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  Therapeutic use of human cloning techologies
A Genetic Interest Group Policy Paper

It is two and a half years since the possibility of using cloning technologies on humans for therapeutic ends was put firmly on the agenda by the cloning of Dolly the sheep at the Roslin Institute in Edinburgh. Progress has been rapid since then. Geron Corporation, the American company which now owns the commercial spin-off of the Roslin Institute, has combined its own expertise in stem-cell research with Roslin's expertise in nuclear transfer technology to lay the basis for beginning work in this area. Another American biotechnology company, Advanced Cell Technology, is also up and running. It is safe to say that many other private sector companies and academic researchers are keenly interested in this area.

It was against this background that the Human Genetics Advisory Commission and the Human Fertilisation and Embryology Authority (HFEA) issued a joint recommendation in December 1998, following a period of consultation and study, that the Government should give the go ahead for the work. To the surprise of both supporters and critics of therapeutic use of cloning technologies, this June the Government delayed taking a decision on the matter; instead it set up an expert advisory group under the chairmanship of the Chief Medical Officer, Professor Liam Donaldson, which is to seek the views of a range of experts from across the world and then report early next year. But while both sides might have been surprised, there seems little doubt that it is the opponents of the new technology who have taken most comfort from the decision. Mark Nicholls of MATCH (Movement Against The Cloning of Humans) said: "We're obviously delighted… this is one battle won, but the war is certainly not over." Conversely, the biotechnology companies at the forefront of the work expressed their disappointment, and Lord Winston condemned the Government's decision as "immoral".

The purpose of this paper is to present an outline of the science and its possible applications, before moving on to a discussion of GIG's approach to the ethical and regulatory issues.

Therapeutic Use of Cell Nucleus Replacement

As the attentive reader will notice, the phrasing in the above sub-heading differs from the wording of the paper as a whole, although it means the same thing. The Human Genetics Advisory Commission / HFEA report preferred 'therapeutic use of cell nucleus replacement' to 'therapeutic use of human cloning technologies', or 'therapeutic cloning', in part for reasons of clarity but in particular because the word 'cloning', especially when attached to 'therapeutic', conjures up entirely the wrong mental image of the research that might be undertaken. This is an understandable concern. The novel Spares is built around a 'farm' where rich people keep clones of themselves in a permanent childlike state, so that their organs can be 'harvested' as and when needed for transplant. Author Michael Marshall Smith has the clones living in tunnels, 'waiting to be whittled down'. The tunnel is the butcher's shop, the clones the meat. Suffice it to say that nothing of the sort is being proposed! Once this is understood, the occasional use of such terms as 'therapeutic cloning' shouldn't cause too much harm, and is hard to avoid at times because the starting point for many of the possible new therapies is the nuclear transfer technology pioneered by the team that made Dolly the cloned sheep.

Dolly is a clone in the popularly understood sense of the term. In precise scientific terms she is not an identical copy of another sheep, but she is very close. Dolly was formed by inserting the nucleus taken from the cell of an adult sheep into an egg of another sheep which had had its own nuclear material removed. The egg was then induced to begin the process of division and implanted in another sheep. In the normal process of fertilisation half the genetic complement of the fertilised egg comes from the mother and half from the father. In the creation of Dolly, the full complement came from the original adult sheep. In this sense Dolly is a copy. But she will differ by a small amount genetically—the part that is not contained in the nucleus of the cell—from her progenitor, and by a further amount biologically due to different environmental experiences.

When Dolly was cloned it was already understood that the same technology could be used therapeutically for humans. In transplants one of the major problems is tissue rejection—the body recognises the donor tissue as foreign and mounts an immunological response. But if cell nuclear transfer could be used to make cells with the same genetic make-up as the patient's, the problem of rejection could be overcome. Unlike in a cloned adult, the cloned cell nuclei would be true identical copies, making the cells the perfect replacements for the damaged or diseased originals.

A major step towards realising this possibility was made at the end of 1998, when scientists working in collaboration with Geron Corporation announced that they had succeeded in establishing cell culture lines of human embryonic stem cells. Karen Lebacqz and colleagues on the Geron Ethics Advisory Board give this summary of the significance of the work: 'because these cells are considered pluripotent (capable of being the precursors to a variety of human cell types) and immortal (sustainable in culture and reproducing themselves indefinitely), they represent a major breakthrough in scientific research, with potential for significant advances in tissue transplantation, pharmaceutical testing, and embryology.' John Gearhart of Johns Hopkins University was one of the pioneers of this work. It is worth quoting his groundbreaking paper at length on the potential of the cell lines having these properties:

'It is exciting to speculate on how human ES lines could be used in tissue transplantation therapies. Obvious clinical targets would include neurodegenerative disorders, diabetes, spinal cord injury, and hematopoietic repopulation. In addition to possibly providing large numbers of pure populations of cells for transplantation, ES cells would also lend themselves to several strategies for the prevention of immunological tissue rejection after transplantation, including (i) banking of multiple ES cell lines representing a spectrum of major histocompatability complex (MHC) alleles to serve as a source for MHC matching; (ii) creation of universal donor lines, in which the MHC genes could be genetically altered so rejection would not occur, an approach that has been tried with moderate success in the mouse; (iii) customization of ES cells through transgenesis and gene targeting so that a potential recipient's MHC genes are introduced into ES cells through homologous recombination; and (iv) production of ES lines containing the genome of the prospective recipient. Blastocysts obtained through nuclear transfer would be used to generate ES cells, which could then be differentiated to specific lineages for transfer to the nuclear donor. Because EG [embryonic germ] cells have been shown to reprogram adult nuclei after cell hybrid formation, it may eventually be possible to do nuclear transfers into pluripotent stem cells, which could then be expanded and differentiated.'

All the areas outlined by Gearhart contain great potential—it is no wonder that Harold Varmus, director of the National Institutes of Health, recently described stem cell research as having the 'potential to revolutionise' the practice of medicine. For our purposes, it is Gearhart's fourth category that is of most direct interest. As he points out, the marriage of nuclear transfer technology and stem cell research promises ES cells 'which could then be differentiated to specific lineages for transfer to the nuclear donor.' This would not involve creating carbon copies of people as depicted in Spares, nor even fetuses with differentiated organs: all that would be required would be to create a very early embryo in the lab using nuclear transfer technology, from which ES and then differentiated cells could be produced.

The next stage in the research is to do what Gearhart suggests: work out how to develop specific lineages from ES cells. This would then open up the possibility of new treatments for degenerative diseases of the heart, liver, kidneys and cerebral tissue. Further into the future, if such lines of stem cells could also be modified to repair genetic defects carried by the patient, the treatment of diseases such as leukaemia and many rarer genetic disorder, of the skin for example, could be revolutionised. ES cells also offer many avenues for basic research. For example, studies of stem-cell differentiation could provide valuable information about the mechanisms of ageing or the causes of cancer.

In its consultation, the Government asks whether there is an identified need for research on human embryos and involving cloning techniques for therapeutic purposes. It also asks whether there are alternatives that do not involve the creation of human embryos in vitro. For GIG the need is clear. But it is unfortunate that the Government feels the need to ask the field to justify itself in such a way. It is creating a hurdle, which could be interpreted as ruling out basic research. As Professor David Latchman, vice-chairman of the medical advisory panel of the Parkinson's Disease Society put it: 'there is a paradox in this announcement. The Government says we need to see if this therapeutic research is likely to be valuable, but it's going to be quite hard to find that out without carrying out the research.'

GIG does not feel that the creation of cloned cell lines for use in the treatment of disease, or similar possibilities which might result in improvements in human health, poses any additional ethical dilemmas over and above those which are created by existing aspects of genetic medicine and assisted conception. Indeed, the possibility of undertaking research and development in this area and choosing not to do it is not ethically neutral, in that such a decision would leave families to be affected by disease or disability that might otherwise have been treated.

When the Human Fertilisation and Embryology Act was passed in 1990, the conservative philosopher Roger Scruton penned an article entitled 'Embryo Farmers: the children of Mengele'. The case against using cloned embryos in research made from this quarter today is essentially the same as the argument made against the use of all embryos in research and IVF procedures back then. And in a sense, the argument for it is also very similar, a point the Government should note. As the philosopher John Harris puts it: 'If it is acceptable to produce spare embryos in pursuit of successful pregnancy then it must be justifiable to produce them in pursuit of something plausibly of the same moral magnitude. Saving a life-in-being surely comes into that category.'

Looking beyond the research stage, GIG believes that the development and applications of the outcomes of research using nuclear transfer technology does not raise any additional ethical implications. Use of derived cells would have to meet safety and efficiency requirements. But assuming these can be met, it must follow on from the successful completion of research.

Legal and Regulatory Issues

It has been determined that both human reproductive cloning and therapeutic cloning are currently illegal in the UK. The former is ruled out because, among other things, the implantation of experimental embryos is forbidden. Research on therapeutic cloning is ruled out because it does not fall within the permitted reasons for the creation and maintenance of embryos outside of the human body as laid down in the Human Fertilisation and Embryology Act. Under the terms of the Act a specific HFEA licence is required for any research that involves the creation, keeping or use of human embryos outside the body. The HFEA cannot grant a licence unless it is satisfied that the use of human embryos is essential for the research, which must be for one of the following purposes:

- to promote advances in the treatment of infertility
- to increase knowledge about the causes of congenital disease
- to increase knowledge about the causes of miscarriages
- to develop more effective techniques of contraception, or
- to develop methods for detecting the presence of gene or chromosome abnormalities in embryos before implantation.

In their joint report of December 1998, Cloning: Issues in Reproductive Science and Medicine, the HFEA and the Human Genetics Advisory Commission recommended that the purposes for which human embryos may be used in research under UK legislation should be extended to include research to develop methods of therapy for:

- mitochondrial diseases
- diseased or damaged tissues or organs

GIG supports this proposal. Both areas suggested would involve cell nucleus transfer. We feel this would be consistent with the spirit of the HFE Act, which was framed so as to allow research into genetic disease.

Winning Hearts and Minds

Shortly after Dolly's existence was announced in early 1997, her creator Ian Wilmut lamented that 'here we have a remarkable achievement, a world first, and there are people who seem to make a living out of spreading angst'. His team's work was published in Nature on Thursday 27 February. But the story broke the Sunday beforehand, leading to near hysteria in the press and among politicians. In America Bill Clinton called for a national commission to review what the White House called the 'troubling implications' of cloning. In the UK, the issue was raised at Prime Minister's Question Time on the Tuesday. The Vatican called for a worldwide ban. Joseph Rotblat, the physicist recently awarded the Nobel Prize for peace after a lifelong campaign against nuclear weapons, argued that genetic engineering could pose a greater threat than the Bomb 'because of these dreadful developments that are taking place there'. And in an unprecedented move, a Harvard academic e-mailed Nature to demand that they pull the article from their journal, on the grounds that such material should not be in the public domain at all.

The cause of most of the unease was simple: the prospect of human reproductive cloning. While forswearing any interest in the idea, and pointing out that it would be illegal in the UK and many other places, Wilmut freely acknowledged that his work brought the possibility a lot closer. All of a sudden, science fiction was nearly scientific possibility, and despite attempts by Wilmut and others to focus on the benefits of what they had done, everybody was determined to discuss human cloning and its dangers.

The passage of time has hardly quelled interest in human reproductive cloning. There is a consensus that it should not be attempted at present. GIG shares this view. Many others want a permanent ban and can foresee no reasons for its use. But one of the interesting things about the debate over the past two and a half years is that when gut feelings against human cloning have been committed to print, many serious commentators have found the arguments wanting. No wonder David Shapiro was moved to comment: 'perhaps it is just as well that human cloning is not yet feasible. We need better arguments for banning it.' Steve Jones, who has just published his update of Darwin's The Origin of Species, sees no reason for an all-time ban. Indeed, it is the arguments for such a ban that he finds objectionable:

'Many find the idea of human cloning shocking. I do not. The objections turn on genetic essentialism, the idea that a clone would be stigmatized, treated as a second-class citizen, with fewer freedoms than an organism produced by sex—in other words that rights reside in genes rather than people. In the 1930s, the Nazis took this "DNA über alles" argument to its logical extreme. A Nazi who received a transfusion of Jewish blood was thrown out of the party. In the old South Africa, blood could not be moved across the racial divide, because biological purity was considered compromised. That attitude is disgraceful, but it is essentialism—humans as products of DNA—in its purest form.

GIG sees no need for a permanent ban. The strength of regulatory and legal restriction should be kept under review in line with advances in scientific knowledge. It seems likely that at some point in the not-too-distant future a human clone will be created; but equally it is difficult to foresee a significant demand for it.

Steve Jones went on to argue: 'the main danger in the essentialist panic is restriction of the chance of copying tissues or organs.' This is GIG's primary concern. But thankfully, after the initial knee-jerk reactions to Dolly, the therapeutic possibilities of nucleus replacement are beginning to be appreciated. And when they are appreciated, there is support for them and the research that might deliver them. A poll commissioned by the newly-formed Patients' Coalition for Urgent Research found that after having been read a statement that "researchers believe that stem cells can be developed into replacement cells to cure diseases such as diabetes, Parkinson Alzheimer's, Cancer, heart disease and others", three out of four Americans were willing for the American government to fund stem cell research.

Winning over hearts and minds to the benefits of human therapeutic cloning, and building upon the support for new therapies that already exists, will help to foster a supportive climate for the science to proceed. A legislative delay to consider the issue is understandable if there are new issues to address or support to be won. The danger must be that unnecessary delay will merely encourage the view that there is something deeply troubling about this kind of work. From scientists, patients and supporters of the therapeutic uses of cloning technologies the message is clear: therapies for many previously untreatable disorders are a real possibility if scientists are allowed to get on with their work.

NOTES

Karen Lebacqz et al, 'Research with Human Embryonic Stem Cells: Ethical Considerations', The Hastings Center Report, 29(2): 31.

Gearhart, J. (1998), 'New Potential for Human Embryonic Stem Cells', Science: 282: 1061-1062. Available at http://www.dti.gov.uk/hgac

Ian Wilmut outlines his objections to human cloning in Prometheus 2. In the same issue molecular biologist Lee Silver and philosopher Dan Brock question absolutist arguments against cloning. For another debate, see The New England Journal of Medicine, 1998, 339. John Harris challenges the full range of arguments against human cloning in '"Goodbye Dolly?" The ethics of human cloning', Journal of Medical Ethics, 1997, 23: 353-360. Raanan Gillon does a similar job in 'Human reproductive cloning—a look at the arguments against it and a rejection of most of them', J. R. Soc. Med., 1999, 92: 3-12. In his piece, 'The Confusion over Cloning' (The New York Review of Books, October 23 1997), Richard Lewontin accuses the critics of cloning, in particular the US National Bioethics Commission, of rationalising a deep cultural prejudice. But it is also impossible to understand their view, he adds, 'without taking account of the pervasive error that confuses the genetic state of an organism with its total physical and psychic nature as a human being.' 'Think before you Squawk', New Scientist, August 2 1997.

'Common Sense About Cloning', International Herald Tribune, March 16 1998.

'Ethicists urge funding for extraction of embryo cells', Nature, 399, 1999: 292.
 
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