M.D.-Ph.D. Program Harvard Medical School Spring 1995 Newsletter

Articles in this issue:

• Students, Mentors, and the Ethical Path in Science
• What's a Clinical Investigator?
• You Can Get There From Here
• Newsletter Marks Fifth Year

Students, Mentors, and the Ethical Path in Science

by Lewis A. Chodosh, M.D., Ph.D.

How does the relationship that exists between mentor and student influence a student's ability-or desire-to follow the "ethical path" in science? Having spent virtually my entire professional career as a trainee, this is a topic that has been of some interest to me in the past. Currently finding myself in the (some would say unlikely) position of training graduate students and postdoctoral fellows in my own laboratory, that interest has become far more than academic.

For the most part I believe quite passionately that science works remarkably well both as a process and as an endeavor and that the great majority of scientific trainees do an admirable job of finding -and of following-that "ethical path." Nevertheless, while it is important to recognize those aspects of the scientific enterprise that work, and that should therefore be preserved, we ought to spend at least as much time examining those aspects which don't work, and asking what we might do to make them better.

The relationship between a graduate student or a postdoctoral fellow and their mentor is in many ways parental. There are few relationships in life which are as intense. At its best, the relationship is one of nurturing, in which a mentor teaches a student how to think and act like a scientist. Together they share their thoughts on the daily issues of experimental science and on the larger questions of biology. To be sure, students-like children (if you will pardon the analogy)-are impressionable. Students see science through the eyes of their mentor; what is desirable, what is acceptable, and what it means to operate in the world of science. It is an extraordinarily powerful bond, and this fact has a number of important consequences. One such consequence is that to the extent that a trainee uncritically assumes the values of their mentor there is at least the potential for outright fraud is clear, that between salesmanship and misrepresentation of data is not. However, unlike those highly publicized acts of fraud in which entire sets of data are fabricated, decisions regarding data management and selection are made on a daily basis and often fall into a gray zone. What do you do when the fifth time an experiment is repeated you get a different answer than the first four times? If it means that you have a better chance of publishing the data are you more likely to believe that a technical reason exists justifying the exclusion of that bothersome aberrant trial? Similarly, what of the author who writes an introduction to a paper that portrays the advances in their field as having emanated largely from their own lab while underplaying those contributions of their competitors? What if the author's work was in fact more confirmatory than pioneering in nature? Is that fraud? Probably not. Is that misrepresentation? Yes. What message does it send to trainees to call this merely salesmanship? Is intellectual dishonesty on even as subtle a point as this tolerable in people who serve as role models?

Finally, although I paint a picture in which trainees are dependent upon their mentors, vulnerable to abuses of power, and pressured by unwholesome views of science, in no way do I mean to imply that trainees are absolved of responsibility for their actions. While recognizing the distinction between a forceful argument and misleading use of data may be difficult, knowing the difference between the pursuit of truth and outright fraud is not. The ability to recognize falsification is learned in many places outside of the laboratory and classroom. Despite pressures or temptations to act unethically, most students and postdoctoral fellows ought to be capable of making intelligent decisions regarding their own ethical conduct. There can be no abdication of responsibility.

So, how do we improve the situation? Let me end with five concrete suggestions:

1) Give students explicit instruction in the responsible conduct of research; avoid scenarios in which students are exposed only to the perspective of a single person, particularly a person to whom they are beholden for professional advancement;

2) Create avenues whereby trainees have the means to discuss their concerns regarding misconduct confidentially and without fear of reprisal;

3) Make trainees fiscally independent of their mentors. If trainees fear that by speaking out they risk their livelihood, little progress is likely to be made in the arena of ethical conduct;

4) Strive to present science as a group endeavor rather than as a competition. Emphasize the intrinsic value in being a solid, careful scientist rather than appearing on the cover of Cell . Good science is itself a deterrent to fraud.

Lastly: define the obligations and responsibilities of mentors; our mission must be to foster reverence for the scientific method, as well as the capacity to survive the pressures, avoid the pitfalls, and prosper while taking the ethical path in science.

Lewis A. Chodosh graduated from the M.D.-Ph.D. Program in 1989 and is an Assistant Professor of Molecular and Cellular Engineering and Medicine at the Institute for Human Gene Therapy, University of Pennsylvania School of Medicine.

What's a Clinical Investigator?

by Thomas P. Stossel

Harold Varmus, Director of the National Institutes of Health, has recently defined clinical investigation as when the investigator and the research subject are both human, alive and in the same room at the same time. Investigators who fit this definition are very important, particularly for the conduct of controlled clinical trials essential for selecting therapeutic options and for FDA approval of new drugs, and they often complain that they do not receive adequate recognition or funding (see for an example E. H. Ahrens, The Crisis in Clinical Research, Oxford University Press, 1992).

I believe that all biomedical research is un-der appreciated and underfunded at the moment and that this definition is too narrow-for example, it excludes epidemiologists. On the following assumptions I argue for the importance of a broad definition of clinical investigation, even though the training and maintenance of a clinical investigator may be somewhat more expensive than the development, care and feeding of a basic researcher.

My definition of clinical investigation is research of almost any kind by someone with a medical degree who has had intensive clinical experience in patient management, e.g. sufficient to achieve certification in a clinical specialty or subspecialty, and who maintains some level of connection with clinical medicine in an environment that actively encourages scholarly research. This contact provides incentives to maintain a realistic view of what current medicine is all about.

Physicians in a proper environment interface with clinical problems that need solving and have the most immediate access to patients and to clinical materials for study. Furthermore, clinical medicine requires integration of broad physiological and management principles and recollection of a large body of often disconnected facts. This mental activity contrasts with intense focus that characterizes success in basic science. Although a clinical investigator may need to apply such focus to particular research projects, it is the broader view that is likely to lead the science into the human biology and eventually to the benefit of patient care. This is especially possible today when biotechnology has speeded up technology transfer.

Physician-scientists (whatever their research interests) are also well positioned to serve as advocates for biomedical research in general by relating it to general public concerns about health.

In preparation for the discussion with the Visiting Committee, I reviewed the thesis topics of all graduates of the HMS M.D.-Ph.D. Program since its inception. My (crude) analysis follows:

Harvard/MIT M.D.-Ph.D. Program Thesis Projects

The three time blocks represent about equal numbers of students, 50-60 in each. From the table it is clear that if Varmus' definition is to be taken seriously, our program is failing miserably, although projects related to human biology have increased significantly. This change is, I believe, a result of the molecular biology revolution which has made it possible to study conveniently the molecular basis of genetic diseases (including cancer) with cell lines. Nevertheless, about a third of the theses have continued to involve whole organisms or at least some kind of integrated physiology. In view of concerns expressed by Nobel Laureates Michael Brown and Joseph Goldstein, the ultimate paragons of clinical investigators, this evidence for integration is encouraging.

... it is difficult to find and support physician-scientists who have the right balance to lead clinical departments in medical schools. At one extreme we have pure clinicians who lack the scientific training necessary to formulate problems in ways that direct the focus of basic scientists. At the other extreme, we have scientists who lack the clinical training and experience necessary to expose the core of a disease. Lacking the leadership of scientifically erudite clinicians, young physician-scientists join the race to answer the next obvious question in some fast-moving field of basic science, abandoning efforts to solve any relevant clinical problem.

The debate about what constitutes clinical investigation is worth entering by students in the M.D.-Ph.D. Program, as they are, however defined, the clinical investigators of the future.

Thomas Stossel, one of four hospital coordinators for the M.D.-Ph.D. Program, is the American Cancer Society Professor of Medicine, Harvard Medical School, and Senior Physician, Hematology-Oncology Division, Brigham and Women's Hospital.

You Can Get There From Here: Two Almost Graduates Tell How

by Molly Lanzarotta and Linda Burnley

Looking back on your expectations as an M.D.-Ph.D. applicant and student, what advice do you have for new students?

Kari: The M.D.-Ph.D. path at Harvard is not free-flowing. It takes personal organization and planning. You have to get yourself through the program. You can't put your sail into the breeze and wait for the wind to blow you in one direction or another.

Pietro: Because the program is varied and individual, you can't know how it's going to go. This doesn't mean you can't plan-you have to plan. You need to research graduate programs before you come to Harvard.

People should know this about Harvard: it requires your own effort to make it work-there really isn't a way to guide you through. However, keeping that in mind, things really weren't as bad as I thought they could be. Whenever I ran into a problem, there were always people to help me through: Keiko Oh at HST, Linda Burnley at the M.D.-Ph.D. Program, Jan Ellertsen at MIT . . .

Kari: . . . Leah Simons at DMS.

Pietro: Also, contrary to common advice, what you learn in the first two years of Medical School is indeed relevant to the clinical years, so it's worth your time to learn that material well.

But you did focus quite a bit on research during your first two years. In hindsight, would you do it differently?

Pietro: I would still do the first two years the same way, because my research time was very productive, but I would keep in mind that I was sacrificing a little clinical knowledge. For HST students, I favor the new recommendation to wait for at least one semester before starting research. The January and summer periods are golden opportunities for solid lab work.

Kari: I was actually surprised at how much time I had to do research during the first two years. The New Pathway curriculum gives the opportunity and time to do research. From what I've seen in applications as a member of the admissions committee, students who get into this program should be able to handle this. During the graduate years, it is much harder to keep up with clinical work.

So what advice can you give about integrating medical and graduate school? Pietro: Keep medical and graduate school separate unless they blend conveniently. Integrating medicine and science is a worthy goal, but it should not be a minimum requirement for happiness in your career since its success depends on too many factors outside of your control.

I believe this is especially important during training. Thesis work and medical school can be best absorbed by immersing yourself in them separately, so I would advise trying to divide your time here into chunks, each composed almost exclusively of graduate work or medial school.

Kari: And always be one year ahead in your planning.

What about choosing a lab?

Kari: If you're considering a big lab with a big name, be sure you are going to be recognized for publications, that you will have respect, trust and opportunity. Having an advisor who gives you room to explore and who agrees that there are time limits to a Ph.D. is extremely valuable.

Pietro: Choose a lab as if you were only doing graduate school, but choose an advisor who at least respects your interests in medicine. A few researchers I spoke to at other institutions made it clear they looked down on medical students, and one very important thing you'll take out of the lab is your advisor's respect (in the form of a solid recommendation letter.)

I wouldn't worry about how applicable your lab work as a graduate student is to your future career. Your goal is to learn how to be a good scientist, and you'll learn the most if the project both interests you and satisfies you.

What do you advise about returning to medical school after completing your Ph.D.?

Pietro: In spite of well-founded anxiety about returning to the wards, being a medical student on the wards can be absolutely exhilarating. You have the maximum amount of learning opportunity with an amount of responsibility tailored exactly to your abilities as well as a whole community out to teach you medicine. Take this once in a lifetime chance and enjoy roaming the hospitals.

Kari: You have to learn how to feel comfortable saying, "I don't know, I've been doing my Ph.D. for ___ years." (This only works for the first two weeks, by the way). It helped that I had done two months of clinical rotations before starting grad school and that I had taken the Longitudinal Course in Clinical Medicine.

How did you two stay on track and finish your combined degree in 7 years?

Pietro: My advisor knew my time frame from the outset. He didn't promise anything, but respected my interest in maintaining a certain schedule. In return for his promise to help keep me moving, he asked for 100% of my time during the full-time graduate school years. My department also did not require rotations through different labs, which saved me time because I liked the first lab I tried and stayed in it.

The rest was good luck. Many of the things that can slow you down while you are a graduate student-an advisor moving away, an experiment producing unexpected results, problems with equipment-did not happen while I was in the lab.

Kari: One of my best educational advances in grad school was to "place out" of the preliminary courses required by my Ph.D. department. I still had to take the same number of classes, but this allowed me to take more advanced courses.

Talk one year in advance to your advisor about leaving and plan with your Ph.D. department about graduating (make sure you've completed all requirements). How has doing a combined degree helped you make decisions about your career and what advice do you have about choosing a career?

Pietro: Doing a combined degree has kept me hopeful that I will truly be able to fulfill my interests professionally. Much as I love basic research, I will be all that much happier personally if I can add a flavor of relevance to disease to my future research. In retrospect, doing both degrees wasn't the only way I could have prepared for what I want to do, but it was definitely the most fun way I can imagine.

Kari: Choose a career you love, not one that others tell you to go into. Choose a career that allows you to interact with others interested in basic science issues and to ask why, not just what. There are specialties now populated with M.D.-Ph.D.s and there are lab residencies. It's important to remember that you can contribute as a leader in both capacities.

Five Years of the M.D.-Ph.D. Newsletter

by Linda Burnley

As editor I am happy to comment that our contributors for feature articles have come from a small group of dedicated students willing to tackle an abundant supply of relevant topics. Among those I would like to acknowledge are: Harold J. Burstein (Class of 1994 and Clinical Fellow at MGH), Lewis Chodosh ( Class of 1989 and Assistant Professor at U-Penn), and David Shaywitz (Year 6 student at MIT in Biology). They deserve praise and special thanks for their articles on clinical opportunities during the research years, health care reform, the paradigm/paradox of the physician scientist, residency training, and the current issue's feature on mentoring and ethics. We are also grateful to alumni of the program whose career profiles have reflected what happens to M.D.-Ph.D. students in the afterlife of such a long program.

Special thanks also to Molly Lanzarotta, associate editor and production manager, who offers her writing and editing experience, as well as her impeccable technical skills in designing the layout.

Our goal is to continue coverage of current topics of discussion for the M.D.-Ph.D. Program. We encourage all ideas from interested readers in developing future articles.

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