Interview: James Thomson
Father of Stem Cell Research

To start with, maybe you could explain exactly what a stem cell is and what it does.

James Thomson: It's actually pretty simple.

A stem cell is something that can make more of itself, and it can give rise to something else. So in your skin, if you go out and get a sunburn today, part of your skin actually sloughs off, and it's the job of the stem cells in your skin to replace those cells. It lives at the bottom of your skin. And in the adult, cells either make one or just a few different cell types, these stem cells. But if you go back early enough in the embryo, there's a cell that can make everything. And in the intact embryo, it's actually not technically a stem cell, because when it goes off and makes everything, it goes away. And a stem cell is supposed to be something that will replace itself. So it's really a precursor cell. But if you take it out of the embryo and you put it in tissue cultures, conditions that are just right, it'll divide and replace itself, as far as we know, forever. And yet it maintains the form of everything in the whole body. And that's what an embryonic stem cell is.

What a powerful little thing.

James Thomson: Yeah, it's remarkable. It means we have access to the human body for the first time, because there's a lot of parts of your body that we can't culture, which means we can't study it in detail, which means we have to rely on mouse models. And as much as those models are different, it's wrong.

Before you succeeded in cultivating human embryonic stem cells -- ES cells -- you worked with primate stem cells, didn't you?

James Thomson: Yeah. We have to go back to the monkey one, 'cause that was actually more important biologically.

We published primate embryonic stem cells in 1995. Mouse embryonic stem cells had been derived back in the early '80s. And a bunch of groups had attempted to do this in other species and failed. At the time we were starting to do this, it wasn't known whether it was just something funny about the biology of the mouse that allowed this or whether eventually it could be successful. So we really didn't know whether it would be successful or not. It turned out that the older conditions that were used for mouse ES cells allowed primate embryonic stem cells to be derived. But the specific factors -- we were just lucky we got it right, because they're all different than the specific factors for mouse cells. So you typically grow -- in the old days you'd grow mouse embryonic stem cells in feeder layers, and they'd make stuff that the cells like. But the stuff that the mouse ES cells like and the human embryonic stem cells like are entirely different. So it was just lucky the system worked. So we derived primate embryonic stem cells, and that showed that this could be done.

So cultivating the primate stem cells was the big breakthrough. What happened next?

James Thomson: So we derived primate embryonic stem cells in 1995, and that showed that this could be done in a species other than the mouse. And given the evolutionary relatedness of humans and primates, we thought we could apply this to humans. So in 1995 I talked to some ethicists on our campus about how we would do this. And we were very fortunate to have two very good people on campus, one who's named Norm Fost, who is the head of our IRB (Institutional Review Board), which is the Human Subjects Committee you have to go through. And the other one is Alta Charo, who's a lawyer that had sat on some national panels dealing with ethical issues and human ES cell -- human embryo research, not human ES cell research -- and discussed how we would do this in an ethical way, and I did a lot of thought about whether I wanted to do it. And then finally we did the consent forms and we did it.

You've said that you had qualms from the beginning, because in your work with the human embryo stem cells, you necessarily destroyed the embryo.

James Thomson: I wouldn't say qualms exactly.

I had to do a lot of soul searching about whether this was something I wanted to do. It's actually a fairly complex issue, but what it comes down to for me is fairly simple, is that the way in vitro fertilization is currently practiced, embryos are made that the couples ultimately don't want. And sometimes because they've had the family that they want, or whatever reason, and they have to come to a personal decision of what to do with those embryos. In our case, they had the option to donate to some other couples if they wanted to attempt to have babies. They could simply discard them, or they could donate them to research if they want, through this consent process. So for the embryos we use, they would simply have been thrown out had not they been used for this research. And for me it would be a better thing to do that than to simply throw them out, since there is a great deal of value to doing this research.

Potentially saving many, many lives.

James Thomson: Yeah, and again, if the decision's already been made that otherwise they'll be thrown out, then it's not like if you didn't do this research those embryos would be saved.

Did you anticipate this being such a huge political issue?

James Thomson: Yes and no.

Dolly had been cloned in 1997, and everybody had been tuned up for this story. And I could see what happened to Ian Wilmut, so I was quite aware what I was getting into. What I didn't anticipate is how long it would last, because it's ten years now and it's still a politically viable story, right? I thought people would get tired of it mostly in three months, and by six months they'd be thinking about something else, and now we're ten years into it. So the political process in the election of George Bush stretched it out a great deal, much longer than I anticipated. I also thought it would be a lot nastier. People were very civil in Madison, Wisconsin. Madison itself is very liberal, but we're in a very conservative state. Nonetheless, the discourse is very civil, and I appreciated that.

Did you have any personal confrontations about this?

James Thomson: Yeah. People would approach me on the street now and then. But like I say, it was pretty civil. It was never violent.

What about your friends and family?

James Thomson: They were mostly supportive, actually entirely supportive. And like I say, Madison is kind of a little bubble that's not in tune with the reality of the rest of the country. It's an academic community. It's liberal, it's been very supportive. The state as a whole has been mixed.

So let's talk about how you actually cultivated the human embryonic stem cell.

James Thomson: You have to remember...

Back then it was illegal to use federal funds for the derivation of these cells, and still is. And the university was extremely nervous about what I was doing, because I could lose all their federal funding. So for a variety of reasons... so I didn't have federal funding and the university itself would not fund it. So a small company offered to fund it, and I didn't have any choice, so I took that funding. So we set up a small lab that was completely devoid of anything that was bought with federal dollars, and I physically did all the work myself, so it would protect other people around. So over a course of I guess about nine months or so, we derive these cell lines. And everybody asked like whether there's this "Aha!" moment that was exciting and all. The reality is pretty much no. It's just kind of this long, drawn-out process, where you kind of think you have the right thing, and it takes several months, little by little, to increase your confidence. So there's no single moment. And at the time that it was all done and it's finally published, instead of being happy, it was more like relieved that it was done after all this work.

Did you ever have doubts about it?

James Thomson: Prior to starting it, I doubted that we'd be successful, especially part of the primate stuff, because part of the primate stuff I really didn't know whether it was possible. At the time we did the primate work, my confidence that this was possible was fairly high. I had doubts whether we'd get there first, 'cause a lot of other people were trying to do the same thing.

It seems to be the case very often in science, that researchers working miles apart get the same results at virtually the same time. Why is that?

James Thomson: I don't know.

It seems that some things are just ready, you know. There's enough infrastructure of ideas that that next step is almost inevitable. And it's often two people on the other side of the world that do it on almost the same day. And it happens fairly routinely. It's curious. So in this case Junying Yu published very similar cells from a different source within a week. And then more recently, Shinya Yamanaka did a reprogramming paper which came out on the exact same day as ours. And usually that happens often.

Were the possible applications of stem cell work to medical research immediately clear?

James Thomson: Yeah.

I think if you looked at original primate work, we pretty much laid out all the stuff that people have been saying. I mean, there's fairly simple categories. One is it gives you access to the human body, which I think is a big one. It's not transplantation. It means that you can study the development and functions of all the bits of the human body for the first time. That's the big deal. And one of the things you can use that for is drug screening. Another thing you can use that for is transplantation. And that was pretty obvious from the beginning that all that was true.

Stem cell research offers some hope for understanding diseases like Huntington's and Parkinson's, doesn't it? Could you explain that?

James Thomson: Yeah, so there's hope, which has been kind of hyped in the press for transplantation for all range of diseases, including neurological diseases like you just mentioned.

I think it's good to be skeptical. I think that there's going to be tremendous parallels between the early days of recombinant DNA and what's happening in stem cell biology, because there was the same kind of social uproar in the early '70s, followed by legislation and compromise and getting on with it. And people predicted things like gene therapy would be here, right? And it's not yet. And I think if you think about all the things that were said about gene therapy over the year, and put stem cell transplantation in the paragraphs, they're the same thing almost. It's not to say that they won't be useful in that way, either gene therapy or transplantation, it's just going to take a lot longer than people are letting on at the moment. That being said, with the recombinant DNA, people underanticipated how it completely revolutionized all of biology and medicine. It's a research tool that's pervasive everywhere, and including fields that we had no anticipation that that would happen.

Do you think that stem cell research will have an impact comparable to that of DNA?

James Thomson: It's going to be a pervasive tool that anybody that's interested in the human body and human medicine is going to use. And they won't call them "stem cell biologists" anymore, it'd just be a tool they happen to use, as many other tools. And I think that's going to change human medicine a lot more than this transplantation, because for Parkinson's, for example, there are people that think that transplanting dopaminergic neurons -- that's the neuron that dies in Parkinson's -- will treat or cure that disease. I hope they're right, but there's a good chance that's going to be very hard. Nonetheless, this is the first time we had those neurons in our hands. And it means that we can finally figure out why they're dying. And if you understand why they're dying in the first place, then you shouldn't have to do something as crude as transplanting cells back into the human brain. Hopefully, something like a small molecule will arrest the progression of the disease once we understand the mechanism. So while I'm skeptical whether transplantation will happen anytime soon, I'm not at all skeptical that over my scientific career, we'll have a much better treatment for Parkinson's based on using these cells to understand the biology of those cells. I think that's true about the human body as a whole, is that in some cases, transplantation will work. But for the most cases, you don't want to do that in the first place. You want to make it so you don't have to do the transplant.

You think we might learn to prevent these diseases?

James Thomson: Yeah. And for tissues that we didn't have access to before, this gives us that new access.

To what extent can you control what an embryonic stem cell turns into? Can it be directed?

James Thomson: Over the last ten years, people have gotten fairly good at that. You can't make everything, but you can make a wide variety of specific cell types now pretty reliably.

How?

James Thomson: There have been a lot of developments of biologists trying to figure out how that happens normally. You can somewhat parasitize that bulk of knowledge from all these other model organisms, whether it's mice or zebra fish or whatever, and a lot of that transfers. Not all of it, but a great deal of it does. So for neural differentiation, people today can already make dopaminergic neurons, can already make motor neurons -- which is what gets killed in Lou Gehrig's Disease -- reliably, in very large numbers. There's other tissues that are harder, but I think over even the next decade, we'll be able to make essentially all the clinically relevant cells in the human body, in essentially whatever quantities you want. But I also think over the next decade there'll be very few successful transplantations and therapies based on these cells.

Do you mean it will take longer?

James Thomson: Yeah, I think so.

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.

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.

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?

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?

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.

Your breakthrough with adult stem cells came more quickly than you expected. So maybe there was an "Aha!" moment there?

James Thomson: Yeah, maybe a little bit more. Because right into it, that's what human embryonic stem cells look like at that point. We were pretty darn sure that they were the right thing at that point.

Were you with your post-doc when that happened?

James Thomson: No. See, there's never a moment. It takes so many weeks, and they look a little bit better. It just doesn't work that way.

You didn't get a call in the middle of the night?

James Thomson: No, it doesn't work that way. So from the time she dumps the transfectionary agents on the cells to the time you actually get a colony that looks half-way decent is like three weeks. And all the way in there you kind of have this gradation of things looking slightly better. You kind of stare at it and hope it looks good. So it's kind of a continuum rather than a moment.

How do you see the ethical implications of this work with adult stem cells?

James Thomson: I think they're huge. First of all, you have to make the caveat that it's not clear that they're equivalent to embryonic stem cells, but they really, really look like it. There's some technical things we need to do to make them more equivalent. The way we make them, genes are actually inserted into the DNA of the host cell, and that's not good. But there are ways around that.

Why isn't it good?

James Thomson: Because every time you insert a piece of DNA into the host cell, it could disrupt an endogenous gene and that can cause bad things: mutations, cancer. So it'd be better to do it in a way that it doesn't actually insert into the genome. There are several ways of doing that, and a lot of people are working on that now. But assuming that we can remove those and not have them actually integrate, it really looks to me like they're the equivalent of embryonic stem cells. Over time, I could be wrong. But my belief is that embryonic stem cells will be used less and less now, and these will be used more and more. There's a huge number of people jumping into the field right now, much more than there was ten years ago with human embryonic stem cells, given all the ethical issues.

There wouldn't be government bans on this.

James Thomson: No, George Bush likes this.

How do you harvest these skin cells?

James Thomson: We got them from a company that banks them. But normally it's just a little sponge biopsy. So it's a very simple procedure, wouldn't be a big deal.

And isn't the cost much lower?

James Thomson: Yeah. I haven't actually done it myself, but it's simpler than getting blood, 'cause blood you have to be there for quite a while, and a sponge biopsy's real fast.

I would think that would be a tremendous relief in your field.

James Thomson: I don't know if relief -- there's a lot of excitement about it. And it's not simply that we found a replacement for embryonic stem cells from a less controversial source, but the idea that you can actually change the identity of a cell by this fairly simple manipulation is really big. And it goes beyond making embryonic stem cells. I think what you'll find over the next, say, five years is there'll be a bunch of papers showing similar screens for looking at changing cell types directly between two different cell types, not going all the way back to the ground state, but say making a skin cell directly into a liver cell, for example. And prior to this work, those screens didn't make a lot of sense, 'cause again, people thought it'd be too complex and couldn't possibly work. But my guess is there's going to be a lot of those screens done now. And people will find ways to change the basic state of your cells in your body to different fates.

You mentioned the possibility of turning one kind of cell -- say, a skin cell -- into another, such as a liver cell. What would be the medical implications of a breakthrough like that?

James Thomson: The possible implications long-term is that when you think about a truly regenerative medicine, you don't want to transplant stuff, you want to give the body something so it repairs itself in a way it will not normally do. And that repairing in a way it will not normally do is based on cells changing their identity. And this means that an identity which is usually very stable can be changed artificially. So in a heart attack, for example, it'd be nice if your heart cells would divide and repopulate the heart and not just simply form heart tissue. This gives us an inkling that that's probably likely to be true someday.

We've heard a number of medical scientists talk about the future of medicine being preventive and predictive. Do you see it that way?

James Thomson: Yeah. It may or may not be true in this case, but say Parkinson's, for example. We don't know why those neurons die, but if we understand precisely why they die, you could probably look at the population and prevent whatever that was. If it's not clearly genetic, it's something else. There's probably something environmental and you have to understand what that is. Then you potentially don't let it happen to that person in the first place.

How do you go about that?

James Thomson: It's not clear, but if you have the neurons that are killed, the dopaminergic neurons, you can look at all the factors that keep them alive and healthy, and come up with ideas of what makes them unhealthy. Precisely how that's going to happen, I don't know. I'm not a neurobiologist. But simply having the normal cells at hand gives you tremendous opportunity to understand what goes wrong when they're killed. Not having that material, you can't do anything.

Will you be able to recognize a Parkinsonian cell?

James Thomson: You can recognize the normal common part of the cell that's killed in Parkinson's disease, and try to understand what keeps it healthy and happy, to come up with ideas which can go wrong to make it not healthy and happy.

How do you manage to have such patience in a field that has such thrilling implications for all of us?

James Thomson: So biology, there's simply a rhythm of the material you work on. And you can't change it. You can't change it by having a lot of hands doing things in parallel, which is happening right now in this field. But these cells divide about once every day. So if you want to make one cell go to a lot of cells, it takes some time, right? So I think you just get used to what you can do with your system, what you can't, and just live with it. And pushing harder doesn't always work.

Do you come from a family of scientists?

James Thomson: No, my father is a CPA, and my mother worked at a university as an assistant. So there was nobody in my extended family who was a scientist.

When did you first feel an interest in this field?

James Thomson: I think every little kid's a scientist. And for some kids it goes away, and some kids in doesn't. In my case, it just never went away.

You grew up in Oak Park, Illinois. What was your life like there?

James Thomson: I guess it was a pretty normal childhood, normal school system. I liked school. I liked science and math as a little kid and just kept pursuing it.

Were you into sports at all?

James Thomson: I didn't like team sports. I liked individual sports. I like tennis a lot. I was a pretty good runner, too.

What about books? Do you remember books that you particularly enjoyed growing up?

James Thomson: I read a lot. I can't say I can think of one off the top of my head that inspired me.

What fields were you reading in?

James Thomson: Just general novels and things.

When did you decide to go into the field of science professionally?

James Thomson: That's a hard one, because it was kind of a continuity. By the time I hit college, I certainly planned to go into science, although I didn't know precisely where I was going. Little by little I found the things I liked in college and pursued them. But I could have pursued computer programming or mathematics or something else at that point in my life.

You got a biophysics degree first, from the University of Illinois. At that point, were you already interested in embryonic development?

James Thomson: Yes. My talent was in math and physics so I studied mostly math and physics. Then I had a biology class with a very influential mentor in my life, and I decided to go into biology. He's the one that introduced me to developmental biology, and I just thought it was really neat.

Who was that?

James Thomson: His name is Frederick Meins, and he was a teacher at Illinois just for a couple years. Then he moved to Switzerland to a place called the Friedrich Miescher Institute, and he was there until he retired.

What was he doing there?

James Thomson: He came out of Rockefeller University, and he studied something called crown gall. This is a cell similar to embryonic stem cells that is from a plant. It can be in an undifferentiated blob, and if you add the right chemicals it would form leaves or roots. It's basically the plant world's equivalent to embryonic stem cells.

Did you immediately see that this had implications for human beings?

James Thomson: I wouldn't say that. I just turned on to biology because I thought it was neat, and he introduced me to some of the literature in mammalian embryology from some basic experiments that I just thought were so amazing I wanted to go into that field.

What did you find exciting about this field?

James Thomson: Well, there's one experiment I liked that he introduced me to.

If you could take an embryo that hasn't yet implanted from a mouse, and one's from a black mouse, and take another embryo from a white mouse and you just nudge them together, they form one mouse. And that adult mouse has black and white patches along it. And it basically has potentially four different parents, but it's all one integrated mouse. And I was just fascinated that embryogenesis was so regulative that you could take two individuals, put them together, and get this single individual. And that degree of self-regulation ultimately is what allows embryonic stem cells to be derived. I certainly wasn't thinking about that at the time, but I just really thought that experiment was fascinating and wanted to be in that field.

When you began your work with stem cells, were you aware of what Dr. John Gearhart was doing at this time?

James Thomson: He's a little bit older than me, but he wasn't terribly well-established in his field at the time.

At some point you decided that you needed a degree in veterinary medicine. That was a surprising move. Could you talk about that?

James Thomson: Yeah, that's an odd one that doesn't fit into my current life very well.

This professor, Fred Meins, one of the reasons he was so influential, he's just a very good storyteller and was very good at relating personal histories of scientists and what they had done with their lives. And he told me about a fellow named Jared Diamond who's written some popular books recently. But back in the '70s he was a biophysics professor, and yet he had this kind of second life where he did field work in Papua New Guinea, and occasionally would be on the front page of The New York Times for describing some new bird species or something. And that just kind of captured my imagination that you could have these two sets of lives. Plus I was already a biophysics major, and I had an interest in endangered species. The veterinary degree was for some of the practical aspects of veterinary medicine and applying reproductive technologies to manage endangered species populations. And I thought that I could combine the basic biology field of doing embryology in these species with some practical aspects. And I pursued both of those for a while, and I went to vet school because of that. And up until the early '90s I was pursuing both. And then the embryonic stem cells kind of took over my life.

You mentioned an interest in endangered species, early in your career. Where do you think that interest came from?

James Thomson: I can't say in particular. It had...

As an undergraduate, one of the places I went was to Woods Hole, and there was a lecture by a conservation biologist named Paul Ehrlich. He talked about captive breeding efforts in zoos. This was about 1980, I think, something like that. And he first dismissed it as being useless, because you need a certain number of individuals to maintain a genetic population. You can quibble about what that number is, but it's a pretty sizeable number. And if you look at the large vertebrates in the world, and you filled up the zoos with that number, you wouldn't cover very many species. I was sitting in the audience, having been just a physics biology person, and not knowing anything practical I thought that environmental people could actually freeze embryos and freeze semen. I didn't know much about that. And that very night, I went back to the house I was living at, and Walter Cronkite was doing an interview at the San Diego Zoo. And there was a woman named Barbara Durrant, with a rat in her hands who had come from a frozen embryo. It was like, "Oh, I was right! You can do that." And it was within the next couple days that I decided that having a veterinary degree would be useful to do that. And ultimately, at the end of vet school, I spent some time at the San Diego Zoo with that particular person. So that's where it dated from. It was this idea that I was interested in field work and also wanted to do some basic science in the lab and trying to bring them together in some way.

Were there particular species that you were interested in working with?

James Thomson: Yeah. It took a while, but after vet school and graduating and finishing my Ph.D., I went to the Oregon Primate Center, because at the time, they had the best access to normal primate embryos. I was interested in using primate embryos as a better model for human development. Mice are the standard model, but they're different in a lot of ways. Oregon had species from Sulawesi, the central part of Indonesia, and I got some money to go to Indonesia to attempt to dart the remnant population of males to collect semen, so there'd be a large leftover population.

Did you say "dart the animals?"

James Thomson: Yes, to anesthetize them. I was trying to get the money to do that. My post-doc was ending, and I had written this grant, and NIH told me that I came in second for whatever grants they got, and they only funded one. So I moved to Wisconsin at that point.

In addition to your veterinary degree, you have another doctorate as well, don't you?

James Thomson: Yes, a veterinary degree and a Ph.D., both from Penn, in a combined program. The Ph.D. is in molecular biology. It was structured just like the combined M.D. and Ph.D. programs, so I got both.

What did you set about doing when you developed your own lab at the University of Wisconsin?

James Thomson: When I worked at Oregon, I was interested in using primates as a model for human development, but primate embryos are very difficult to get, very expensive. The cost back then was like $2,000 an embryo. So you couldn't do 100. It was just physically impossible. So even though there were experiments I wanted to do, I was starved for embryonic material.

Who were you buying the primate embryos from for $2,000?

James Thomson: We were part of the Primate Center, and they're just costs associated with the monkeys. Ultimately the federal government was paying for it. Wisconsin also has a primate center. At the time there were only seven in the United States. So I came to Wisconsin both to do a pathology residency -- that was kind of a practical, "had to pay the mortgage somehow" kind of decision -- and to pursue a post-doctoral fellowship, specifically to derive embryonic stem cells for primates. These embryonic stem cells would provide a much more accurate model for human development than the mouse. That was the goal.

You say you took a pathology residency to make a living. What were you doing in that capacity?

James Thomson: Doing necropsies and reading slides, and doing what human pathologists do, but for the primate center. So I did that for a number of years, did all the necropsies of all the dead monkeys to figure out why they died.

So you had two jobs in a way.

James Thomson: I was the chief pathologist, and I had 50 percent of my time protected for research. And what that allowed me was incredible flexibility on what kind of research I wanted to pursue. And I made a conscious decision not to go in the normal tenure route, because you had this six-year clock and then that's that. So you're very much forced to hit certain milestones at certain dates, otherwise you don't get tenure. Because I had 50 percent of my time protected, and I had a very good job that paid quite well, I could do what I wanted. And this embryonic stem cell project was a very high-risk, long-term project. From the time I got to Wisconsin to the time human embryonic stem cells derived, it was seven years. So had I been a tenure track person, I would not have gotten tenure. So this allowed me a lot more flexibility than the average faculty job would have.

It probably didn't allow you a lot of sleep, however.

James Thomson: Yeah, it was a hard job, but again, I had the freedom to pursue what I wanted to, and that was the important thing.

What would you tell a young person who might be interested in science? What makes it so rewarding?

James Thomson: It has to come from within. So I wouldn't even tell a young person. They'd have to come to me and say, "I'm really turned on by this," 'cause I don't think I can transfer that to somebody. Now, I can give them ideas of what are cool directions to go in, but they almost have to have that already by the time I see somebody like that. I think you either have the passion within you or not, and it's not a question of just pushing people in a direction that they're not -- like, inside -- going to go.

What makes your work rewarding for you?

James Thomson: I think the cells are neat, right? I can't tell you precisely why, but I think it's good, whatever you work on, to just think it's cool, right? And I really hope it does help people someday. But it's also not the reason I go into work today and do my work. It's just because I think that thing is really interesting, and I want to work on that. But then, when I step back a little bit and look like, you know, what I want to accomplish over my career, I very much hope that what I do in my laboratory does benefit people. I think my career would be extremely satisfying if that's true, but I don't think about that day to day. Which is probably the patience thing, again, is that I'm more focused on the questions I'm trying to address and trying to do as efficiently as possible, but I'm not thinking about the direct translational benefits of my work every day.

Do you turn down a lot of interviews just so you can keep working?

James Thomson: I'm better at my work than I am at interviews, yes.

On that note, thank you. It was wonderful talking to you.

James Thomson: Well, thank you for taking the time.