M.D.-Ph.D. Program Harvard Medical School Spring 1997 Newsletter

Articles in this issue:

Star-Crossed Beginnings: Dean Adelstein Shares History and a Vision of the Future

S. James Adelstein, M.D., Ph.D., Cabot Professor of Medical Biophysics, has been a prominent figure in the life of Harvard's M.D.-Ph.D. Program since its inception. Before he leaves his longstanding post as Dean for Academic Programs to continue his scientific career in nuclear medicine, we didn't want to let him go without sharing with Newsletter readers some of his thoughts about the past and the future of the M.D.-Ph.D. Program.

Tell us about the beginnings of the M.D.-Ph.D. Program at Harvard and about your early involvement.

The M.D-Ph.D. Program at Harvard started in the face of opposition and handicap--members of the faculty, including Dean Berry, who thought one degree was sufficient; a university bureaucracy that would not allow the same course to count toward more than one degree; and a complete absence of resources. Much of my information about the start of the program comes from Bert Vallee, who chaired the group of proponents and wrote the first MSTP application. Even that was star-crossed when President Nixon declared a moratorium on training grants on the day that ours was approved. Moreover, Vallee's committee was cautious and slow to action. Eventually, he wore the members out by calling meetings on Friday at 5 p.m. when everyone was tired and hungry and might approve anything. The new dean, Robert Ebert, and the new chair of pathology, Baruj Benacerraf, were supporters and helped push the initiative through. When the MSTP was awarded, Vallee asked me to assist him and a few years later I took over direction of the program.

What changes have you seen in the program during the last twenty years?

In the beginning, we had a unique admissions policy, admitting students only after their second year, and only if they had demonstrated a capacity for research by working in one of the university laboratories. The restriction was predicated on a desire to have students clearly dedicated to a research career and those who would see both degrees through to the end. Actually, in the early years, we had no drop-outs, with the exception of one student, who never finished his M.D. requirements but went on to a distinguished career in basic science. I recall going to the program directors' meetings in those days and always being warmly greeted by those directors who liked Harvard not going head-to-head for college graduates; actually, many of the best still came here, despite the absence of the MSTP support in the first two years.

Another unique feature of the Harvard program was, and is, the option of earning the Ph.D. in any of three graduate divisions: DMS, FAS, and MIT. This provides a great range of opportunity for our students. I was delighted, also, when the MacArthur Foundation elected to provide funding for students in social sciences, giving us a dimension not enjoyed by other programs. I regret that that funding has not continued.

In the past several years, the graduate programs have become much more exacting, a good thing that prepares our graduates for the competitive scientific world that now exists. I do think that too much course work is demanded of graduate students, Ph.D. or M.D.-Ph.D., and a rethinking of graduate education is in order, but that is another subject.

In the current environment, what does the M.D.,Ph.D. have to offer that either a physician or scientist alone cannot offer?

As much as ever, and perhaps even more so, future advances in medicine will rest on those in science and technology. Although careers at either end of the spectrum will attract some of our graduates, I see the bulk of them working at some point in the bench-to-bedside/clinic continuum, whether it be turning out general scientific findings into particular ones, seeking in them the pathogenesis of disease, developing technologies and therapies based on some findings, or being the initial demonstrators of their utility. Given the span of their knowledge and experience, I see them also as the quintessential academic leaders of tomorrow.

As someone who has been with the Harvard M.D.-Ph.D. Program from its inception, what parting words of encouragement do you have for those pursuing dual degrees?

Forty years ago I was exhilarated to be a graduate student with a medical education. It gave me a perspective different from that of other students and enormous motivation to learn. I am certain it still can. I hope that today's students will see their dual education as "enabling" and "empowering," using the contemporary parlance. I can think of no circumstance that better combines a passion for discovery with the desire to help the sick and suffering. Our students are all being prepared for a remarkably satisfying professional career. I wish them the joy of it.

Translational Research

by Andrew Elia

On April 10, the M.D.-Ph.D. Program hosted its first lecture in a series focusing on clinical research. Dr. William F. Crowley, Jr., Professor of Medicine and Chief of the Reproductive Endocrine Unit at Massachusetts General Hospital, was the featured speaker. He described his research on the neuroendocrine and genetic control of human reproduction, offering students a glimpse into the work of a translational investigator. As Director of the Clinical Research Program at MGH, Dr. Crowley is committed to identifying students who demonstrate potential for a career in translational research.

Translational research is the present catch-phrase in clinical research circles. It can be defined as the process of translating discoveries made in the laboratory into clinical interventions for the diagnosis, treatment, or prevention of human disease. Translational research is a two-way street, as observations made in the clinic often increase our understanding of cellular physiology and lead to the development of novel experiments.

Dr. Crowley's story is replete with traffic going in both directions. Early in his career, he translated basic discoveries about the pulsatile nature of GnRH release from the hypothalamus into treatments for precocious puberty and hypogonadotropic hypogo-nadism. He then returned to the bench, using these new therapies as experimental tools and GnRH deficient patients as "human knockouts," in order to further elucidate the endocrine control of human reproduction. Dr. Crowley cautioned us about viewing the development of a therapy as the end, "for it is a probe to study another problem and thus the beginning of an opportunity."

The unique opportunity to apply recent advancements immediately and directly to the care of individual patients, and potentially cure their diseases as in Dr. Crowley's case, is what makes translational research attractive to many. "If I ever had any doubts about translational research," Dr. Crowley explained to us, "they died when the mother of my first patient with precocious puberty thanked me for giving her back her daughter." Crowley expressed his wish that more students could share in such moments because he believes that if they did, no one would return exclusively to the laboratory to stay.

M.D., Ph.D.s are ideally suited to translational research, Dr. Crowley informed us. Trained in both medicine and research, they are able to translate the jargon of both fields and therefore play a critical role at the boundary between the two. The completion of the human genome project will spell an extraordinary opportunity for M.D., Ph.D.s and others trained at this boundary because phenotyping will become an important skill. Dr. Crowley indicated that the ability to recognize subtleties in phenotype will gain importance, as it will figure prominently in mapping the relationship between genotypes and their expression. This valuable skill will not lie in the hands of the geneticist, but of the translational investigator and the M.D., Ph.D.

Andrew E. Elia is in his first year of HST.

My Life As a Rapidly Aging Dog

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

Dear Diary, 30 June - Well, here I am about to start my first faculty position. Finally, no more idiots asking me where I see myself ten years down the road. Medical school, graduate school, internship, residency, a fellowship in gastroenterology and a postdoctoral fellowship in genetics-all behind me now. Yes sir, fourteen years of my life-vanished. I'm so excited I can hardly sleep.

1 July - What a rush. Jack Dunbal, Assistant Professor of Medicine. Has quite a ring to it. Got a lab with my name on the door, and Bob (my technician) is busy labeling all of our belongings-the scientific equivalent of marking territory with urine. Everything seems to be running without a hitch.

6 July -Slight hitch. Noticed today that all of the equipment in my lab is labeled "Dumbell." Either Bob has a hearing problem or a wildly self-destructive sense of humor. Ran into the head of the MD-PhD program who asked me to interview prospective students. Said she had seen that Cell paper I had last year as a postdoc with Roger Steel. Yessir, I have really arrived.

7 July - I'm so anxious I can hardly sleep. Had our first Departmental Faculty meeting this morning. Told we will be expected to attend 2 months a year on the Medicine service, 3 months a year on the GI service, supervise the fellows in clinic one afternoon a week, and have two RO1's and a PO1 in place in two years. For those of us interested in the tenure process, the average faculty member attaining tenure last year had published 79+/-11 papers (not that anyone's counting). The room was very quiet.

31 July - Why isn't anything working in the lab? We can't seem to get through any experiment without realizing that we are missing a reagent or a piece of equipment. Thank God we have that pinworm paper ("Molecular mechanism of crescendo pinworm infestation") to write up. It'll be my first paper as senior author. Can't decide whether to send it to Cell or Science. I can see the cover now...

14 August - Called Ben Lewin to let him know my paper is on its way to Cell and that I want an expedited review. Figured, since Ben is familiar with my work from that last paper I had in Roger's lab, it would probably make things go more quickly. Secretary said she was sure he'd be grateful I had called.

28 August - Nothing from Cell yet. Maybe it's already been accepted and they are just trying to decide about the cover? Couldn't get a hold of Ben-he must be awfully busy.

29 August - Heard from Cell today. They didn't even send it out for review. Demanded to speak to Lewin. Told the secretary to tell him that it was Jack Dunbal. I got turfed to the assistant associate editor who explained to me that Lewin didn't have the slightest idea who I was.

30 August - Reformatted the Cell paper for Molecular & Cellular Biology, despite my better judgement to send it to Science. Oh well, better just to get it out.

1 September - Started working on my first RO1. Tom (office next to mine) asked how it's coming. Told him so far I had an outline of the science. He seemed surprised that I thought I could write an RO1 in a month. What's the big deal? A couple of all-nighters and I'll be set. How different could it be from that fellowship application I wrote?

7 September-I've got the PHS398 headache. What's with all the forms? And how am I supposed to fill them out without a typewriter?

14 September - Nasty call from the head of the Animal Use Committee. Said my protocol doesn't meet the minimal guidelines for humane treatment of pinworms. Also I apparently used the July 1997 forms instead of the September 1997 forms and I failed to turn in appendices III, VII, IX, XIII, XVI and XXIII.

20 September - Big fight with Sally. Says I never do anything around the house anymore-I'm never home for dinner, I'm no help with bedtime stories, no help on yard work, no help on the cleaning, no help with the dog, no help paying bills, and I hardly earn any money. Why can't I sleep at night?

28 September - Finally got my RO1 formatted correctly. I've spent more time on the headers and footers than on the Specific Aims. I think I'm going to make it.

29 September - Computer crashed. Oh my God. Oh my God. Oh my God.

30 September - Got my RO1 to FedEx at the airport 90 seconds before they locked the door. Got lost coming home-I realized that since we moved here I haven't driven anywhere except home to work, and work to home. I should really buy a map.

8 October - Started interviewing MD-PhD candidates this morning. I can't believe how young they are. It's very invigorating, though, to see their enthusiasm. I'm really going to enjoy this.

16 October - Got the pinworm paper back from MCB - they didn't send it out for review either. I'm getting the feeling they know something that I don't. Where to send it now? Perhaps the Journal of My Paper Is Too Good For This Journal, But....

11 January - If I have to interview one more prospective MD-PhD student I'm going to scream. Today while interviewing a guy from Duke I ran out of questions after about 5 minutes. What I really wanted to know was, why is one of the MCAT scores a letter? Out of desperation, I asked him where he saw himself ten years down the road. I may have to shoot myself.

26 January - Nothing's working in the lab. Not even the kits. As I was walking to the parking lot, I could swear I heard someone whisper, "Industry."

13 March - Got the pink sheets back on my RO1. Elation! Stopped reading after I saw the words "91st percentile"-just like all those algebra exams in eighth grade. Called my wife, whipped off a self-congratulatory letter to my department chair, and planned what I would do with all the money that will soon be raining down upon my lab. Why is everyone always talking about how hard it is to get grants? Is this a wonderful system or what?

14 March - Re-read my pink sheets today. Tom explained that 91st percentile meant that 90 percent of the grants received were rated better than mine, not worse. I suppose I should have been tipped off by the beginning of my summary statement: "This disap-pointing application from an otherwise talented young investigator..."

15 March - Stared at the ceiling for most of last night. What if I don't get any grants? What if I can't publish any papers? What if we get scooped on the pinworm story? I just wish I could get to sleep. Of course, even if I could, my two year-old is screaming in the next room, my four year-old needs a drink of water, and Sally keeps reminding me that we waited to have children because of my training schedule.

16 March - Saw the cover of Cell today - Roger's article on p53's role in the molecular mechanism of crescendo pinworm infes-tation. I can't stand it.

1 April - Just got back from vacation- Sally had me committed at a spa in Arizona for a week of compulsory attitude therapy. I'm starting to work on resubmitting my RO1. Just gotta think positive. I think I can, I think I can, I think I can. . . At least the boomerang paper from hell finally got accepted. One down, 78+/-11 to go. . .

Lewis Chodosh (aka Jack Dunbal), Class of '89, is Asst. Prof. of Molecular and Cellular Engineering and Asst. Prof. of Medicine at U-Penn School of Medicine.

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