Cloning - Dolly and Beyond
Chris - Thank you very much for joining us, it's 11 years since the Dolly days I guess you could say. At that time, when you created the worlds first cloned mammal, there was no precident for doing this so why were you doing it?
Ian - The ambition was to be able to make genetic changes in farm animals so they would produce proteins needed to treat human disease. That was the aim when we first started.
Chris - So how successful was it? I mean we know you got Dolly out of it, but it must have been tremendously difficult to actually make this happen, which is why you got such an accolade for doing it, but why is it so difficult?
Ian - I think what you have to consider is, the mechanisms which control development. We all came from a single cell of an embryo, which is smaller than a grain of salt, and almost all of our cells have exactly the same genetic information in them. The way in which the many different tissues that we have are formed is because the functioning of the gentic information is changed systematically to produce muscle, skin, bone, in them and all of the different tissues that we have. We used to believe that the mechanisms that bring that about are so complex and so rigidly fixed that it would not be possible to reverse them. The most important thing to come form the Dolly experiment was to show that's not true, because what it's led to now is people thinking well, can we find other ways of re-setting the genetic clock, without producing an embryo and people are making exciting advances with that area.
Chris - Do you have any feeling as to what the chemicals are in an egg that have those special effects of re-setting the genetic clock in a cell that would normally be a skin cell, I mean you used a skin cell from the udder in Dolly didn't you? Do you have any fell for what those factors are?
Ian - Very little, I would say this is the most disappointing thing of the past decade. People have shown that putting in four specific proteins in mouse cells can make those go back to the beginning of development but as far as we know, nobody has been successful in applying the same approach with human cells. And the efficiency is extraordinarily low, we've less than 0.1% of these cells being changed in that way so the teams have a lot more still to learn about this mechanism.
Chris - So to put that into perspective, you are making say 1000 potential embryos and one of them would turn into a potential Dolly.
Ian - The 1 in 1000 is actually cells without making an embryo, th efficiency if you go through the embryo route at the present time is something like 2 or 3 % would become offspring depending on species and all sorts of things like that.
Chris - Why do you think it's so low Ian?
Ian - I think we should still be surprised that it works at all. Because the mechanisms are so rigidly fixed, that's why tissues tend to stay in a particular state in a relatively stable way, and of course the egg did not evolve to achieve to this particular change. What we're doing is taking advantage of mechanisms, which normally function to modify the mechanisms on the DNA coming in from the sperm and different mechanisms for the DNA, which is already residing in the egg at the time of fertilization. There's no reason why they should work perfectly with genetic information coming in from an adult cell.
Chris - Why do you think it's relatively easier to do this on a mouse than it is say on a bigger animal?
Ian - It may well be that its easier to do experiments with the mouse and therefore more experiments have been done and if it were able to do as many with other species the efficiency would become similar. But there are differences between species. To give you one example, if you put the genetic information into an unfertilised egg during ordinary cloning, you also have to stimulate the egg to resume development. If you do this in the sheep, it really makes no difference at all, as far as we know, whether you introduce genetic information and stimulate development at the same time or differently. In the mouse, you have to delay the process of activation, as we call it, you have to delay the time when you stimulate the egg to resume development. The cow is between the two, it's an advantage to delay the activation but its not actually essential. Just a simple thing like that can have profound effects on the success rate, and again, we don't understand that.
Chris - Some people have said, that when you do this technique, there is a danger that you may genetically alter the individual concerned and they may have some premature ageing phenomenon going on. Is there any evidence for that? And if so, why?
Ian - I don't think that the premature ageing is associated with genetic change in the sense of a mutation, and there probably is some evidence of mutation, but comparatively little. The main problem seems to be whether or not the functioning of the cell is restored to a normal state for an embryo or not. The business of premature ageing is just a small component of resetting the length of bodies called telomeres which are at the end of our chromosomes and each time a cell divides the telomere is shortened, so that beyond a certain point the cell is no longer able to divide. The answer to your question about that is there are one or two experiments, and the Dolly experiment is one, the other I can think of is on cattle carries out in Japan, there are one or two experiments where the telomere length was not restored but in the vast majority of experiments where people have looked, telomere length has been restored perfectly normally.
Chris - Encouraging news. Thanks you very much Ian Wilmut., from the University of Edinburgh. He was the creator of the first cloned mammal, and that was Dolly the sheep back in 1996.