Chapter 11: Training Physician-Scientists at MD Anderson

Chapter 11: Training Physician-Scientists at MD Anderson

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Description

Dr. Bast explains the Office's role in training and supporting physician-scientists. He talks about funding: the success in bringing the translationally focused SPORE grants to the institution and MD Anderson funding for collaborative, translational projects. Next Dr. Bast describes career development programs: the Physician-Scientist Program and a course in development teach young scientists how to approach problems translationally. Dr. Bast comments on the static number of physician scientists in all disease areas and comments on medical education. He describes a plan for an innovative patho-biology course offered at the Graduate School of Biomedical Sciences. He talks about the role that pharmaceutical companies currently serve in funding and driving research. Academic medicine has a role to play, he explains, in identifying biological processes that pharmaceutical companies can target in developing new drugs.

Identifier

BastRC_02_20140724_C11

Publication Date

7-24-2014

Publisher

The Making Cancer History® Voices Oral History Collection, The University of Texas MD Anderson Cancer Center

City

Houston, Texas

Topics Covered

The University of Texas MD Anderson Cancer Center - Building the Institution; Building/Transforming the Institution; Multi-disciplinary Approaches; Growth and/or Change; On Research and Researchers; Understanding Cancer, the History of Science, Cancer Research; Business of Research; Women and Diverse Populations; The Life and Dedication of Clinicians and Researchers; Overview; Industry Partnerships; On Pharmaceutical Companies and Industry; Discovery and Success; Healing, Hope, and the Promise of Research

Transcript

Tacey A. Rosolowski, PhD:

So to go back when you stepped into the role, what did you feel was your mission and the stated mission for the new office?

Robert Bast, MD:

Well, our mission was and is to facilitate translational research. Translational research goes on all over MD Anderson. Each department really has a translational component, some more than others. And so the responsibility for that is centered in each department and clinical center. The purpose of this office is to facilitate those activities. We’ve done that in several different ways. We’ve also expanded our role in shared resources to include not only the shared resources that are partially funded from the core grant, but also the instrumental resources that are shared by different departments outside of the core grant. That’s been more developed over the last two or three years since Ron DePinho became president. We’re also working with the shared resources in each of the centers that John Mendelsohn established. In Alan McClelland and Kat Hale, we’ve got two people who really are experts in the management of shared resources. They’re able to use that expertise not only in the core grant and in the center shared resources but also most recently Alan has begun to help out with the moon shot platforms in terms of being sure that they’re being run optimally. So a portion of our office facilitates programmatic activities and keeps track of the programmatic activities around MD Anderson scientifically, and we also help with the shared resources. Early on we began to work with multi-disciplinary research programs. Now that’s a euphemism for program project grants (P01s) from NCI, and also Specialized Programs of Research Excellence (SPOREs) from NCI. And SPOREs have really become a house specialty. Because we’re so large and so deep and have four or five investigators who are funded from other mechanisms for research in ovarian cancer or in lung cancer or in other areas, we’d started I guess more than fifteen years ago in a collaboration with UT Southwestern with John Minna and Jack Roth. John is from UT Southwestern and Jack of course had headed thoracic surgery here. They developed a joint SPORE, but that the principal investigator was from UT Southwestern. Our ovarian SPORE was the first SPORE to actually be developed here, to come from MD Anderson. We had collaborators at UCSF and the like over the years, but that was our first. Over the years we’ve actually had at peak at about thirteen SPOREs. I think we’re back to six now. And there are only about sixty SPOREs nationally. So it’s been up to twenty percent of the national SPOREs. Each of those grants in the past has contributed up to $3 million annually. They’re down to $2.3 million a year total cost, but it is still a major source of funding for translational research. The purpose of those grants is purely translational. You have to have four or more projects that take an idea from the laboratory to the clinic and ideally back again within five years. And that’s been a very successful program that fortunately has recently been renewed at a national level by NCI. We also have had a number of program projects. Some are more translational than others, but we have established a system where we could provide seed money to encourage investigators here at MD Anderson to get together to establish a track record for collaboration and for publication of preliminary data they need for successful applications to the National Cancer Institute either for program project grants, P01s, or for SPOREs. And with the institution of the Cancer Prevention and Research Institute of Texas there are also multi-investigator awards for CPRIT. So as the going has gotten tougher for funding in Bethesda particularly for P01s, it’s been possible to compete successfully within the state for the multi-investigator awards using the same mechanism. These MRPs involve $250,000 over two and a half years and it’s a competitive program. We usually have—you can award two to three of these a year. And we usually get about five to seven applications for each one that we can award. And it’s evaluated by a faculty committee that we coordinate. And basically these are awarded based on what the perception is of the probability of getting funded after a year or two if the people are working together and developing the preliminary data that they need and the like. And so it’s been a remarkably successful program. We’ve invested about $8 million of institutional funding in that and we’ve received more than $120 million of NIH and CPRIT funding for those awards. And it’s ongoing. It’s still I think a very effective program. So that’s one of the ways that we’ve facilitated translation. Another has been to work on career development for translational scientists. We’ve done that in two different areas. One is for physician scientists. And there had been a physician scientist program that had started just—I guess actually we really formalized the physician scientist program within our office.

Tacey A. Rosolowski, PhD:

When did that program begin?

Robert Bast, MD:

Probably around 2000. It was very shortly after our office was formed. And obviously again there had been physician-scientists at MD Anderson long before that and there had been people training to be physician scientists. But this really brought together a formal program where we could support two or three of our best and brightest young MDs or MD/PhDs to do laboratory-based research with eighty percent dedicated time and still be in the clinic at least twenty percent of the time and in the case of the surgical physician scientists, usually a little bit more than that. With that program we’ve actually had forty-one physician scientists that have been supported across seven divisions. So this has not just been medicine where many of the physician scientists nationally are found, but in surgery and radiation oncology, cancer prevention and pediatrics, internal medicine, pathology, lab medicine. We’ve not been totally successful. Three physicians—we evaluate this each year. Three were actually terminated and four resigned to pursue opportunities at other institutions. And currently six are in the program and there have been twenty-eight graduates. The purpose of the program is actually for people to get their own individual investigator funding either from NIH or from the American Cancer Society. More than 80% of graduates have obtained an R01 or equivalent.

Tacey A. Rosolowski, PhD:

People have said—a number of people that I’ve interviewed have talked about the challenges of supporting a career that is bifurcated in that way. How do you see the challenges? What are the obstacles for someone who wants to take on a physician scientist pathway?

Robert Bast, MD:

You’ve got to do two or three things at the same time really well. Not just being a really competent compassionate clinician, but also being a really cutting-edge scientist who’s completely up to date in what’s going on in increasingly complex fields. But it’s also having a life in addition to that. Increasingly over the last twenty or thirty years people have been “working to live” rather than “living to work”. And I certainly come from a generation of kamikaze physician-scientists who would walk through walls to be able to do their research. But I think that increasingly life balance is becoming an important issue. And I think it’s particularly acute for women because if you want to have a family there’s a time limit on that. And consequently recruiting and supporting careers of women physician scientists has been all the more important. Fortunately, this is one of the few places on earth where you can do that effectively. But it’s still a national and international problem because you really need to be fully trained in medicine and fully trained in research. At this point MDs who get their first grant on the average get that grant at age forty-three.

Tacey A. Rosolowski, PhD:

That’s late.

Robert Bast, MD:

It is. And PhDs are a couple years younger than that. But that’s late too. And basically the career path for physician-scientists would be twelve years of grade school, four years of college, four years of medical school, and if they get a PhD during medical school that’s at least three more years, sometimes more. And then usually residency training, depending on your specialty, requires anywhere from three to five years. Subspecialty training in medical oncology, for example, is another three years. Generally you still need a postdoctoral fellowship or instructorship. There’s no hard and fast rule, but in general if somebody’s going to be effective in the laboratory and be able to get their own grants, on average you have to have about five years of laboratory-based experience. You can do that by earning a PhD. You can do that by pre- and postdoctoral fellowships. But you need to be able to write important papers with mentors to establish your reputation. You need to have been in labs long enough to know how to do experiments and how to interpret them and also you need to have read enough articles and be familiar enough with the areas to be able to have ideas that are worth funding. And all of that takes about five years of laboratory time.

Tacey A. Rosolowski, PhD:

Is there also a dimension of the physician scientist—because there’s so much collaborative work and listening to people in other fields and being able to interact effectively with other vocabularies of science, do you find that there’s a skill set or personality type that is more successful than others or that is more attracted to that career path than others?

Robert Bast, MD:

There are a variety of different kinds of people who end up as physician-scientists. Increasingly there has been more team science in translation perhaps than other areas. But there certainly are people who have individual laboratories as physician scientists that are pretty insular. So, you have posed a great question, but I think it’s difficult to generalize. A lot of basic scientists are excited by the possibility that their fundamental observations might help people. By and large physician- scientists are motivated in Texas parlance from the get-go in terms of wanting to see science help people and to learn from patients and their body fluids and biopsies how to make more effective treatments. So it’s the Arrowsmith approach. There’s a long tradition of course that goes back 100, 150 years for physician scientists in medical history. The majority of Nobel Prizes in medicine went to physician scientists until about fifty years ago. That trend has really changed. And now the majority of Nobel Prizes are awarded to PhDs working in the laboratory rather than to translational investigators.

Tacey A. Rosolowski, PhD:

What created that change?

Robert Bast, MD:

Well, certainly science has gotten a whole lot more exciting. And very often it’s necessary to spend full time in the laboratory to understand and to develop that science. Too, the reward system has been directed toward understanding general principles and truly novel ideas rather than to work out the nuts and bolts of how you help individual people, each of whom can be quite different. Dealing with the individuality of medical practice and dealing with the generality of basic laboratory science are the challenges of translational research. Putting those two things together is the goal. One of the things we’ve worked out in the last five years is a course in Translational Cancer Research for the Graduate School of Biological Sciences (GSBS). That’s a course that I put together and has only a few different lecturers, rather than the usual fifteen different lecturers per course, to achieve a bit more continuity. The classes include graduate students, clinical fellows, postdoctoral fellows and junior faculty. The initial lecture concerns enough tumor biology to understand the principles that underlie translation. Then we’ve looked at how you develop conventional drugs, how you develop targeted therapies, how you develop molecular diagnostics, and how you put molecular diagnostics and therapeutics together for personalized or precision therapy. Then we consider what academe does best, what pharma does best, what NCI does and what the FDA does and the like, hopefully to provide the nuts and bolts of how the system actually operates, and to provide a way for potential physician-scientists and clinician-investigators and translational PhDs to navigate that system going forward. We have also established a new GSBS Clinical and Translational Sciences program with Khandan Keyomarsi and some co-conspirators in UTHealth. Over the years and we finally managed to formalize the courses and get approval from Austin and the like for a brand-new program. I had mentioned translational PhDs. If you look at the statistics for physician- scientists over the last thirty years, the number of docs in the United States over the last thirty years has about trebled to 900,000, mostly from immigration, because only recently have we begun to increase the number of graduates of US medical schools. But there are people from all over the world who’ve wanted to come to practice medicine in the United States. And because there have been a lot of hospitals that have training programs, some with medical schools, some without, it’s been possible for foreign-educated physicians to get training in the US and then join our physician force. The number of physician scientists for clinical research, for laboratory research, not just for cancer but for heart disease and neurosciences and endocrinology and the rest of medical disciplines, has been about 15,000 for the last thirty years. So, less than two percent of physicians have been involved in full-time academic research in the laboratory and in the clinic. And depending on how you count it could be down as low as 13,500 now. So physician-scientists and clinician-investigators are a shrinking or at least a barely stable labor force. One of the realities is that we’re going to need to have PhDs who want to work in translational science both as leaders and as members of groups who really understand enough medicine to recognize an unmet medical need, and enough whole-person biology to be able to function in translational science. When I was going through medical school forty years ago at Harvard, PhDs who were earning their degrees from the medical school spent the first two years taking all of the medical school courses. Consequently, they were exposed to anatomy, histology, pathology, physiology, bacteriology, pharmacology, and more. With developments in science over the last forty years, there’s so much more to learn about molecular genetics and cell biology that the curriculum has changed. But it’s swung almost totally in the opposite direction, where there’s almost no pathophysiology or human biology. One of the things we’re trying to do with the graduate portion of the Clinical and Translational Science program is to provide a crash course in human pathobiology. There’s a new revamping of this GSBS curriculum this year which involves basically a very thorough cell biology course for the first semester to be sure everybody in the Graduate School is on the same page and has the same background. Second semester for the students who are interested in clinical and translational sciences we’re going to have a pathobiology course with a month or two of pathology and normal tissue histology and organ structure. And then go through each kind of disease: heart disease, lung disease, GI disease, and the rest, talking a little bit about cancer for sure. We will provide a general idea of what can go wrong with each one of those organs, but also pick out a couple of the best examples where molecular medicine has informed more effective diagnosis or treatment in each of those areas. Hopefully, that will begin to provide some medical background. In the second year there are programs like “Translational Cancer Research” and “Bench-to-Bedside and Back” that will provide translational expertise. We are also planning a “Clinical Oncology” course where we would discuss lung, breast and colon cancer and cancers at other sites, providing a clinical description of each form of cancer as well as the molecular genotypes and phenotypes and where we are with targeted therapy at different disease sites. So hopefully in that if a PhD graduate student is interested in pursuing that we can provide some of the background for doing that. In addition, graduate students would shadow clinicians to learn how medicine is practiced and to begin to recognize unmet needs.

Tacey A. Rosolowski, PhD:

One of the themes that I’ve been observing as I’ve talked to people, and this conversation that we’ve been having about training has addressed it, is how—people were reflecting back on strategies in Developmental Therapeutics for example and how do we approach a clinical question, how do we start to address this clinical need. There wasn’t really a model. There was well, we’ll just try. And then we’ll go back and evaluate what worked. We’ll try everything and then evaluate what worked. But then it seems that what’s emerging now is much more of a formalized approach. How do we understand a model of what translational research might look like? And it sounds enormously complicated from what you’re describing. And I’m wondering. Do you see it that way? I mean is there a model to be taught? Is it a style of thinking? Is it an approach that each person makes their own because of their own cluster of interests and expertise? How does that work at the training level?

Robert Bast, MD:

One of the things that we’re trying to accomplish with these individual courses and with the overall program for both MDs and PhDs is not only to focus on the laboratory-based problem with which they’re often dealing, but also to develop a reflex to identify the path you would need to take to move that observation to help people in the clinic, and to know what the steps would be, and to anticipate with whom you’d have to work and collaborate, what you’d have to negotiate in terms of intellectual property and working with biotech or with pharma or whatever. At MD Anderson we now have the capacity thanks to the IACS [Institute for Applied Cancer Science] of being able to take a drug all the way to the clinic, if necessary. But even IACS seeks to partner at some point with pharma companies that can help facilitate drug development and to pay for clinical trials.

Tacey A. Rosolowski, PhD:

I haven’t heard that word before, IACS. What is that?

Robert Bast, MD:

IACS is the Institute for Applied Cancer Science. When Ron and Lynda Chin were at the Farber they recruited Giulio Draetta to head the Belfer Institute. When Ron and Lynda moved here they brought the Belfer with them. It’s now the IACS on the South Campus.

Tacey A. Rosolowski, PhD:

Okay, I’d never heard that acronym.

Robert Bast, MD:

And that means that we have the ability to develop drugs in house. A lot of it is done through outsourcing. We’ve got seventy pharma professionals who are developing drugs and biologicals, but most institutions don’t have that capacity. Even here the IACS has a finite capacity and so I think it’s very important for all investigators to understand how you get from a laboratory observation to a clinical advance and also how you actually take advantage of clinical material to study human biology. One of the challenges is to have effective models for human disease. And this isn’t just in cancer, but across the spectrum of human illness. Genetically engineered mouse models have helped and are increasingly useful, but only some of those actually mimic precisely the genetic changes that occur in humans and in human cancer. Pharma tries very hard to identify drugs that will be effective in the clinic. They’re pretty good at identifying toxicities. About eighty percent of the time or more we can figure out that a drug will be toxic and not take it to the clinic. So very few drugs actually flunk out on toxicity during phase I trials. For cancer drugs, only one in twenty drugs introduced into the clinic turns out to be approvable by FDA, if all potential indications are considered. At best, it is one in eight if only the primary indication is considered. The FDA is not to blame. If anything, the FDA has relaxed its standards a bit with some of the targeted therapies. They used to require an overall survival advantage. Now three or four months of improvement in progression-free survival, without any overall survival will get approval for one of the new targeted therapies. So I don’t think that one in twenty can be blamed on the FDA. The real problem is that we don’t have the preclinical models to be able to predict clinical activity, i.e., which drugs are going to work more effectively. So, developing predictive models is a huge need in translational research. With that batting average the pharmaceutical companies are having real challenges. Every time you hear about a merger of a pharmaceutical company. That has happened a lot in the last ten years. When you merge you can lose up to a quarter of the value of both companies.

Tacey A. Rosolowski, PhD:

Really.

Robert Bast, MD:

Mergers are used by Pharma to acquire new drugs and capabilities, but also to cut down on the labor force. Largely because they have to invest in seven drugs to get the eighth, the drugs are priced at an outrageous level. Progress is slow and the future of the companies are uncertain. So at a time when the National Institutes of Health is suffering from the crossfire of the ideologic gridlock we’ve got in Washington these days, the pharmaceutical companies are also struggling. And if you actually look at the numbers, about seventy percent of all the investment in cancer research is from pharma. Much of that investment is in moving things from the lab to clinic and then developing drugs of course. And not so much on the basic side of what you need to know in order to be able to identify the targets. I think that’s one of the areas where academe can help hugely and I know Ron DePinho really sees this very much the same way. Our deep understanding of cancer biology should drive our identification of targets at which we should aim. If you find the right targets, pharma is remarkably good at making molecules that would inhibit those. Some targets aren’t druggable, but increasingly many are. And so with that I think one of the things we really need to do in academe and places like MD Anderson is to understand the molecular, cellular and clinical biology of cancers, what is actually going wrong in different cancers even in the same organ or the same apparent histology, and to try to develop the combinations of drugs that you need. It’s also obvious that with targeted therapies, with a few notable exceptions like chronic myelogenous leukemia, one drug isn’t going to do it. You’re going to need combinations, and then the right combinations will differ from person to person. Working out the ground rules for that is obviously one of the challenges we’re facing in translational medicine here and elsewhere. And I think increasingly that’s going to be true for diseases other than cancer as well.

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Chapter 11: Training Physician-Scientists at MD Anderson

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