Phillip A. Sharp

INTERVIEWER: As a youngster in Kentucky, your first encounter with biology, it seems to me, was in an agricultural setting.

SHARP: Yes, I grew up on a farm. And my father was a tenant farmer, until we were seven, until I was seven, and we bought a small farm. And I grew up on the farm, did the chores in the morning and in the evening. Worked in tobacco. Even though I'm a cancer biologist, the early days were, in part, used in growing tobacco.

INTERVIEWER: What were the chores?

SHARP: Well, we raised milk cows, and we milked them in the morning. And we had pigs. And I had to feed them and make sure they were all right. Actually, when I was seven or eight, we had horses. And I have actually worked in the field with a horse. Because by the time I was sort of eight or nine, my father — the end of the time we had horses — we were plowing a field. And my father thought I should get the experience. He put me behind the plow. And that was something. Then the horses got replaced by tractors. And it was a small family farm.

INTERVIEWER: Hard work?

SHARP: Hard work. You learn how to focus on a farm.

INTERVIEWER: A lot of biology, I can just imagine the biology thinking of slopping pigs, but most people who grew up on a farm, I think, ultimately view the endeavor as a business that's close to the land, but more of a business. You, however, seemed to observe the biology that was there, in all of its richness, from the plants to the animals. How did that occur to you?

SHARP: It's fascinating. Animal behavior is really fascinating. And at the time, as I was growing up, you could recognize so many human traits in animal behavior and their emotional state that it became very clear that there was a continuum in the way the brain works between animals and humans. And you could see behaviors that were quite similar. And it was instructive in terms of leading me to questions about biology and evolution that were quite interesting.

INTERVIEWER: What did plants, themselves, teach you outside of focus and the difficulty of making all the deadlines that farming requires?

SHARP: I think there's two things that plants taught me. One is the diversity of plants. And it's just an enormous diversity of plant life when you're on a farm, ranging from weeds to trees to crops to all the other things in the middle. And then this was the time in which hybrid crops were introduced; and increasing yields of hybrid crops.

So, you know, as a young person, I saw corn being raised that was hybrid, that was larger than what we had previously raised; an increased yield. And talking to my father about what it meant to be hybrid, we couldn't plant the seeds again. They wouldn't germinate and produce the same plant. So I didn't have explanations, but he didn't have explanations. But it showed me the impact on plants that human breeding and selection could have.

INTERVIEWER: How did you evaluate or encounter this tension or balance, perhaps, between the impulse to control nature that you see on a farm and the sense of mystery that nature delivers in the activities on a farm?

SHARP: I enormously enjoyed the feeling of being outside, of being among that noise and diversity and, just, it's overwhelmingly beautiful to me. And went for long walks, you know, on Sunday afternoon. You would come home, not much to do. You had a big lunch. And then just go for a walk, just to be outside and just see it.

You know, when you're working in a crop, obviously define a territory and you control that territory for the crop. And that was work. The rest of the outdoors and the farm was always pleasure.

INTERVIEWER: In the initial understanding of how using agricultural techniques you could control and steer nature, did you have a sense of what modern biotechnology could conceivably be? Is there a continuum you can draw from the kinds of techniques that you use to control and defend the territory for a crop, and the techniques that really become this much deeper inquiry into the nature of cells and plants themselves?

SHARP: Well I didn't think about it in those terms. I clearly understood that we were controlling nature with her besides, and things we used on the farm to control crops and weeds.

I think the relationship was that I was very comfortable as I came into biotechnology, thinking of this technology as being useful to produce things. And it's some piece of biology we now understood, and we understood how to control it and direct it. And we could do that to make things that were useful for people. So that transition came to be naturally, and I was pleased to be able, totally excited, in being able to be part of that.

INTERVIEWER: When did you first understand the mechanics of a biological processes as you observed it on the farm? Say, how a seed becomes a plant, how a plant specializes photosynthesis. I'm just pulling out of my head the kinds of things you must have observed.

SHARP: I observed all those things, but as I moved through school, I got deeply infatuated with math and in, subsequently, chemistry and physics.

So I turned my intellectual curiosity to those disciplines. And it wasn't until I was a young adult that I came back to biology in a meaningful way. When I was in high school, I had to take, you know, biology. It was taught by rote memory. It was terribly uninteresting. I couldn't apply principles in general to what I was learning. And when I walked into chemistry, I could learn a few rules, a few equations, and, you know, understand an enormous amount of natural science. So that let me into chemistry. And what let me back into biology as a scientist, actually, as I was finishing my PhD, more than that's when I made the transition, was that I understood the principals that we were learning in molecular and cell biology were very broad, very powerful, and would lead me into one of the greatest mysteries. And that is what's the nature of the human being. And that's when I came back to biology as a science.

INTERVIEWER: So as a mathematician and physicists, you left the farm. But as a PhD, you came.

SHARP: Yes.

INTERVIEWER: That's a great narrative. Let's talk about who might have noticed that this fellow, Phillip Sharp, had any talent whatsoever in science, in those early days of high school.

SHARP: You would not have known it a lot. I was very strong in math when I was going through school. I went through the public schools in the real part of the state. Butler was the grade school I went to. We had maybe 16 students in a class.

INTERVIEWER: I understand they renamed the school.

SHARP: They have renamed the sixth through eighth grade to Philip Sharp School, high school.

INTERVIEWER: Congratulations.

SHARP: So it's really nice. It's right at the end of the road of where I lived. And I'm quite proud. One of my MIT colleagues looked at me after that was announced and said, "Philip, you can't mess up. Because you're gonna let down all those kids if you do." But it is quite an honor. But I went to a great, small school in a small town.

And then, as I was in one through sixth, I was strong in math, very poor in english. And conduct was never my high point. And then as I got in the sixth grade, I became increasingly fascinated with science; reading books about science. Anything I could get my hands on. Anything quantitative. Anything about science fascinated me. I started talking to my friends. I got a reputation of somebody who talks about science. And that feeds on itself.

And as I move onto junior high school, I become increasingly distinguished in science. And teachers take note of that. And I was put in the more accelerated classes.

And then as I moved into high school, we consolidated. I had a couple of teachers who took a lot of interest in me; a math teacher and a chemistry, physics teacher. And that encouraged me. And I stood at the top of the class. So I got encouraged all along through school, though my parents didn't really understand graduate work.

When I was six years old, my parents started talking to me about going to college. And I was given a — I paid for and bought a small calf, which turned into a cow. And I got her calves to sell to save money for college. I raised some tobacco to save money for college. So by the time I got out of high school, I was pretty well motivated to go to college. I paid for a year and a half of it with that money.

INTERVIEWER: So you were your own biotech start up, even back then?

SHARP: Yes.

INTERVIEWER: On the farm. Tell me about your early undergraduate years and when you thought that college could be a platform for you to actually be a scientist, as opposed to just study science.

SHARP: I went to a small college in Kentucky called Union College. It's down in the mountains in a town called Barbourville. The county itself is Knox County, and it is a very poor part of the state. Half of the young males that came out of that part of the state during the Vietnam War failed a physical. They had malnutrition when they were younger, and they just — their health was so bad they couldn't be drafted. So it was a very poor part of the state.

The college itself had about 200 people in a class. 800 altogether. And again, I was majoring in chemistry and math. Really enjoyed those courses. Was well known for standing at the top of the classes. And then a professor from the University of Illinois came to teach my junior year. He was recruited. Dan Foote. And Dan taught me organic chemistry and inorganic and several other courses I TAed the rest of the day. I basically spent a year and a half with him. And he encouraged me to apply to graduate school. And I thought this would be fabulous. If they paid for me to continue to learn chemistry, I was gonna do it. So I knew I couldn't afford it unless I got a fellowship. And luckily Sputnik went up, and there was a lot of federal fellowships to support students. And I got admitted to the University of Illinois and got a fellowship and started graduate school in chemistry there.

INTERVIEWER: And Champaign-Urbana?

SHARP: Champaign-Urbana. Down state Illinois.

INTERVIEWER: Still in the corn fields, but compared to where you came from, the big city.

SHARP: The University of Illinois is a first rate campus. And the chemistry department at the University of Illinois was a really strong chemistry department. Clearly ranked in the country in the top ten, and they took themselves seriously. The teaching was excellent. Coming from a small school, I flunked most of their entrance exams. They said, fine, just take our senior classes again, or for the first time. I'd never had that material. So I took those courses in a semester and took off on my graduate work. It went very well.

INTERVIEWER: Early mentors at the University of Illinois?

SHARP: The most important was my PhD advisor, Victor Bloomfield, who was a young assistant professor who'd just come a year before I arrived. I was his second graduate school student. And a very long haired liberal off the west coast to a short haired kid out of Kentucky. But we communicated very well. And he was committed to his students, and I immensely enjoyed working for him. And after three years, I had published several papers with him. And he made sure that I went to meetings and got exposure and promoted me. And then I went off to the west coast for a postdoc with Norman Davis, a chemist at Caltech.

INTERVIEWER: At the time you were with Bloomfield, what sense did you have of the horizon of understanding and the kind of work that you were doing? And where did you want to get to in terms of problem solving, publishing, the problems you wanted to work on?

SHARP: When I was in Illinois, it was again in the chemistry department. And I enjoy chemistry and was excited about it. But as I looked at the horizons, I didn't find the problems that chemistry had in front of me fascinating. And I picked up a book from Cold Spring Harbor called the Cold Spring Harbor Symposium. It was in 1968, and I read it. It was about DNA and trying to determine the structure of the DNA, how long it was, how much genetic material was there. And my PhD thesis dealt with some aspects of DNA, its polymer statistics. And so I started reading this book, and I started reading more and more about DNA and started reading about genetics, and decided that I wanted to make the transition into what we now call and didn't call molecular biology.

INTERVIEWER: Was it the fact that it involved life that attracted you, or was it the raw complexity of the molecules that fascinated you?

SHARP: There were two aspects that fascinated me. One was it became clear to me why I was reading that. That I could use molecular biology and DNA, specifically, as an entree to understand more about the human being. That's what fascinated me. I wanted to understand more about human thought, processes, culture, and health. And so this seemed like an entree that just had never been offered before in history. And the problems were just from my perspective unexplored. So it was a new territory. I felt I could really learn something new in that area.

INTERVIEWER: So as a chemist, you could appraise the DNA molecule as clearly and almost limitless horizon of description of life. But as a biologist, you would have to learn the mechanics.

SHARP: I had to learn biology and learn how to use it and learn the traditions of biology and the genetics and all the other bichemistry. But I knew from my background in chemistry that it provided me the tools to do that. Training in chemistry is a very powerful training, because almost everything you deal with is materials and molecules and reactions. And so if you have that fundamental ground, then as you move forward, you're able to learn by yourself. And though I've been head of the Department of Biology at MIT, I've only had one biology course in my life. And that was in college. I had a general biology. Everything else I've learned through my whole career.

INTERVIEWER: Wow. So from University of Illinois you went to —

SHARP: Caltech. Looking for a postdoc, I wrote to two or three people. The person I was really most interested in was a man at Caltech named Norman Davidson, who was a physical chemist, who had made the transition to biology. And I'd read his papers, and I found them fascinating. And I understood where he was moving from DNA into more biological processes. I knew he'd understand my background. And when we contacted him, I was fortunate enough that he said yes. And I then applied and went to Caltech. And it was by far the best possible decision.

INTERVIEWER: And, again, looking at this horizon of the problems short of the grand one you've already mentioned, understanding the human being, but as you look toward the horizon from the perspective of being at Caltech, what were the problems that seemed to have promise, that excited you the most.

SHARP: So, first thing I have to say is that the movement to Caltech taught me something that every young person needs to know. And that is I knew I was among the best of my generation. And if I could hold my own and make contributions there, I knew that I could make contributions anywhere. And that's what Caltech means, and that's what MIT means. So if you're able to come to MIT and do interesting science, then you're able to do interesting science anywhere.

INTERVIEWER: Let me just hold you back there for a second. So really what you're describing is this scientific community of people working at the absolute top of their game that you discovered at Caltech.

SHARP: Yes. And not only the professors, who you know is there, and that's what a great institution is about. But the young people who come to work with those individuals, all about your age, as you enter that community. And, you know, you look around and you say who's got the most valuable and interesting ideas. Who's getting things done? Who's moving the show? And if you are, you know, contributing to that picture in a significant way, then you've answered an important question. And that is, you know, what you can do and where you should think about going. At that stage, I was interested in learning more about the chemistry of DNA and how to use that DNA to look at a gene. So with Norman and his colleagues, Ron Davis being a very important one, I started doing electron microscopy, looking at the mapping of genes on chromosomes. This was totally new. I mean, this was something that no one else was doing. Norman had the idea to do it. I had to devise some tricks in getting it to work, but I was able to get it to work. I established a new area of research, literally in his lab and much of the country. And it was in bacterial genetics and sex factors and looking at chromosomes. And recruited students to the problem and another postdoc, and so we had a group doing it. So it went very well, but it led me into, then, a full time focus on molecular biology. And the approach to molecular biology through DNA. And that's where I wanted to be.

INTERVIEWER: Here we begin to see an approach to a problem that draws from various disciplines. Electron microscopy is sort of a physics —

SHARP: Physics zone.

INTERVIEWER: You've already mentioned the chemistry and, of course, the biology; choosing the organisms and the genes that are going to matter to you. How important is that?

SHARP: It's terribly important. Primarily from the perspective that few people have that mix. So new problems appeared to you when you're sitting in that zone of the interfaces of different disciplines that don't appear to other people, and new ways of solving those problems are apparent to you that aren't apparent to everyone else. And so, you know, it puts you in a very powerful and productive position. In addition, it takes you out of the traditions. So you get used to working in your own environment with your own judgment. And that freedom not to depend on others for your thinking and your selection of problems and how you go about them is really an important step in a development of an intellect. It allows you to become yourself.

INTERVIEWER: Is it fair to say that you took the widespread understanding that there was a relationship between chromosomes, genes, and DNA. And through your sort of understanding of chemistry and exploration of the DNA molecule grabbed electronic microscopy as a way of, you know, if we can see these things, we can figure out the mechanics of what's going on?

SHARP: You're right. If you can see it, you can understand it. A picture is worth a thousand words. And then, if you can see it, you begin to manipulate it. So you can see changes and how those changes correlate with biology. And so then if you see DNA changes related to biology, you know you're dealing with the fundamental material of biology. And that's what DNA presented at that time. This was in the early 1970s, this 1969 to 1971, when I was there. And the first time we could see DNA at a gene level, using this technique of electron microscopy.

INTERVIEWER: Was it these techniques and these discoveries that led you to an extraordinary mentorship at Cold Spring Harbor?

SHARP: It did in a way. But it was another part of this evolution. So at Caltech, I was working with bacteria, which was the organism that most molecular biology was done with. And I was having great luck and success. I went out to look for a job. This was in the early 1970s. It was a bad economic time. There was a recession in that period. There was very few academic jobs. I was interviewed at some great places. I didn't get an offer. In fact, I'm pleased now I didn't get an offer. I was contacted by some other places that wanted to talk to me, but I didn't want to be there. I wanted to be in an environment which I would be stimulated to do the best science I could.

So I also wanted to begin to work with human cells. And I wanted to work with viruses that infected human cells, because, again, I could isolate their DNA. And I could understand that DNA. And I got that experience from working with Jerry Vinograd at Caltech, who was also a professor there. And I collaborated with him and Norman once while I was there. So I wanted to learn virology. And I contacted three labs to do a second postdoc for a period of time. Dave Baltimore, who was here at MIT, Howard Temin up at Wisconsin, and Jim Watson at Cold Spring Harbor. And Jim invited me to come to Cold Spring Harbor. I moved there to start working with animal viruses. He had just come down from Harvard to take over Cold Spring Harbor and was expanding the tumor virus program there.

So I joined that program and started to work with mammalian cells and DNA tumor viruses that cause tumors in animals. But to me they were a tool as well to begin to look at gene structure and function in the human cells.

INTERVIEWER: So as a humanist, for lack of a better word, you were interested on some level in the potential for the curative powers of biology by studying viruses; but as a chemist you saw viruses as this platform, a window, into the structure of DNA.

SHARP: That's right, and the structure of cells. How the complex human cell worked. Because in the early 1970s, we really didn't have the tools to begin to understand the biology, molecular biology, or cell biology of human cells. It was really a totally unexplored at the level of a gene and how it functioned. And I saw this as a chemist as a tool that I could move into that question. And I knew that question was central to human biology. I mean, you can't understand the biology of an organism without understanding the gene. So it seemed pretty apparent to me. It's sort of written on the wall, understand what the gene is.

And so I, you know, had multiple reasons to begin these studies. Some was, you know, how cancer developed. Others were fundamental. What was a gene.

INTERVIEWER: Most people who've understood James Watson by reputation at the time that you went to study with him viewed him as a towering pillar of science who had answered an enormously important question in biology for all time. But when you went to study with him, you were, in fact, seeing it from the other side, that, in fact, Watson's work was just the beginning of an extremely long journey that we're still on. How did he understand that we were at the beginning of something, versus how you understood it. And how did that work in your relationship?

SHARP: Jim at that stage, you know, he had done so much. He had discovered the structure of DNA. He'd built the Department of Molecular Biology and Biochemistry at Harvard, the most outstanding department in the country focused on that. Written his text book, The Molecular Biology of the Gene, which was the introduction to students of this fascinating field. And took over Cold Spring Harbor and resurrected from a lab that was not going to survive much longer. He constructed, he understood that DNA was a critical tool in understanding complex biology. And that this subject would lead to increasing insights. He obviously had a much greater vision of all the relationships of, you know, different parts of biology to these questions than I did. And he gathered around him very bright, energetic, interesting people. And he's sort of chit chatted at the top, left him alone. And when he found something that was interesting that happened in that mix, he would sort of pluck it out and say, "nice work", you know. "Write that up. Tell other people about that." And so he played that sort of, you know, very senior mentor and creator of a community. And in that community, I found some really wonderful people, very talented people. Joe Sambrook who I collaborated with. And Ulf Pettersson and Mike Botchan and a whole host of others who are now all leaders around the world. So it was just a very stimulating environment.

INTERVIEWER: Again, this sense of a team of people working at the top of their game, focused in any way they can, using all the disciplines of knowledge at their disposal on the problems that excite them.

SHARP: That's true, and a team in which there are different disciplines. Jim understood this, that he needed someone with more physical chemistry; and he needed someone with chemistry. And he needed a biologist. And he needed this biochemist. And he sort of, you know, mixed people that would complement one another. And I was the individual who came in with a broad interest in biology, new and physical chemistry, new electron microscopy. And there was a lot of people in the environment that were virologists and cell biologists who needed this sort of tools to do their science. So we complemented each other and stimulated each other.

INTERVIEWER: So that fellow Sharp over there, he has a big tool belt. He can do a lot of stuff.

SHARP: He can do a lot of stuff. So let's get him involved.

INTERVIEWER: So is it in part some of those qualities that led you to MIT?

SHARP: In part, but mostly what led me to MIT was Dave Baltimore. I had learned about Dave when I was at Caltech, and then how, you know, he was working with virology and had this broad interest in cell biology and in tumor virology. And very exciting investigator. Dynamic individual, charismatic. And I knew around him would be very good people. I also knew a lot of other young scientists here at MIT. And you'd go to a meeting, and they're on the platform. In the first position would be this young cell biologist or virologist from MIT. So I knew this was an environment that was incredibly powerful in this area of science, the area that I was interested in. And that is how cells and genes cause disease and how they function.

INTERVIEWER: But in general, MIT wasn't known for biology at that time, in the broadest sense.

SHARP: Not in the broader sense. But for the people in this field, it was known. And it was known as a place in which change was happening. And they at the time I came here, they were developing the Cancer Center, which was this strong step into the human cell and a problem fundamental to the human biology, cancer. And you know, Salvador Luria articulated very clearly that understanding the fundamental basis of the cell would allow us to understand this disease process. And Dave Baltimore was using viruses. And Bob Weinberg was a young guy who was working with viruses and learning in how to move to cellular genes that were involved in the process. And immunologists and cell biologists were there.

You know, I waited six months to get a call from MIT. I had job offers elsewhere. I was hoping they would call me, and they ultimately did. I interviewed and they gave me the job.

INTERVIEWER: So you went to work at the Center for Cancer Research, became the Koch Institute.

SHARP: Yes. I mean this was 30 years ago, and it was the new center for cancer research and came out of the War on Cancer from Nixon.

INTERVIEWER: Before we talk about your initial experiences in research at MIT, from your, I think, relatively unique perspective on this, describe the strength and limitations of an institute focused on a specific curative mission as a driver of fundamental science versus a lab that is just purely focused on basic understanding. Does one have strengths? Does one have limitations? You've worked in both. Which is an ideal strategy, or how do you compare them?

SHARP: It's an interesting problem. And I think this issue of focus objective and science and basic science and science. And and I think that the power of those fields change dependent upon the field you're interested in. So in the case, in the situation I developed as a young scientist, I thought that the most important question to be addressed in my time was, you know, what the nature of the genetic control of genes was like in human cells, and that that human being is surrogate for all multi-cellular organisms.

So then medicine became — or medical science became a field in which there was an objective. You know, cancer, immunology disease, immune diseases, other diseases. But to approach those problems you had to understand the fundamental process. So I joined this community as a community that had objectives. It's a community that reaches outside the Institute and solves problems. It's the tradition of in MIT to be engaged in society and to solve problems. But it is also a tradition at MIT to understand the fundamental processes so you can go solve those problems. So that, it was in biology, that was exactly the right mix for the time in the 1970s and 1980s. Because you've got the resources and the critical mass of people together to handle these big, complex problems, because you were attacking a disease process. And yet you had to fill in the basic science to make progress. And I filled in the basic science. And that led me to the insights of the structure of a gene in human cells and many other aspects of cellular biology. So it's always been a very stimulating environment to be a scientist. And it's stimulating in chemistry and stimulating in physics, because you know that as you add information and insight, it stimulates a lot of people around you to go out and solve problems. And they bring tools and ideas back to you. So then you see from different perspectives what your contribution is like and new ways of actually solving problems. And so this interface is fascinating.

INTERVIEWER: So you arrived at MIT, and really now you spent a good, considerable amount of time looking at that DNA molecule.

SHARP: Still do.

INTERVIEWER: And wondering and doing a lot of experimental work on trying to identify what are the mechanical processes that actually account for the things that we see in the cell. As you began your work at MIT, where did you suspect that those processes were going to be revealed? And where did you begin to discover the mechanical platform, whatever, of all these tools and switches and whatever was going on there? Where did you discover?

SHARP: I knew that I needed to understand at its most fundamental layer, this mechanical process of how a gene worked. And that was the initial information transfer from the gene to the cell in a substance called RNA. And the synthesis of that DNA-like material from the DNA is the transfer of information to the cell. And I knew, I suspected. I didn't know at that stage, but I suspected that that process was going to be different in higher cells than in multi-cellular animals like humans then in the bacterial systems we had been studying.

INTERVIEWER: Let me just encapsulate then. Biologists understood that there is a process whereby genetic material gets from the nucleus into the outer reaches of the cell, the so-called cytoplasm.

SHARP: Yes.

INTERVIEWER: And so you were extrapolating that number one, the process needs to be understood; two, that if we could understand it at the cellular level, we had a template for virtually all of the genetic mechanics that occur for an animal in every species. And you understood that doing single celled creatures alone wasn't going to solve the problem.

SHARP: And I understood there was something new to be discovered there. At least I suspected it. And then that led me to then focus on comparing this transfer of information to the structure of the gene. And when I did that, I discovered that our genes were split, meaning that the information that was transferred in our genes is broken up into little pieces, and then assembled in the cell as it is being transferred. A process I called RNA splicing. And that insight is true for almost all our genes. And it's true for almost every gene in every multi-cellular organism, including plants. So focusing on that question, I was a first, among the first, Cold Spring Harbor, using the same systems I was using, because I came from there and helped set them up there, came to a similar insight at the same time. But that led us to a whole new insight as to how genes were structured and how they were used to transfer information.

INTERVIEWER: And at the time you began this inquiry, DNA was seen as the center of it all. And RNA was something of this kind of Xerox machine that assisted in a kind of copying process and didn't appear to have much importance.

SHARP: That's right. And then when I looked at this RNA, it turns out, it is actually being assembled into genes. So you know, this discovering that we really didn't know in a chemical sense what a gene was. And so then knowing this, we could go back to all sorts of information that had been developed in different biological systems and interpret it in the structure what the genes looked like in those cells.

INTERVIEWER: So far from thinking that DNA is this encoded mystery molecule, in fact, what you discovered is that the interaction of DNA and RNA is like the DNA is the blank paper. The ways in which RNA interacts with the DNA are like the letters on the page.

SHARP: Yeah. And the letters are edited. Edited by the cell.

INTERVIEWER: How did you discover that, and what did you feel when you first saw it in action?

SHARP: I literally saw it. So I discovered it using the electron microscope techniques that I had developed at Caltech, or used at Caltech. And then I took some more physical chemistry, combined it to that, and animal virology, you know, mixing all these disciplines together. And there in front of me, in that electron microscope, was that structure.

INTERVIEWER: And it was the chemist in you that gave you the discipline to go, see what's happening? It's connecting here and disconnecting here.

SHARP: That's it. So, you know, chemistry not only led me to look that way, seeing disconnects and connects and saying this is chemical unity that I have to be able to mix, but it also gave me the technology to do it. And so I was receiving papers from other chemists around the country, Norman Davidson, in particular, sent me a critical paper. I looked at his paper, and said, oh, if that's true I can do this in the laboratory. I ran into the laboratory and did it.

And so, you know, I was mixing chemistry and the cell biology in making that discovery.

INTERVIEWER: And describe the team and how each of you worked on different kinds of problems, and your collaborators were really all over the country, all over the world, in some sense.

SHARP: At this time, this was in 1977. I came to MIT in 1974. So I had been at MIT three years. First year, you are by yourself. I got bored just being in the lab by myself. I had a colleague, postdoc Jane Flint, who came with me and a technician. Three people in the lab. So I went to Dave Baltimore down the hall and said Dave, I need some more people to talk to. I'd like to be able to attend your weekly group meeting where all your people are talking. And I'll participate just like them. I'll talk about my science as I did. And Dave said that's fine with me. And, you know, Bob Weinberg was already another assistant professor there, and so a couple more joined. So we had the floor meeting every week. Now it's 34 years later, Dave Baltimore is at Caltech. We're still having the floor meeting. I just came from it today. You know, 150 get together, and two people, postdoc, graduate students, talk about their science. So that was a big community I was looking at.

But specifically in my lab, Sue Berget was a postdoc who was doing microscopy on DNA and interested in this problem. Claire Moore was the electron technician who I had trained and recruited. And myself. And we were interested in this problem. We started looking at the structure of these RNAs that are being transferred, recognized something was different, didn't make sense from a chemical perspective. I said if I understand the biochemistry of these processes, that shouldn't be happening, when I looked at it in the microscope. We started working on why is that happening. And that led us to insight of the split gene and the splicing process. So it happened over six months or so. And I have dialogue with all the people around me about the whole thing as I was doing it.

INTERVIEWER: Now you've described it very powerfully on a fundamental, scientific, molecular biological level. But for people who come at this from the standpoint of how can this deal with tumors. How can this assist us in curing cancer, what was the immediate sort of application even way off in the future of the exciting discovery that you had made? What did people say, okay, if we can do this, maybe this could happen?

SHARP: I mean, immediately what we understood is that a large number of the mutations in human genes that cause disease inactivated this process. So it was an immediate explanation for why a large number of human disease genes were defective.

And then, almost immediately thereafter, my colleague here at MIT Bob Weinberg isolated the first human oncogene from a human cancer cell. And when he isolated that gene, he realized the gene came in pieces. So, you know, you couldn't understand how that gene worked as a oncogene making cancer without understanding that the gene was in pieces, and you had to put the total gene into position to get activity. Started looking in viruses, and the viruses that were causing cancer, they were stitching together the genes that were causing cancer, just like the processes I was looking at.

INTERVIEWER: So the virus was taking over what the RNA would have been doing in a healthy chemical situation?

SHARP: Yep. And it was using that process to make activities that made tumor cells. So, you know, it just touched everything. And, you know, if you looked at a fly, the same thing was going on in a fly. You looked at a worm, it was going on in a worm. So it was a great continuity of new discovery that happened at that time. So when this fundamental structure of a gene was different then, you know, how a gene was turned on and turned off was different. You know, all the nature of mutations that cause disease genes was different. You know, around the world, within a month, everybody knew this.

INTERVIEWER: Wow. How did this discovery — also describe the other thing that you talked about a month ago. That you suspected that there was a fundamental difference in complexity between the traditional study of organisms, single celled creatures, and the higher order vertebrates that you wanted to get to.

SHARP: The puzzle, part of the information we knew at the time I made this discovery was that in higher organism cells, such as our cells, there was just much too much DNA. You know, there was an enormous amount of DNA there. And we knew there shouldn't be over 20,000, even 100,000 genes. But there was DNA present for a million genes. Just too much DNA. We didn't understand how the cell would function with that DNA. We knew DNA encoded genes. Enormous amount of DNA. Did we have a million genes? If we have a million genes that are all important, you know, couldn't mutations in those genes at the rate we knew about it be inconsistent with us functioning? So I knew there was, everyone knew there was just too much DNA in these cells. And therefore, when we found that the genes were structured differently with these editing pieces and pieces separated, we understood something about why all this DNA was there.

INTERVIEWER: So let's, I mean, there was this period of the initial discovery. And then, what was the track of research? Because we're talking about a long period of time through the 1980s and early 1990s when your life really began to change once again. Take me through this period of once the initial mechanics have been isolated, where did the inquiry go from there? And how did you work on it here?

SHARP: So I mean there were, I mean from that initial discovery, there was a whole number of branches that came off. One branch that came off was what we we're talking about. How genes created disease. And, you know, my colleagues here at MIT, Dave Baltimore and Dave Weinberg, are interested in cancer causing genes developed in that area.

There was a whole area of-- we now know what a gene is, but we have to understand how it's turned on and turned off. So, you know, there was a whole biochemical process, and I undertook to investigate that. I knew I wanted to understand how genes turned on and turned off. Because the difference between your skin cell and your blood cell is different genes being turned on and turned off. The difference between tumors and non-tumors is genes being turned on and turned off. So I wanted to understand the chemistry of that so I could contribute to those general problems.

INTERVIEWER: This turned on, turned off businesses is the gene expression.

SHARP: Gene expression. Turn a gene on, you get activity. Turn the gene off. So each of our cells has the same genetic material it it. The same number of genes. But they're very different. You know, your eye cell is different than your bone cell. So that's all a product of in that cell, there's a system that keeps genes off in one cell type, your eye, and on in the bone. And vice versa.

INTERVIEWER: And it's all this RNA —

SHARP: It's all this RNA, all these proteins all interacting within the cell, to maintain that cell identity. And therefore, you had to understand the chemistry of that. And that's where I launched in that area. And then the other area I launched in was at the RNA level, this editing process which we called RNA splicing. And that was central to how genes were structured, and I wanted to understand the chemistry of that. So those two areas I focused on. I worked on that and related to cancer and diseases for about 15, 20 years. And you know, the material is in the text books.

INTERVIEWER: Oh yeah. Sure. In 1990, you were faced with a pretty harrowing choice between where you would go and what your relationship might be with MIT. Where you would go as a researcher versus just what you might do here in a leadership role at MIT. Describe how that choice was presented to you and what it caused you to think about, both yourself and your field.

SHARP: So in 1990, Paul Gray stepped down as president. And in the tradition of MIT, the Corporation — that's the controlling body at MIT — formed a committee to look for the next president. And they asked the faculty to form a committee. And I was asked to be co-chair of that Faculty Committee with Bob Solow, an economist, Nobel Prize winner. Wonderful guy.

And so we put the committee together, and we met with various departments and various things. And as that process was unfolding, we interviewed a lot of people around the country. And the committee got to know me, because at that stage, this was in 1990, so I would have been something like 46. As this process unfolded, they began to think about, well, shouldn't we think about that guy over there named Sharp. And ultimately the Corporation head of the committee came in and asked me if I would be willing to be considered for a candidate.

It was such an honor. I love this place. I mean, I owe it so much. And I love it. I love what it does. And I love its mericratic way of doing things. And I felt obligated to, you know, if the Institute came at me and said we want to consider you to be our leader, I felt obligated to say yes. And so I said yes, stepped on the other side, interviewed.

That was a big world. I really didn't expect the Institute to come to me and ask me to be president. I hadn't, and this is the biggest mistake I probably made in my life, I hadn't thought through what my emotional state would be if I had to give up science.

INTERVIEWER: And you understood that was the choice.

SHARP: And that was the choice. I knew I couldn't do that job and do science.

INTERVIEWER: And at this point in your career, you had done enormously important work. You knew that. Everybody knew that, or else you wouldn't have been asked. But you still were far from your original quest, and that was to understand the human being.

SHARP: That's right. And I —

INTERVIEWER: That's where you wanted to go.

SHARP: That's where I wanted to go, and I wanted to have time to myself to think about and learn as I moved along. So I had a lab of 20 people. At that time, wonderful young people all doing interesting things. And they came and asked me to be president, if I would accept the offer, came at me one moment. I said yes. I went home. I talked to the family. Talked to family and then came back the next day, got my research group together, and said, you know, I've made this decision, and I'm going to have to give up all my research. We've got about six months. But I really can't continue much beyond that. And I had so many doubts that I could be happy and committed to that administrative position and giving up science that I said, look, if I have that degree of uncertainty, I'm not going to do MIT any good. And I'm not going to do me any good. And I should basically deal with this issue now, and so I did.

And, you know, the only thing that I was disappointed about is that it cast a negative shadow on MIT for a while. However —

INTERVIEWER: The last thing you ever wanted to do.

SHARP: Last thing I ever wanted to do. But, you know, the great news was MIT and its way of soldiering on, basically said fine. We'll go off and continue the search. They found Chuck Vest. Vest took the position. I established a wonderful relationship with Chuck Vest. And for the next 10 years, we worked. You know, he was president of MIT. I became chair of the Department of Biology. You know, we worked together on numerous things in life science and across MIT. And it was an incredibly successful time for me personally, for MIT, for him. So it worked out wonderfully at the end. And we got a great leader who just immensely enjoyed MIT and immensely enjoyed leading the country in science and technology. Chuck Vest became the spokesmen for science and technology in this country as president of MIT. And he had incredible effect across the country. So he was a magnificent leader at MIT, now head of the National Academy of Engineering.