Albert Lasker
Basic Medical Research Award

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An Interview with Mario Capecchi
Interview by Harold Varmus

Harold Varmus, President of Memorial Sloan-Kettering Cancer Center, interviews Mario Capecchi, whose research on gene targeting led him to provide the groundwork for manipulating the mouse genome with exquisite precision.

Date of interview: September 20, 2001

Varmus: Good afternoon. I'm Harold Varmus, President of the Memorial Sloan-Kettering Cancer Center. I'm here to conduct an interview with Mario Capecchi, professor at the University of Utah and one of this year's Lasker Prize winners.

Mario, you've lived an exciting life. You've spent many years now developing technologies that have changed the way most of us who work with mammalian systems do biological experiments, and you've made profound discoveries about development of mammalian organisms.

But the excitement in your life goes well beyond your science. You've written movingly about your experiences in World War II, in Italy, your native country, and the fact that you were, a dozen or so years later, working in the laboratory of James Watson at Harvard University. And now, only a few days after one of the greatest disasters in the history of New York, here you are receiving the Lasker Award at a fancy lunch at a hotel in New York City.

I'd like to explore some of those themes. The science and your personal experiences, which you've been very forward in telling people about, as a way of describing for people the effect of science in the life of someone who's been through some hard times. Maybe we could start with just a brief review of where you come from and what your early life was like.

Capecchi: Yes. Well, my mother was a poet. She belonged to a group called The Bohemians, who were very active in writing against Fascism, Nazism. She actually anticipated being picked up by the Gestapo, so what she did was to sell everything she had.

Varmus: Where did she live, Mario?

Capecchi: This is in, at this time, was in the Tyrol. I mean she was actually working mostly in France, when she was a poet. They moved to the Tyrol in Northern Italy, actually just before I was born. We lived there about three and a half years.

Varmus: Was your father active politically as well?

Capecchi: My father, he was a juxtaposition almost. He was in the Air Force, the Italian Air Force. And it was actually a romantic affair. She actually decided that she wouldn't marry him. And they had me though. That was actually, I think, probably an extremely difficult decision at that time. So this is in the late 1930s. So she sold all of the things she had and gave the money to a family, an Italian farming family, and then about when I was three and a half, then actually the Gestapo did come and picked her up and took her to Dachau. That's actually one of the very first memories that I still retain, is all the people coming and all the uniforms. And I had a sort of a sense that I wouldn't see her for a long period of time. Then after living with this farming family for about a year, somehow the money disappeared. They were poor and they needed the resources. So they sent me on my way. Then I started my trek essentially from Northern Italy slowly wandering south.

Varmus: Who were you with during this wandering?

Capecchi: By myself. I mean this was ...

Varmus: How old were you?

Capecchi: This is four and a half to nine. And sometimes we work as gangs. And sometimes we work alone. And sometimes we were just a small number of people.

Varmus: Where were you sleeping and eating?

Capecchi: In the street, anywhere we found. Often houses that were vacated because they were bombed out. And so that was, and that took me all the way to about year eight, when I was eight years old.

Varmus: And this is 1947?

Capecchi: And this is ... No. This is earlier. This would be 1945. By that time, things weren't going that terrific because essentially I was malnutritioned, and I was put into a hospital. I was there for about a year. Then my mother...in the spring of '45, Dachau was freed. My mother happened to survive, which is about 25 percent of the people survived the camp. She spent about a year finding me. She retraced the steps and finally did hook up with me, and then we took, we went, a week later, we were on a boat to America, because her brother lived there. And they had, that's a complete juxtaposition because there I lived now in a commune. I mean ...

Varmus: This was in New Jersey, as I remember.

Capecchi: This is in Pennsylvania.

Varmus: Pennsylvania.

Capecchi: And so you go completely from a life where there's no civilization in essence to one that's highly structured and everybody knows everything. And so it's a ... and then I was nine.

Varmus: Nine. And did you speak or read English?

Capecchi: None. No. But I did go to school the next day I arrived in New York ...

Varmus: Did you read ...

Capecchi: Ellis Island. No, I hadn't gotten any schooling. But I did go to school. They decided I should be in third grade, because that was my age. So I went into third grade. And things were completely different.

Varmus: Can you remember the experience of walking into a classroom for the first time?

Capecchi: The teacher was very thoughtful. I mean, what they did for me was to, they gave me enormous rolls of paper. And they said, "Make a mural." So I started drawing murals. We were studying about Holland. So I made a mural about Holland, and about cheese, the whole works, and spent, I think, about a month working on these enormous murals. By that time, then, I picked up the language. But unfortunately I also lost Italian...so that I would learn English as quickly as possible.

Varmus: So by the fourth grade, fifth grade, you were reading English?

Capecchi: Yes. And from then on, it was interesting, because I think they didn't know. I mean there are some theories of education which say that after a certain period of time, you actually can't learn to read if you just don't go through the early parts. So they were very confused. My tests were showing, you know, wild fluctuations.

Varmus: So when did you know that you were smart?

Capecchi: Smart? I think in high school. I didn't take things seriously. But I did very well. I mean, I was mostly concentrating on sports and getting to know people and those kind of things. But I could do mathematics and physics fairly easily. So I thought I must have some gifts in that direction.

Varmus: Did your history make you...how did the other students treat you? Were they in awe of your experiences? Or did you keep quiet about them?

Capecchi: No. I think, well they decided very early, because I was very streetwise, I would take care of the class. I was the person who would beat up all the people in the other classes. That was my first duty essentially, certainly in third grade, was to be champion of the class, and take, you know, take advantage of my physical aspects. And only later that I became, I mean I think it was an enormous socialization process. My aunt and uncle were, you know, terrific at that.

Varmus: Your mother was with you at that point?

Capecchi: My mother was with me. But she was, she was actually affected, I think, by the war much more than I was. I think one of the things is that children are enormously resilient. And it doesn't matter what they're given, they accept that as the reality. You don't feel sorry for yourself that you're in a bad situation, you simply, you know, the first thing first. I think in those first years, survival was the most important thing. The next thing was to become socialized and become an acceptable human being. And then slowly, they were Quaker, and so they had a strong influence in terms of ...

Varmus: They, your aunt and uncle?

Capecchi: My aunt and uncle ...

Varmus: How did that happen? They must have been...they were Italian presumably.

Capecchi: Their history goes back even further. My grandmother was actually from Oregon. She was a painter. And then she moved, actually she and her grandmother, or her mother, my great grandmother, moved to Florence to paint. So she retained essentially her American citizenship. The three children that she raised also retained their American citizenship. Two of them, two brothers, came to the United States and they became physicists. And then the mother stayed in Italy as a poet.

Varmus: We talk a lot these days about how we interest young people in science. There's a lot of emphasis on trying to teach even first graders something about the experimental method. Obviously you didn't have that very early experience. There was some science in your family background, but also some poetry and art. What was the moment at which you knew science was of special interest to you, beyond sports, beyond defending your class mates?

Capecchi: Oh, I think that really started in college. I entered college actually as a political science....

Varmus: College was?

Capecchi: Antioch College in Ohio. And...

Varmus: How did you choose Antioch?

Capecchi: Because of work, the work experience. I mean there every quarter you go, one quarter you study and then the next quarter you work. So that flexibility seemed very attractive. And it turned out to be very important.

Varmus: ...important because of its impact on your state of mind, or because of the work experiences you had?

Capecchi: All of the work experiences themselves, because they have a very good program, and you work all over the country. For example, I got introduced into molecular biology by working in Alex Rich's lab at MIT. And there, I also met a lot of other molecular biologists.

Varmus: Is that your first lab experience?

Capecchi: Ah, no. I've worked in other, at the Kettering Foundation, at...we had quite a few ...

Varmus: Kettering Foundation where?

Capecchi: And that's in Ohio. That's the same Sloan Kettering ...

Varmus: I know it's named for an executive at General Motors.

Capecchi: Right. Right. And he was an amusing guy, quite a...He was a very ...

Varmus: So you met Charles Kettering?

Capecchi: Oh, yes. Yes. Met him. And he used to fly down in his own plane at age 80. One of my early very projects was to put in, at that time, a chromatograph; chromatography was just being invented in essence. I was putting together a machine to do it. He came in and looked at it. And the first thing he does is to rip it all apart to see how it works. You know, this is months of work. After pulling it all apart, and all the parts laid in the floor, he was satisfied, left, and then I had to put it back together again. So it's ...

Varmus: Probably time to go back to Antioch at that point.

Capecchi: So, no, I think the experience of working and studying made it real, much more real, than I think having four straight years of just class work. And it gives you an enormous experience just to be working in different labs. I mean ...

Varmus: Well, going into a lab like Alex Rich's at an early age is, of course, is a daunting experience. And what happened there?

Capecchi: It was fun. I mean, one of the very first projects...DNAs are long strings of particles, enormous. Imagine that it's being a bowl of spaghetti. And the first thing that he gave me, he said, "Well, line all of these molecules up, because what we want to do is to look at the optical properties both along the axis of the DNA, which isn't very long, and across the axis." So I had to figure out how to do it. You take this bowl of spaghetti and line all of the spaghettis all in a line. I spent a little bit of time. And it's worked out very simply.

Then what we did was just to make a rice jelly, and then put it between two glass plates, and then just slowly shear them. And that lined all the molecules up. It was perfect. I mean, 99.9 percent of the molecules were all lined up. Then we could look at the interactions for example. The DNA has bases. This, sort of, the stairs of the helix. And what we were interested in was the interaction between the bases. That allowed us to do that. So that was my very first project. It was satisfying that with a little bit of thinking and a little bit of fooling around, you could do something that seemed impossible.

Varmus: So by then you were committed to a career in science.

Capecchi: By that time I was committed to science. I mean initially, I was interested in physics. But I was, I mean I liked the individual aspect of molecular biology. Physics looked like it was going to be very large programs, with many, many people working on the same project, whereas molecular biology allowed you to be creative in a small way.

Varmus: But it also sounds as though your first experience, serious experience with biology was a physical experience of trying to analyze the physical properties of the most important biological material, namely DNA. Now you went off to Harvard in the special category. You were a member the Junior Fellows program.

Capecchi: Right.

Varmus: And that gave you, as a junior fellow, some access to some of the best minds at Harvard. How did you end up working with Jim Watson?

Capecchi: That's...Well I probably can't say that on television. (Laughter)

Varmus: The archives will ask you about that. Feel free.

Capecchi: Okay. So, at that time, I was trying to decide essentially between two California schools, Cal Tech and Berkeley, and then MIT and Harvard. And so I went to Jim, Jim Watson, of Watson and Crick fame, and asked him, you know, "Where should I go?" And his response, he looked at me and said, "You would be a f-beep crazy to go anywhere else." So, that seemed very direct and convincing. And I decided to go to Jim's lab.

Varmus: Some were probably convinced. Some were probably repulsed.

Capecchi: I found it very direct. And I think that's one of the beauties of Jim. I think he's extremely honest, very stark honest.

Varmus: Jim is an interesting mentor, because he tends not to be overly directive, and doesn't necessarily put his name on papers. So how did you work with him?

Capecchi: I think very well. He gives you an enormous amount of freedom. He inspires you. He's one of these people that can take a text and just read it, and page after page, and then retain it, and then discuss it with you. So it's just a remarkable experience. I really enjoyed that period. It was very exciting. It was an exciting lab not only because Jim was there, and also Wally Gilbert was there, Walter Gilbert. He was a physicist. And these two people couldn't be more opposites. I mean one's extremely intuitive. Wally's quantitative. Working with both of them, it was hard to satisfy both. But at least you could see very different minds at work and different approaches, and that you could do science in different ways.

Varmus: One of the things that's always interesting to me about scientific careers is that people tend to be remembered for one or two things that they did. And in a career like yours, where many things were done, and many techniques were used, you are thought of by most people in the scientific community as somebody who developed homologous recombination as a method for knocking out genes and making knockout mice. But is that the thing that you found most important in your own career? Is it the thing that gave you the greatest pleasure? Or were there other things that people should remember you for? What do you remember yourself for?

Capecchi: I think that it was the certainly the most prolonged project, and the one that we put the most energy into, in the sense that very early we saw what could be done. But we had no idea of how to get there. And so it took about ...

Varmus: How could you see that?

Capecchi: The initial experiments were very simple. We took DNA molecules, the same sequence, and injected them. We were using very fine glass needles and put them right into the nucleus. And what we found was that indeed they were randomly inserted into the genome. But they were all on one place. And all of them were in the same direction. DNA's just like a book. It has a directionality. In the English language, we read from left to right. DNA is also read as a particular direction. What we noticed was that all the DNA molecules were in the same direction. So you could only generate them in two very simple ways. One is some kind of synthesis where you would use one as a template and keep synthesizing that when turning it. And that would all be in the same direction.

The other is to actually use the information on the DNA to line these up and to stitch them together using the machinery that we're talking about, homologous recombination, which is a way of putting molecules together that looks at the sequence of the basis on the DNA as being pertinent to how you line up the DNA molecules. And only like ones line up. So we could very easily actually distinguish between those two models. And we did those experiments. I was homologous recombination. Now, why is this startling? The reason is that people always thought that homologous recombination, this machinery, was involved in dispersing all of the parameters within the cell. That is, how much of the information, what information is from the father? And what information is coming from the mother? Rather than giving very large pieces of information, this allows you to split it up and disperse it among the progeny, so you get much greater variety of progeny. That's what this machinery is thought to be. But we were looking in cells that had nothing to do with germ cells and nothing to do with sperm and eggs. These were just skin cells, fibroblasts. So that says all cells have the machinery. Then it was very simple. If they have the machinery, could we fool it to do what we wanted to do instead of what it was supposed to be doing? That is, can we provide it, a piece of DNA that we modified, and make it or use that information and replace the information that's present already in the cell?

Varmus: At that stage, could you foresee what that technology would mean? I remember actually our labs had some collaborative activity in those early stages. And I frankly could not have said then that I would have been able to foresee that this method would transform the way we did biology.

Capecchi: We were looking way in the future. We even thought about mice. At that point, that part didn't look very promising. But at least we could see that there were maybe some ways of doing that. So we very much directed our thought to understanding this machine and how could we fool it, and how could we make it use our substrate as opposed to its normal substrate within the cells. That was very directed. But it took ten years.

Varmus: Now, you say you could think ahead to mice. Well, most people watching this might think, "Well, could he envision something so these technologies could be used for the betterment of man, more directly?"

Capecchi: I think so. And I think once we're wise enough, we will be going in that direction. What we normally do is to use this machinery to actually make defects in genetic information. By looking at the effects of the defects, for example, if the little finger now disappears, we know that we're in a program that's required for making the little finger.

But the exact same operation could be inverse. That is, if you have a defective finger that's a result of that same genetic manipulation, if we somehow could correct it, then we would regain that finger. And in the future, I think this technology will be used to do corrections of...there are over 5,000 genetic defects that are already known. And more that involve many, many genes as opposed to just single genes. So I think we look forward to it. Looking forward means 20 years from now.

Varmus: Well, of course people still have grave reservations about tampering with the germ line of human beings, and the issue of doing no harm. Do you think 20 years is a realistic time line for that kind of correction?

Capecchi: I think so. I'll take as an example what we're already witnessing in this Lasker Prize with Edwards. Twenty years ago, the shock of having a test-tube baby was enormous. That was splashed all over the world press. And now, one million children have been born using the technology.

Varmus: I was in England when it happened and it was front page news for days and days.

Capecchi: And so I think, and that shows how much society has changed. They realize there's a problem. Fourteen percent of couples are infertile, and they cannot have children unless they take advantage of in vitro fertilization. So there's a come ground in essence. And I think the same thing will be true with respect to correcting genetic defects. I think we don't have the knowledge and the wisdom to do it right now. But I think by the time we will, I think then society will also see the same things slowly opening up—like the use of stem cell.

Varmus: An important factor in the development of your work and your ability to make changes that are corrections or deficiencies in the mouse germ line depended upon the availability of embryonic stem cells. So that obviously came from another quarter of this prize collection. When did you become aware of that discovery and when did you think, "Gee, this really has meaning for me?"

Capecchi: I started to attend meetings that involved EC cells, these are the precursors of embryonic stem cells, around 1980. Just to see where, how they were developing, how it was going along. And at that stage, it was clear that you had cells that could contribute to most of the body cells, nerves, muscle, bones and so on. But it wasn't successful in going into the germ line. The first meeting that I went to that said, "Aha, now things are beginning to work," it was in 1984 at a Gordon conference. And at that meeting, there they first described their success of actually making germ-line chimeras in mice. And then we knew that we were on the right road.

Varmus: So you were watching for this.

Capecchi: I was watching for this. And follow the field and seeing how this was going along. In 1985, I actually went to Martin Evans' lab to learn how to do work with these cells and learn how to work, not only in culture, but also to make mice from them and so on.

Varmus: There must have been a time when you knew you had made your first mutant mouse with this technique. What was that like?

Capecchi: That was very exciting. It was both exciting and also a disaster. I mean we actually, we had made the mice. And then we found out our mouse colony was infected.

Varmus: Infected with ...

Capecchi: With a virus, a hepatitis virus. And I called Bar Harbor up, and they said, "The best thing to do is just to start over, eliminate the colony," and the problem was we were working on a mouse house that was also being used by people who were using wild-type mice. It was completely messed up. And so it was not improbable that we would actually get an infection. But in essence, it terminated the experiments. We actually had to get money to rebuild a new facility in order to shut ourselves off from the other people and then start all over again. So I had a peak and a real drop, because we never found out whether we were getting germ-like chimeras. When we had the chimeras and then had to quit....

Varmus: Then you did ...

Capecchi: ...and finally got them. And that, and it was only, I mean by that time, actually many labs, there were four labs actually that made germ-line chimeras. So there was an enormous celebration at that point, because it was not only could we do it, but other people could do it. And one could see now that it may be a useful tool.

Varmus: Do you know how many targeted mutations have been made in mice at this point?

Capecchi: Our estimate is 7,000 right now. And that's very gratifying, because it's happened as a cottage industry. That is, people in individual labs all over the world are doing it. You don't have a big program that says, "Do it." It's people individually coming out and studying the things that they really enjoy look at.

Varmus: Should there be an organized effort? After all, duplication and quadruplication may not be the best idea.

Capecchi: To me, that's a very difficult.

Varmus: And I would hate to have to make that decision, because I think both have their advantages. But I'm glad my opinion doesn't count.

Varmus: There are probably others that feel the same way.

Capecchi: I think what is important, I mean the importance of individuals making their own mice is that they have an interest in that mouse and will look at it as carefully as possible. So I think that's the good part. The bad part is that it's not very efficient, and there is duplication. And I think one could save a lot of time and money if one did it in a more organized fashion, and somehow made it easily available to other researchers so they could take advantage of that. I think in a sense, the latter approach will be done. And I think it is important to do it that way. But I think a little bit will be lost, because sort of the individual, the maverick aspect of the technology...but I think we're moving to a new area. I think we have to take advantage, for example, of the Genome Project. And this, now all of a sudden, we can do science in a very different way.

Varmus: Now that we are reaching the end of our talk, was there something you wanted to place in the archives or say to the audience that we haven't discussed?

Capecchi: Well, I mean to get to a personal note. I think the one message that I've learned, at least for myself, is that you can't predict where things will come from. So my own message is that what's really important is to give an opportunity for anybody to do as well as they can. And if we can do that, I think then we'll have a great world, particularly in these times when we have these horrendous things happening. I think it is important for us also to look forward and be bright about the future, and have something that we can look forward to.

Varmus: In many ways, you come out of an atmosphere of geopolitical unrest that even exceeds the way in which the southern part of Manhattan Island feels right now. And you exemplify by your own career in science that recovery occurs. That could be a message for today that a life in science is possible from any background.

Capecchi: You know, humans are resilient. Children are resilient. And I think all we need is to be given a chance. And we can do the aspirations that we hope to achieve.

Varmus: Well thank you for speaking so movingly.

Capecchi: Thank you.