereas embryonic stem cell research is considerably more recent, with the first human embryonic stem cell being isolated in at the University of Wisconsin—Madison by James Thomson.
These patents were revoked in April by the U. Many of the adult stem cell trials are also oncology studies rather than regenerative medicine studies.
This research encompasses treatment of various disorders including organ regeneration, cardiovascular improvements, diabetes, and neurodegenerative conditions. They comprise the complete continuum of research from preliminary explorative studies through preclinical and clinical trails.
Promising results include the promotion of liver regeneration by bone marrow stem cells in patients with hepatic malignancies, 72 the formation of blood vessels in mice from human embryonic stem cells that have been made to differentiate into endothelial precursor cells, 73 the treatment of stroke and heart ischemia animal models by human umbilical cord blood transplants in rats, 51 , 53 , 54 and the ability of embryonic stem cells to differentiate into functioning heart tissue myocytes.
Also, Yacoub 75 announced that his team has been able to grow a heart valve from bone marrow stem cells using a collagen scaffold. This procedure has yet to be tested to determine if the valve is functional in vivo, but it clearly represents a promising discovery. Similarly, preliminary testing of the recently discovered stem cells in amniotic fluid for treating heart disease has demonstrated some encouraging results that require further study and verification.
Elsewhere, a study using embryonic stem cells has shown considerable improvement in mice specially bred to exhibit symptoms of Sandhoff disease, a childhood disorder. The disease was found to eventually return, but Lee et al.
Preliminary findings from other studies involving fetal neural stem cells in culture and in animals have shown rescue of retinal cells after injury or disease. In general, considerable research is underway to ensure that the development of treatments involves only those cell types being sought, and that it includes ways of ensuring desired outcomes—i.
Currently, at least 33 states have specific guidelines with respect to the use of embryos in research, which in several cases e. This technique would not necessarily replace the use of embryo-derived stem cells, as further characterization is necessary to confirm that the cells do possess all of the same characteristics—including the same receptors and response to treatments. The disease was found to eventually return, but Lee et al. Suzuki, M. For instance, ReNeuron, Inc. More recent evidence suggests that the paper was flawed, adding further consternation to this area of investigation.
The 20 embryonic cell lines that are federally permissible represent only a small fraction of the genetically and immunologically heterogenous population of the world. Research involving adult stem cells is not limited under the current federal restrictions.
Although the potential benefit of these cells still remains relatively unexplored, the practice of banking them already has at least one undeniable benefit: providing donors with a source of their own cells, which considerably reduces the chance of rejection if they ever do need them for medical reasons. Slippery slope The slippery slope argument can be considered as having two variants, one empirical and the other logical. 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. Inasmuch as current knowledge of stem cells is a combination of scientific reality and cautious speculation, considerable research is required to identify the true, long-term potential for medical advances from these cells.
Suspension Technology Induced pluripotent stem cells iPSCs draw more and more attention because of their therapeutic advantages in enabling the generation of high-quality disease models, derivation of individual-specific iPSC lines, improving the predictability of drug action, and as a source of cells for regenerative medicine [ 23 ]. S—, Yang, and C. A second controversy surrounding stem cell research is the apparent groundbreaking outcome of studies performed by a research team in South Korea. Between these extremes are various intermediates.
View at Google Scholar M. Thus, stem cells may help to support the cells that are already present and protect them from further injury or death due to the factors that cause or perpetuate the initial disease or injury. Hyde, M. A seminal paper from a group led by Catherine Verfaillie see Jiang et al. Bieback, S. 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.
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. Consequently, these cells became known as multipotent cells. To date, however, hEG cells have been difficult to isolate and culture, with only one research group reporting success Shamblott et al.
Ripoll, L. Stephen K.