Dolly at 30: the legacy of a cloned sheep

Thirty years ago, Dolly the sheep, the first cloned mammal ever to be created from an adult cell, was born. The work was done at Edinburgh's Roslin Institute, where Ian Wilmut led a team whose insights were crucial to making the experiments come to fruition. Their work was inspired by science carried out on tadpoles almost a century prior; however, the objective, when the work began in the 1980s and early '90s, wasn't simply to clone animals: it was about genetically manipulating them for therapeutic purposes. Sir Ian has since passed away, but Kat Arney spoke with him on The Naked Scientists in an interview marking a decade on from Dolly...

Ian - The very earliest experiment was trying to answer a biological question as to whether essentially all of the cells retain the same DNA during the course of development because there was a suggestion, a hypothesis, that development was brought about, differentiation was brought about by the loss of sequences which were not important for a particular tissue type. A series of very simple experiments were done to address that question and the answer was there was no evidence of DNA being lost.

Kat - So this is the idea that somehow cells are shedding genes as they're making decisions to become brain or muscle. What was the key experiment that showed that couldn't be the case?

Ian - The nuclear transfer experiments which were done by Briggs and King and subsequently by John Gurdon demonstrated that you could take differentiated cells from tadpoles and produce adult frogs from them. So that clearly showed that those differentiated cells still had all of the information necessary to control development.

Kat - But they never managed to go from an adult cell to another adult.

Ian - That's a really intriguing point. I think you can only suggest that there must be something different in the way in which gene expression is regulated and that whereas we have methods which overcome these now for early stages of development we haven't yet got that for adult frogs.

Kat - So that was frogs and you thought, okay, let's try this in sheep. Why sheep? What was the background to that?

Ian - We got started because I heard that Willadsen had cloned from blastocysts in cattle. What I was looking for was a way of having cells which you could culture for a while to allow you to make precise genetic change and then use as nuclear donors. And it seemed if he was growing cells from blastocysts and then cloning from them that maybe we were reaching that point.

Kat - So that's taking cells from a very very early embryo putting them into an egg and making another animal. So the idea was can we do this from cells in a petri dish?

Ian - Exactly.

Kat - Then what about Dolly? Tell me about her biological history.

Ian - Well the classic thing for developmental biologists to do when they're studying these sorts of mechanisms is to look at the very early stages, foetal tissue and then adult tissue. So we always had it in mind that we would progress along that sequence of development. As you say we'd worked with early stages, we worked with foetal cells and then because we'd been successful with both those early stages we started with adult tissue.

Kat - So then to create Dolly, just if you can really briefly explain the process. How does it work? What is cloning? How does it work with an adult cell?

Ian - You need two cells. You need an egg from which you remove the genetic information, the chromosomes and you need a nuclear donor which will provide the nucleus that controls development. So in the case of Dolly this was a mammary cell which was in culture which was used and proved to be able to control development.

Kat - What did make the difference that seemed to make it work?

Ian - What we did as preliminary work was look at the best way to coordinate the cell cycle of the two different cells and we came forward with a scheme of using cells which had, donor cells which had been serum starved in order to make them quiescent.

Kat - So this kind of just put them to sleep basically?

Ian - Yep, exactly. And oocytes which were at metaphase II because we knew that they had a great potential to stimulate a transferred nucleus to enter into the cell cycle in such a way that it might well also be able to reprogram the expression of genes in the nucleus at the same time.

Kat - So you've got the donor cell that's quiet, it's all asleep, it's not doing anything and you've got an egg cell that's really ready to go for it. That's the key.

Ian - That's exactly it.

Kat - And when Dolly was born how did you feel? That must have been incredible.

Ian - Oh yeah. I think we were almost shocked because it was such a novel thing and we knew how important it was going to be both immediately from the point of view of the media and from a career point of view, from the point of view of building a reputation for the group.

Kat - This may seem like a bit of a silly question but what was she like?

Ian - The best way to describe this, I live down in the borders, in among sheep farmers and if they have a lamb which is not being mothered either because its mother's died or she's got too many lambs, they take it into the house and it becomes accustomed to people and that's exactly what happened to Dolly. There were so many people visiting her wanting to see her, to get her to be in photographs and this sort of thing that she became accustomed to people, in actual fact came forward to people whereas no, as it were, ordinary farm sheep would do that. It would automatically turn and run.

Kat - And what happened to the rest of her life? I understand she ended up having her own lambs, they weren't cloned were they?

Ian - No, she had six lambs by normal reproduction and I'm pleased to say they were all healthy.

Kat - So she became a mum and then what happened to her? How long did she live for?

Ian - Six years.

Kat - That's quite short for a sheep.

Ian - But we euthanised her because sadly there is a virally-induced cancer which occurs in sheep, particularly in Scotland as it happens and the infection got into the flock and unfortunately there is no treatment for it so after she'd had it for a number of months we decided it was kinder to euthanise her because what happens is the tumour gets so large that it restricts the animal's ability to breathe and it's then only kind to end their life.

Kat - Absolutely. And where is she now?

Ian - Now she's I think one of the most frequently visited exhibits in any British Museum. She's in the National Museum of Scotland.

Kat - You are the father of Dolly, I suppose, scientifically speaking at least. What do you feel has been her key scientific legacy and your key scientific legacy?

Ian - She made biologists think differently because we showed that cells can be changed. Many members of your society will know that Shinya Yamanaka was awarded the Nobel Prize because of the work that he did to take advantage of this new knowledge to develop ways of changing cells, of reprogramming cells. He says himself that he was stimulated to start the project because of the birth of Dolly and his work then led to the development of methods to induce iPS cells. So I may be the father of Dolly but I think I'm the grandfather of iPS cells.