Sir John Gurdon Interview: Conversations with History; Institute of International Studies, UC Berkeley
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This is a very important moment in the history of the biological sciences. What was that feeling of creativity like, that "wow," when this happened? Here you were, tinkering. I gather from what I've read that the complicated thing here is taking the cell out and moving it around. So, [for] somebody who's worked with delicate items like sailboats in walnuts -- talk a little about the difficulty and then the "aha" moment.
An early event in my Ph.D. work was to attempt this experiment, which as I say, completely failed. The most obvious reason why it failed was that when you used a microglass needle to put into the egg, you could push it in and it came out the other end but it actually hadn't entered the cell at all. It had taken the membranes with it, pushed the whole lot through, out the other end and come back. It turned out to be impossible to get through this very viscous jelly. So, that was the first major problem, and that was solved largely by the fact that my mentor had recently got a grant for a new microscope, which had nothing to do with this work. It was an ultraviolet microscope, and we discovered more by chance than anything else that it happened to emit light of a wavelength that dissolved this elastic jelly. As it happens, it also killed the resident nucleus. So, it was an extraordinary piece of good fortune that that worked, and then suddenly things started developing. You found you could do the experiment. That was a key point. If that had continued to fail, I really don't quite know where one would've gone.
Talk a little about your feelings, about that "aha" moment. I guess what you got was a tadpole, right?
You got a tadpole. That's absolutely right, when previously nothing happened at all. Suddenly this thing! You thought, "Well, this was amazing. Could it actually be right?" That's the thing one always thinks, even at my stage. Whenever you get a result, you think, "Could there be an artifact?"
There was an obvious [potential] artifact, and that would be that the resident female nucleus in that egg had not been destroyed, and all you'd done by pushing a needle in was to somehow activate that. So, we needed a way of proving that that was a real result.
Then another piece of partly good fortune, partly wisdom of my mentor, came about. He had a student who was doing completely different experiments, and they failed, too, for an odd reason. Instead of him saying, "Well, do something else," he said, "There must be a reason why these are failing." He discovered what turned out to be an exceedingly important mutation which acted as a genetic marker. And so, we could put in the nucleus of one cell which was genetically marked into this egg, grow the embryo up and prove that the embryo carried that genetic marker appropriate to the nucleus you put in and not appropriate to the resident nucleus that you hoped to have removed. That was really why the general scientific public believed our results. They probably wouldn't have done it otherwise. So, that was very important.
Now in terms of science, this was a turning point in the road that led to the cloning of Dolly many years later. I want to help our audience understand this. You won the Copley Medal, which recognized that your work that had given decisive evidence that specialized cells are genetically equivalent and they differ only in the genes they express and not the genes that they contain. Explain that.
Well, it's a very precise and accurate statement. The idea, just going back a little, is that particularly after the results of Briggs and King, the thought was that the nucleus (the collection of genes we have) would actually change as the egg develops into different cells, so our skin, intestine, brain, blood and muscle, would all have different sets of genes, because they would lose the ones that you no longer need. So, for example, the skin cells don't need brain genes. Indeed, it was an idea of someone in the 1880s called Weissman that that's how development worked. It was a plausible idea. As the egg develops it sheds off these genes, and so as the cell decides to follow a particular pathway, that's a very neat way of doing it. You get rid of the [other] genes so that it gets narrowed down to that fate.
The really important thing about this question and the experiments was that that turns out not to be the case. All our cells, with very minor exceptions, contain the same set of genes. That's fundamental in any kind of cell replacement therapy which we might envisage. Obviously, had that not been true, Dolly the sheep could not have been formed, but it turns out it is that way. And so what we now understand is that as cells develop they contain the same set of genes, and the only difference is that something decides to read the skin genes in the skin, and brain genes in brain. So, that's what they meant by "expression" in that statement.
Why did it take so long? We're talking about a thirty-year interval. Your experiment was in what year?
The first time we got an adult successful animal was 1958.
Oh, really? Okay. So, why so long?
Very good question, and I've wondered about that too, and I've tried to explore that. One reason for that was that when they were doing these experiments in mammals -- and I might just add that I had a Ph.D. student in the early 1960s who did indeed try transplanting nuclei in rabbits, and it didn't work, or at least not significantly well. And then that got left aside. Now why?
The reason is that someone called Devolsolta took this very seriously and did a lot of experiments, and he found that the best you could do was take a nucleus out of a two-cell embryo and put it back into a one-cell embryo. If you did anything else, anything further, it didn't work. It turns out the explanation is that if you transplant a nucleus into a fertilized egg, an activated egg that's already started, it's extremely difficult to do. It doesn't like to receive that nucleus. We had always chosen to do experiments using an un-activated egg, they're sort of naïve and waiting to go. For reasons that I'm only partly clear about, that was not done in the early mammal work. They felt that a better route would be -- and they had reasons for doing that -- going into the fertilized egg. But it essentially doesn't work. Devolsolta did very careful experiments, published very good journal articles explaining that this particular route he used does not work, and indeed it doesn't.
But switching back to the route that was done with amphibia, it actually does work, and that's how Dolly the sheep came to be successful. So, it's not entirely clear to me why they wouldn't have tried that. I think it was technically more difficult. But that seems to be the explanation. So, you're quite right. It took about forty years for this essentially similar result, in many respects, to be obtained.
I gather it was out of industrial experimentation as opposed to coming out of university science. Is that so?
Dolly the sheep? Well, I'm not so sure that that's right. I don't really know whether -- perhaps that is [right, but I've] not really asked. It came out of an institute that had a lot of industrial support called the Roslin Institute, but I don't believe that they were being told, "We want you to do this work because it's going to be profitable." I don't think there was a perceived profit. It was more that it was exploratory work with animals, hence the sheep, not a mouse.
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