Ian Wilmut Interview (page: 4 / 6) Pioneer of Cloning	Print Interview

You have said on occasion that if not for a conversation you had in a bar, a major development would not have occurred. Can you explain that?

Ian Wilmut: Absolutely right. We were using the technology which we had at the time to add genes into sheep. It's a very inefficient process. You can only add a gene, whereas what we often want to do is to change genes that are there, but it does work. The director and I were at a meeting in Ireland talking about the work, and listening for ideas, thinking of different approaches to use.

Get the Flash Player to see this video. In a conversation in a bar one evening we were told that somebody working in that lab that I mentioned in Texas had achieved a step forward with nuclear transfer and was getting development from cells taken from embryo. And, it sparked across to the fact that in mouse there are ways of culturing those cells in the lab, they're called embryonic stem cells. A specialist population of cells which can give rise to every other tissue. Now, what the person in Texas had done was to take cells from just a day or two earlier than that, so there's sort of a short gap. But, the point that excited me was that if we could bridge that gap, then we would be able to have ways of being able to make genetic changes in animals and make lots of copies of animals.

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After that meeting in -- I think -- January 1986, I went back with the director, very excitedly trying to persuade him that this was the way that we had to go. And so it was just that chance conversation that brought a number of ideas together.

Was it easy to convince the director?

Ian Wilmut: Fairly easy with the director. Not too difficult with the potential sponsors of the work, but it all takes time. It took a couple of years to get the money in, then we began to work on this area in a systematic way.

Along the way, the field went through its ups and downs. Can you talk about the controversies?

Ian Wilmut: There are two issues which were very important, and had a big influence on the process. There was a suggestion that an experiment that had been reported was a complete fraud. There was evidence of tampering with the data. Actually, since Dolly and since the technique which led to the production of Dolly, the group at Roslin have come to think that there may actually have been some truth in that report as well. Some people have always felt that, but because there was evidence of tampering with the data, it was dismissed.

Now, developmental biology in mammals is mostly done in mouse, but the embryology of mice is extreme in one particular facet. Very early development in all mammals is initially controlled by proteins and things which are produced before ovulation. At a specific time the genes in the embryo take over. In the mouse it's very early on, when there's only two cells. In sheep, cattle, humans, it's eight cells. In frogs it's about 5,000.

Nuclear transfers have always been much more efficient in frogs and least efficient in the mouse, and it seems to be an important relationship. People had tried doing nuclear transfer in mouse, and they'd drawn a conclusion and said, "It's just not going to go." That massively dominated the view of nuclear transfer that people had, and that was misleading.

The initial step which Steve Willitsen had done in Texas was to show that you could go past that barrier. He was working with cattle embryos, probably with 32 cells, well past this barrier of eight. That led to my optimism. If you could get to there, maybe you could get to this specialist population of cells.

You met with a lot of skepticism. How do you deal with that as a scientist?

Ian Wilmut: You just have to believe it, don't you? You have to be prepared to defend your interpretations and to justify them as well as you can. Science makes progress by advancing new ideas, hypotheses which can be tested by designing good experiments. I just had faith in my hypothesis.

There were unsuccessful attempts. What were the problems?

Ian Wilmut: When you do nuclear transfer you're taking two cells and putting them together. Cells have mechanisms which enable them to grow and then divide. It's called the cell cycle, because it is a cyclical sort of process. You need to coordinate that. A colleague, Keith Campbell, came into the group in '93, and with him, we not only proved this was important, but figured out how to do it. So the first step forward that we made was how to coordinate cell cycles and that gave us a significant step forward.

It was limited though. It was useful, but not eye catching. That led us to investigate other ways of coordinating cell cycles. I had always expected that the particular cell populations I was hunting for would work. When we got lambs from a similar type of cell, I wasn't too surprised. But then as things progressed we began to realize that it was much more powerful than we'd expected and that it was going to work with a variety of different cell types, including some from adult animals.

Was that very exciting?

Ian Wilmut: Oh, absolutely. But often what happens is that there's sort of theoretical moment, if you like. In the case of adult cells that would have been two or three years before the event. It takes quite a long time then to bring the thing to fruition.

Is it hard to keep the excitement going through two or three years?

Ian Wilmut: No. I would characterize myself usually as a naive optimist, and so no, it's not a problem.

You eventually used a mammary cell. Was that just an arbitrary decision to try this cell?

Ian Wilmut: We had shown that you could work with the embryo cells, and we had money to take it on to different cells. We collaborated with a company and set up a project to test two or three cell lines for them, which they could then go away and use. The sheep season in the northern hemisphere goes from roughly October to March, that's when we can work with the sheep. And by Christmas, we had tested a new embryo line for them and got pregnancy started.

They had contracted us to test three new embryo lines, but they'd only got one to work; they'd had technical failures. So we were looking for other things to test. The mammary cells were in the lab for a completely different purpose, so why not use them? I can't believe that we would have used mammary cells if we'd been starting with a clean slate.

What did you have to do to the cell?

Get the Flash Player to see this video. Ian Wilmut: The trick that we introduced to coordinate them was to starve them, to make them inactive, there's a technical name of quiescence. And, there are two reasons why we think that's important. One is it's this process of coordinating the cells cycles, so that they begin to go off at the same time. The other is that they're easier to make go back to the beginning of development. And, I think we need to think about this for a minute, what happens in development is that a single cell will become all of the different tissues of an animal, and it happens by cells dividing and then becoming more and more different. And, what biology said was that this process will become more complex, and more difficult to reverse. Now, what happens when we make a cell go relatively inactive is that we think that there are differences in structure in the nucleus, in the genetic information. Which then allow the factors which are in the egg, which really are the magic ingredients, to act on that nucleus and to bring about the complete reversal of development. Now, we haven't formally proved that and we certainly have no idea how it works, but that is our current hypothesis as to why we produced Dolly.

Is that going to be a new area?

Ian Wilmut: Absolutely, and it's very important for a whole range of other things.

Get the Flash Player to see this video. Once you've shown that you can do this with an egg by taking a nucleus and an egg, you can ask, what are the factors? Can we find ways of putting those factors into the cell without doing a nuclear transfer? If you can do that, then you can find a way of -- let's say you have a patient with Parkinson's disease, taking a cell from that patient, treating it in the sort of ways that we're beginning to dream about now and it will go back to a very early stage of development. Now, the value of that in principle is that if you got a cell back at that stage you can make it differentiating to everything else, including the nervous cells which are damaged in Parkinson's disease. So I'm quite sure that one day somebody will be describing to you how to do this and to provide cells to treat Parkinson's disease, diabetes, perhaps to reconstitute the immune system in somebody who's had leukemia. To reconstruct the immune system with AIDS, all sorts of different treatments like that.

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