s It Time to Give Up on Therapeutic Cloning? A Q&A with Ian Wilmut

The creator of Dolly the sheep has ended his focus on somatic cell nuclear transfer, or cloning, in favor of another approach to create stem cells




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.


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