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Descriptions of Programs Participating in the Workshop on Training Programs in Patient-Oriented Pathobiology for Basic Scientists Programs Ph.D. Program in Molecular Medicine University of Chicago The Harvard-Markey Biomedical Scientist Program Graduate Program in Cellular and Molecular Medicine Johns Hopkins University School of Medicine University of California) San Diego Markey Fellowship System Markey Molecular Medicine Graduate Program University of Virginia . Lucille P. Markey Special Emphasis Pathway in Human Pathobiology Washington University 74

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APPENDIX E 75 PH.D. PROGRAM IN MOLECULAR MEDICINE UNIVERSITY OF CHICAGO Overall Program Description The Ph.D. Program in Molecular Medicine at the University of Chi- cago bridges the gap between basic science research and its relevance to human biology and disease processes. It educates students in the practical application of modem biological techniques to problems of human biol- ogy, particularly the etiology of disease. Nancy Schwartz is the program director. The program accepts second-year students from any one of a number of degree-granting departments and committees, and then provides a focus in molecular medicine for these select students with a specially designed curriculum; faculty-sponsored research projects in clinically relevant areas; a forum for interactive seminars, symposia, and the like; student research presentations or faculty lectures at quarterly lunches; and a clinical mentor. In 1995-1996 Dr. Louis Philipson served as associate director. Dr. Philipson, who holds a combined M.D./Ph.D. degree, is active in both clinical work and research. Bridging the Bed-Bench Gap In consultation with the mentor, students must carefully select a re- search topic that preserves and strengthens the translational aspects of the thesis research. Human biology and relevance to disease are crucial to the Ph.D. Program in Molecular Medicine. The program is unusual in that students also select a second mentor with clinical expertise in areas appropriate to the students' research inter- ests to guide their clinical exposure throughout the research years. In some cases the research mentor and clinical mentor may be the same person. Dr. Louis Philipson assists in finding an appropriate mentor and reviews this aspect of the training with each of the students annually. He or other faculty also periodically provide bench-to-bedside lectures on appropriate topics. The students host an annual seminar speaker in the area of translational research and actively participate in symposia co- sponsored by the Molecular Medicine program. Students may receive their Ph.D. through those departments and com- mittees in the Division of Biological Sciences that concentrate on the cellu-

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76 APPENDIX E lar and molecular aspects of biological research and teaching. In the first year, students take a broad core curriculum drawn from the basic science offerings across the division. There are four specific components of the Molecular Medicine pro- gram: coursework, symposia, seminars, and lectures. A description of each component is presented below. Coursework During their first two years students take courses that were specially designed for the Markey Molecular Medicine program and are a major feature of the program. Three courses infection and immunity, cardio- vascular disease, and cancer biology were developed early in the pro- gram. They have evolved such that the first two have been combined into molecular mechanisms of disease, and cancer biology has expanded into a two-part course. These courses concentrate on an understanding of dis- ease processes, such as a focus on atherosclerosis, AIDS, or the wide range of cancer diseases. Students analyze the disease process by studying Me basic biology of the disease as well as its clinical manifestation. This is accomplished through a series of lectures and readings, supplemented by current journal articles, discussions of actual case histories, and patient presentations. Approximately 40 students enroll for these courses each year. Symposia A second component of the Molecular Medicine program is a series of cosponsored symposia. Recent examples include a symposium on neu- rofibromatosis and molecular approaches to the analysis of complex ge- netic traits. Seminars The third component consists of a series of seminars that are cospon- sored by the program on such titles as In Viva Regulation of Sonic Hedgehog Signaling; Kazbanian, an ADAM Family Metalloportease that Regulates Notch Signaling in Drosophila and Mouse Development; Molecular Control of Neuronal Migration: Tales from an Ataxic Mouse; From One to Four Dimensions: In Vivo Libraries of Large Insert Transgenic Mice for Functional Genomics; Translation Factors in Control of Gene Expression, Cell Growth, . ~ . . ana ~umorlgenesls;

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APPENDIX E The Cellular and Molecular Basis of Neurofibromatosis, I; and Human Achondrogenesis: Biochemical and Molecular Aspect. Lectures 77 Dr. Philipson has prepared a series of lectures. His most recent lecture topics include the following: Cystic Fibrosis A Sticky Problem; G Protein Mutations and Endocrinopathies; Short Stature and Dwarfism: Collagen/Connective Tissue Gene Defect; and A Weighty Disease: Molecular Biology of Obesity. Characteristics of Students Prospective students declare their interest in the Ph.D. in Molecular Medicine program when applying to do graduate work at the University of Chicago. Financial aid has been restructured in the Division of Biologi- cal Sciences and all first-year students are supported by divisional funds. They are considered for entry to the program in their second year, once their research interests have been established. For the Molecular Medicine program the student's program of study must be relevant to human biol- ogy and in a field where we can offer them clinical expertise and expo- sure. The number of applicants has varied each year from three to ten, with a maximum of four students having been accepted in any one year. Appli- cants all have a minimum grade point average of 3.5, excellent letters of reference, and a broad interest in their fields of research, including the clinical applications of their work. Financial Data Thirteen graduate students have been supported, beginning with the 199~1995 academic year, at an average direct cost of $38,000 per year. This amount included an annual stipend, tuition, and health and student fees. Most students were supported for three years. Additional costs com- prise nominal amounts for honoraria for outside speakers; receptions and student and faculty lunches; and part-time administrative staff and pro- gram recruitment. Because funding has been used primarily as a training grant, the program has been able to stretch funding for two more years. The long- range goal is to continue this program by identifying funding from addi-

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78 APPENDIX E tional sources. The University of Chicago has taken over programmatic costs so that all funding can be applied directly to student costs. THE HARVARD-MARKEY BIOMEDICAL SCIENTIST PROGRAM Overall Program Description There is a critical shortage of young scientists whose expertise in cell and molecular biology is matched by a sound understanding of the patho- physiology of human diseases. In order to address this need the Harvard Medical School, in 1991, undertook a new initiative, the Harvard-Markey Biomedical Scientist program, supported by a five-year grant from the Lucille P. Markey Charitable Trust. The program director is Franklin Bunn. This program offered a new pathway of graduate education de- signed to give Ph.D. students a broader knowledge of human biology and disease and to enable them to formulate and carry out original and rigor- ous research that is relevant to clinical medicine. It took advantage of the scientific and clinical resources of Harvard Medical School to provide comprehensive, integrated multidisciplinary training. The curriculum described below enabled these Ph.D. students to work in class sections and tutorials with second-year Harvard medical stu- dents. It was hoped that this close interaction would enable the graduates of the program to be more effective teachers of future medical students and better collaborators with physician investigators. Finally, this train- ing would benefit Ph.D. scientists who choose a career in the biotechnol- ogy or pharmaceutical industry since they will have gained a clear under- standing of the medical relevance of the projects that they are asked to undertake. Bridging the Bed-Bench Gap Ph.D. graduate students apply to the program during the fall term of their first year. They are selected on the basis of motivation, perceived ability to fulfill the workload, and perceived value of the program to the students' career goals. The curriculum for Markey scholars is illustrated in Table E.1. The Harvard-Markey curriculum begins in the spring semester with a course in anatomy, which features small group discussions stressing biologically relevant relationships between structure and function with de-emphasis of minutiae and memorization. Liberal use is made of dem- onstration materials, including anatomical images derived from comput- erized tomography and nuclear magnetic resonance. During the summer, students enroll in a biochemistry course designed

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APPENDIX E TABLE E.1 Curriculum for Markey Scholars 79 Month riam ~ 11 | 12 | ~ | 2 | 3 | 4 | 5 | 6 | 7 | lst~ year ~~ ~ ~ ~ :~ ~~ Graduate- casework ~~:~ ~ ~~ ~ ~ : i; ~ ~~ ~ ~^at~y::~: ~~ Biochemistry flab ~~ ~~:~ i: ~ i: ~~ :~: ;~ ~~ glib rotaii>ns~:: ~ ~~:~ ~~ ~~ ~~ ~~ ;~ Physiology ~~:~ ~ ~~ Rotation . _ 2nd year HST pathology HST human systems Lab rotations or Immunology Integrated site visits thesis research ~~ 3rd~:year~ Graduate coursework ~ ~ ~ ~~ ~~ ~ ~ Qualifying examinations ~ ~ ~ : : ~~ ~ ~ ~~ ~ ~:~ ~~es~s~wsearch~ ~ ~~ : ~ ~ ~~:~ ~ ~ ~~ ~ ~ i:: ~~ :~ ~~ ~~ :~ ~~ :: ~ ~~ : 4th-6th Thesis research years to supplement material covered in the Division of Medical Sciences core biochemistry and cell biology course. Emphasis is placed on intermediary metabolism and on biochemical pathways that are relevant to specific human diseases. Lectures are interspersed with group discussions and patient-based case-solving problems. The students also take a physiology course that stresses mechanisms underlying the organization and regulation of specific organ systems and interactions between them. Lectures are supplemented with group dis- cussions and problem sets. At the begir~ng of the second year the students enter a pathology course in conjunction with medical students in the Harvard-MIT Program in Health Sciences and Technology. This course has been a particularly valuable experience for the Harvard-Markey students, enabling them to interact with a subset of medical students with strong backgrounds in and aptitude for science. Harvard-Markey students not concentrating in immunology also take a course comprising lectures, discussions, and case problems de- signed to cover the principles of immune defense, again with an empha- sis on human biology and pathology. These courses are sufficiently small so that active student participation is not only encouraged but also readily realized. At the beginIung of the fall term each Harvard-Markey student joins one of the four Harvard Medical School societies and thereby is included in their curricular and extracurricular activities. Each society organizes a program of student advisement, the core of which is a relationship be- tween student and advisor to foster goals of self-assessment and profes- sional development. The societies also plan extracurricular and social

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80 APPENDIX E functions that bring faculty and students together. In early November they and the second-year medical students embark on human systems, which is organized according to organ systems: pulmonary, cardiovascu- lar, hematology, gastroenterology, endocrinology, nephrology, and mus- culoskeletal. Before the course begins Dr. Bunn gives a two-hour session on clinical terminology and the principles of clinical history taking and physical examination. The bulk of the human systems course is taught in small interactive classes and in tutorials, both of which are organized by the society. The Harvard-Markey students are distributed among the tu- torials so that each of them is in daily, close contact with a group of six or seven medical students. The collective experience of these groups has shown that the students have gained considerably from such close con- tact with the medical students. During the human systems course the students' experiences are enriched by attending a site visit about once every two to three weeks at one of the nearby teaching hospitals. Here they have the opportunity to interact with an investigator involved in research at the interface between basic science and clinical medicine. At some of these sessions the students talk to patients and observe clinical facilities and procedures. In addition to the curriculum described above the students meet regu- larly with the director and administrator of the program to discuss courses in progress as well as to review those that have been recently completed. A dinner is held bimonthly at which an invited speaker, generally from the faculty at Harvard or MIT, provides an informal presentation or dis- cussion of a topic of special interest to the biomedical community. Characteristics of Students The program is first introduced to our Ph.D. graduate students by a brochure sent to all those accepted by the Division of Medical Sciences at the medical school. Soon after they arrive in September an orientation meeting is held to explain the goals of the program as well as the curricu- lum and the commitment required of them. Most students apply to the program during the fall term of their first year, however six students have entered the program during their second year. A committee consisting of Dr. Bunn, the director of the Division of Medical Sciences, and the Harvard-Markey program administrator interview all applicants. Stu- dents are selected on the basis of motivation, perceived ability to fulfill the workload, and perceived value of the program to the student's career goals. During the program's existence approximately 75 percent of appli- cants have been accepted. To date, 57 students have been accepted into the program. Eighteen students have graduated and entered into a wide range of positions.

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APPENDIX E 81 About half of the graduates have entered into postdoctoral positions. Several students have assumed research positions in pharmaceutical com- panies. Other graduates have entered into nontraditional positions, in- cluding consulting and investment banking, and one student has accepted a faculty position in a medical school. One student who had completed all coursework elected to assume an executive position in a biotechnology venture capital firm. Currently 38 graduate students are actively engaged in the program. Financial Data With the cessation of Markey support the overriding problem was the need to obtain continued funding. In 1996, 30 biotechnology and pharma- ceutical companies were approached with proposals for funding our pro- gram, but continuing support was not forthcoming. The Howard Hughes Medical Institute was contacted on two occasions to obtain support for the program. Again this contact was unsuccessful. In 1997 the program submitted a training grant application to the Institute of General Medical Sciences of the National Institutes of Health. The proposal was carefully reviewed and deemed meritorious, but was not funded, primarily be- cause it did not fit the NlH's customary criteria for graduate training programs. Their support is reserved for programs that carry students from matriculation into graduate school through the award of the Ph.D. degree. Without external funding Harvard was not able to offer the pro- gram to this year's incoming graduate students. During five years of the program yearly operating expenses were approximately $740,000 (see Table Em. The largest cost categories pro- vided funding for tuition and stipends. TABLE E.2 Annual Operating Expenses Administration Salaries Student travel ( one scientific meeting per student) Office expenses Harvard Medical School tuition (12 students) Division of Medical Sciences stipend (12 students) Course expenses Human systems Pathology Biochemistry Anatomy Physiology TOTAL $102,000 7,500 51,000 $302,000 $203,000 $26,620 27,040 10,150 5,440 5,900 $740,650

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82 APPENDIX E GRADUATE PROGRAM IN CELLULAR AND MOLECULAR MEDICINE JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE Overall Program Description The Graduate Program in Cellular and Molecular Medicine is the newest interdepartmental graduate program at the Johns Hopkins Uni- versity School of Medicine. The program was developed in response to the 1991-1992 School of Medicine strategic planning retreat, which fo- cused on preparing the institution for the twenty-first century. During the previous two decades the number of faculty in basic science departments increased only slightly. In contrast the number of faculty doing basic research in clinical departments increased dramatically, although most of these have not had access to graduate students, since the existing gradu- ate programs were restricted to basic science departments (e.g., the Bio- chemistry, Cell, and Molecular Biology program) or were restricted to specialized research teachings (e.g., human genetics, immunology). Most importantly no program existed at Johns Hopkins to train graduate stu- dents to perform basic cellular and molecular research on clinical prob- lems, an area of anticipated need with the emergence of molecular medi- c~ne. An advisory committee was named to evaluate the possible solutions and an application was submitted to the Lucille P. Markey Charitable Trust for a graduate program in cellular and molecular medicine. This application was funded in 1993 and provided a nonrenewable source of support to initiate the Graduate Program in Cellular and Molecular Medi- cine (CMM). All Johns Hopkins School of Medicine department directors were notified that CMM would consider faculty nominations, and more than 300 faculty were proposed. From this group 50 core CMM faculty were selected after reviewing multiple criteria: scientific prominence and independence; previous record as a mentor; achievement of substantial NIH funding; and direct clinical significance of their research. Although selection was based on overall merit, faculty from clinical departments were given slight preference, since one mission of the CMM was to pro- vide students for outstanding laboratories in clinical departments that have traditionally not received Ph.D. students. The number of core CMM faculty has risen to 61. These individuals represent 11 clinical depart- ments (42 faculty) with the majority coming from medicine, oncology, pathology, comparative medicine, urology, neurology, and pediatrics. Members of eight basic science departments also participate in CMM (19 faculty). Approximately 40 other associate CMM faculty are invited to attend CMM activities but do not have independent access to CMM graduate students.

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APPENDIX E 83 A separate CMM Admissions Committee was established to identify and recruit the most qualified students. The first incoming class of six students began in September 1994, and this number has risen in subse- quent years to approximately 10. Each year this group usually includes one student from the Hopkins Medical Scientist Training program (MSTP). Although the Markey funds were not restricted, the majority of students are U.S. citizens or permanent residents (26~. Several of the inter- national students have faculty positions awaiting them when they return to their countries of origin. The program anticipates achieving a steady state of approximately 50 students. CMM students have joined laboratories throughout the medical cam- pus, and this has served to enhance interactions among Hopkins faculty. Current CMM students are pursuing thesis projects in multiple clinical departments: medicine (10 students); oncology (7~; psychiatry, pathology, urology, neurology, and comparative medicine (1 each). A smaller subset is pursuing thesis projects in basic science departments: biological chem- istry (3 students); neuroscience (3~; cell biology, microbiology, molecular biology (1 each). The hallmark of CMM students is their cellular and molecular approach to human disease, and all thesis projects are directly relevant to specific human diseases. Current CMM students are pursuing thesis projects directly related to specific clinical problems, including co- lon and prostate cancer, hematopoiesis and leukemogenesis, brain edema, sudden cardiac death, coronary thrombosis, AIDS, diarrhea! diseases, trypanosomal infections, and slain wound healing. Bridging the Bed-Bench Gap Program Directors The CMM program directorship employs a rotating system involving members of the participating departments. The plan is to have most ad- ministrative activities overseen by the director, who will serve three years. To ensure smooth transitions the director is assisted by a codirector, who will subsequently serve the next three years as director. The past director will assist the new director for one to two years, when the CMM Organi- zational Committee and CMM Advisory Board will elect a new codirector. Thomas Pollard, M.D., served as the first director (1993-1996~. Peter Agre, M.D., served as codirector for three years before becoming the sec- ond CMM director in September 1996. Dr. Agre is professor of biological chemistry and medicine, and has been a Hopkins faculty member since 1982. Stephen B. Baylin, M.D., has served as codirector since 1996. Dr. Baylin is Ludwig Professor for Cancer Research and has been a Hopkins faculty member since 1974. John T. Isaacs, Ph.D., has served as codirector

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84 APPENDIX E of CMM since July 1998, and he assumed the directorship in July 1999. A Hopkins faculty member since 1980, Dr. Isaacs is professor of oncology, professor of urology, and codirector of the Division of Experimental Therapeutics in the Johns Hopkins Oncology Center. Advisory Board This group of distinguished senior faculty members has been drawn from multiple basic science and clinical departments. The Advisory Board initially oversaw the formulation of CMM, but as the program developed the Organizational Committee took over most details. The Advisory Board meets formally annually to review the director's annual report and to make suggestions. Although the Organizational Committee elects new directors, the Advisory Board must approve them. Members of the Advi- sory Board are available for numerous ad hoc needs of the CMM program and students. Organizational Committee This committee is the functional body that undertakes the various recruiting and teaching activities of the CMM. The Organizational Com- mittee includes representatives of most participating departments as well as chairs of subcommittees. Subsets of members may meet monthly, and the entire Organizational Committee meets quarterly to review the pro- gram and make administrative decisions. Frequent discussions include composition of the subcommittees, potential changes in curriculum, changes in funding policies, admission of new members to the CMM faculty, and review of student academic problems. The Organizational Committee nominates and elects new CMM directors. CMM Faculty The directors, members of the Advisory Board, and members of the Organizational Committee also serve as laboratory mentors for CMM students. Members of the core CMM faculty were nominated by their departmental chairmen and were reviewed by CMM directors and Orga- nizational Committee members. Every effort is made to employ uniform criteria for membership in CMM. Scientific prominence is evaluated by leadership in various societies and programs, chairing of national and international scientific committees, and organization of meetings and con- ferences. Scientific independence is assessed by senior authorships on studies in highly regarded publications. Core CMM faculty must have sufficient laboratory space to accommodate CMM students. It is generally

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98 APPENDIX E experimental science to the understanding and treatment of human dis- eases. Enrollment is limited to 21 students, with preference given to full- time graduate students in the Molecular Medicine program, first-year students in the Medical Scientist Training program, and medical students participating in graduate research programs. The class meets on lThurs- day afternoons and the format is similar to the molecular disease rounds. At one session both a physician and a basic scientist introduce a disease topic and papers are assigned that investigate the molecular basis of the disease. At the session the following week students present, discuss, and analyze the assigned papers. The course has been extraordinarily well received. The only difficulty we have had is integrating the course into the medical school schedule. The most recent offerings in "Topics of the Molecular Basis of Human Disease" were Diabetes; Growth Hormone Action in the Cell and in the Organism; Retinal Degenerations; Molecular Genetics of Colorectal Neoplasia; Mitochondrial Dysfunction, Neurodegenerative Diseases and Ther- apeutic Strategies; and Pathobiology and Therapeutic Approaches to Melanomas. Characteristics of Students The Markey Molecular Medical program gets as many as 60 appli- cants per year. At least half of the applicants are qualified to enter the program, however fiscal restraints have limited the number of offers to 6 per year, with an average of 4 students admitted each year. A total of 20 students have been admitted to the program. One, admitted as an ad- vanced student, has already graduated from the program and is currently employed by Genentech, doing translational research. One student left the program to continue studies with his science mentor, who moved to another university. Two students have decided to graduate with a mas- ter's degree. Currently there are 16 students enrolled in the program. Financial Data The major barrier to further development of the program has been funding. The resources have not been committed to admit a cohort of students large enough for this group to achieve an institutional identity. Currently the university is supporting the program at a steady-state level, and there are funds to support second-year and some third-year students.

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APPENDIX E 99 Markey funds have been shepherded to fund first-year students, as there are no institutional funds for that. The Markey Molecular Graduate pro- gram has attempted to secure additional funding from extramural sources. These attempts, however, have been unsuccessful. The small class size also makes it impractical to develop specific course offerings. An additional barrier has been the fact that the program occurs in a matrix of departmental graduate programs, which also creates identity problems for advanced students, who typically feel more at home with their departmental colleagues. LUCILLE P. MARKEY SPECIAL EMPHASIS PATHWAY IN HUMAN PATHOBIOLOGY WASHINGTON UNIVERSITY Overall Program Description The Lucille P. Markey Special Emphasis Pathway in Human Patho- biology at Washington University School of Medicine was established in 1992 through a grant from the Markey Charitable Trust. The pathway is dedicated to training bright, young Ph.D. students and postdoctoral fel- lows in various aspects of human disease. The overall purpose of this innovative educational experience is to produce a cadre of excellent young investigators who will carry out basic research in areas related to human disease and serve as role models for future generations of students. The long-term objective is to develop research faculty at the Ph.D. level who are familiar with human diseases and who regard research in human disease as an exciting opportunity. The driving force behind the development of the Markey pathway at Washington University was (and continues to be) the widening gap be- tween clinical and basic research, and the pressing need to develop train- ing programs that bridge this gap for Ph.D. researchers in the life sci- ences. U.S. health statistics have documented the magnitude and explosive growth of biomedical science in the past two decades. The basic sciences, including molecular biology, have expanded and evolved rapidly. Ad- vances in basic science have created extraordinary opportunities for un- derstanding the fundamental biological basis of clinical medicine and using this information in innovative ways to help patients. At the same time, however, the changing landscape of the U.S. health care system and serious financial pressures facing academic medical centers have had a significant negative impact on the investigative activities of clinical fac- ulty. Traditional approaches to addressing these issues have been success- ful to a large degree, but new initiatives are needed. M.D. /Ph.D. training

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100 APPENDIX E programs provide one mechanism by which physician-investigators ac- quire the basic science skills and education to approach complex biomedi- cal problems. One untapped area in which a major long-term impact on biomedical education can be achieved is the introduction of the biology of human disease to the pool of competent young Ph.D. investigators. A1- though the rationale for this approach may appear obvious, successful implementation of this strategy has required careful thought and plan- ning, the enthusiastic and dedicated commitment of an energetic faculty, and the institutional will to provide an environment that nurtures inno- vation, excellence, and an interdisciplinary approach in scientific training and research. All graduate research training in the life sciences at Washington Uni- versity is administered through the Division of Biology and Biomedical Sciences. All predoctoral programs and degree-granting units in the bio- logical sciences at Washington University are both interdisciplinary and interdepartmental. The division was established as an independent ad- ministrative unit with its own endowment in recognition of the increas- ingly interrelated nature of all aspects of research in the biomedical and biological sciences, and to facilitate cooperation among faculty in the in- terdisciplinary training of future biological scientists. At the present time the Division of Biology and Biomedical Sciences is responsible for admin- istering several university programs, including the Ph.D. portion of the M.D./Ph.D. training program, the M.D./M.A. program, the Young Scien- tist program, as well as the Markey Special Emphasis Pathway in Human Pathobiology. The Markey pathway emphasizes training a subset of graduate stu- dents and postdoctoral fellows to provide them with a basic understand- ing of human disease without distracting them unduly from the main objective of becoming first-rate basic scientists. The clinical specialties provide limitless opportunities for important, challenging research in the understanding and treatment of human disease, and the main goal of this program is to make these opportunities and challenges known to Ph.D. students and fellows and to entice a number of them into these areas. Alan L. Schwartz, Ph.D., M.D., Spoehrer Professor and head of the Department of Pediatrics at Washington University, was the principal investigator of the original proposal to the Markey Trust and served as director of the pathway from its inception until 1998. In July 1998 Jeffrey E. Saffitz, M.D., Ph.D., Lacy Professor of Pathology, accepted the post of program director and assumed responsibilities for the day-to-day admin- istration of the program. Dr. Saffitz has been involved with the Markey pathway since its inception. He served on the original Steering Commit- tee and directed the Clinical Mentor program prior to assuming his cur- rent position as program director.

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APPENDIX E 101 Timothy I. Ley, M.D., and George I. Broze, Ir., M.D., both professors of medicine at Washington University, were original members of the Steering Committee and served as coursemasters for the first seven years. In 1998 Dr. Broze stepped down as coursemaster, and was replaced by Daniel C. Link, M.D., assistant professor of medicine. Drs. Ley and Link now serve as co-coursemasters and work together as a team to organize the course, select faculty members who lead the three sections presented each year, and assume overall responsibility for seeing that the course runs smoothly. As new faculty members join Washington University and participate in Markey pathway programs either as faculty members in the course, clinical mentors, or research mentors of students in the pathway, selected individuals are invited to fulfill leadership roles. Recent additions include lean Schaffer, M.D., assistant professor of medicine) and Samuel Speck, Ph.D., professor of pathology, who are now members of the Steering Committee and serve on the Postdoctoral Fellow Admissions Committee. Bridging the Bed-Bench Gap Although much of the nation's basic biological and biomedical re- search takes place at academic medical centers, pre- and postdoctoral Ph.D. trainees (including those who train in the laboratories of physician- scientists) have traditionally had little or no access to the clinical enter- prise at these centers. Until the development of the Markey Special Em- phasis Pathway in Human Pathobiology there had not been a training model at Washington University designed to engage Ph.D.-level scientific trainees in the clinical realm. The three principal components of the Markey pathway through which Washington University bridges He bed-bench gap are a course in human pathobiology; a clinical mentorship program; and enrichment ac- tivities, including an annual retreat and guest lecturers. The following is a brief description of each of these components. The Markey Pathway Course on the Pathobiology of Human Disease States A fundamental premise upon which our philosophy is based is that all pathophysiology is an integrative function. Each cell type, organ sys- tem, physiological state, and pathological stress involves complex inter- actions that can be dissected and studied in isolation but which must also be evaluated as a whole. A single disease state provides a paradigm in which students can experience several of He principal areas in human pathobiology. The Markey Pathway Course on Human Pathobiology is organized into three sections, each of which focuses on a major disease state. The

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102 APPENDIX E course is offered each fall semester. Because the pathway encompasses two years, each student will have been exposed to course curricula on six different diseases. Diseases covered include sickle cell anemia, AIDS, acute leukemia, multiple endocrine neoplasia, osteoporosis, and rheuma- toid arthritis. The selection of disease topics and the organization of each component of the course are the responsibilities of Drs. Timothy Ley and Daniel Link, coursemasters, together with the program director and Steer- ing Committee. The course is presented at an intermediate or advanced graduate level appropriate for second- and third-year graduate students. As noted above, Markey pathway trainees include postdoctoral fellows. The mixture of pre- and postdoctoral trainees enriches the milieu for both students and faculty, and also ensures that the level of teaching and dis- cussion is on a high plane. Enrollment in the course is limited to Markey pathway trainees to maintain a forum for active interchange between the teaching faculty and students and to encourage student participation in the course. The Markey pathway students evaluate every section presented and comments are relayed to the coursemasters, the faculty section leader, and the program director. Course faculty are selected each year to include both clinical and basic science faculty, with special attention paid to teaching skills and enthusiasm, as well as their ability to integrate into a cohesive educational effort. The majority of the course faculty are young and active investiga- tors in the clinical sciences. In general the course material for each disease state is presented in 10 sessions of 1.5 hours duration (total of 15 hours). Each week there are two sessions, typically including a 60-minute lecture (or other type of presentation, including patient interviews) and a 30- minute discussion of papers from the historical and current medical lit- erature. Students lead the literature discussion and the faculty participate as moderators. The focus of these discussions is to address major disease states of comparable complexity and importance that affect society. An obvious benefit of a disease-oriented course is the attraction of students to future research opportunities in that disease state. One example of a disease state covered in course material is chronic myelocytic leukemia (1998 course topic). Chronic myelocytic leukemia (CML) is an acquired clonal disorder of hematopoiesis that is manifest by an accumulation of mature and immature granulocytes in the blood. A cardinal feature of CML is Me presence of the Philadelphia (Ph) chromo- some in leukemic cells. Of note, the Ph chromosome was the first chromo- somal abnormality associated with a specific human cancer. Subsequently it was determined that the Ph chromosome is a result of a translocation between chromosomes 9 and 22 t (9; 22~. Nearly 20 years ago it was discovered that this translocation fuses the BCR gene with the ABL gene,

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APPENDIX E 103 resulting in the production of a novel chimeric protein termed bcr-abl. Since then extensive studies have been directed at characterizing the mo- lecular mechanisms by which bcr-abl induces leukemia. CML provides an exemplary model to study the impact of basic re- search on clinical medicine. Throughout this course the students were asked to consider two questions: (1) How has the study of bcr-abl contrib- uted to our understanding of the pathogenesis of CML and impacted its clinical management? and (2) What are the important clinical problems in CML and how can basic research help to resolve them? During the course the students developed a thorough understanding of the clinical presentation and management of patients with CML. Pa- tient interviews were performed on two separate occasions and served to highlight therapeutic dilemmas. More importantly these interviews pro- vided the students with valuable insights into the emotional and social aspects of this disease. Interspersed with the clinic-oriented lectures was a detailed presentation of the molecular biology of bcr-abl with an empha- sis on its impact on clinical management. As is readily apparent from this model there is enormous potential to integrate vast areas of human pathophysiology. The key is integration and achievement of a moderate degree of depth (i.e., avoiding superficial- ity while not attempting to provide an entire medical education). The curricular format based on a single disease requires that faculty relate their particular discussions to the central theme, chronic myelocytic leu- kemia in this case. During some courses Washington University invites outstanding lec- turers to complement the Washington University faculty. For example, Orah Platt, M.D., Harvard Medical School, has spoken twice on sickle cell disease; I. Joseph Marr, M.D., Searle, has spoken on malaria; and Richard Lawn, Ph.D., Stanford University, has spoken on coronary artery disease. James Griffin, M.D. also from Harvard Medical School, spoke on cell biology of CML. Washington University has also invited keynote visiting professors to present seminars to the entire medical center community toward the end of each theme. For example, in the case of cystic fibrosis, Michael Welch, M.D., Ph.D., professor of medicine and cell physiology, investigator of the Howard Hughes Medical Institute, University of Iowa, presented a lecture titled "The Pathway of Discovery in Cystic Fibrosis." The Markey Pathway Clinical Mentor Program Another central element of this approach to bridging the bed-bench gap and developing basic scientists who aspire to focus on investigative aspects of human disease is the Clinical Mentor program. The overall goal of this pathway component is to enhance awareness of the underlying

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104 APPENDIX E biology and pathobiology of human disease. Thus, Washington Univer- sity has established a mechanism for sustained interactions of trainees and clinical scholars in an area of mutual investigative interest. The clin- ical mentor component re-establishes the traditional student-mentor re- lationship, a foundation of scientific training but one that has been rel- egated to a minor position in many of today's graduate education programs. This provides for a close interpersonal relationship between student and mentor. Under the guidance of Dr. Jeffrey Saffitz, professor of pathology and medicine and clinical mentorship director for the pathway, trainees to- gether with their research advisors will select members of the faculty with clinical involvement to serve as clinical mentors for the students. This liaison in essence establishes a basic science and clinical science mentor pair for each student. The clinical science mentor will be a top-notch investigator. Ibe principal goal here is to provide a forum for and conti- nuity with the exciting issues in clinical medicine. In practice this is ac- complished by having the student join the clinical mentor for about two hours per month to participate in any of the various clinical activities of the mentor. Often students attend combined specialty conferences with their mentors. The medical center has a well-organized, ongoing series of interdisciplinary clinical specialty conferences, which are interdepart- mental and interdivisional. These conferences generally meet weeldy or biweekly and provide an interactive forum for discussion of current con- cepts and emerging ideas in clinical medicine. Examples of these confer- ences are Medical genetics conference (includes faculty from obstetrics, pediatrics, medicine, pathology, and surgery); Autopsy conference (includes faculty from pathology, radiology, medicine, pediatrics, and surgery); Allergy-clinical immunology conference (includes faculty from medicine, pediatrics, and pathology); Metabolism-endocrinology-nutrition conference (includes faculty from medicine, pediatrics, pathology, and surgery); Hematology-oncology conference (includes faculty from medicine, pediatrics, pathology, and surgery); and Transplantation biology conference (includes faculty from medi- cine, pathology, surgery, and pediatrics). These conferences expose the student to the concepts and the faculty in the targeted areas. In addition, students and mentors are encouraged to participate together in inpatient attending or consultation rounds, outpa- tient activities, various clinical procedures, or other activities that the

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APPENDIX E 105 clinical mentor would normally perform as part of clinical responsibili- ties. It is important not to micromanage the type of interactions between students and mentors. The best results usually come from providing some basic ground rules for the program and then allowing two highly moti- vated and energetic people to develop their own mutually fulfilling rela- tionship. The goal is not to detract from investigative scholarship, which is the major focus for graduate students after their first three semesters, but to supplement it. The clinical orientation of the mentor interaction provides a longitudinal program during the thesis years. The trainee's time commitment is typically small (a few hours per month) but the po- tential impact can be great and long lasting. The clinical mentor component of the human pathobiology pathway has been a major success since it was begun seven years ago. For most of the pathway students this program has provided the first (and for many probably the only) opportunity to participate in the clinical activities of an academic medical center and to do so as the personal guest of an out- standing physician-scientist. Responses of the students to annual surveys about the program have been uniformly strongly positive. Many have commented that their experiences significantly broadened their scientific horizons and deepened their commitment to careers in which basic re- search is directly linked to important clinical problems. Many medical mentors and students mentioned that their relationships lasted longer than the required three semesters and frequently was for many more hours per month than the proscribed minimum. Both the program director (Dr. Saffitz) and the program administra- tor (Ms. Deborah Sinak) evaluate the mentor program on an ongoing basis. In addition to the annual survey, which gives participants an op- portunity to comment in detail on their individual experiences, Dr. Saffitz and Ms. Sinak communicate informally with both students and faculty mentors throughout the course of the 18 months of this portion of the program to monitor progress. When students and wisely chosen mentors are brought together under the aegis of this program, they tend to de- velop extremely effective working relationships to the great benefit of both parties. The Markey Pathway Human Pathobiology Annual Retreat One of the important components of the pathway in human disease is providing the students with a sense of identity and of being part of a group accomplishing something meaningful. For this reason several spe- cial activities have been organized, including an annual two-day retreat to provide students with an opportunity to present their own research and exchange ideas. Each year in late spring all pathway students, men-

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106 APPENDIX E tors, course faculty, steering committee, and selected medical school schol- ars are invited to participate in a retreat. There is always a keynote speaker, generally from outside the university. For example, in May 1997 Professor Kari Raivio, M.D., Ph.D., rector of the University of Helsinki, Finland, and a world-renowned human developmental biologist and phy- sician, scientist, and educator, served as the keynote speaker and dis- cussed educational pathways for human biologists in Europe. The retreat provides an environment of intimacy for personal and scientific interactions between trainees and faculty. It includes a session devoted to student presentations and roundiable discussions of selected scientific topics, including a critique of the course in pathobiology and the clinical mentor program. The retreat offers a chance to exchange informa- tion and ideas in a rural setting (at selected sites a few hours' drive from St. Louis), where recreation and social events are also featured. After dinner on the first evening a lecture is presented, which provides a way for introduction of the keynote speaker. Roundtable discussions are planned to acquaint students and junior faculty with elements of professional life. Senior faculty and guests pre- sent information on various topics, such as how to select a postdoctoral position; how to acquire funding for research; the nature of positions in academia, government, and industry; and the changing climate of bio- medical investigation. Characteristics of Students The Markey pathway program is now in its eighth year. It is obvi- ously too early to formally define the long-term success of our program. The academic growth of the trainees, the ability of the trainees to success- fully secure peer-reviewed grant support, their election to esteemed sci- entific societies, and selection to peer-review panels are criteria that will be used to judge the success of the program. Long-term success of Markey trainees will ultimately be judged on the basis of successful application of sophisticated tools of biological inquiry to studies of human disease. Recruiting and Admissions Process Recruiting for Markey pathway students has employed the usual bro- chures and listings in Peterson's Guide. There is also a Web link from the division's Web page (~. The mainstay of the re- cruiting effort has been the contacts with a number of smaller colleges known for the quality and rigor of their programs. Washington Univer- sity offers a program of summer research internships to students from these colleges. The Markey pathway is announced to all students who

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APPENDIX E 107 apply for graduate research training in the Division of Biology and Bio- medical Sciences, as well as publicized nationally through mailings to undergraduate schools, for example. The result of these intensive efforts was that the division received greatly increased numbers of applications from these high-quality sources, and the overall quality of the applicant pool has been trending steadily upward for the last several years. Over the past eight years the Markey pathway in human pathobiology has provided a powerful recruiting incentive that has enhanced the qual- ity of the overall pool of applicants to the Division of Biology and Bio- medical Sciences. Another advantage of the pathway has been the poten- tial to attract undergraduate students who have leanings toward both human disease and basic science. This can most effectively be done with the pre-professional advisors (i.e., general pre-medical advisors) at most colleges. In order to maintain the integrated strength of the Division in graduate education, Pathway students are generally selected during their first year of graduate studies and are formally enrolled during years 2 and 3 of their 5 to 5.5 years of graduate education. Following their two years in the pathway students continue to attend seminars and usually maintain close relationships with their clinical mentors. As stated above, graduate students are selected for the Markey path- way in the second half of their first year. Students apply to the pathway by April 1 of each year. Applications along with academic credentials (including graduate record exams and grades in undergraduate and grad- uate school), course evaluations, lab rotation evaluations while at Wash- ington University, letters of recommendation from mentors for the pre- doctoral applicants and project and goal statements for the postdoctoral applicants are reviewed and ranked by the Admissions Committee. Pre- and postdoctoral admissions committees (subcommittees of the Steering Committee) endeavor to recruit the brightest, most motivated applicants, while achieving a good mix of graduate students and postdoctoral fel- lows, and a reasonable balance among various interests (e.g., neurobiol- ogy, immunology, genetics) such that substantial cross-fertilization will occur during the courses and other activities of the program. Financial Data The Markey pathway at Washington University has operated much like the other components of the Division of Biology and Biomedical Sci- ences. Finances are required to support trainee tuition and stipends, ad- ministrative costs of the division, programmatic costs of the pathway (faculty leadership), and ancillary costs directly associated with the path- way (e.g., annual retreat, invited speakers). The total costs per annum supported by the Markey Trust were approximately $600,000. Since ter-

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108 APPENDIX E mination of the Markey support it has been necessary to shift some of the costs for tuition and stipends to the trainee's laboratory, thus allowing the pathway to continue with total costs per annum of approximately $173,000. This cost shifting consisted primarily of eliminating tuition re- imbursement for graduate students and stipends for postdoctoral stu- dents. In addition, because all current funding is intramural, overhead costs are not applicable. Additional economies were achieved by reduc- ing expenditures for the Markey retreat and visiting scholars, and elimi- nating funding for invited speakers.