Tracking the man behind the map

The genome journey of College alumnus Francis Collins.

By David Z. Rose (Biology '00)

Remarkable. In about a year from now, laboratories across the globe will have collectively blueprinted the DNA of our species.

Having always been interested in science (perhaps it’s in my genes), I was eager to learn about this massive enterprise called the Human Genome Project, especially since its director, Dr. Francis S. Collins (Chemistry ’70), attended the University of Virginia.

I knew that recounting this former Wahoo’s journey from studying chemistry at Mr. Jefferson’s university to hunting genes at the top of America’s largest scientific endeavor would make a tremendous article for The Cavalier Daily. However, my term as Health & Science editor for the student newspaper had just expired when an NIH receptionist informed me that Dr. Collins had agreed to chat. Rather than pass up an interview with such an accomplished individual, I talked to Dr. Collins by telephone in November 1999.

.................

David Z. Rose: Doctor Collins, what was it like to grow up in Staunton, Virginia?

Francis S. Collins: We lived on a 95-acre farm that had no plumbing until I was 12 years old. It was a fairly interesting way to grow up. My dad was a professor at Mary Baldwin College and he was the one and only member of the Drama Department. In the summertime, we had a theater which ran five shows every summer. About 10 of the Mary Baldwin students would stay at our farmhouse to work at the theatre. So summers were always a lot of fun, with lots going on. I didn’t go to school until the sixth grade.

DZR: Were you home-schooled?

FSC: My mother taught me at home, along with my brother Fletcher, who is also a U.Va. alumnus, CLAS ’69. Nobody in my family was interested in science or medicine; they were more involved with theater or the arts or business. But I was fortunate enough to have parents who encouraged me to chase down whatever sort of interests I had. They gave me a lot of leeway.

DZR: Did you aspire to any particular vocation before coming to U.Va.?

FSC: [Laughs] The usual line of truck driver, fireman ... it wasn’t until I got to high school that I began to imagine something that might actually happen. I liked mathematics. It was very sensible and logical. Then I encountered chemistry in high school, taught by someone who really ignited my imagination in science. I decided in 10th grade that I wanted to be a chemist. It was fun to learn about and I thought that that is what I should do with my life.

DZR: How was your first-year experience at Mr. Jefferson’s university?

FSC: When I got to UVA, in the fall of ’66, I was 16 years old, a bit younger than most of my classmates, in part because when my mother taught me at home, it gave me an early start. By the time I got to college, nobody could really tell, and I didn't tell anybody. I didn't wish to be singled out that way.

DZR: At 16, were you surprised at what college students do?

FSC: Well, a little bit. I was an Echols scholar, so I was hanging out with a bunch of fairly brainy kids, some of whom, to be honest, were a little weird. All of us were sequestered in Echols Dorm. I was on first floor Echols, room 105, looking out the window at the psychology building.

DZR: Where did you live second year? Did you join a frat?

FSC: I moved off campus and decided I was not going to do the fraternity route because that did not appeal to me. So I roomed with a guy I knew in high school, my guitar-pickin’ buddy. I spent most of my first year playing guitar and not doing much else. We got an apartment near the gymnasium.

DZR: Did you live on The Lawn?

FSC: Never did, in part because I got married between my junior and senior year. I was 19. I married my high school sweetheart, who I had started seeing when I was 15, so it was either get married or break up at that point.

DZR: What classes did you take at U.Va.?

FSC: I was very focused on chemistry. To be honest, I was too focused. I didn’t take advantage of the opportunity to sample other things. I took every chemistry class that was offered, and a bunch of the mathematics, but not much else. I took one drama and didn’t really like it because it was reading and not actual performance. But mostly I was one of those science nerds who you would not enjoy being in class with. But I had a good time; it was a wonderful place to go to school and I am sure it still is.

DZR: Oh, absolutely. I am curious to hear if any particular class you took here nourished your desire to go into medicine. Did you realize that something like the Human Genome Project could be in your future?

FSC: I had no clue, David. I left in May 1970 with full intentions of becoming a research chemist. Certainly genetics was the furthest thing from my mind when I walked out of there at age 20. I did not take a single biology course during my time at UVA, which is really too bad. I had a bad experience in high school with biology that completely turned me off. There didn't seem to be any logic to it -- all we did was dissect things and memorize body parts. That did not seem at all appealing to me intellectually. Of course I missed the boat there, there’s enormous substance to it; it just wasn’t presented that way.

DZR: Did you participate in any undergraduate research?

FSC: Yes, my most intense experience was with that research. Professor Carl Trindle had just arrived out of his Ph.D. from Yale, working in quantum mechanics, which I thought was the most exciting thing on earth. He was a wonderful mentor! He gave me a lot of responsibility and let me pursue things a lot further than I think most undergraduates get the chance to do. There were times when I was completely confused -- floundered -- and I’m sure I wasted a huge amount of his time with parts I just didn’t get, but still it was awonderful opportunity.

DZR: So when was the epiphany?

FSC: Later. I went off to Yale to get a Ph.D. in chemistry and about a year and a half into that, I finally did take a really good course in what was called biochemistry, but was really molecular biology. I was totally blown away! It destroyed all my misunderstandings about what biology was all about. At about the same time, I got a little disillusioned about what my own work was, in quantum mechanics. I spent all my time in the Yale computer center carrying around boxes of Fortran cards, because that's what you did.

DZR: What did you do next?

FSC: While it was enjoyable on a day-to-day basis, I didn't have a sense I was going to enjoy doing this thing as my life’s work. I missed the human contact and the feeling that you are doing something for humanity. I woke up to what was going on in biology, which clearly was going to have implications for humans. I had one of those terrible decisions to make: do you continue on a path that you put a lot of time into, or do you take a right turn and start in another direction? I wasn’t quite sure what to do so I visited with Carl Trindle. His counsel was, “Don’t worry, finish your Ph.D. and then do a post doctoral fellowship in a biologically oriented lab and you’ll be fine.” I probably could have done that but instead I took a more drastic step and decided to go to medical school because I was shaken enough by this experience that I wasn’t sure I was cut out for research after all, and medical schoolgave me a lot of options.

DZR: Which medical school struck your fancy the most?

FSC: Chapel Hill, because they offered me a fellowship, which was a way I could avoid paying tuition. At the time I not only had a wife but a kid and it was pretty important to me not to accumulate a massive debt. There, I encountered human genetics as a way to marry together my desire to work with something that was logical -- which is what DNA really is -- with something that has direct application to human beings. That was in the fall of ’73 -- three years after I left UVA -- before I really had a glimpse of what I wanted to with my life.

DZR: How did you get appointed to the Human Genome Project?

FSC: Only by a series of happenstances that I didn’t expect. As a first year medical student, “genome” hadn’t even been coined yet. I did a residency in internal medicine and then started on the faculty of Michigan as a professor trying to set up a lab to study the genetics of human diseases. I settled on a major course of research: to try to track down the gene for cystic fibrosis. It took six years before it paid off. The frustrations at times were enormous but that experience convinced me that if we were ever really going to understand the hereditary basis of disease, we had to have a much more systematic way of doing things, which meant we had to have the genome. We had to have technology to allow us to determine its function and sequences of model organisms and not just humans to do evolutionary comparisons.

DZR: How did the HGP intersect your life at Michigan?

FSC: In 1990, when the genome project started, I had a center at Michigan with a bunch of other investigators working on this approach to try to understand disease. You could see things were starting to gather momentum although it was a little slow going at first. Jim Watson was the legendary figure who played a very significant role in giving this project credibility, even though Watson is quite an unpredictable character and is sometimes incredibly rude and capricious; just the same his reputation attached to this project guaranteed that it would go. I assumed he would continue that leadership role for at least five years, but of course that did not happen. He got into a big battle with Bernadine Healy, who at that point was the head of NIH, so that meant she was his boss. Eventually she tired of his insulting remarks and fired him.

DZR: How did you feel about Watson’s departure?

FSC: I thought, “Oh boy, this project is still young enough and fragile enough that it could collapse.” But over the course of several months the search got started and people began to come around with ideas of who might lead the enterprise. My name appeared on somebody’s list, so I got a call to come and interview for the position. I went but I wasn’t all that interested. Healy offered me the job. I turned her down.

DZR: You did?

FSC: Yes, because I said, “You know, I’m having a great time.” I was running a lab, seeing patients, teaching medical school students genetics -- which I really get a bang out of -- so why would I want to give that up? To be a government servant? [Laughs]

DZR: So what happened?

FSC: They started the search over again. A few months went by, and then I began to wonder, “What am I really doing here? Are you, Collins, really going to turn around and walk away just because it’s not convenient?” Ultimately I did decide to take the job and I started in the spring of ’93.

DZR: Do you still have ties to Michigan?

FSC: I do. I still go back there and teach a couple of guest lectures to the medical students. My daughter is there; she’s a social worker in the medical center so I have another excuse to go back there. I recently remarried and my wife lives in Ann Arbor, so we have a commuting marriage.

DZR: I take it you’re not planning on leaving the HGP anytime soon.

FSC: This would be a very difficult time to walk away. Right now we are in the most intense phase this project has ever seen and I am spending most of my waking hours trying to oversee, organize and manage an incredibly complicated but exciting enterprise. This would be a very bad time to change jobs, but perhaps in two or three years.

DZR: Why did the head of the NIH, Dr. Harold Varmus, announce he wanted to leave his job?

FSC: We’re all grieving about his departure, because for almost the entire time I’ve been here, he has been my boss, and a wonderful boss he has been. To every issue that needed a solution, he answered, “What’s the scientific basis for this? We’ll get to the politics later.” As a person with incredible judgment, you could hardly imagine somebody who could do this job better then he has. He will be the standard for a long time to come. He said when he came here in November of ’93 that he was going to stay for five years. He actually stayed a year longer. He is 59 and wants to run Memorial Sloan-Kettering and I’m sure he’ll make a remarkable mark on that place.

DZR: Do you have any interest in his job?

FSC: Not at the present time. Three or four years from now I would be potentially interested, but right now I have a job. The thing I can do that is most useful is what I'm doing.

DZR: I imagine that you would want to finish what you put so much energy and time into.

FSC: Yes. It would be very painful not to see it through after having come this far. We are on the path to having 90 percent of the sequence in working draft form, which is five years sooner than when most of us thought we’d ever see that happen. We still have an incredible six months ahead of us, and we are stretching the genome center’s capacities to the limit. People are getting pretty stressed out.

DZR: When do you expect the entire human genome to be complete?

FSC: I’m guessing we’ll be done in 2002.

DZR: Does gene hunting get easier or tougher with time?

FSC: Trying to figure out which gene goes with which disease gets easier because there is all this data to work from. You don’t have to define the neighborhood where the gene is; it’s already defined for you. You can go straight to the step of trying to see if there is a difference in a sequence between [the DNA of the affected and unaffected individuals]. But some parts of the genome just don’t clone very well and the expectation is that those are going to take us longer.

DZR: In other words, although this needle in a haystack search is frustrating, it’s becoming easier with more findings.

FSC: Right. It used to be worse than that: it was like a needle in a haystack, in the dark, with gloves on! But now we’ve shined a light on it, and we’ve categorized all the straws in the haystack so we know what they look like. We’ve also given you some nice tools to distinguish metal from straw. So, literally, what we took 10 years to do for cystic fibrosis can [now] be done by a single researcher in six months. The whole process is telescoping dramatically. You don't have to wait until it’s all done to start using it. It’s not like a superconducting supercollider, where you don’t get any data until you’ve already invested billions of dollars digging a hole in the ground. The genome project is done in an incremental way and each milestone has been extremely useful.

DZR: Since this is a government project, do people tend to think of it as slow and bureaucratic?

FSC: Yes. I constantly try to fight that. People assume since it’s federally funded, it is bloated and inefficient, but the actuality could not be more different. I say to people who carry those stereotypes that this is a government-sponsored project that is ahead of schedule and under budget. I think one of the best things government does is support science; the National Institutes of Health is, after all, a government agency but it is the envy of the rest of the world in terms of what it does in biomedical research.

DZR: Where is the source of the DNA?

FSC: It is a bit of a collage of DNA from a small number of individuals, about five, who answered a newspaper ad and volunteered to be donors. We don’t know who they are because their samples were anonymized. That was done on purpose because all of this information goes on the Internet every 24 hours. Part of the cardinal principles that we followed from the beginning of the project is that data is immediately released into the public domain. Would you want your DNA sequence on the Internet?

DZR: Probably not.

FSC: Maybe not. There might be a few things in there that would be awkward or cause you to have trouble with your health insurer or your employer. To avoid that risk, we set up this anonymized plan.

DZR: Do you consider part of your job tackling societal consequences and ethical dilemmas of the HGP?

FSC: Absolutely. I in fact find that I spend almost as much time on those issues as I do on hard science. The project from the beginning included an ethical, legal and social implications component, on which we spend five percent of our budget. This is the largest investment in ethical research ever, on any topic. Out of that has come a wealth of good scholarship to point to what some of the issues are for the present and the future. We all have to take some responsibility to try to fix some of the problems that have been identified or we may have this genetic revolution and people will wish we hadn’t. This involves the urgent need to prevent genetic discrimination in health insurance and the workplace. We have seen considerable progress in many states and to some degree at the federal level, but there are still loopholes that need to be filled in order for people to feel totally safe learning genetic information about themselves.

DZR: How much are you involved in the political process?

FSC: I spend half a day a week on Capitol Hill talking to members of Congress. Our elected officials are fascinated by genetics and it is fun to talk to them and explain what this project is about. Many are quite heroic in their view of what their role is as public servants, although there are also some idiots who I won't name. This part of the job causes me to rub elbows with people that I never would have; to spend time with the President of the United States is something I never imagined.

DZR: Will the completed project be one of the most amazing accomplishments in the history of science?

FSC: There are over 1,000 people now whose full-time activity every day is trying to get the genome project done. They range from technicians working at the lab bench to people building robots to get more work done. They all believe in this so passionately as the most significant thing they could be doing. I interact with some of the best and brightest minds in the entire field. Not only are these fun people to be around but you get a sense of history and significance about what’s being done here, which is quite powerful. Once in a while I just stop and think about what this means and it makes me marvel that we are right now in the midst of something which history will look back on as probably the most significant thing that ever happened in biology. There will be other significant things down the road, but over the past several millennia, what we’re doing will probably be viewed as the most major step in reading our own instruction book. You only have to do it once. We’re doing it.

DZR: Doctor Collins, thank you so much for your time. Good luck with the rest of the project!

**********************************

Sidebar: Mapping the human genome

The Human Genome Project (HGP) is a worldwide effort to identify the 50,000 to 100,000 genes in human DNA. Project findings could revolutionize medical treatment of inherited diseases such as Huntington’s, Parkinson’s, Sickel Cell and Tay-Sachs Diseases. However, social, legal and bioethical puzzles continually emerge. Genetic discrimination in the workplace, for instance, is what alumnus Dr. Francis S. Collins, director of the National Human Genome Research Institute, has to ponder once a week on Capitol Hill. “We have seen progress in many states and at the federal level, but there are still loopholes that need to be filled in order for people to feel safe learning genetic information about themselves,” Collins says.

HGP scientists expect to complete a high-quality sequence of the human genome by 2003. Although the task is enormous, scientists understand what they face, because each milestone, starting with the mapping of chromosome #22 in 1999, adds fresh data to the study of human genetics.