Sir John Gurdon Interview: Conversations with History; Institute of International Studies, UC Berkeley
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What directions then did your research take after this? Help us understand that, and then we'll talk a little about what you were lecturing about here at Berkeley.
The fundamental question I've always been interested in [is], how does an egg make another one? It's an extraordinary process, I should emphasize, because no one tells this egg what to do. [It's] just one cell, and somehow it knows how to make another one. How is that? We were satisfied then that that's not by any loss of genes, the genes are there, so something must weed the genes, decide which genes to read and which ones not to.
That then took me off in a number of directions, much of which I talked about yesterday, which is what kind of thing tells a cell that it must read one gene, not another. That was how we got into what I call morphagen gradient signals that come from another cell and say, "I want you now to read that gene, not another one." That then was a large part of my mid-career and dealt with the morphagen gradient community effect, signaling, and so on.
Much more recently I've gone right back to the original question of how is a transplanted nucleus re-programmed, what I'm going to be talking about today. I see that as all connected. It's all the same question, just going off one direction and then coming back to the same one, perhaps another direction, and still going back to the same question, to try and understand ultimately how this happens.
Yesterday I noticed the headline on the slide which you were showing was "Cell Commitment to Future Development." Now that I know you were a classicist, I think [the term "commitment" is particularly interesting.] Let's talk a little about that, because you were telling us four ways that a cell, after formation, would commit to a path of development. What are those four elements?
One of the things which you certainly absorbed very well, and which I refer to again today, is this surprising fact that when a cell begins to set out on its career and pathway to become something like skin or muscle, at an amazingly early stage it refuses to change direction. Even within a matter of hours, it says, "I'm going in this direction, I'm not going to go in any other direction, as long as I'm left as a whole cell." So, inside that cell it's re-instructing itself to keep going in this direction, won't take another pathway. The point that I will make today is that if you then take that cell apart and take the nucleus away, then it's completely happy to change direction. So, it's a surprising contrast between a whole cell which is committed to a particular pathway, hence commitment, as opposed to the individual parts of the cell which are not.
In this initial process you identified four elements that set it on this path. To repeat them, the pre-fertilization controlled development, asymmetric cell division, signaling between cells, and then what you call a community effect. Summarize that for our television audience. What you have is a set of processes at work that say, "You're going this way, fella."
Yes, that's right. That's exactly right, what you say.
A surprising thing is this egg which is -- you know, we eat a chicken's egg or see frog eggs, but the egg before it's received any sperm already has a fair amount of information in it. In fact, it's taken in many cases as much as a year to make that egg from a very specialized cell. Already, a part of the whole of our life is determined before fertilization. So, that's point one.
The other things I emphasize: this asymmetric division is a way of, again, telling cells to choose one pathway as opposed to another. And then of overall importance is this signaling by which a cell receives molecules telling it which way to go, of which the community effect is a variant. So, it's a progressive process, that's a logical way of viewing it, with four steps that are fundamentally responsible for deriving a thing like a heart or a brain cell from an egg.
Now the humanist in you made the comparison between the phrase "faith, hope, and charity, and of these the most important is charity," and you turn that around to say "space, time and concentration," with concentration being the most important. So, these are the factors that set us on this course.
Yes. I've increasingly become intrigued with how precisely things work. Let me give you an example. There's a phrase called "haplo-insufficiency syndrome." What that means is that you and I have one gene inherited from our mother and one from our father, so we have two genes that should do the same thing. Sometimes things go wrong and one of them isn't any good, so we only have one. Now amazingly, in a number of cases, if you have one copy of a gene instead of two, things go wrong. That means that a factor of two difference makes an enormous difference, and indeed other experiments refer to factors of three [that] make a huge difference.
Everything in us is regulated to an extraordinarily precise degree in actual concentration. When you go into this in detail, as much of my career has been involved, it turns out that the single most pivotal component in making things work the way we do is the concentration of things. That was why I chose to emphasize that point.
Talk a little about this reverse process, which you're going to be talking about this evening. I haven't had the fortune yet to hear that lecture, but what then becomes the implication for all this work in stem cells? What might we achieve with that?
What I will be saying is that if you take the nucleus, genetic material, out of one of these cells that are quite clearly committed (they know what they're going to do and nothing will change it), but [when] you take that nucleus out and put it into the egg, then that essentially rejuvenates that nucleus in most cases. What I'll show is that you can take a cell from an adult, put it through this process, and it then essentially forgets everything it knew about following that pathway, and starts life again.
There are things called stem-cell-gene genes which mark the fact that it's gone back to the beginning of life again. That in a sense creates a stem cell, because if you go right back to the beginning of development, the ultimate stem cell is an egg because it can form everything at all, totally potent. We create these universal stem cells by this procedure. That's why I refer to my talk as "from egg to adult and back again," take it right back to the beginning again. Of course, if we could make that work really efficiently, I do believe this would give the opportunity for cell replacement in humans.
So that one could use one's own materials to actually make repairs?
That's absolutely right. Yes, that's right. The key thing, which I haven't said yet, is that in terms of replacement all of us eventually would welcome some replacement of parts, you'd really like to have cells of your own genetic constitution. So, you can receive cells from other people but you may know that if you do, you have to be subjected to what's called immunosuppression. It means you can't reject the cells, and of course, you also can't reject any infections that you get. So, immunosuppressed people are quite disadvantaged. In an ideal world, we would give ourselves rejuvenated cells of our own genetic constitution. And this whatever-you-call it, cloning, or anything like that, is actually the only efficient way in which you can hope to derive rejuvenated embryonic cells from your own adult cells.
What are the big obstacles to achieving this, both in terms of a lack of information, or [other factors]?
The big obstacle is that it works, but not very well. That's the fact of the matter. When you do this you sometimes get amazing results, like I mentioned -- the adult animal derived from an embryo cell, or Dolly the sheep derived from mammary glands. Spectacular, and it can work. But the efficiency with which it works is actually extremely low. That is the reason why my own work, for example, is completely committed now to trying to understand the molecular mechanism of how it is that you rejuvenate a nucleus, send it back to the beginning again. My view is that only if we understand that mechanism can we hope to make this work efficiently enough to actually be useful in a therapeutic sense.
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