The regeneration game

Of all the promises for medical applications of modern molecular and cell biology, the development of stem-cell therapy - or, to give it its more popular if entirely inappropriate title, therapeutic cloning - has raised the greatest expectations and some of the most bitter controversy. This should not surprise us. Transplant surgery has its limitations; the possibility of a ready supply of cells to replace diseased tissues, even parts of the brain, is exciting, particularly to those of an age at which a few new organs would not go amiss. But although the potential benefits of research on stem cells are enormous, our understanding of their biology is at a primitive stage and the type of work that will have to be carried out to explore the possibilities of this field raises ethical issues that are of genuine concern to many people.

At the moment of fertilisation, an egg contains all the genetic information required to make a human being. In the earliest stages of embryonic development, its cells have the capacity to form any of our different organs and tissues. With further growth, they become more specialised towards their functions in particular parts of the body, and lose this property. Stem cells are self-renewing cell populations that have retained the ability to differentiate down different pathways and hence to produce progeny that can form different tissues in response to appropriate regulatory stimuli. They can be obtained from early embryos, some adult and foetal tissues, and - theoretically, at least - from other adult cells.

Embryonic stem cells, which retain the greatest plasticity, are present at an early stage of the developing embryo, lasting from the fourth to the seventh day after fertilisation.

Human embryonic stem cells were grown in the laboratory for the first time in 1998. Although there has been some progress in coaxing them to produce specific cell types, much of the potential for this field has come from similar studies of mouse embryonic stem cells. For example, they have been transplanted into mice with a condition similar to human Parkinson's disease and the symptoms partially relieved. Similarly, they can be transplanted into animals that have spinal cord injuries, and neural function may be partially restored. While promising, these results do not provide any definitive evidence that similar treatments will be effective in humans.

There are other sources of stem cells. Many adult tissues retain stem-cell populations. Bone-marrow transplantation has been applied to the treatment of a range of blood diseases, and it is clear that human marrow contains stem cells capable of differentiating into the full complement of cell types found in the blood. There is also evidence that marrow stem cells can, under some circumstances, be persuaded to differentiate into other tissue types. For example, preliminary, and as yet unconfirmed, studies suggest that when injected into the heart after a heart attack they can improve its function, intimating that they may be a source of heart muscle or blood-vessel cell populations. In recent years, there has also been a great deal of work directed at trying to isolate stem cells from other organs. In mice, they exist in the brain, muscle, skin, digestive system, retina, liver and pancreas. However, research in characterising similar cell populations from humans is at a very early stage, and some of the results are controversial.

One of the major obstacles to stem-cell therapy with cells derived from embryos or adult sources is that, unless they came from a compatible donor, they would be treated as "foreign" and rejected by a patient's immune system. One way round this problem would be to transfer a cell nucleus from an individual into an egg from which the nucleus has been removed, after which the newly created "embryo" would be used as a source of embryonic stem cells for regenerative therapy for that person. This technique, called somatic cell nuclear transfer, does, of course, follow exactly the same steps as would be required for human reproductive cloning. Since there would be no intention of placing the egg treated in this way into a uterus, however the objectives of the procedures would be entirely different. Like the use of embryonic stem cells derived from human embryos, this approach would, in addition, require a large source of human eggs - unless, as has also been suggested, human nuclei were transplanted into eggs from an animal source.

It is clear then that, while this field is still at an early stage of development and there are many uncertainties, enough is known already to suggest that the medical benefits of a better understanding of stem-cell biology might be considerable. But it cannot be advanced without a source of human embryos. While it has been suggested that a better understanding of the properties of embryonic stem cells could be achieved by work in the mouse and other animals, it is already clear that there are many differences between species in the properties of these cells. And information obtained from this source will be vital for a better understanding of the properties of adult stem cells, which appear to have a more limited repertoire of differentiation potential - that is, the variety of cell types that they can form - than their embryonic counterparts.

Similarly, it will be necessary to explore the possibilities of somatic cell nuclear transfer, particularly since there is no guarantee that it will be possible to manipulate stem cells such that they can escape immune surveillance by a potential recipient.

It is not surprising that this field has caused and still causes considerable controversy. It is particularly unfortunate that the term "therapeutic cloning" has been applied in an uncritical and blanket fashion. It is difficult to dissociate it in people's minds from reproductive cloning, the objective of which is totally different. It is a field that is a complete anathema to those who believe that it is wrong under any circumstances to use human embryos for research purposes. And it raises a number of ethical issues that are completely new. In the long term ,it might be necessary to create human embryos to produce embryonic stem cells, which would lead to their destruction. Would it be acceptable to ask, or even pay, women to undergo repeated cycles of hormone treatment and egg retrieval for research or therapeutic uses? Would it be right to obtain human eggs from cadavers or aborted foetuses? Even more controversially, would it be safe, or ethical, to use eggs from other species in which to develop human cell nuclei?

Many countries are finding it difficult to sort out these ethical issues and to define a code of practice for work in the stem-cell field. In the UK, after an extensive study followed by a report from the chief medical officer's expert group, and wide debate in Parliament, it is permissible to use human embryonic stem cells derived from "leftover" embryos not required by the genetic parents for reproduction, or from embryos created for research purposes by in vitro fertilisation, or the nuclear transfer technique, for specifically defined areas of research. The legality of this position is still questioned by those who oppose any form of research on embryos. In Germany, research on human embryonic stem cells was prohibited, although it is allowed in exceptional cases, provided it is carried out on imported stem cells derived before January 2000 from surplus embryos. In the US, President George W. Bush announced on August 9 2001 that federal funding for research in this field could be used only for work on 60 stem-cell lines that had been derived from excess human embryos before his announcement. There is, however, no federal law or policy prohibiting the private sector from creating stem cells by in vitro fertilisation or nuclear transfer. This bizarre situation has not yet been rationalised. Nor is it likely to be if therapeutic and reproductive cloning remain associated in people's minds. The recent announcement of a "success" in reproductive cloning in the US will not help to cool this highly charged debate.

Some of these issues are described in this very readable account of stem-cell research, based on the work of a committee chaired by the distinguished cancer researcher Bert Vogelstein under the auspices of the US National Research Council This short publication gives an excellent account of the state of the art in research and a short discussion of the ethical issues involved. It recommends that work in this field should continue, and it looks forward to a more logical approach to its regulation in the US. It is aimed at non-specialists and can be recommended to those who wish to learn more about the complexities of research on stem cells, although those interested in the ethical issues will find a much broader discussion in Stem Cell Research: Medical Progress with Responsibility , a report from the chief medical officer's expert group, published by the Department of Health.

Although research in this field is at an early stage, there is little doubt that stem cells will be hitting the headlines frequently in years to come.

It is important, therefore, that all of us become sufficiently well informed to be able to contribute to the debate on the ethical and social issues involved. The NRC report reminds us how difficult it is to develop an ethical framework for a research field that is so full of uncertainties and potentials, and one in which the technology skates close to activities that are repugnant to many people. But one thing this increasingly bitter debate has already made very clear is that scientists must be much more precise, and less emotive, in the language they use to describe what they do.

Sir David Weatherall is emeritus regius professor of medicine, University of Oxford.