The ethics and myths of stem cells

The interest that human embryonic stem cells represent to researchers derives from the fact that they are capable of developing into virtually any cell of the body, given appropriate conditions; they are ‘pluripotent’. Human embryonic stem cells can be obtained by the in vitro fertilisation (IVF) procedure. Embryonic stem cells can also be derived by removing the nucleus from a cell of a person’s body and placing it inside an ovum (egg cell) provided by a donor, and from which the nucleus has been removed. This nuclear transfer procedure—somatic cell nuclear Transfer (SCNT)—has become known as ‘therapeutic cloning’, as the resulting cloned human embryo is almost an identical clonal replica of the human subject from whom the somatic cell nucleus was taken. Stem cells can be generated from this cloned embryo, and those cells used as the source of specialised cells, which are unlikely to be rejected as foreign if they were to be used in the individual from whom they were derived.

If, on the other hand, the manufactured embryo were to be implanted into a uterus, it would be called ‘reproductive cloning’. It is this approach that was used to yield the now famous sheep Dolly. Human reproductive cloning is rejected entirely by scientists, as well as by numerous politicians, and is completely contraindicated for a number of reasons. Where legislation has been passed that permits therapeutic cloning, reproductive cloning has been unequivocally rejected.

Obviously, these approaches to deriving embryonic stem cells involve destruction of the embryo, and it is here that the major ethical issues arise. These issues are relevant to legislation on this matter by the governments of several countries, including Australia. They relate to concerns of a broad spectrum of the community, embracing virtually all the religions, and those of no religion at all.

Most media attention focuses on embryonic stem cells, and the urgent pressure to use them in medical treatment. The media gloss over an important distinction regarding stem cell research. One branch is embryonic stem cell research, which can only be conducted by using a developing embryo in a process that necessarily destroys it. The other is adult stem cell research, which makes use of the evidence indicating that virtually all tissues of the body contain a number of stem cells that are ‘multipotent’, that is, they can develop into several different types of adult cell. They can be used without the ethical constraints surrounding embryonic stem cells.

For many years it has been known that the haemopoietic stem cell (HSC) is able to generate all cell types of the blood and immune systems, and this has been put to great therapeutic use. We know also that a primitive marrow stem cell (MSC), or blood vessel wall cells mobilised from marrow, are able to repair heart muscle after damage from infarction. Such MSCs, or vascular cells, have been injected into immune-deficient rats in which a ‘heart attack’ has been induced. The infarction results in heart muscle death, but the injected bone marrow stem cells successfully integrate with the affected part of the heart muscle and promote blood vessel formation and healing. In the past year, in addition to these discoveries, multipotent cells have been grown from umbilical cord vein blood, and from cells taken from the lining layer of the nose. These findings with adult stem cells provide every reason to lend strong support to research seeking their eventual application to treatments of certain human diseases. Besides, the science of adult stem cells is moving at a fast pace. There are now many examples in experimental animals that suggest that adult stem cells can be used successfully in medical treatment. Clinical trials in human subjects are being undertaken.

For all the rapid progress, there remain many questions, and much needs to be done in adult stem cell research. In the case of embryonic stem cells the problems besetting this work are so great that one must question the presumption that it is so urgently needed. The promotion attending work on human embryonic stem cells seems to suggest that it is both essential and urgent in order to discover new treatments for previously untreatable chronic diseases. The usual list of such conditions includes diabetes, Parkinson’s disease, Alzheimer’s, muscular dystrophies, the replacement of dead heart muscle following heart attacks, and of brain tissue following strokes. For several of these conditions there are appropriate experimental models that may be studied in animals. Yet, in no case have embryonic stem cells been shown in animal research to provide a cure that is sufficiently prolonged and free of complications to warrant human studies. This should be a minimum requirement if the urgency of work on human embryonic stem cells is to be accepted in spite of the ethical barrier.

An example is provided by a study in which human embryonic stem cells that have been converted to dopamine-producing neuronal cells were injected into the brains of immune-deficient rats subjected to a chemically induced Parkinson’s disease. There were highly encouraging improvements in motility and behaviour of the animals. However, five of 19 animals developed teratomata; tumour formation being a major complication of embryonic stem cell transplantation. This approach to utilising embryonic stem cell research in the treatment of Parkinson’s disease recently advanced a step further.

In experiments with monkeys, a form of Parkinson’s was chemically induced, and monkey embryonic stem cells transplanted. Some symptomatic improvement was noted, but dopamine production by the cells was low, and the short observation time allowed no conclusion to be drawn about the serious possibility of tumour formation. This propensity to develop teratomas has been a feature of all the animal studies so far with embryonic stem cells.

Also, in the case of embryonic stem cells transplanted experimentally into the heart, serious abnormalities of heart rhythm occurred—a complication not encountered with adult stem cells used for the same purpose. When spinal cord injury has been experimentally induced in rodents, some partial improvement in mobility has been achieved both with adult and embryonic stem cells. In each case a major factor in this improvement has been that the transplanted cells have influenced the formation of the protective myelin sheath around the nerve fibres. Progress with this condition, however, is likely to be very slow, and dependent upon understanding how the severed ends of nerve fibres join together appropriately. If it becomes apparent that cell therapy is needed, there is no good reason to suspect that embryonic stem cells offer an advantage over a number of alternative cell therapy approaches. Alzheimer’s is a global condition of the brain and its causes are unknown. The very nature of this disease makes it virtually impossible to conceive that any form of cell therapy could be helpful. And yet Alzheimer’s disease appears almost invariably in the lists of possible curable diseases that are promoted to the public.

At present there is no evidence from animal experimentation with either human or animal embryonic stem cells to justify even the most limited human trial of embryonic stem cells in therapy. Furthermore, some of the proposed cures are highly unlikely, and others are on a very long time frame. An essential requirement is that ‘proof of concept’ ought be provided for the efficacy of embryonic stem cells in treatment of even one of the suggested targets. The way to do this is to use animal models of disease. Any attempt so far has only illustrated major difficulties confronting the embryonic stem cell approach. If there were no other possible way of finding stem cells capable of adopting functions other than those of their tissue of origin, then perhaps the case for undertaking human embryonic stem cell research would be very much greater.

If one is endeavouring to prepare embryonic stem cells for use in medical treatment, it may make much more sense (from a purely scientific perspective) to use embryonic stem cells obtained via the SCNT process, than utilising unrelated embryonic stem cells sourced from IVF excess. The latter are much more prone to destruction by the recipient’s immune system.

However, this involves the deliberate cloning of human embryos in order to achieve whatever promise is offered by embryonic stem cell research. This method of producing embryonic stem cells derived by nuclear transfer involves removing the nucleus from a cell—be it muscle or skin—and placing it inside an ovum provided by a donor, and from which the nucleus has been removed. Although this has come to be called ‘therapeutic cloning’, this name is inappropriate and misleading. Human embryonic stem cells, obtained either from IVF embryos or through cloning, have never been used in treating human disease, and no trial could be planned based on present evidence.

The practical difficulties associated with using cloning as a source of cells for medical treatment are overwhelming. The earlier enthusiasm for this approach has waned substantially. The currently favoured application of cells obtained by the SCNT procedure is to use them in studying the mechanisms of specific diseases. For example, a clonal cell line could be established by transferring a somatic cell from a subject with a particular chronic and unsolved disease, into an enucleated donor egg. The molecular controls of cloned cells developed from the embryo, might then be studied during differentiation. The hope is that this approach might lead to a better understanding of the molecular mechanisms, thus providing clues to possible prevention or treatment of disease. As a result, the ethical question associated with the SCNT approach to cloning has changed. Rather than arguing for its use to provide for medical treatment, the aim would then be to undertake research that might help in understanding disease. So, should this method be used to generate embryonic stem cells that might be utilised in research into the treatment of a number of diseases?

The SCNT method is not permitted in Australia, although permission under licence can be obtained by scientists in the UK. The birth of Dolly the sheep proved that this procedure was capable of generating an embryo. Yet Dolly was the only successful embryo resulting from 277 attempts. This reproductive cloning has been carried out with other species including mice, cows and pigs. In all cases the method is highly inefficient, requiring a large number of eggs for each success, and is accompanied by a very high abnormality rate in the animals that have been born.  In recent months much publicity surrounded  the publication in a prestigious  scientific journal of the success of Korean research group in developing cell culture lines from 11 human subjects, using the nuclear transfer procedure. It was hailed  by several commentators as a ‘stunning’  scientific achievement. As a scientist this author rejects this  assessment—all that had been done was to repeat what had been done some years earlier in animals, with some minor technical changes to improve  efficiency of what remains  a very inefficient and expensive  procedure. Although use of the nuclear transfer method to generate embryonic cells has been called therapeutic cloning, the name should best not be used. Such cells have never been used in clinical studies, and the practical difficulties associated with their preparation for therapeutic purposes are presently insurmountable.

There is widespread agreement that there is an ethical issue involved in experimenting on cells obtained from human embryos. Sufficient agreement, in fact, that the topic is one that receives major attention by the governments of many countries, including the UK, USA, EU and Australia. As is always the case in medicine and related research when a certain procedure requires that ethical barriers be surmounted, the more formidable the barrier, the greater must be the benefit of the proposed work. While it can be agreed that from the time of fertilisation the human embryo should be treated with respect because of what it can potentially become, it is the timing of application of that respect, and its level, that is argued. This issue presents serious ethical problems for a significant proportion of the population—to virtually all the Christian denominations and to people of the Jewish, Hindu and Muslim faiths. It is also a view shared by people of no religious proclamation.

This ethical difficulty needs to be taken into consideration when formulating public policy. In Australia, at present, scientists can be licensed to undertake research on embryos that are maintained frozen in excess of requirements for IVF therapy, and made available with permission of the parents. That is our legislative status quo. It gives those interested in that research the opportunity to pursue it. The Federal Government is currently considering whether to approve the production of embryos specifically for research, using the process often referred to as therapeutic cloning.

When the UK’s House of Lords’ Select Committee considered this question, it concluded with a recommendation that accorded with the British Government’s approval of human embryonic stem cell research, including the generation of embryos specifically for research purposes. This is something no other government had done. It is interesting that their document contains a very clear statement that ‘if there were no morally serious reasons for undertaking research on human embryos, then the mere possibility that the early embryo is a person would be sufficient reason not to do such research.’ What compelling, morally serious reasons provided the House of Lords with the necessary imperative? The main stated reasons appeared to come from evidence given by people suffering from previously untreatable chronic diseases, who believed that cures might be provided from embryonic stem cell treatments.

In all branches of medicine it is mandatory that ‘proof of concept’ be obtained through extensive preclinical experimentation in animal research before human studies are performed. Such proof of concept has not been obtained in any of the diseases so commonly invoked for the use of embryonic stem cells in medical treatment. Further, it is abundantly clear that much more animal experimentation is required, even to establish in the first instance that any human clinical trial would have any chance of success. If its proponents could prove, in even one experimental disease model, that transplantation with embryonic stem cells results in a prolonged cure, free from the currently  expected complications (such as tumour formation), this would go some distance toward meeting the House of Lords requirement of ‘morally serious reasons’ for supporting embryonic stem cell research.

Just as much has been learned about the biology of development in studying mouse embryonic stem cells, it would be of great scientific interest to study developmental processes in human embryonic cells. The public arguments of scientists in favour of embryonic stem cell research have shifted significantly in the last year. The arguments have moved away from talk of cures for disease, to the pursuit of knowledge, particularly by generating embryonic cells that provide for the study of mechanisms of specific diseases.

The pursuit of knowledge of nature, and of disease, from the study of human embryonic stem cells is an attractive scientific prospect. What has to be decided is whether doing this with human embryonic stem cells, on the basis of the pursuit of knowledge alone, provides sufficient good to overcome the major reservations held by a significant proportion of the community.

There is an ethical problem in dealing with human embryos in these ways and so there needs to be a very compelling case for working with them. A minimum requirement is that extensive animal experimentation must establish the validity of this approach, especially given the fact that adult stem cells have to date been superior in performance in experimental and clinical therapeutics. 

Professor T. John Martin ao faa frs is Emeritus Professor of Medicine, University of Melbourne, and John Holt Fellow at St Vincent’s Institute of Medical Research.

 

 

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