SCIENCE AT THE SHINE DOME canberra 4 - 6 may 2005

Symposium: Recent advances in stem cell science and therapies

Friday, 6 May 2005

Professor Bob Williamson
Honorary Senior Principal Fellow, University of Melbourne

Bob Williamson became Professor of Molecular Genetics at St Mary's Hospital Medical School, Imperial College London, in 1976. He worked there until 1995 when he moved to Australia as Director of the Murdoch Institute and Professor of Medical Genetics at the University of Melbourne. He retired in October 2004 and is now Honorary Senior Principal Fellow and Professor of the University of Melbourne. He has over 400 refereed career publications, including about forty in Nature, Nature Genetics, Cell and Lancet. He worked on the identification of the genes for cystic fibrosis, Friedreich ataxia and Alzheimer disease. More recently, he has taken a major interest in national science policy and ethics. He Chairs the OECD Committee on Pharmacogenetics, and has worked extensively for the World Health Organization. He has been a member of many editorial boards, including that of the Journal for Medical Ethics for the past twelve years, and edited several books on genetic engineering and on ethics and the new genetics. He is a Fellow of the Australian Academy of Science and of the Royal Society, and an Officer of the Order of Australia.

Striving for an ethical way forward for stem cell research in Australia

After Julian Savulescu's exciting talk, I will try to translate some of what Julian said into an Australian legal context. First, however, I want to thank all of the speakers today, and thank my colleagues on the organising committee for working with me to help this Academy annual general meeting to look at all of the issues involved in stem cell research.

Some of us who grew up in the 1940s remember when the public supported science. Indeed, I remember when the public thought that science and medicine represented the future. You know, 'Trust me, I'm a doctor,' and that sort of thing. These days, we are dealing with a sceptical public, a public which needs to be engaged in scientific debate, needs to be engaged in talk about both the process of research and the outcomes of research. I think that is a new situation for many scientists, a dialogue that we are going to have to master.

Genetics is the area where this dialogue is most critical. After all, what are the issues that genetics deals with? Sex, race, children, ethnicity – all of these things. These are things people go to war over. These are things people really care about. I believe that many of us who are in this field underestimate the extent to which the community has genuine concerns about genetics because genetics is so closely integrated with the gestalt of what we think we are that matters. So I think that when we look at genetic modification, at cloning, and at genetic screening, we have to understand that people will start with a very sceptical and more questioning attitude to what we are doing.

Now, what about research? It seems to me that research is very important in our society, and not just because we like doing it. I can tell those of you who are not researchers, who are not in the Academy, who do not aspire to be in the Academy, that those of us who do research love research. It is a wonderful occupation. If you are a researcher, as I have been for the whole of my life, then every single day when you get up, you meet new challenges in what feels like the best job in the world.

But research, from the community's point of view, has other features. Research is a major driver for change. Medical research is the major driver for change both in clinical practice and in the prevention of disease. Research provides the evidence to improve both individual health and population health.

Research is also precious because it is a contract between the community, the researchers, and people who are sick and their lovers and carers. Research is inherently of value to society. It is inherently ethical.

Research particularly empowers disadvantaged groups. I get very irritated when people tell me, 'Oh, all of this research will only matter to people with lots of money in First World countries.' All of the data suggests that it is people who are disadvantaged in health care – women, indigenous people, people with intellectual disability, people who are handicapped, the mentally ill – that are the ones who are empowered and changed by research.

And, in this context, it is unfortunate that many human research ethics committees in Australia and throughout the world have become risk averse. They have become dissociated from patients and families and the research and medical communities. They have lawyers on them. I really don't have anything against lawyers, but I can tell you that when you are on a hospital research ethics committee, and the hospital lawyer joins that committee as the primary adviser on what you can and can't do, what you get is a risk averse situation which is not in the interests of research and not in the interests of the patients. Indeed, I have been on several human research ethics committees, and none of them have had a young person with cystic fibrosis, a young person with Friedreich's ataxia, as a member, the very people who are the most interested in research in our community. Human research ethics committees have to be reminded that risk aversion in research is unethical.

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We have heard about embryonic stem cells today, how they are derived and how they work.

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This slide summarises how embryonic stem cells are obtained. I will just make the point that human ES cells are still more difficult to grow than mouse ES cells. We don't know for sure whether human ES cells are inherently more difficult to grow and handle, or whether it is just that we haven't had 20 years' experience with them yet. As everyone has emphasised, stem cell science really is a new field.

At the moment, in Australia, where do we get embryonic stem cells from? We get them from so-called spare embryos – spare embryos from IVF programs. And one point I do want to make, because I don't think anyone has made it yet, is that the reason there are lots of embryos made from each couple in an IVF program is medical. It has nothing to do with the needs of researchers. It is because superovulation , which then involves an intrusive entry into the woman's body to retrieve the eggs, followed by the fertilisation and the storage of the fertilised embryos, is the right way to conduct an IVF program. The decisions on how to conduct IVF have nothing whatever to do with the people sitting in this room who eventually hope that these may be available, if they are no longer needed for IVF, as a source of research material.

If they are left over when a family has the children that it wants, until very recently the law has stated that the IVF unit has to throw them out, in practice pour them down the sink. Today, we are allowed to use them in research into genetic disease and infertility – if a couple wishes to donate them and if an ethics committee says that the research is appropriate.

As Julian Savulescu has just pointed out, the law that allows only the use of 'embryos surplus to an IVF program' for research is illogical. If the particular embryo that we need, to do research on cystic fibrosis, on Tay-Sachs disease, on muscular dystrophy, can only be obtained by in vitro fertilisation from a couple that has already completed its family, I do not see the ethical difference between an embryo that is surplus from an IVF program and one that is knowingly fertilised for research into a disease that affects that family. There are people – I know them in the context of situations of genetic diseases involving children- who are passionately interested in developing new and better treatments for these diseases. At the moment we are not allowed to do this research in Australia.

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We know that several groups, of which the one from South Korea has received most attention, are doing nuclear transfer from a somatic cell to an enucleate egg. These, obviously, may have immunological advantages – I am not at this stage going to repeat what Konrad Hochedlinger said in his excellent explanation of some of the reasons why these are exceptional research tools. I want to make one point about who is going to benefit.

We don't know, at the moment, what specific uses for stem cell therapy are going to come first. Doctors are already using stem cell reconstitution therapy for people with many hematological disorders and leukaemia. And, as Gesine Kögler said, there have already been 8000 or so stem cell transplants to bone marrow, to rescue children who have failed therapy for leukaemia, or for children with metabolic and other genetic disorders.

We do know that genetic and congenital handicaps are major causes of disease in children, not only in Australia, Germany, Britain and the United States but also in large areas of China and India. I say this lest people think we are only talking about something occurring in traditional white, First World countries.

Approximately one child in 20 is affected by some sort of genetic or congenital handicap from birth. I would also note that most of us will be affected by some handicap or other by the time we are in our 70s or 80s. Although we tend to categorise genetic and congenital handicaps as the things that happen from birth, obviously there is far more handicap that is acquired .

My belief is that stem cells are most likely to be of value to treat infants and children. The reason was clearly illustrated in Gesine Kögler's talk. Early childhood is the time when the stem cells are there, and the stem cells are there because they can be used. The stem cells are there because they are used: they are used during embryonic development and during that first year or two of life. So I think that, if we are looking for the place where the most predictable successful uses of stem cells will happen, this will almost certainly be in the context of infant and paediatric disease.

The reason why I am excited by Gesine's work is not just that the idea of a pluripotent, infinitely dividable stem cell being present in cord blood is exciting to me as a researcher. It is because we know that this is a safe method of treatment that has already been used in 8000 cases.

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There are many examples that have been put forward during today's meeting. However, did you see last Sunday's report in the Sunday Age, 'Vision restored'? There are now persons who are blind, in the UK, who have been treated with stem cells – autologous stem cells in some cases, although the whole story is not completely clear from the report. These are people who have had damage to their eyes as a result of an accident, usually trauma , and stem cells are used to restore the corneal layer.

Part of the problem with overselling of stem cell research is that it is made to sound as if people who are totally handicapped will jump up and run the 100 metres, or a person who has a medical problem is going to cured, just like that. Medicine, in my experience , doesn't work like that. What you get is small advances, gradual advances, but advances that make a difference.

In the case of cystic fibrosis, the advances that have made a difference have been small – no single one has been dramatic – but the life expectancy of a child born with cystic fibrosis today is 31 years , as against 16 years of age in 1965. I don't think it is going to be any different for stem cells. I think we are going to see stem cells making a difference. I don't think the woman who was pictured in the Sunday Age as having stem cell therapy for eye damage is seeing with 20/20 vision. But I think that for the first time she is seeing – albeit with blurred vision – her children move around her. And for her that is incredibly important.

What about the law in Australia? The current law, which was passed two and a half years ago, says that we are not allowed to create an embryo other than by an egg and a sperm. Let's think about this. What is an embryo in this context?

Is a cell made by nuclear transfer an embryo? It seems to me that an embryo has three contexts. It has a genetic context, and that genetic context is bound up with its individuality. All of us who have children know the most delightful thing about children is that they are not just like you and your partner; they are mixed up. Obviously they have inherited things from you and your partner, but they have inherited a jumbled genome and all that that implies, genetically and in terms of the outcomes of genetics. Then there is a biological context, the ability to develop and grow as a biological entity. And finally, there is a social context, the choice of two people to have a child and bring up that child.

Nuclear transfer ES-equivalent cells, grown in a petri dish, have no genetic context, no social context, and one chance in a thousand of having a biological context. I think that cells from nuclear transfer are diploid cells, just the same as the cells we grow from patients all the time. They have a greater potential to differentiate into many different cell types, but otherwise are just another diploid cell, for from the person from whom the nucleus was derived. I don't regard this as an embryo in any sense.

I think that this becomes more obvious when we look at the way this research is developing. Scientists are developing techniques so that any diploid cell can be wound back to a point where it is totipotent. These cells then also have a theoretical chance of becoming an embryo. I will predict – and I will predict it unequivocally, and although not everything I have said will be on the web, this will be on the web – that in the next two or three years we will have ways so that any of you will be able to donate a cell, a diploid cell, and have it modified such that after shocks, after cooking, after doing this or that, it could be implanted to create an embryo, without the involvement of either an egg or a sperm.

Does that cell then deserve the respect that we offer an embryo? If your answer to that is yes, then we are in a position where we are committing genocide every time we wash our hands, by killing 10,000 or 20,000 potential embryos. And that is a nonsense. Thoughtful theologians are trying to think of ways of redefining, in terms of the primitive streak or in terms of implantation or in terms of other characteristics, the time when we should offer an embryo respect. At the moment, in Australia, it is lawful to conduct research on a healthy embryo that is surplus to IVF, which has a one infour chance of developing into a fetus and a child. It is illegal to conduct research on a nuclear transfer entity which has no social or genetic context and has at best a one in a thousand chance – probably less -of developing into an embryo or a child, and then only after you do all sorts of things to it.

I have changed my views recently. I used to think the law was too restrictive. I now think the law is just a nonsense. The law has got into a position where it doesn't make consistent sense.

Let's take another example. It is illegal to mix the genomes of three people. And amongst the genomes people talk about are mitochondrial genomes. People with mitochondrial disease have abnormal mitochondria. The therapeutic approach is to use healthy mitochondria from an egg and introduce it into the normal nuclear genomes of a one cell embryo from the sperm and egg donated by a husband and wife.

Mitochondrial genomes don't confer anything that we normally think of as the genetic individuality we respect in humans. And the ethical issues involved in using healthy mitochondria from an unrelated donor – which is illegal in Australia – to treat mitochondrial disease are far less complex than the ethical issues involved in, say, embryo surrogacy, which we permit, albeit under regulation.

Research on preimplantation genetic diagnosis embryos, until the government agreed to allow the rule giving a cut-off date of 2002 to lapse, was illegal even when they had been proven to have Tay-Sachs disease or cystic fibrosis or muscular dystrophy or thalassaemia. Those had to be thrown away because they were created after 2002, while the use of healthy embryos, which are of less interest for many purposes to those of who work on genetic disease, was lawful. Fortunately, this restriction has now expired.

There is a provision in the Acts in Australia that an independent review must be conducted as soon as possible after the second anniversary of Royal assent – that is, as soon as possible after 19 December 2004. The status of this review is unclear. We don't know who the independent reviewers will be. To the best of my knowledge they have not been named; and those of us who work in this field are not certain what is happening. (Note added in proof: The names of the review panel were announced in mid-June 2005, six months after the statutory date. They will have a difficult task to finish their work by December 2005.

All embryo research is already subject to strict scrutiny by strong local and national ethics committees. And, lest anyone who is here thinks that these committees are merely filled by researchers and their cronies, I should tell you that the Australian Health Ethics Committee (AHEC) contains on it not only public representatives but religious representatives – Bill Uren, who is the head of the Jesuit Order in Australia, is a member of it. Many members of local Human Research Ethics Committees would disagree with the points I am making to you today. And I personally think that I have confidence in the ethics committees and AHEC when it comes to regulation. I do not believe we need another layer of regulation on top of the national and local ethics committees that already do a good job.

If our objective is to prevent reproductive cloning, surely the solution is to make reproductive cloning illegal, defining reproductive cloning as placing any embryo other than that created by a sperm and egg in the womb of a woman. Let's make it a serious offence. That is, I suspect, what the community wants. And I have no problem with doing what the community wants in this context.

But we must not allow Parliament open slather to regulate research that is carried out in laboratories, growing cells from a living person, with neither the intention nor the possibility of obtaining an embryo, a fetus or a baby. This research is of great potential value, and is not embryo experimentation. Two years ago, the Australian Law Reform Commission and AHEC issued a long and well documented report recommending the creation of a Human Genetics Commission of Australia. I think this is a great report. I don't know how many of you have read it but it has many excellent recommendations. Yet this report has been ignored by government. I think we need a Human Genetics Commission of Australia. I think it should meet in public, develop policy, and be representative. (Note added in proof: in June 2005, the Government agreed to fund the Human Genetics Commission of Australia, a welcome move even if rather late.)

My final point is that we have just had an incredible decision, particularly knowing the Minister for Health's views . I am very excited by Gesine Kögler's report showing that cord blood contains neonatal stem cells, which may well include ES-equivalent stem cells. But only two or three weeks ago that the Minister for Health cut the funding (in order to save, I may say, the grand total of $2.5 million per annum) for cord blood cell banking. This will reduce the number of cords that will be collected in Australia in the national scheme to roughly 50 per centof what it is now.

Stem cell research matters. But I think the key point – one of the points that Julian Savulescu taught me – is that there is an ethics of not doing as well as an ethics of doing. If we do not pursue research which is to the long-term benefit of our community, our population, and our infants and children, we are doing something unethical. The pursuit of appropriate research that will bring benefits to a community is of a high order of ethical importance. I think that today's discussions, discussions of the fundamental science, the clinical applications and the ethical importance, gave us all an insight not only into how we might deal with these issues, but how we should deal with these sorts of challenge in the future.