CAMR

Scientific American
July 22, 2008

Is It Time to Give Up on Therapeutic Cloning? A Q&A with Ian Wilmot

Ian Wilmut, famed for creating Dolly the cloned sheep, announced recently that he is abandoning the technique to concentrate on a popular new approach: making induced pluripotent stem (iPS) cells. Such cells would get around the ethical and legal issues surrounding embryonic stem cell work, of which cloning, or somatic cell nuclear transfer, has been an integral part. For the Insights story, "No More Cloning Around," in the August 2008 Scientific American, Sally Lehrman asked Wilmut about his change in focus, whether somatic cell nuclear transfer is still relevant, and what lessons he learned in his experience with Dolly. Here is an edited excerpt of that interview.

You are now director of the Scottish Center for Regenerative Medicine in Edinburgh, where you oversee 20 principal investigators, including a team that hopes to use iPS cells to observe amyotrophic lateral sclerosis (ALS) in progress and develop treatments. What are some of the questions related to the iPS system that must be worked out?
The limiting factor is not literally getting cell lines anymore; it's going to be studying them. The first thing you'll have to do is to look at the cells for the usual quality control things to see that they're expressing the right markers. And for quite a number of years, until you get confidence in the procedure, you'll have to at least form embryo bodies and differentiate them into different lineages. You'll then have to do quality controls to be confident that you've got what you want.

What are some aspects of your studies with somatic cell nuclear transfer that will carry over into the iPS work?
We've been trying, without any success at all so far, to understand how reprogramming works in nuclear transfer. The strategy that we adopted was to use frog egg and oocyte extracts and to expose the nuclei from alien cells to those extracts and look for reprogramming. That seemed a very reasonable approach, because John Gurdon [a renowned British developmental biologist] showed 30 years ago that if you put mammalian nuclei into frog eggs, some of the mammalian nuclei are switched on. I mean, this was done by very, very simple techniques 30 years ago.

But I still find it puzzling. We failed. We worked for two years to try to make this system work before we gave up, because we couldn't get consistent effects. So we changed over to using mouse embryo stem cell extracts to reprogram human cells, and that works. So that's put us into a position where we can now begin to think of using that as an assay system and begin to try and identify active factors in the embryonic stem cells. So, obviously what we'll do is complement the iPS technology with other things, just to see. For example, if you treat cells with the extracts first and then use the iPS system, is there an enhanced reprogramming?

In your scientific career you've shifted almost entirely from animal science to a focus on treating human disease. Why did you choose ALS as a target?
It's a nasty disease, and there isn't an effective treatment. But you could say that about a lot of things. I guess I'm surprised that more people haven't recognized the way in which the iPS system, presuming it works, will revolutionize the study of inherited diseases.

The idea that things which we collectively do might contribute to treatments for ALS, for example, I find really exciting. One of the best-known ALS sufferers in Britain was a soccer player called Jimmy Johnstone. He played for Glasgow Celtic when they were the first British team to win the European Cup, in 1967. And here you had a man who was extraordinarily gifted in this sports activity. He was known as "Jinky" because he was so fast and light on his feet. And he was struck down so that, by the time I met him, he was on a sort of an eye-level bed, not able to move anything. You know, I think that's hellish; I don't know how people cope with that illness. And to be able to contribute to development of a treatment for a disease like that is fantastic.

You've said that the center is studying embryo stem cell derivatives as a tool to repair bone, the liver, neurodegenerative disorders, cardiovascular disease and, potentially, diabetes. You emphasize basic science and the development of cell lines for drug discovery. What are some of the center's other priorities?
The center is building on from what was known as the Institute for Stem Cell Research, which was led by Austin Smith, who is one of the most distinguished stem cell biologists in the U.K. We go all of the way from basic research with mouse stem cells and human embryo stem cells, from any stage of development, potentially through to the clinic.

We have three sets of stakeholders: the basic scientists, the clinicians, and the companies—if you like, commercialization. Two thirds of the money for our new building is coming from different branches of the Scottish government, explicitly with the aim of job and wealth creation. There is the medical school next to a research hospital on what you would think of, I think, as a small biotechnology park by United States standards. But by British standards, it's quite large. And there is the explicit expectation that we will commercialize our work. There is also training.

You've had a long relationship with Geron Corporation ever since it acquired the Roslin Institute and obtained the license rights to your cloning technology. Now Geron is attempting to test cloned cells in acute spinal cord injury patients. Is Geron involved in the center?
They're setting up some research in the center. They've clearly invested huge amounts of money in work with human embryo stem cells, and our ambition in Edinburgh is to establish it as a U.K. center, perhaps a European center, for work with pluripotent cells. We are very keen to retain [Geron's] interest and presence so that as these things emerge into a clinical role, they would regard Edinburgh as being a natural site to establish a clinical presence.

As scientists begin to think about moving into clinical research with embryonic cells, they have begun to discuss potential voluntary guidelines to ensure that scientists move ahead in a measured, safe manner. Has your perspective on this changed since Dolly?
No, no, no. I mean, there is a very difficult balance, isn't there? We should be ambitious to try to see what we can achieve using these cells. But you do have to consider the risks carefully and see that the patients are informed of the risks. The people who were involved in the development of revolutionary treatments in the past, like, for example, organ transplantation, will tell you that you do not make progress unless you are prepared to, with the patient's consent, take risks. And if you think of things like spinal cord injury, there is a huge potential benefit there. So it seems appropriate to me that those are the sorts of things that you would try first. But I don't think that we should be under any illusions that the reason why you do these phase I trials is because there is a risk. And you have to measure it, you have to define it, before you can go on to the next stage.

Are patients eager to participate in trials?
Most of my conversations have been with patients with ALS and other neurodegenerative diseases. I can tell you that they are very positive about taking part in trials like this, even though they know that the probability of a benefit to them may be very small. But they feel they're contributing something to the next generation of people that will suffer from these conditions.

Can any of these patients expect to benefit personally from the treatments?
For some of them, at least, I think treatments will arise from research with stem cells at some time in the future. You can get a perspective on this sort of thing if you look back to the development of new approaches to therapy in the past. So if you were to look back at, for example, the use of antibiotics, the first really powerful one was penicillin, which emerged during the Second World War. And I think probably soldiers and other war victims were among the first to be treated. You can see a continuing process that's still developing in antibiotics now, 60 years later. The same sort of thing would apply if you think of vaccination. It's centuries since approaches to immunization were first being developed. But even within my lifetime, the person who was my best man, he suffered from polio as a boy, just before the Salk vaccines first came through. Over a very long period, treatments develop. And I think we should expect the same thing to apply to stem cell–devised treatments, that some will come through in the next few years, but 50 and 100 years from now, people will still be developing new therapies.

Are there things that you learned from your experience with Dolly that now shape your thinking in this area?
Well, I guess maybe it made the world seem a bit grayer, if you like. You would think that there are merely positive benefits to come from something new like this, but you also see that there are problems as well. And so there is a sort of gray area in the middle, where things are not just as rosy and as satisfactory as you might like.

For you, what were the hardest parts of the whole process?
It would be the media side of things. It's not something that you do, as it were, until you're put in a situation where you have something that people are interested in. You know, most of us at least do some of our work on taxpayers' dollars. And so, in that sense, there's an obligation to explain what it is you're doing and where you've got to so far. Also, because a lot of these things have a social impact, whether it's cloning or stem cell research, it's important to explain the state of things.

You've written a lot about social and ethical issues related to cutting-edge science, particularly in the area of reproductive cloning. Some scientists have begun raising concerns about unethical promises being made for embryonic stem cell treatments. Should we also be worried about rogue scientists experimenting with human cloning?
The thing which provides the most protection at the present time is the sheer inadequacy of the technology. But I've thought about this, and I think you're right that it would become a risk at some stage. I was one of a group of people led by Bernie Siegel to try to get human reproductive cloning made a crime against humanity. Intriguingly, it was the White House that blocked that through a surrogate because they wanted to block all human cloning rather than just reproductive cloning. Now, it will be interesting to see whether that could happen with a new regime, whoever it is. The advantage of getting it made a crime against humanity is that there would then be no escape. No matter where you did it, it would be a crime.

Why do you think a ban on reproductive cloning is important?
Quite apart from anything else, I think it would be entirely appropriate to get a ban at the present time because there is a very significant risk of dead babies or of children with severe abnormalities. The list of abnormalities which we've seen in livestock and in mice is very long and quite horrifying if you think of it in terms of children. In one lamb, it panted all of its life, even when it rested, because of restricted blood flow through the lungs. After two weeks we decided that it was kinder to end its life because we could not correct the abnormality. And, of course, it wouldn't be without risk to the woman who was giving birth to the child because there are often difficulties. And so, on those grounds alone, I would have thought that there would be pretty well a unanimous wish to prevent that sort of thing happening.

My own view has not changed at all that there are other reasons why reproductive cloning should be prohibited, which are essentially because of the psychological effects of being a clone. We do tend to anticipate and expect that children will be like their parents. And I think that would be even stronger if the child were a clone. And so that's the reason why I would be concerned about it.

It seems as though there is increasing sentiment among scientists that some form of reproductive cloning would be acceptable for clinical purposes. Would you agree?
There always has been a difference of opinion about that. I think you need to define the terms very, very closely. As a way of getting people to think about things, I've asked, "Suppose it was possible to use this technique to correct a genetic error in an embryo?" You know, say, if you had a family who were inheriting one of the diseases we've already talked about. If you produced an embryo by in vitro fertilization (IVF), grew out cells, corrected the mutation, and then cloned to make a new embryo, you're using it as a tool for correction of genetic disease—and that child would not be a genetically identical twin. I personally wouldn't find anything wrong with that. Whether it's likely to happen or not is a very different matter, simply because of the technical challenges and the costs involved.

And as far as treatment for infertility is concerned, the odds are that there would be other ways of overcoming the problem. If IVF cells are equivalent in their developmental potential to embryo-derived stem cells, then it might be possible to produce gametes. So if you have, let's say, a man who has no sperm, you produce iPS cells, you produce sperm, and you can then produce babies through IVF. Naturally, it would be a much more satisfactory approach, because it is a child who is the product of both parents and is not a genetically identical twin to anybody.

Have you thought about renewing your effort to get a cloning ban in place?
No, this is the first time I've discussed this for quite a long time. But if Bernie said, "Would we do it again?" I'd certainly join in, yeah. And I know the British government was very supportive of this.