James Thomson Interview (page: 4 / 8) Father of Stem Cell Research	Print Interview

For the lay person, can you describe how you make a stem cell into a particular neuron?

James Thomson: Yeah. There's things called growth factors, which are little proteins that sit on the receptors of cells and do things. By adding different combinations of these growth factors, you can make them go in different directions, because they make different decisions, depending on what they see in their environment. So there's a specific group of growth factors that makes them go neural. And then those specific growth factors will make them grow into specific kinds of brain cells. So usually they're cultured in these tissue culture dishes, with this pink fluid, and you add things to that that make them go in specific directions.

Cool!

James Thomson: Yeah, it is cool! The fact that you can have a cell that lives forever that forms anything in your whole body, it's just really neat. The typical cell in your body doesn't do that. If you take the cells from your skin and just culture it, it'll go 60 or 70 doublings and then stop. It undergoes something called senescence, and that's it. Embryonic stem cells just keep going. So there's no limit to the number you can make.

Do we know why?

James Thomson: There's a lot known about why that is now.

Get the Flash Player to see this video. It kind of makes sense that your germ cells, way back when, wouldn't have any limits to the number of times things drive them and could replicate. Otherwise, you know, if an 80-year-old man had a child, that child would be in trouble, right? So in the early embryo, the ability to divide forever is there, and then it's shut down probably to prevent cancer so that your adult cells don't have that. Embryonic stem cells are at such an early stage that they still have this ability and it hasn't been turned off yet. And there's a fair amount known about the genetics of how that works now.

Let's talk about the latest innovation in terms of using adult stem cells rather than human embryos.

Get the Flash Player to see this video. James Thomson: Dolly was cloned in 1997, human embryonic stem cells were derived in 1998 by my lab. And people put those together pretty fast. The idea was that if you took a skin cell from your body and put it into an oocyte, and grew that product up to the point you could make a stem cell line, that stem cell line would be completely matched to you. And then if you want to do transplantation therapy, there'd be no immune rejection, no immunosuppressive drugs. It'd be just the perfect match for you. And what Dolly taught us -- I never thought that was practical myself. The making a commodity out of women's ovaries basically is -- a lot of ethical issues there. But the economics of it was just horrendous, 'cause it took 300 nuclear transfer events to make one Dolly. And the number of oocytes you can get is very limiting. So there's no biological reason why you couldn't do that the way Dolly was done, to make a stem cell line that was matched, but I thought the economics would just never be there.

Could you elaborate?

Get the Flash Player to see this video. James Thomson: There's over a million people with Parkinson's in the United States. So you would have to make a million cell lines. And if you need 100 oocytes per cell line, you need 100 million oocytes. There's simply no source to get 100 million oocytes. It's just not practical. And to get them, there's a procedure which puts women at a certain amount of risk, deriving hormones and things. So I just never saw the economics as being such that my HMO would pay for it. And if my HMO won't pay for it, then the average person in the United States doesn't have access to this therapy. That's not to say that it wouldn't work. I think it would work, and I think that it could be done. But I always thought the technology would go around it. The real message with cloning a Dolly was that the differentiated state could go backwards. We never thought that was true prior to Ian Wilmut's work.

How do you mean?

Get the Flash Player to see this video. James Thomson: Usually everything kind of goes with this forward arrow of time. You start with one cell, it goes to two-cell, goes to four-cell, and they undergo this very exquisitely choreographed program of differentiation. And it's always that way, it's going from simple to complex. And a cell in your body doesn't tend to go backwards. It doesn't do this at all, naturally, as far as we know. But Dolly showed it artificially could happen. And it meant that there's something in the oocyte which hadn't been identified that was sufficient to make things go backwards. And it was only a matter of time before scientists could tease out what those things were. And when we started this work about five years ago, the post-doc that ended up doing it, I hired her, and we talked about it, and we thought it was like a 20-year project. We thought it would be very complex, that it'd be ten to 100 different things we'd have to work out. Nonetheless, she set up a screen to look for things that would allow this reprogramming to occur. And it turned out to be extraordinarily simple. We were doing this at the same time Shinya Yamanaka was, but he beat us to publication by a fairly wide margin in the mouse. He showed that in his system four factors were required. We did this independent screen with human material, and we came up with four factors also, but it was a different set of four factors. It's really astounding that such a small number of factors can make things go backwards like that, and really unanticipated. I've certainly thought it wouldn't happen. That's why, in fact, we did the experiment. I thought it would fail. And I thought it would give us some insights in how we might go forward, but I didn't think it'd work that easily.

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