Francis S. Collins, M.D., Ph.D., and director of the National Human Genome Research Institute (NHGRI), was on hand at the National Institute of Environmental Health Sciences (NIEHS) in Research Triangle Park, North Carolina, last month to deliver the prestigious Rodbell Lecture. In addition to his responsibilities as the "public face" of the genome project, Collins has a major role in serving as a liaison between the genome project, the Clinton Administration, and Congress in helping to guide public policy. He is a staunch advocate of large-scale education in genetic information and in the establishment and implementation of ethical guidelines that address the work and implications of the genome project.

Indeed, as Science's Next Wave found when the NIEHS's two Next Wave campus representatives--Judy Stenger and Trinnia Simmons--caught up with him, Collins is "very heavily into" the ethical implications of the genome project, and he speaks eloquently to the responsibility of the project and its participating scientists to consider and address ethical issues. Collins spoke at length on these and other topics of interest to Next Wave readers during a lunchtime roundtable sponsored by the NIEHS's Trainees Assembly and Science's Next Wave following the lecture. His responses to the questions posed by Next Wave are summarized briefly immediately below; click on the questions to get to Collins's full answers.

Could you tell us about how you got to where you are now?

In outlining his professional biography, Collins states that he took a non- linear career path, admitting, "I did not have a life plan when I started and I probably still don't. I don't know what I'll be doing 5 years from now.

What do you think about the ethical implications of the human genome project?

Collins, who points out that the commitment of the genome project to address ethical issues as well as generate data came at the project's inception, describes four categories of questions: Fairness and privacy; implementation of new medical practices based on genomic data (e.g., genetic testing); use of human subjects; and public education. ("People are scared to death of this stuff," says Collins.)

What impact will completion of the human genome have on young scientists?

Not surprisingly, Collins believes that the impact will be enormous, particularly in terms of the kinds of experiments that scientists can contemplate. "What it really does is open the doorway toward experiments in which the whole genome is your laboratory," he says.

If you were embarking on a scientific career today, in what direction would you head?

Collins suggests that computational biologists are already heavily in demand. "The need for people with that kind of expertise is just going to grow and grow and grow," he says.

How best might one go about getting an education in computational biology?

Collins suggests that there are a number of ways to go about doing this. But in the absence of a formal program at your institution, Collins suggests that you join a lab that already knows the ins and outs of the various software approaches used to answer complex genomics questions.

Do you foresee universities offering graduate degrees in bioinformatics/computational biology?

"Absolutely," says Collins. But he also points out that few universities have assembled the faculty necessary to do this.

What do you see as strengths and weaknesses of your job? What skills do you find most useful?

Collins would have liked more formal training in how to handle some of his responsibilities, and he sees his ability to persuade ("cajole," he says...) a diverse group of scientists to work cooperatively toward the common goal as among the most critical aspects of his job.

Next Wave: Could you tell us about how you got to where you are now?

Collins: I took a nonlinear path to get where I am. In college I stayed away from biology completely. But then I went off to graduate school at Yale University, obtaining a Ph.D. in physical chemistry. I spent my time in the computer center carrying around boxes of Fortran cards, trying to do calculations of collisions between simple atoms and molecules using quantum mechanics. It was entertaining, but was not a particularly inspiring way to think about spending the rest of your life. So I had a crisis as far as what my future was supposed to be.

I decided, well, I'll go to medical school and figure it out somewhere in there. So I went to the University of North Carolina as a medical student and got introduced to medical genetics. Although my experience was very brief, there was an inspiring connection there because there was something that appealed to the part of me that liked mathematics. Medical genetics was also something that was clearly going to be going someplace in the next few years and I wasn't sure quantum mechanics was. So that led to what I wanted to do: Some sort of combination of research and clinical practice involving genetics.

But it took another 11 years before I actually got to the point of doing that, because of medical school, my residency and my fellowship. Eventually I went to the University of Michigan and set up a lab which was involved in trying to find genes that were the cause of various frustrating human diseases.

My lab worked on developing methods to allow you, once you had established linkage, to actually go to the gene. Out of that we cloned the cystic fibrosis gene in 1989 and the neurofibromatosis gene shortly after that. I moved to the NIH in 1993 to take on this role of directing what was then called the Center (and is now called the Institute) of Human Genome Research, stepping into the shoes of Jim Watson. This was an interesting experience--when I stepped into them, those shoes had been untied for quite a while!

NW: What do you think about the ethical implications of the human genome project?

Collins: Well, from the beginning of the genome project--an experiment that raises ethical, legal, and social issues (ELSI)--it was decided that this was a scientific effort that ought to take on some responsibility toward trying to answer these types of questions. That has not been done before, but I think we've come a long way in the last 10 years. We now have a really remarkable cohort of scholars that have been studying which of the issues are in most need of attention and what kind of solutions might exist. I put them into four categories.

First of all is this whole business of fairness and privacy. Is the ability to detect predictive genetic information going to be good for us, or bad for us? Will information that might allow you to avoid some medical catastrophe down the road also be used to take away your health insurance or your job, in which case you may wish you hadn't found out after all. There's been a lot of work on this, and it leads to a clear conclusion that we need federal legislation [to address this]. Having an ELSI program in the genome project lays the groundwork for that. You can have the analysis recommend policy changes, but at some point the political process has to kick in, and that is much harder to implement. That is probably the highest priority--to deal with privacy and fair use.

The second major issue is the question of how these new genetic discoveries get introduced into the practice of medicine? When is a test--for BRCA1, NF, Alzheimer's, or whatever--ready to be part of the standard of care? Who makes this decision anyway? Are we leaving this entirely to the market place, where the testing laboratories basically go out there and advocate that any physician who knows what they're doing ought to be ordering all these tests on all of their patients? This may not be the best [course] to avoid trouble. Once again, a lot of good scholarship [has been implemented], and a number of task forces [are considering these questions]. For example, I serve on an advisory committee to Secretary Shalala that is trying to wrestle with the issues of whether we need more oversight. We essentially decided in the last month that we do and that the FDA is probably the one to do it.

The third big area is the whole business of human subjects and ethical conduct in genetic research. Under which circumstances is it ethical to do a DNA test on a sample of tissue that was archived 10 years ago without proper informed consent? What do you have to do to be sure that you are not treading on long-held and important principles about those issues? There again, I think we've made a lot of progress in establishing guidelines.

The forth area is the educational one. We are not going to see this flowering of genetics that we all hoped would lead to public health benefit unless people understand what it's all about. By people I mean both the public at large, but particularly the primary care providers, who are going to be the ones who become the practitioners of genetic medicine. Most of them aren't ready. Most of them don't know nearly as much about genetics as they need to. So it becomes a high priority to try to implement some way of achieving genetic literacy.

Another current emphasis of our research in the "educate the public" domain is to anticipate the consequences of the study of variation, which has now become a major part of the genome project--trying to understand the 1% of the genome where we all vary. That's going to be really powerful for uncovering susceptibility to disease, but is also likely to be used for all sorts of nonmedical purposes. How will people adjust to that? How will it affect our view, which is already a complicated enough one as it is, of ethnicity and race? The more you study the science of human variation, the more you conclude there is really no scientific basis to the categories we use to describe ethnicity and race. There really aren't any precise boundaries at all. That forces us to say that many of those definitions are really social and cultural. It's a bit of a long answer, but I am very heavily into this.

When I came to NIH, I thought, well, this was an important program and I better pay attention [to ELSI], but I'd bet I spend half my time on the ethical, legal, and social issues and I wish I had more [time] to spend on them. They are so critical. If you don't put every bit as much attention on these issues as you do on the science, you'll find that all of the happy consequences won't come to pass, because people are just scared to death of this stuff.

NW: What impact will completion of the human genome have on young scientists?

Collins: A lot. Eighty percent of the human genome is already in GenBank, either in finished form or as a working draft form, which is still pretty good [data]. So this is not necessarily a question for the future. It's also a question for the present. I hope it frees people up from doing stuff that maybe hasn't been all that rewarding, such as cloning and sequencing pieces of DNA that hadn't been sequenced before. Of course people will still want to clone and sequence to look for variations. That's going to be important for a long time to come. But I think what it really does is it opens the doorway toward experiments in which the whole genome is your laboratory. I would think that's where a lot of the really interesting [research] of the future is going to come--whether it's doing comparative analysis of large genomes, like human versus mouse versus the fly versus roundworm; whether it's expression arrays, where you're looking at tens of thousands of genes at once; whether its proteomics, where you're trying to look at protein-protein interactions of a large genome; or whether it's computational biology, which is going to be part of all of these things, but will itself, I think, be one of the most exciting places to be.

NW: If you were embarking on a scientific career today, in what direction would you head?

Collins: If I was a first-year graduate student looking for a place to land right now, computational biology is very, very attractive. We don't have nearly enough of those [scientists]. Many [computational biologists] are being siphoned off to industry. The training programs that exist are not as numerous as they might be, but some of them are pretty good. The need for people with that kind of expertise is just going to grow and grow and grow.

People that are most successful at this primarily started out studying biology but also had an interest in acquiring some sophistication in computational methods. This is something you might want to consider building your strength in--having the ability to do sophisticated computational analysis of large data sets and figure out what they are really telling you--because it is going to be essential in terms of fundable research.

NW: How best might one go about getting an education in computational biology?

Collins: I think if you really want to become experienced at a sophisticated level, you probably need to identify a laboratory where this is a major priority. Find an investigator who knows the ins and outs of the various software approaches to answering complex questions, be it population genetics, expression analysis, or sequence analysis (i.e., comparative genomics).

We are spoiled up in Bethesda because we have the NCBI [National Center for Biotechnology Information] right there on the [NIH] campus. That organization has doubled in size in just the last 2 years. There are a couple of hundred people at NCBI, about half of them are postdocs doing incredibly interesting [research]. That is probably the largest collection of bioinformatitions in America. [NCBI] would be a very exciting place to spend a little bit of time.

There are a variety of short courses that are now being set up at various institutions. We have one at NIH that Eric Green, Mark Bogulski, and Andy Baxevanis are running that is incredibly popular this year. About 250 people signed up, virtually none of them from the genome institute. That short course has all of it's materials and problem sets on the Web. Also, Andy Baxevanis and Francis Ouellette have a book out on bioinformatics that is very hands-on and practical. It's a very good way to survey what's there and get a chance to increase your strengths in some of these areas. So depending on how deep you want to go into it, there are various levels of opportunity.

NW: Do you foresee universities offering graduate degrees in bioinformatics/computational biology?

Collins: Absolutely. In fact we are trying to encourage that. The NIH commissioned a study on bioinformatics that was led by Larry Smarr, who runs the Supercomputing Center at Illinois. Their recommendations were several, but one of them was we've got to make a high priority of [establishing] training programs. I think the students are out there who are interested. The problem is, a lot of the universities don't at the moment have the faculty together. There are relatively few such folks who haven't already gone off to pharmaceutical companies, where the grass is greener.

NW: What do you see as strengths and weaknesses of your job? What skills do you find most useful?

Collins: That's a good question. I am certainly not very well trained for a lot of things that I do. One of the things I do is serve as the project manager overseeing the sequencing phase of the genome project. I didn't know this was going to be part of the job when I arrived here. About a year and a month ago, in February of '99, it was clear that we really were going to push this working draft over the finish line in a very short period of time and we had to be much more coordinated than we had ever been before. The centers that were doing this had to get together someone to organize this--me. That means I have to cajole people to work together; to make sure the genome is all it's intended to be; to keep a wonderful collaboration on the international stage. I don't have formal training in this at all, so I do wish I had a little more formal background.