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Closing the Bed-Bench Gap Against this background the Markey Trust began to dedicate some of its grants to programs offering innovative ways of training physicians to enable them to engage in basic biomedical and translational research and to expose Ph.D. scientists to disease-oriented research. Through the General Organizational Grants program the Trust requested proposals for two types of grants from selected institutions for training programs: (1) programs that offered significant clinical exposure for Ph.D.s during their student years and (2) programs that permitted M.D.s to engage in research during their years in medical school and residency. The Trust's support of organizational grants began with two large awards to the University of California, San Francisco, and Rockefeller University that were intended to stimulate organizational change. A law- suit interrupted dispersal of funds (see Introduction). When the Trust resumed its grant malting the intention of Me grants had changed from stimulating organizational change to supporting the training of physi- cian-scientists. Grants changed from supporting He training of Ph.D. stu- dents to training both types of students. The Trust funded a wide variety of training programs for M.D.s. These programs provided for intense research integrated into medical school curricula, offered protected time for research during residency, and developed refresher courses in basic science for M.D.s. In addition) the Trust funded several programs to provide basic clinical training for Ph.D.s. For both physician and scientist training programs the Markey 24

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CLOSING THE BED-BENCH GAP 25 trustees wanted to aim for the best candidates at the best institutions, but institutions differed in how they selected trainees. General Organizational Grants programs were funded for approxi- mately five years, although many grant recipients were able to extend the grant's duration. This section describes the kinds of programs supported by the Trust to enhance the workforce needed to address bed-bench gaps. TRAINING PROGRAMS FOR PHYSICIANS The Markey Trust provided funding to seven institutions that pro- vided training in basic research to medical students or young physicians. These programs identified physicians at various stages of medical train- ing and provided opportunities for them to receive intensive training in a 1 ~ 1 basic research. The eight programs provided training and support to 132 physician- scientists during the 1990s. The total cost of these eight programs was $14.9 million and the average cost per program per year was about $317,000. There was a great deal of variation among the programs. One provided five years of protected time. Other programs provided stipends for a two- or three-year postdoctoral fellowship. One program offered an intensive summer program. Programs also varied in terms of the career stage of participants, duration of funding, and training strategies. The average cost was about $113, 000 per physician-scientist. Descriptions of programs that provided training in basic science to physicians are presented below. Children's Hospital Boston/Harvard University ($2,250,000 ~ 1993-1998~. The Markey Child Health Research Center program, co- directed by Philip Pizzo and Stephen Harrison, was aimed at providing research training for pediatricians. Pizzo believed that pediatricians were the most endangered group of physician-scientists. A total of 17 young pediatric investigators received fellowships for one or two years, depend- ing on the availability of independent funding after the first year. Each fellow was assigned to a senior faculty mentor to assist in the training process. The focus of the program was on providing protected tune for immersion into research. The Rockefeller University ($2,500,000 1993-1998~. This grant, developed by Jules Hirsch, provided support for the Clinical Scholars program in molecular medicine to allow research experiences for physi- cian faculty. The program established independent laboratories and train- ing opportunities in research techniques and concepts of modern biology. Salaries and startup costs for two assistant professors and two medical fellows were funded.

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26 BRIDGING THE BED-BENCH GAP College of Physicians and Surgeons of Columbia University ($2 million 1993-1998~. The Career Tracks Program in Postgraduate Medi- cal Education, codirected by Sharon War~llaw and Christopher Schindler, received a $2 million award. The program was modeled after the success- ful Johns Hopkins National Research Service Awards program. Its goal was to provide research training and experience to talented medical school graduates early in their residency training. Fifteen fellows were selected for the two-year program after the second or third year of their house staff residency. During the research-training period residents continued to fol- low their own patients in the general medicine outpatient clinic in order to maintain their clinical skills. Four Schools' Physician-Scientists Program in Internal Medicine ($3.5 million 1991-2001~. Alfred Fishman was the coordinator of this program to develop physician-scientists in the departments of internal medicine at the University of Pennsylvania, Duke University, Washing- ton University, and Johns Hopkins University. The four schools program introduced physicians to basic research in three phases. Phase 1 was a year of research following the third year of medical education. Phase 2 consisted of clinical research experience during residency. Phase 3 was two years of postgraduate research experience. Forty-six physicians com- pleted the program. Yale University ($2.1 million 1993-19981. This grant supported the physician-scientist training program in which physicians retooled over a three-year period. Training consisted of a six-month period of labora- tory courses and 2.5 years of in-depth research supervised by mentors from both clinical and basic research departments. Developed by I. D. Jamison, the program provided exposure to basic research for 12 practic- ing physicians. Each summer the program conducted a two-week inte- grated lecture and laboratory program in molecular and cellular biology designed to reacquaint physicians with the basic science necessary to submit grant applications. This program attracted 20 to 30 participants annually. University of California, San Francisco ($2.5 million 1992-1999~. The Molecular Medicine program, directed by Marc Shuman, enabled 31 physicians who were just completing their residency to spend three years in laboratories of molecular medicine in the university's Program in Bio- medical Sciences. In addition to research experience fellows also received extensive coursework in biochemistry, cell biology, and molecular genet- ics, ensuring that the fellows had a theoretical background comparable to that of graduate students in biochemistry. Brigham and Woman's Hospital ($50,000 1994-1995~. Under the direction of Thomas Stossel this grant supported development of a sum- mer training program for physicians who were beginning laboratory re-

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CLOSING THE BED-BENCH GAP 27 search training. The program focused on three two-week blocks consist- ing of biochemistry, molecular biology, and cell biology. Seven students participated full-time, all day for six weeks through lectures, journal clubs, and hands-on laboratory experience To gain a better understanding of how these programs worked and their impact on biomedical science training, the Markey Evaluation Com- mittee chose to visit three programs that were representative of this type of General Organizational Grant: University of California, San Francisco; College of Physicians and Surgeons of Columbia University; and Chil- dren's Hospital, Boston/Harvard University. Detailed site visit reports for these programs are presented in Appendix F. Unfortunately lack of outcome data on the trainees prevented a deeper evaluation although the Committee believes the support of such training programs is worthy of philanthropic attention. Future funders of graduate training programs should ensure that a comprehensive program evaluation and prospective monitoring of outcomes is an integral part of the overall design of project. The approaches taken in many of the training programs, especially those that provided an extended and in-depth experience in research, are still in use in many academic centers. The value of flexible and generous dollars in resource-constrained times was noted by leaders of these programs during site visits. Summaries of these site visits are in Appendix F. TRAINING PROGRAMS FOR PH.D. SCIENTISTS The Markey trustees funded 12 programs that provided clinical expe- rience to basic scientists. These are listed below. These new experiments attempted to determine whether Ph.D.s with a better understanding of clinical problems could better alleviate the ongoing decline of physician- scientists. One program, at Stanford University, subsequently changed its focus from clinical to basic research. Of the remaining 11 programs the programs at Tufts University and Rockefeller University were already under way when they received Markey grants, having been started in 1986 and the 1970s, respectively. The remaining programs were newly created with Markey Trust funds. These 12 programs provided training in patient-oriented pathobiol- ogy to 430 basic scientists during the 1990s. These programs varied greatly in form and content, ranging from highly structured four-year programs to single summer courses. 1h addition, programs offered training to a wide variety of scientists including undergraduate and graduate students, postdoctoral fellows, and young faculty. The total cost for the 12 pro- grams was $39.2 million. The average cost was about $552,000 per pro- gram per year and about $60,000 per participant.

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28 BRIDGING THE BED-BENCH GAP A brief description of each of these programs is presented below. . Tufts University School of Medicine ($400,000 1989-1996~. This program, built around coursework in pathobiology, has basic scientists at the graduate school and postdoctoral level analyzing 20 major human diseases. The students study gross and microscopic pathology, observe major diagnostic procedures, witness specialized patient care such as re- nal dialysis and transplantation, and participate in clinical rounds. The Trust provided funding for 105 students. The program at Tufts is ongoing and continues to produce scientists versed in disease-oriented research. Outcome data provided by Arias (2003) show that trainees are working in research jobs, many in clinical departments. Washington University School of Medicine ($4 million 1992- 19991. This grant, directed by Alan Schwartz and Jeffrey Saffitz, provided support for the establishment of the Special Emphasis Pathway in Human Pathobiology. The program provided clinical exposure to 33 predoctoral and 18 postdoctoral scientists through a series of courses that focused on a specific disease. In addition to participating in three courses each gradu- ate student or postdoctoral fellow had dual mentors. The clinical mentor had the role of integrating students into the culture and practice of the hospital. This program has been maintained through the combined ef- forts of the 19 departments in the biological sciences that provide support amounting to about $200,000 per year. Harvard Medical School ($4 million 1992-1996~. This project, directed by Franklin Bunn, emphasized the concept of "New Pathways" and the restructuring of biomedical scientist training. Interaction between biomedical scientists and student physicians was stressed. Ph.D.s received a master's degree in medical science. In addition, the program was con- cerned with career outcomes of Ph.D.s and focused on placing Ph.D.s into clinical departments. A total of 57 students participated in the program. University of California, San Diego ($2.5 million 1992-1997~. This program, developed by George Palade, supported the development of graduate studies in cellular and molecular biology. The program fo- cused on inter-institutional training at the UCSD School of Medicine, the Research Institute of Scripps Clinic, the Salk Institute, and the La Jolla Cancer Center (Burnham Institute) for 89 UCSD graduate students. University of Virginia ($800,000 1993-1997~. This program, di- rected by Michael Webber, was designed to prepare scientists to study the molecular basis of human diseases and to facilitate the interaction be- tween clinical and basic scientist researchers. The program, which used a dual-mentor approach for four students per year (a total of 20 students), consisted of one year of course work followed by two years of blended clinical and laboratory experience.

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CLOSING THE BED-BENCH GAP 29 Stanford University ($900,000 1993-20011. This grant was in- tended to enable medical school faculty to develop a new Ph.D. program in molecular mechanisms of disease under the direction of Michael Lieber, a Markey scholar. Because of changes by which graduate student tuition could no longer be reimbursed at universities and He financial difficulties common to all private medical schools, the program as intended became financially untenable. Consequently Stanford received permission from the Markey trustees to use the award to support Ph.D. students in existing interdepartmental programs whose work focused on the studies of hu- man disease. These students were under the direction of Joseph Lipsick and Michael Cleary. Ten students were funded for two years each. University of Chicago ($3.2 million 1993-1998~. The grant, di- rected by Nancy Schwartz, provided support for a new Ph.D. program in molecular medicine. The program recruited graduate students to focus on the biology of human disease using a dual mentor approach. The pro- gram was part of a new interdisciplinary biological science complex with clinical and basic science components. Thirteen scientists participated in the program that bridged the gap between basic science research and its relevance to human biology and disease processes. Johns Hopkins University ($3.2 million 1994-2000~. This grant, directed by Thomas Pollard and Peter Agre, developed a cross-depart- mental program in cellular and molecular medicine. Students took course work in biochemistry, cellular and molecular biology, neuroscience, hu- man genetics, and physiological and pathological basis for human dis- ease. Trainees had access to research opportunities in basic science and access to clinical faculty with joint appointments. There were over 450 applicants to the program and 43 graduate students participated. The Johns Hopkins program was able to redefine its orientation so that it received a training grant from the National Institute of General Medical Sciences of the NIH. Carnegie Mellon University ($1.4 million 1994-1999~. This grant supplemented National Science Foundation-funded support for the Sci- ence and Technology Center. The program provides training in advanced technology and equipment for nine young faculty members in basic sci- ences, five postdoctoral scientists, four graduate students, one computer engineer, and two technicians. This program anticipated the interdepen- dence of modern medicine and technology. The primary areas of empha- sis included structural and developmental biology, computational biology and chemistry, microscopy and imaging technology, and in viva imaging. Lansing Taylor was the program director. University of Cincinnati ($50,000 1995-19961. The program on pathobiology and molecular medicine was developed to encourage and foster the performance of translational biomedical research by graduate

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30 BRIDGING THE BED-BENCH GAP students and was modeled after Irwin Arias's program at Tufts. Gregory Retzinger, a Markey scholar, used funding from the Markey Trust to develop the course in pathobiology of disease taught by the departments of pathology and laboratory medicine (taken by eight graduate students). Intramural funding has allowed this approach to translational research to continue. University of California, San Francisco ($13,750,000 1988-1995~. Under the leadership of Michael Bishop, the Markey award, combined with funds from other sources, was used to fund an extensive reorganiza- tion of the graduate programs in biomedical sciences. Under this proposal the programs in biochemistry and molecular biology, cell biology, immu- nology, neurobiology, and genetics were merged into a new program in biological sciences. Unlike the other General Organizational Grants this award was used primarily to restructure the programs in biomedical re- search and included a component to provide medical experience for graduate and postdoctoral students. Most of the funds were used for equipment, supplies, and construction. Rockefeller University ($5 million 1989-1993~. Markey Trust funds supplemented the University Fellows program, originally devel- oped in the 1970s. University fellows were mature scientists with at least three years of postdoctoral experience and established research agendas. Thorsten Wiesel directed the program. Markey Trust funds supported 13 university fellows as assistant professors and included salary support, equipment, supplies, and renovation. Four of the university scholars were also Markey scholars and seven subsequently became Howard Hughes Medical Institute investigators. The directors of six of these programs participated in the National Research Council-sponsored Workshop on Training Programs in Patient- Oriented Pathobiology for Basic Scientists in October 1999. These direc- tors presented detailed information on the overall description and history of their program, the program's efforts to bridge the bed-bench gap, characteristics of applicants and students in the program, and a summary of program finances. Summaries of the presentations of each of the six programs are presented in Appendix E. TRAINING PROGRAMS FOR BOTH PH.D. SCIENTISTS AND PHYSICIANS The Markey Trust funded three programs that provided training in translational research for both physicians and scientists. A wide variety of predoctoral, postdoctoral, and young faculty received funding from these hybrid programs. A total of $6.4 million was expended to cover the sti-

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CLOSING THE BED-BENCH GAP 31 Fends of 55 scholars. The cost was $320,000 per program per year, or about $116,000 per fellow. A brief description of these programs follows. University of Utah ($2 million 1994-1999~. This grant supported an expansion of the program in human molecular biology and genetics, an interdepartmental effort to strengthen the interface between clinical and basic investigators. The goal was to provide protected time, a five- year research experience without interruption for six M.D. and Ph.D. young faculty. While the majority of funding was restricted to faculty salaries, a significant proportion of funding (about 30 percent) was for equipment. Stephen Prescott and Raymond White were the co-principal investigators. Cornell University Medical College and Memorial Sloan-Ketter- ing ($2.4 million 1994-2000~. This grant supported multidisciplinary training in both institutions. Trainees included 10 Ph.D. candidates, 10 M.D. postdoctoral fellows, and 6 M.D./Ph.D. physician-scientists. The goals of the program were (1) to train a new generation of scientists to be competent to perform modern molecular and cell research and possess the knowledge to identify and address questions related to human dis- ease and (2) to create an environment that enabled laboratory scientists with expertise in basic biology to interact regularly with investigators who approach research from a disease-oriented perspective. This pro- gram was delayed due to external factors; the initial cohort of students arrived in 1995. The majority of funding was directed toward salaries. Marvin Gershengorn and Richard Rifkind were the principal investiga- tors and, because of the flexibility of funding, were able to extend the program several years. Emory University ($2 million 1994-2000~. This program estab- lished a new department in neurosciences. While it was more research oriented than the other General Organizational Grants, the focus of fund- ing was on the development of the Center for Neurological Sciences. The grant provided stipend support for M.D. /Ph.D., M.D., and Ph.D. postdoc- toral fellows, junior faculty, and visiting scientists in neurodegenerative diseases, movement disorders, psychiatric syndromes, and epilepsy and stroke through shared courses, seminars, and grand rounds. Eighteen postdoctoral and two predoctoral fellows, three junior faculty, and one visiting faculty was supported by Markey Trust funds. The co-principal investigators were Donald Humphrey and Jeffrey Houpt.