M.D.-Ph.D. Program Harvard Medical School Spring 1994 Newsletter

Articles in this issue:

• Physician-Scientist: Paradigm or Paradox (Part II)
• Role Models Offer Advice, Experience
• A Conversation with Gary Nabel, M.D., Ph.D.

Physician-Scientist: Paradigm or Paradox (Part II)

by David A. Shaywitz

Here, we will begin by considering three particular physician-scientists who are trying to integrate very productive bench research with an interest in and a commitment to patient care.

Dr. Michael Kastan
Michael Kastan, a Pediatric Oncologist at Johns Hopkins University who studies the p53 gene, feels that maintaining both interests "is possible at the appropriate institution, if the clinical situation is appropriately structured. For example, I attend one or two months a year; otherwise, I'm not responsible for emergencies-these situations are handled by residents, fellows, and the attending on service, with me acting as a type of consultant." Kastan says that at scientific conferences, "people seem surprised when they find out that I see patients," and adds that his clinical responsibilities "don't negatively impact my research." In Kastan's view, "big discoveries are serendipitous, and you need to get the big picture to advance the way we think. In graduate school, I thought that the questions we were asking in the lab were the most important things there were. I've since realized that it's not optimal, for me, to approach science that way; in addition to being good at the details, as a principal investigator you need to know how your work fits into the big picture, so you can ask big picture questions. This is the biggest advantage of clinical work: you can keep your perspective, you can keep your priorities straight, you can better understand the overall picture."

Kastan also feels that his ability to do both has been quite strongly influenced by the department he is in, and by the subspecialty he chose. Kastan asserts that in some subspecialties, there is much more chance for an "interface" than in other subspecialties, and he strongly advises students to "get experiences that will help you make the decision. Get apprenticeship training so you know what you're getting into. Many MD/PhD students, in doing a very abbreviated clinical stretch, miss this chance."

Dr. Don Ganem
Don Ganem, an infectious disease specialist at the University of California, San Francisco (UCSF) whose research focuses on the mechanism of reverse transcriptase action in hepatitis B, is also attempting to pursue both careers. On the one hand, Ganem believes that "the idea of going from bedside to bench to bedside is an organized myth, and is largely untrue," and also that "medicine and science are nowhere as close in career as people would have you believe. The worlds couldn't be more different, the approach is very different. In medicine, you have to make a quick decision based on incomplete information. In science, you have six months to dot the i's, cross the t's, and make sure that every possible control has been run. It's not like having six hours to decide whether or not to amputate a limb." On the other hand, Ganem believes that it is "enormously satisfying to do both."

Ganem acknowledges that he has had to make compromises in order to compete with those doing research 100% of the time, but says that "if you're well trained, you can still function at a high level in your field. The sacrifice you make is that you can't lateralize as much. It's possible to stay well read in areas that are important to your daily work, but it's harder to stay up on things further afield-I just can't do primary reading in these areas. For things further afield, such as drosophila development, I try to stay current at the seminar and mini-review level. Similarly, I find that in medicine, I must concentrate on things directly affecting my specialty."

Ganem also asks, "what happens to `pure' scientists at 50? They're doing committee work, etc., filling up the time I'm spending on clinical work. There are a lot of activities of full-time scientists which are not part of science per se."

Like Kastan, Ganem feels that the choice of subspecialty is very important, and suggests that, in addition to the more frequently mentioned subspecialties-heme/onc, pathology, infectious disease -MD/PhD students should also consider laboratory medicine.

Dr. Stuart Lipton

In the eyes of Stuart Lipton, a neurologist and neurobiologist at Harvard Medical School, there are two sorts of approaches to biomedical research. "In the first," says Lipton, "you start with the disease, and then go after the gene; you don't need to have an MD for this-for example, look at Louis Kunkel's brilliant work on DMD (the gene for Duchenne's Muscular Dystrophy). In the second scheme, you start off doing basic research, and then make a clinical connection; in this case, having a particular knowledge of disease can be quite helpful."

This second pathway describes the course of Lipton's own career. Educated as an MD and PhD at Penn and Harvard, Lipton pursued an internship and residency, then entered a post-doc (though he continued to see patients once every other week "in order to keep current"). Lipton says that his clinical commitment has gradually increased, from about 5% of his time when he first started his lab, to its current level of attending 2-3 months/year plus one or two outpatient clinics per week.

Lipton reveals that initially, the connection between his research- which focuses on "the role of ion channels in neuronal outgrowth, plasticity, and survival"-and his clinical work "wasn't very clear." However, Lipton adds that "recently, these two interests have really come together, particularly with recent discoveries linking neurological disorders with overexcitement of the NMDA receptor" -discoveries, Lipton says, which were facilitated by the ability to integrate basic science and clinical understanding.

Lipton feels that doing both science and medicine well "is possible, in individual circumstances; it is possible in certain fields, less achievable in others." Lipton continues, "It would be very difficult in neurosurgery, for example; if you're choosing a surgeon, you want one who operates at least every other day; in medicine, while you need an intense initial training, it is not necessary to be in clinic every day."

In his own experience, Lipton observes that "while I may lose something by not being in clinic full-time, I'd like to think that I'm able to bring something to my house staff and my patients others may not-for example the application of recent advances in basic research."

Lipton advises students that the ability to do both depends on the individual field, and points to neurology as a "very attractive" example of a discipline where this is possible. "We have so far to go," he says, "but this is a very exciting time. Right now, we are where cardiology was 35 years ago."

Lipton also believes that synergy between medicine and research is "possible, with a little bit of luck." Lipton continues, "the education received in medical school and graduate school are quite different. In graduate school, you get narrower and narrower, you learn how to be skeptical, how to question each piece of data that you come across. By contrast, in medical school, you get broader and broader, and have to assimilate such a huge amount of information that it is hard to be critical. In theory at least, these two approaches should complement each other."

Finally, Lipton stresses the importance of selecting "good role models," and emphasizes the value of identifying "the right mentor, someone who is interested in you as a trainee."

Alternative Approaches
While the MD/PhD Program represents one approach towards bridging the gap between clinical medicine and bench research, it is not the only option. For example, National Institutes of Health (NIH) Director Harold Varmus states that he "would like to see more diversity in the kinds of programs we offer students; for example, PhD programs with more clinical material." Varmus says that he has seen post-docs "who are interested in a clinical problem, and want the access and the respect represented by the MD. I would like to see a PhD pathway in which you learn clinical medicine." Such programs have already been initiated at Harvard and UCSF, as well as at several other medical centers around the country.

Varmus adds that he also "used to favor MD programs which offered more science, but now I think that if you really want to do science seriously, you need the PhD. Life has changed, technically, in the last 20, 25 years. Back then, it was much easier to get going. It's hard to learn cloning. People who do best-as post-docs, as young scientists-have either a PhD or good, solid lab experience. In the old days, you could get started in a day, and begin to get results immediately. Now, it takes six months just to make constructs."

The Harvard-Markey Biomedical Scientist Program, initiated in 1991, is an innovative example of the effort to bridge the PhD-MD gap. The Markey Program-which "represents an effort to broaden the training to the PhD," according to Director H. Franklin Bunn-differs from the typical PhD program in several important respects. First, the students dedicate a full year to the study of human biology, taking classes with the medical students and participating in supplementary sessions (including visits to clinical research laboratories and special clinical units) designed to build upon the classroom material. Second, in addition to their affiliation with a particular graduate department, the students are also invited to become members of the Medical School's five Academic Societies, facilitating the integration of the Markey students into the medical student community. However, while the Markey Program is geared to graduate students with an interest in the interface between biology and medicine, it "is not an end-run around the MD/PhD," Bunn emphasizes. "It serves a different need, and a different kind of individual."

Other exciting ideas have been suggested- and, indeed, instituted-by University of Washington Biologist Leland Hartwell. One approach, which aims to "encourage graduate students in basic research to think about clinical implications, to think about the connections between science and medicine" -involves a twice-a-week human genetics seminar. Before the first meeting, several papers are selected which involve a problem in clinical medicine approached through a model system. In the first meeting, the papers are discussed, and questions generated. Later in the week, a second meeting is held with an invited guest from the clinical side who is generally an expert in the field. By asking questions, rather than listening to a seminar, says Hartwell, the students "appreciate how little is usually known, and may develop an interest in pursuing these questions themselves."

Implications
The dramatic changes experienced by biology during the last twenty-five years represent both a challenge and an opportunity for today's physician-scientist. At first blush, the direction much of basic science has taken might seem to represent a barrier to the physician-scientist, or at best, a distraction: worms don't look much like people, yeast don't get cancer, and it is sometimes not immediately obvious that months of sorting through fly mutants or microinjecting xenopus embryos is going to lead to incisive clinical inferences. On the other hand, the molecular study of model organisms has allowed us to increasingly appreciate what Harwell has termed "the unity of life." Genes involved in processes from cytoskeleton organization and secretion to cell-cycle regulation and apoptosis have been exquisitely conserved throughout evolution -conserved not just structurally, but also, it has become increasingly clear, functionally as well.

To the extent that scientists and physician-scientists agree on the utility of model systems, the distinction between "basic" and "applied" research can become extremely grey; is the study of the role of the ALS gene in worms basic or applied? What about the study of the p53 gene in transgenic mice? Indeed, as the study of disease increasingly focuses on the examination of specific genes, and as the study of fundamental cellular processes increasingly turns up genes implicated in disease, the targets for both the scientist and the physician-scientist have become, in many cases, substantially the same.

Yet, does the argument that basic research and disease research are moving closer together define or obviate the role of the physician-scientist? Why not just encourage MD's and PhD's to work closely with each other? An answer, perhaps, is that MD's and PhD's still speak very different languages, and often conceptualize problems quite differently. Physician-scientists, having trained rigorously at both the bench and in the clinic, have the unique opportunity to articulate each perspective. In doing so, they can serve as mediators, and help clinicians and scientists to understand each other's perspective, as well as to formulate questions in a manner meaningful to the other group. Yet, physician-scientists clearly have the potential to be much more than mere translators; as members of both camps, they often have the first opportunity to identify and then pursue meaningfully the most important questions, whether at the bench or in the clinic.

In the long view, then, the hope is that the combined-degree training, as well as alternatives such as the PhD track suggested by Varmus (and exemplified by the Markey Program), and courses such as the graduate class in human genetics initiated by Hartwell, will not just provide the basis for productive collaboration, but will also allow us to better understand natural systems-whether the protein is from Aplysia or a primate, whether the vesicle is in a nematode cell or an islet cell, whether the goal is to understand yeast or to treat humans; the point is, at a certain level, both the questions we all ask as well as the approaches we all take are essentially the same.

And finally, for MD/PhD students in the midst of their training, it seems meaningful to note that nearly all the physician-scientists interviewed for this article felt that their own experiences were somehow idiosyncratic or atypical: "I didn't follow the usual route" or "I'm a special case" or (most frequently) "I was really lucky ...." If there is a designated route to becoming "a successful physician-scientist," there aren't many people who follow it. This responsibility to carve our own paths, while perhaps somewhat intimidating, is also empowering; it suggests that we have the real opportunity to help define for ourselves-and for our generation -what it means to be a physician, what it means to be a scientist, and, perhaps, what it means to be both.

David Shaywitz, a fifth-year MD/PhD student, studies protein sorting in the laboratory of Chris Kaiser, Department of Biology, MIT.

Role Models Offer Advice, Experience

by Molly Lanzarotta

"If you have 20 people with M.D., Ph.D.s, you 'll have 40 degrees and 50 opinions how to go about getting them." So said Dr. Lee Kaplan to a committee of students, alumni and other faculty affiliated with the M.D.-Ph.D. Program who came together recently to establish guidelines for advising M.D.-Ph.D. students.

The individuality of pursuing a dual degree notwithstanding, things have definitely changed since the days when the M.D.-Ph.D. Program was a small, loose affiliation of Harvard medical students and anecdotal, "grapevine" information sufficed. Now, with an enrollment of 165 students across Harvard Medical School, Harvard University and the Massachusetts Institute of Technology, the Program has grown to the point that the "grapevine" needs to be supplemented and balanced by less subjective information.

Dr. Merton Bernfield, chairing the new committee, explained that incoming M.D.-Ph.D. students express uncertainty about what is expected of them: When is it best to start rotations? Which rotation does it make sense to do first? How should they begin to winnow down the myriad research opportunities available to them? What is the relationship between rotation labs and the final choice of a thesis lab? What does an M.D.-Ph.D. student do during the summer?

To clarify this uncertainty, the committee suggests both a set of written guidelines and the strengthening of formal and informal advising mechanisms. The written guidelines could include estimated dates for completing aspects of the Program, various graduate department requirements, and information about faculty who are available to advise or answer questions.

Dr. Benjamin Neel, a graduate of the Rockefeller/Cornell M.D.-Ph.D. Program, suggested that incoming students be paired with both a faculty member and a senior M.D.-Ph.D. student. "Senior students could advise on inner workings, while the faculty member could provide the `where does this fit into the rest of my life?' perspective."

Several students on the committee concurred that the most important part an advisor could play would be that of a role model who could provide experience and perspective. Second year M.D.-Ph.D. student Alice Tsang stressed that role models are especially needed for women in the Program. "For female students who may encounter only one female lecturer each semester, female M.D.-Ph.D. advisors could serve as role models and could discuss issues that come up concerning gender." In response, Dr. Nancy Andrews volunteered to organize a special seminar for women in the Program.

Questions about "how" led to discussions of "what:" the actual structure of the M.D.-Ph.D. Program. Dr. David Golan pointed out that, in light of the fact that many students are taking longer to complete their degrees, the advisor's role should also concern the end of the Program as well as the beginning. Issues such as whether allowing students to complete three years of medical school rather than two, before entering graduate school, are becoming part of the advising discussion.

Dr. Neel emphasized that "streamlining the clinical" and recognizing the overlap between medical school and graduate school is crucial to clarifying direction and facilitating graduation in six or seven years. "We need to stop acting like a medical school and a graduate school and start acting like an integrated Program."

As Administrative Director Linda Burnley pointed out, there are already supports in place for directing students along the M.D.-Ph.D. path: orientations, retreats, informal advising and the new innovation of afternoon teas. Additional ideas and possibilities are being explored by the advising committee: expanded orientations for first and second year students; advising seminars for students in different stages of the Program at critical decision making times; clear mechanisms for establishing faculty contacts.

Overall, more structure, continuity and definition are needed not only for first year students, but for all students in the M.D.-Ph.D. Program. The new committee hopes that increased interaction between faculty, senior and junior students will foster a greater sense of community in the Program.

"As long as there is a sense of community among students and faculty," says Dr. Kaplan, "the important information will be communicated."

Molly Lanzarotta is Special Projects Coordinator for the M.D.-Ph.D. Program and Associate Editor of the Newsletter.

A Conversation with Gary Nabel, M.D., Ph.D.

by Pradeep Atluri

Dr. Gary Nabel graduated from the M.D.-Ph.D. Program in 1980. His current research involves a radical new approach to battling cancer and other disorders through the use of DNA as a drug. Dr. Nabel and his colleagues reported recently in PNAS that the injection of new genes encased in liposomes directly into a patient's tumor tissue is a safe procedure that can help impel the immune system to destroy the malignancy. Dr. Nabel is Professor of Internal Medicine and Professor of Biological Chemistry at the University of Michigan and Investigator for the Howard Hughes Institute.

How did you decide to pursue both degrees?
I think it's one of those things where I couldn't stand not to do both. When I was doing the clinical side of things I was aching to get back to research, and when I was doing research I liked getting back to the clinical stuff. So rather than close off my options too early I thought this was the best way to get a flavor for what I could do in each area and then decide afterwards.

Was there any time during your MD-PhD training that you were tempted to forgo either one?
I suspect there isn't a day that goes by that any MD-PhD student doesn't ask, "Why do both?" That was always a consideration. Overall, I'm glad that I did both-probably more so now than when I was in training. The combined degree is very helpful in providing perspectives that you just wouldn't have otherwise.

Do you feel your training in both fields influenced the way you chose and developed scientific problems?
Yes, I think it impacts how you approach problems, certainly on the scientific side, but also medically. My general feeling is that you do have to make a choice at some time in your career, whether you predominantly want to do research or clinical work, and you have to do one or the other. Having had the exposure provides a different way of looking at problems and gives you insight on how to build bridges from the basic sciences into the clinical sciences. I think there the MD-PhD training is really invaluable.

Can you give me examples of the way your MD or your PhD training affects the way you think of problems now?
I think there's a different culture behind the PhD and the MD. From the perspective I have now-we are beginning to do things like human gene therapy and intervene in an active sense using molecular genetic tools in human disease-you see this kind of tension all the time. PhDs are really geared toward asking questions directed at fundamental biological problems. If you're an MD-PhD usually you're a little more interested in human biology, as opposed to other aspects of biology, but nonetheless you are still committed to doing good science, which means setting up experiments that are rigorous and can maximize the information you can get, and then going on to the next level.

In contrast to that, physicians are faced every day with having to make decisions and to do the best they can with the information that's at hand, and that's a much different culture, a much different environment. Having been in a position in which you have seen patients, treated patients, talked with families, and appreciated what it means to have fatal diseases, to have to make those decisions-and also to have been in a position where you understand what is required to do good science, to make fields move forward, to try to work on exciting new problems-it gives you an appreciation for what the two disciplines can do. One of the most impressive examples I've experienced in my career was when we began our human gene therapy trials. Until the point when you actually reach the patient, it is largely a scientific exercise, where you justify arguments, try to understand mechanisms, prove feasibility, convince yourself that what you're seeing and doing are real. You do all of that, and when you finally get your approval for clinical trials, the first day you walk in and tell your patients what you're going to do to them, they couldn't care less about any of that. They want to know one thing: Is this going to help me? In many cases, we really can't say yet whether it will.

You're looking at the same problem from much different perspectives. To the extent that you've been able to train and to appreciate what it's like to be a physician caring for a patient , who has a very real interest in doing something that's going to treat the problem, versus a scientist, who's trying to understand it, I think it just makes you more understanding of both areas. It also gives you an appreciation of how you can go about designing protocols or designing strategies that take advantage of both. For example, both in our basic research and in our clinical gene therapy trials, we try to design our protocols so they maximize our understanding of the disease process at the same time that they maximize the likelihood they will benefit the patient. I don't think you can do that so easily if you haven't been schooled in both fields.

You mentioned that one must choose between a research career and a clinical career. When, and how, did you make that decision?
I first realized that decision was inevitable when I was a third year resident and I was arranging to go back and do a post-doc in David Baltimore's lab. I used to go to MIT for the lab meetings. I remember one day-I was the senior resident in the intensive care unit at the Brigham and Women's Hospital and was rounding on these extremely sick and complicated cases, going over all the nuances of what we should be doing, and how to adjust the lines, the pressures, and all the rest, and dealing with extremely sophisticated physicians, people who knew the clinical literature. Then I drove over to MIT and went to a lab meeting, where I was suddenly immersed in an entirely different culture, surrounded by a bunch of post-docs, who were unbelievably bright, high-powered, completely dedicated just to research. The dichotomy of these two groups, how specialized they were, and their juxtaposition within the space of one hour-I recall thinking to myself then that there was no way I could do all of what each of those groups was doing, that I would have to make a choice. I think at some level there was always a part of me that knew I would primarily do research. I just like the challenge of exploring new areas, and the creativity that's involved in research. I always knew at some gut level that when I was forced to commit, it would be in that direction. The pleasant surprise over the years has been that I have been able to maintain some contact with the clinical side, and that there are some ways to do things constructively that make use of the science in a clinical setting. One of the exciting aspects of what's evolving in our work in gene transfer is that now there are opportunities to do rigorous science in humans. That was an unanticipated turn of events.

Would you have been able to pursue this line of research without an M.D.?
I think you can pursue it at some level, but you don't have the same range and depth of experience to draw upon. There are plenty of PhD's who work in gene transfer, but they can't go that last step-many of them may not want to, and may be wise in not wanting to-but, I personally find it very gratifying to be able to apply the work to human disease, to go that last step. It gives you more options, more tools to bring to the problem, and allows you to be more effective.

Given the current funding climate, what advice do you have for those interested in research careers?
I still believe there's something innate in people that want to do research-a curiosity and a desire to understand things, and I think it's that burning desire to know that drives people to do research. I don't think that has changed, or will change. It's still the people who are totally dedicated to pursuing whatever problem they are interested in who will succeed. It would be a mistake if people felt, for the sake of funding, that they ought to modify their goals. For example, some people talk about wanting to go into the area of gene therapy because they think it's more fundable. In fact, it's not-a relatively small percentage of the NIH budget goes to gene therapy. I think people should do basic science that will expand our understanding of human disease, or whatever biological process interests them. If opportunities occur to do something constructive in a more clinical area, then you can pursue them. I think there will be more of those opportunities that will make sense to pursue in a scientifically rigorous fashion. But I wouldn't change priorities. I wouldn't say, I need to do gene therapy because it will be better funded in the future. Stick to basics.

I do feel that the world of research is changing-I don't mean to minimize that. Obviously it is becoming tighter with respect to funding, and there are more people who are choosing biotechnology as an option, or pharmaceutical companies. But I don't think you should decide too early, especially not while you're still a student. That's a time when you should study what you like to study, just because you're interested in it. There shouldn't be any compromising on that.

Is it a realistic goal to do both clinical and research work?
It depends on how you define "both." In some ways, I could be said to do both. I attend in medicine at our clinical research center when I have patients in our gene therapy protocol. But in fact I spend 90% or more of my time in research. I get a tremendous kick out of doing the clinical work that I do, but I don't kid myself that I'm really a good clinician. I'm not the clinician you'd want to send your mother to if she has coronary disease; I might be the guy you'd send a family member to when they've exhausted every known treatment for cancer. But that's really very, very different from being good at research and good at dealing with patients. I think you can straddle both as long as you understand your limitations. If your question is, "Can I do both well?" I really don't think so. If your question is, "Can I do one well and maintain contact with the second one?" I think yes, and that can be very rewarding.

That's the major positive thing about doing the MD-PhD. If you make those contacts too late in your career, if you do your MD, then four or five years of clinical training, and then try to go back into the lab, it's difficult. If you're truly interested in research, you will have wanted to get in sooner, and be doing research. You want to be exposed to both early enough in your training so that you feel reasonably comfortable in each, so that when you go back to one later, that will be a fairly easy thing to do.

What sorts of things did you have to sacrifice, whether in your personal life or in other areas, in order to do both degrees? Was it worth it?
The major thing you lose is time. It takes longer to train, and you postpone certain things. I postponed a lot of the "lifestyle" sorts of things that other people have at an earlier age. You live as a poor student for a longer period of time. But that was something that wasn't so important to me, so I didn't consider it a big sacrifice. All MD-PhD students look around at their cohorts, their medical school class, and see them riding forward into the future, while they are off in their labs toiling away. They wonder, "Am I being left behind?" In retrospect, it all works out. If you are going to pursue academic medicine, it doesn't make a big difference. I probably put off having kids until I was a bit older, but I have them, and I love them. And I didn't put it off that long-I still get wrestled to the floor by my kids without having any broken bones to show for it.

Any regrets?
I don't think so. If you're human you always doubt, and always wonder. But there really is nothing that I'd rather be doing than what I'm doing now. If you were a physicist, you'd really want to have been working in the early 20th century when Heisenberg and Einstein and those guys were doing physics. This is the golden age for biology, and I feel really lucky to be doing basic biology now. I think we're about to enter an era within this golden age of biology in which human biology will be growing at an exponential rate. I feel very lucky to be doing it. And people who are doing MD-PhDs now are even more lucky, for as time goes on there will be more opportunities than ever to combine the two. The short answer is, no regrets.

Pradeep Atluri is an M.D.-Ph.D. candidate in the second year of HST.

top