Albert Lasker
Basic Medical Research Award

An Interview with Martin Evans
Interview by Virginia Papaioannou

Virginia Papaioannou, Professor at Columbia University, interviews Martin Evans, whose discovery of embryonic stem cells provided the techniques necessary to manipulate the mouse genome with exquisite precision.

Date of interview: September 20, 2001

Papaioannou: Hello, my name's Virginia Papaioannou. I'm a professor at Columbia University, in the city of New York. With me here today is Martin Evans, who is the director of the Cardiff University School of Biosciences and one of the co-recipients of the Lasker Award in the basic biosciences. Martin, very good to see you again.

Evans: It's very good to see you, yes. It's been many years.

Papaioannou: And may I congratulate you. This is a really wonderful honor and I'm delighted to see you here in New York.

Evans: Oh, thank you very much.

Papaioannou: I remember many years ago and I'll say, probably about thirty years ago ...

Evans: I don't think we need to mention that ...

Papaioannou: ...you and I met at perhaps for the first time in Aberdeen, and at that time, I remember you talking about stem cells ...

Evans: Yes.

Papaioannou: ...and discussing it. And I wonder if you had any idea then that your work would be on the front page of all the world newspapers?

Evans: Well, probably not. But I do think that we did have the concepts and ideas right back then, and it's been a long time bringing them through into fruition. Really, the old cells that we had from tumors that we never...you and I worked together on them...we never...

Papaioannou: So we did.

Evans: ...actually managed to get them to really do everything we wanted to do. And then it was after really quite a few years of trying, it was the intervention of Matt Kaufman who produced the delayed embryos which was just the trick I needed to get the stem cells. And of course once we had them, we learned how to do them again and again. So...

Papaioannou: Were there moments in those years that were really dark moments for you scientifically? Did you think you were going up blind alleys and think that you might never reach your goals?

Evans: I think so, yes. There have been numbers of times when the funding's been very difficult, when I think probably one of the hardest times was after that goal when I had some really nice people with me...Liz Robertson, Allan Bradley, Alan Clark, among others. And really because of the funding situation, all of them had to leave and go elsewhere, and I was left really all by myself to start it all over again. And I remember one of my colleagues saying to me on one of these miserable sort of pessimistic approaches, saying, okay Martin, you've done it once. You'll never do it again. You're finished.

Papaioannou: And what brought you out of that dark alley?

Evans: I'm a basic optimist and I keep going. (Laughs)

Papaioannou: Martin, many times scientific breakthroughs are made by the lone scientist struggling away in the laboratory, and often they're made by team efforts. What, in your case...what do you think has been the most important in your career?

Evans: I don't want to be immodest, but I think it's probably been my own idea of where I wanted to go, so it probably is to some extent...it's not a lone scientist in the lab by himself, but certainly a lone scientist sometimes crying against the general mood and getting on with what I wanted to do. I've often found, particularly I find in grant applications, that I apply to do things and I'm told they're premature, can't be done, and so on. And then five years later I find everybody's doing the same thing. It's an upward struggle like that.

Papaioannou: Let's go back to long before these discoveries were made or perhaps even thought about. What was it that brought you into science?

Evans: I think I've always been a scientist. I can remember when I was four being totally fascinated with why cement should set solid when you added water to it, and I was forbidden to go anywhere near the contractors' materials.

Papaioannou: Very wise parents.

Evans: But I of course (laughs) I have the same...it's interesting, you're the same person all through, and I had exactly the same determination to go and get some cement and try it, which I did. And I can remember that to this day.

Papaioannou: But you didn't become a physical chemist, you became a biologist.

Evans: I started off going to become a chemist. Chemistry, organic chemistry is the thing I really loved. But I moved then toward biological sciences firstly, in my high school, just as sort of ancillary subject, and then at Cambridge University, when I became very interested in botany and in biochemistry to go with it, and eventually moved from the chemistry stream I was in, to a biochemistry stream.

Papaioannou: Were there certain people who helped you along the way, or perhaps...

Evans: Oh yes. I remember my tutor there, David Coombs, who was a lovely man who certainly helped me along, and the other people I remember really are...it's quite interesting. I became very interested in messenger RNA and how it worked and during my final year, Jacques Monod came and gave a series of seminars in Cambridge about the famous work of induction of Lac-z. And that was a revelation to me. I hadn't heard about that at all before. Then of course we also had Sidney Brenner who put on...at that time, our main course didn't cover these things...but he put on a special seminar series in his rooms in Kings, which was packed and we all sat on the floor. He gave the first couple of them and then he had his postdocs prancing around and giving us the rest of them. But all of that, you know, what the code was, then how it was being expressed, was coming out at the time I was just finally graduating.

Papaioannou: And some wonderful personalities teaching you.

Evans: Oh yes.

Papaioannou: Were there special heroes that you had any time in your career, perhaps when you were younger, who were scientists?

Evans: Yes, but I think it's so difficult to nominate individuals here. One of the interesting things...I looked through the Lasker Awards, the previous laureates, and really that represents a pretty good list of my heroes.

Papaioannou: Martin, now that your name is on this illustrious list of Lasker Award winners, what does this mean to you? How does it affect your work and how you're going to go about your work?

Evans: The most important thing it means to me is recognition. As I was saying earlier, to some extent I've always felt that there's the line of soldiers marching by and I'm the only one out of step, and my proud parents are saying, "Look at Martin, he's the only one in step." But to some extent, I've always felt a little bit of an outsider, and it is very solid recognition. It's recognition that comes out of the blue. I had no idea I was being considered for this, and it comes from a very important jury, an international jury.

Papaioannou: Is there one experiment that you can think of that you're especially proud of, that you've done, that may not be the one you're winning a prize for...but are there certain experiments or lines of work that you are most proud of?

Evans: I feel that the research I've done was standing on the shoulders of giants before. And I would be particularly proud if I felt that my shoulders could be part of that chain.

Papaioannou: What a wonderful image. What do you think the most important applications of your work are? What will those people standing on your shoulders actually be doing?

Evans: I see it at the moment, this snap in time, as two-fold. First of all, it's extremely important that it has provided a route to experimental genetics and this has allowed us to really have the methods of checking our ideas about what the genome really does in the real world, actually in a living organism—and of course being mice, this refers very solidly to human genetics.

I think a great deal of fundamental knowledge and information is coming out, is already flowing out of this—going to illuminate our understanding of human genetics and will have a big impact on human medicine.

The other side, which hasn't yet been worked on very much in mice but is so important with the human embryonic stem cells, is that these cells are pluripotential—they have the ability to develop into virtually any different tissue. And what we need to do is to study the ways of controlling this so we can have, for instance, replacement heart muscle cells. And I think that the other side—this potential for human cell therapy is going to become extremely important. I'm very pleased that it leads onto that as well.

Papaioannou: With the current administration essentially putting the brakes on human stem cell research by limiting the derivation of new cell lines, what do you think the policy will do to the pace of this kind of science?

Evans: To be honest, I think it's well balanced. There is...in the States, as you know, this very...to my mind...peculiar distinction between federally funded research and research in general. And there's one rule for one and one for the other. In Britain of course, we have one legislative system that covers any research, and this has been carefully set up now to allow human embryonic stem cell derivation with all the checks and balances in place. I think that what's been done here in the States is to say yes, the work can go ahead on that very important middle piece between derivation and therapy. And that's going to allow most of the important work that's needed right at this moment to take place. It may well not inhibit future benefit, if such there be.

Papaioannou: But might it designate the geographical areas where that work is done if different countries have different restrictions?

Evans: Sadly, yes.

Papaioannou: This Lasker Award is a shared award between the three of you. I'd be interested to know what your contribution was and how it relates to the work of the other two nominees.

Evans: What I did was to discover embryonic stem cells and to develop them into a method for taking genetic modifications through to the germ line in mice. The other two awardees have both developed the method for very specific gene alteration in cells in tissue culture. I provided the cells and tissue culture, which would allow us to put this all together and get an experimental genetics in mice.

Papaioannou: Now these cells are very special cells. They're embryonic stem cells. Can you just explain what an embryonic stem cell is?

Evans: Well, I'll try to. During development, we all start from a fertilized egg and that single cell...I should say that we're made up with millions of cells, skin cells, bone, muscle, hair, the lot. And they all have specialized functions. The original embryo has to...the cells have to divide and divide, and some of them become specialized in one direction, some of them in another. Interestingly, the embryonic stem cells represent some cells of a very early embryo, something like a tenth of a millimeter in size, where these cells still have the ability to go in any way. Interestingly, we can keep them marking time. In a normal embryo, there's an...inevitable time progression going on, but taking them out into tissue culture, into the Petri dish, they're marking time. And we can keep these cells, still with their ability to develop in any way, as millions and millions of cells, in our Petri dish.

Papaioannou: And we can now do this not only with mouse cells but with human cells?

Evans: Yes, we can. Recent developments have shown that human embryonic stem cells, which to all the degrees that we know so far, are virtually identical in their abilities to the mouse cells. Now with human cells, we can't and wouldn't want to do the genetic experiments what we're doing with mice. But these cells have another very important property or potential. The property is just the one I've described, that they will differentiate into any different type of body cell.

In the case of the humans, this provides the possibility of a cellular-based therapy. For instance, somebody with a heart attack may have lost so many of the heart muscle cells the heart cannot continue to function normally. You can make heart muscle cells from embryonic stem cells in the Petri dish. The trick's going to be to be able to make the right cells at the right time, suitable for the individual, and then to develop therapeutic protocols from that. So there's a very exciting future there.

Papaioannou: So basically what you're telling me is that there are two quite distinct avenues that stem cells are now used for ...

Evans: Yes.

Papaioannou:...and they are...would you like to explain?

Evans: Yes. Well, we have first of all the basic fundamental science. We now know for virtually all of human genetics in outline terms. But we know very, very little about what all these genes do. Something like 40 percent of the genes there's no known function for as of yet. Something like, I would say, 80 or 90 percent of them we really don't know what they do. And when I say we don't know what they do, I mean in the context of the whole organism, the whole human, mouse, whatever.

And really the experiment to find that out is an experiment which we can only do on something like a mouse where we can say "suppose that gene were not functioning or were functioning in a different way. What would happen?" And those are the experiments which we can now do in mice and are going on very much, and are providing us with the fundamental background information about what genes really do in a real living organism.

Papaioannou: So the mouse can serve as a model, if you will, for learning about other animals such as humans.

Evans: Absolutely. The mouse is proving to be really quite a useful model for humans. The genetics are very similar.

Papaioannou: Martin, when you return to Cardiff, what will be the first thing you will do when you get back into your lab?

Evans: It's interesting you say get back into my lab. The first thing I will do when I get back into Cardiff is go to a celebratory dinner for this Lasker Award. When I go back into my lab, I'm hoping that I will have confirmed funding for my next series of experiments that I was telling you about.

Papaioannou: What areas of basic stem cell research do you find the most interesting?

Evans: Well, what I'm doing at the moment...and obviously I always find what I'm doing at the moment the most interesting (laughs)...is I'm going back to looking at the stem cell differentiation in vitro. When I started the whole thing, I really wanted to have a tractable system to study early cellular development and differentiation. To some extent I've been side tracked, and everybody else has, too, with the experimental genetics appeal of these cells.

However, they have this ability to develop very much as an embryo, and we now have the tools which we didn't have before, of being able to study expression of all...for virtually all the genes in the organism—parallel "transcriptomics." I'm therefore embarking on a study of comparing and contrasting between the embryonic stem cell differentiation and normal embryo differentiation in terms of the transcription of genes that is controlled.

And I think the exciting thing is that of course with the embryonic stem cells, there are upcoming rapid methods for closing the circle between observation and experiment. We will be able to knock down, for instance, expression of some genes and then see what effects this has in a global sense. I'm very excited about that.

Papaioannou: Do you see direct applications of the basic research that you're doing to medical science?

Evans: Absolutely. Yes, certainly.

Papaioannou: Can you explain some of the connections that these might have?

Evans: Can I explain the connections in terms of the stem cell differentiation? We need to not only understand how to get it to go, how to control it and how to recognize the products, but we also need, if we're ever going to have this as a therapeutic route, controls for knowing that in a particular case the cells are behaving properly. And one of the best methods is some form of analysis of their transcription, their differentiated state.

I think we'll probably find that DNA chips are going to be used to say, yes, this is a perfectly good whatever cell, it passes all the tests, and off it goes.

Papaioannou: Martin, do you have advice for young scientists?

Evans: Yes. The simple advice is hang in there. I think it was actually easier when I was there, because there was more core support than there is now. I was able to spend six or eight years getting my systems established before I really needed major grant funding. Now, sadly, this isn't so easy these days. But I think hang in there, have a vision, have confidence, go for it, say what you think, not what you think people want to hear, and good luck to you.