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Funding Biomedical Research Programs: Contributions of the Markey Trust Appendix B Site Visit Reports Lucille P. Markey Charitable Trust Large Research Program Grant Awards THE YALE UNIVERSITY SCHOOL OF MEDICINE PROGRAM IN MOLECULAR ONCOLOGY MARCH 2001 The site visit team had an informal dinner meeting with Vincent Marchesi, Director of the Boyer Center for Molecular Medicine, and Renee Dobos, Administrator of the Center. Dr. Marchesi briefly described the background of Markey funding for the Program in Molecular Oncology. Background of Markey Funding By the end of the 1980s, leaders at Yale had come to the realization that molecular biology was becoming the core of biomedical research and that Yale was falling behind other academic medical centers in its molecular biology research. Leon Rosenberg, then Dean of the School of Medicine, sought to remedy this by establishing the Boyer Center for Molecular Medicine. Boyer and the Howard Hughes Medical Institute had funded the Boyer Center building. The $12.1 million Markey funds were originally planned for developing the Program in Molecular Oncology, a part of the Boyer Center in July 1990. Markey funding was to be used for most of the equipment ($2.95 million) for the Program in Molecular Oncology and core facility needs and to fund individual investigators during their first five years. The Program in Molecular Biology was to be built around six inte-
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Funding Biomedical Research Programs: Contributions of the Markey Trust grated research programs, each headed by a principal investigator. Additionally, research training was to be an important part of all programs at the Boyer Center for Molecular Medicine and especially for the Program in Molecular Oncology. It was to have its own training director with responsibility for developing a cohesive program, and for integrating the Program’s students with fellows of other programs in the center and other departments in the medical school. An important goal of the Program was to have clinical fellows with an interest in cancer spend approximately one year learning advanced research techniques that will have later application in a clinical setting. The Markey funds were intended to support 10 predoctoral candidates and 10 postdoctoral fellows over the five-year term. In fact, 7 postdoctoral and 14 predoctoral fellows received support from Markey funding. However, staff at the Program in Molecular Biology were unable to provide data on the identities and current locations of these fellows. Site visit members were told that four young faculty were supported by Markey funds—Dr. Glazer, Dr. Stein, Dr. Xu, and Dr. Fearson. It was hoped that the Program in Molecular Oncology would become the “molecular research arm” of the Yale Cancer Center. However, with the arrival of a new Director, the Yale Cancer Center also took on molecular oncology, which directly competed with the Boyer Center’s Program. Therefore, the Program now has a new focus in development and space has been reallocated away from oncology. The site visit team had the opportunity to meet with two young faculty who were recruited with Markey funds. Peter Glazer, who was the third faculty recruit into the Program was offered a large start-up package with equipment and supplies. This package allowed him to explore new directions in his research in developing gene-targeted drugs, research that he described as initially “risky” (his original NIH application was not funded) but which now has attracted external support. Although his clinical department paid his salary, Markey funds paid for 50% of his secretary and supported a postdoc for 12 months until an independent NRSA fellowship was obtained. Tian Xu came to the Boyer Center from the University of California, Berkley, as a postdoctoral fellow in 1993. Although he was offered an HHMI fellowship at that time, the Boyer Center provided larger lab space and more equipment than most junior faculty received. Markey funds paid for five years of his salary, a postdoctoral student, and a lab technician. He became a Hughes Investigator in 1997. Similar to Dr. Glazer, Dr. Xu also believed that this support provided him with the opportunity to pursue more “risky” research. Dr. Xu is certainly a rising star. His science is extremely impressive so use of Markey funds in his recruitment was well worth the investment.
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Funding Biomedical Research Programs: Contributions of the Markey Trust Sherman Weissman, Chair of the Boyer Center for Molecular Medicine, was at Yale before Markey funding. At the onset, the Program in Molecular Biology had decided to work with existing departments. For example, a committee of relevant individuals in medicine was formed to “find people and offer them to departments—a school-wide recruiting effort”. This approach had never happened before at Yale. This goal of Program as being a “people incubator” led to the development of the Clinical Scholars program. The Clinical Scholars were to spend five or more years at the Boyer Center and then return to their departments. However, this approach did not work, because some departments were reluctant to have their brightest come to the Boyer Center. Also, problems with space meant that the Clinical Scholars, rather than having their own “module” and space, had to function more as postdocs. Dr. Weissman believed that the legacy of the Markey funding is the recruitment of outstanding young faculty and the provision of a start-up package that enables them to begin research in new and underdeveloped areas. Markey money was used to support the development of several investigators: Dr. Stern (who returned to his department); Dr. Glazer, who received generous equipment and start-up funds, but also seems to be very well connected with the Cancer Center; Dr. Fearson, who was recruited to another institution, and Dr. Xu, who is now an HHMI Investigator. While the dollars were used well to catalyze an individual scientist’s career development, it appears that they were not used to develop a coherent program of molecular oncology. Conclusions Other than support for a few young scientists, three of whom remain at Yale, the site visit team could find no evidence of a lasting legacy of Markey funds at the Boyer Center. It is very unfortunate that the plans for the $12.1 Markey funds did not develop into a thriving Program in Molecular Oncology. Moreover, the program’s stated goal—“The money from the Markey Trust will provide the bulk of the financial support for each research program … and then phase out over time as grants from NIH and private agencies begin to phase in“—certainly was not fully achieved. The Markey Committee’s assertions about what elements make a successful program seem to be absent from Yale. Below are several examples of critical factors contributing to the failure of the Program: Unfortunately, after a new Director of the Yale Cancer Center began to emphasize a more molecular approach to his program, the Program in Molecular Oncology began to compete for distinguished faculty. Since the programmatic concept (a program that is staffed by faculty from
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Funding Biomedical Research Programs: Contributions of the Markey Trust other departments) was foreign to traditions of Yale, the departments were reluctant to let their brightest and best faculty go to Boyer. Yale’s focus on the departmental structure of the institution inhibits leadership from exploring new ways of training and collaboration with the Boyer Center. The Program in Molecular Biology did not fit into the overall vision for the institution. Almost immediately following the Markey award, Leon Rosenberg left Yale University to assume another position. Additionally, Dr. Fearson’s departure from Yale left a gap in identifying potential collaborators for the junior faculty. While principal investigators often leave an institution after funding arrives, there is often vigorous, committed, and effective leadership in the wings. But along with other changes occurring at Yale (such as the arrival of a new Yale Cancer Center Director), the lack of leadership resulting from Rosenberg’s, and Fearson’s absence caused a lack of cohesion in the Program on Molecular Oncology. One lesson for future funders is the importance of program leadership and in having that leadership in place for the duration of the funding. There appears to be a lack of interdisciplinary collaboration among researchers and faculty at the Center. The more successful programs that the Committee has visited have strong emphasis on collaboration and cooperation among not only the faculty, but also the students. The Program in Molecular Oncology was able to build bridges to the clinical departments, but was unable to build similar bridges to the basic science departments. Basic science faculty retained their primary position, salary, and research identification with their basic science departments. They did not identify with the Program in Molecular Oncology. Sherman Weissman’s final comment was “it’s a shame that the funds had to end”. Even though the original goal of the Program in Medical Oncology was to create a program that would sustain itself indefinitely through succeeding NIH funding, the Program failed to thrive after the Markey funds ended. The Markey Committee finds that private funders should consider program intent and goals in making awards, monitoring progress, and providing “assistance” to ensure program success. For example, could Yale’s lack of “enthusiasm” or “commitment” to cross-department collaboration have been picked up at either a pre-award site visit or at the early stages of the program (e.g., a year after Rosenberg left)? The Committee is not suggesting heavy-handed “oversight” by a Foundation; however, it is nearly always the case that some number of projects/grants may not flourish as intended. In some cases, there may be nothing a sponsor can do, but in others, they may be able to help leverage some
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Funding Biomedical Research Programs: Contributions of the Markey Trust change or at least circumstances that help a project get “back on track.” Even at the very least, being more proactive about progress reports and record keeping seems to be not unreasonable. UNIVERSITY OF CALIFORNIA, SAN FRANCISCO PROGRAM IN BIOMEDICAL SCIENCES MARCH 2001 The site visit team met with the university and program administrators during an informal dinner. During the course of discussion, the Vice Chancellor emphasized the importance of the leadership of University of California, San Francisco (UCSF) just prior to the Markey award. Because leaders such as Holly Smith, Bruce Alberts, and Mike Bishop had an unselfish approach to bringing the institution as a whole up to a higher standard, the foundation of collaboration was laid that enabled the Program in Biological Sciences (PIBS) to flourish. Those early leaders were willing to devote the substantial award wholly to the program with no or very little administrative costs. UCSF has been able to sustain PIBS after Markey funding ended because it has been institutionalized by the university leadership. Background of Markey Funding During the 20 years before the Markey award, UCSF had developed a distinguished faculty whose scholarship had gained international recognition. The renaissance was initiated largely in the Department of Biochemistry and Biophysics, but soon spread to other departments with recruitments often made in collaboration with the Department of Biochemistry. The collegial and altruistic example of this department greatly facilitated the rise of excellence of other departments at UCSF, which were soon populated with scientists who considered themselves citizens of the university and not of a single department. The prominence of the Biochemistry faculty made possible the creation of an outstanding graduate program in Biochemistry and Molecular Biology. Diversification led to the establishment of promising programs in cell Biology and Genetics, whose full potential required the establishment of PIBS. The remaining program in the initial PIBS consortium, Neuroscience, was sponsored by the Department of Physiology, and also benefited greatly from its proximity to and support from the Department of Biochemistry. In 1987, UCSF applied to the Markey Charitable Trust for funds to form a unified program of research and graduate teaching that would unify biomedical research on the UCSF campus. The purpose was to foster and exploit unity and collaboration among the research faculty and
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Funding Biomedical Research Programs: Contributions of the Markey Trust their scientific disciplines. Using Markey funds as a catalyst, UCSF hoped to establish new alliances for research, to diversify the faculty, and establish new programs for graduate and medical training and initiate new research programs to use recently developed technologies to address central problems in biology and medicine. PIBS has left a positive and permanent mark on the UCSF community. The impact of this award exceeds that of any other grant given to UCSF. Thus in 1988, UCSF had several excellent graduate programs plus several additional programs of less distinction under the sponsorship of individual departments. These programs developed their own curricula, set their own standards for admissions and for the Ph.D., and had in most instances failed to develop adequate support mechanisms to support the initial years of graduate education. There were few mechanisms for communication between programs, particularly for graduate students. The Markey grant provided the impetus to develop a collaborative and interactive approach to graduate education and faculty recruitment that has continued to impact the UCSF campus. This model for scientific development and graduate education made possible by Markey support has continued to influence UCSF. At the time of its formation, approximately 96 faculty participated in the graduate programs of PIBS. During the period of Markey support between 1988 and 1995, PIBS assumed the responsibility for graduate education previously divided among the basic science departments and created a collaboration with basic science and clinical departments for recruiting to UCSF outstanding young scientists. Using Markey support, PIBS collaborated with clinical and basic science departments in 21 successful recruitments, who have established creative research programs of international note. Since the expiration of the Markey Grant, PIBS has retained its responsibilities for faculty recruitment, graduate education, and promotion of modern medical research. UCSF has been successful in continuing and expanding the support provided by this grant. Including the initial 21 recruitments, PIBS has now cosponsored 76 successful international searches for promising scientists, utilizing alternative sources of support. While the vast majority of the searches have sought assistant professors, PIBS has collaborated in the recruitment of directors for the Cancer Center and the Gladstone Institute in AIDS Research as well as the Chair of Pathology. PIBS currently consists of seven graduate programs with shared governance and standards. The programs in Biochemistry and Molecular Biology, Cell Biology, Genetics, and Developmental Biology are closely aligned with a shared admissions process and largely overlapping curriculums. These programs cosponsor a single annual retreat and a common seminar series. Some of the individual programs have their own
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Funding Biomedical Research Programs: Contributions of the Markey Trust journal clubs and retreats. The other graduate programs—Immunology, Neuroscience, Biophysics, and Chemistry and Chemical Biology—are much more loosely affiliated. Each program has its own admissions process, graduate curriculum, and seminar series. PIBS is governed by an executive committee consisting of two members of each of its graduate programs. While this committee has responsibility for graduate education, its primary mission is to provide scientific leadership for the school. The PIBS executive committee is proactive in discussing the future of UCSF. All programs that are members of PIBS have agreed to a common governance including common and rigorous standards for participation by the faculty membership, periodic review of the faculty in each program, shared scrutiny of applicants for open positions, and common standards for graduate admissions and teaching. PIBS sponsors an annual retreat for each of its graduate programs, an orientation day for new students, a weekly faculty-student journal club, an annual course in the Practice of Science, and other activities. Today PIBS has expanded by incorporating the Biophysics Graduate Program. To meet PIBS standards, this program conducted a rigorous internal review to ensure that only faculty who participated actively and maintained productive research programs retained membership. Recently, PIBS has sponsored a new graduate program in Chemistry and Chemical Biology. PIBS has a mission of sponsoring new programs and initiatives as opportunities arise in the medical sciences and will collaborate in the establishment of several major initiatives in the near future. PIBS has also been expanded by successful applications from other professors at UCSF. The activities sponsored by PIBS have encouraged the participation and membership by faculty who were not initially involved in graduate education. A total of 223 faculty have been members of PIBS between 1988 and present. Of these, only 36 have left PIBS, either for retirement or to accept prominent positions elsewhere (e.g. President of the National Academy of Sciences, Director of the National Institutes of Heath, Dean of the Pharmacy School at Michigan, chairmanships of Cell Biology at Harvard and Neurology at Stanford). Notably, only 5 of the 76 scientists recruited by PIBS in international searches have accepted positions elsewhere. There are currently 185 active members of PIBS. Meeting with Graduate Students and Post-Doctorates The site visit team had an opportunity to meet with both graduate students and post-doctoral fellows in PIBS. It is interesting to note that many of the graduate students were not aware of PIBS when they applied to UCSF. However, most of the post-docs came to UCSF specifically because of PIBS. They may not have understood the exact structure of PIBS,
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Funding Biomedical Research Programs: Contributions of the Markey Trust but they knew that UCSF had a unique program of collegiality and collaboration among different biomedical disciplines. So while PIBS may not be easily recognizable as a specific program, it is well known that biomedical research at UCSF will offer individuals more exposure across many departments. Conclusions The replication of a program like PIBS greatly depends upon the institutional leadership and culture. PIBS would probably not be successful in institutions that have strong departmental governance and entrenchment. However, with the right leadership, PIBS is a strong model for creating important collaborations across disciplines in both research and training. The Committee believes that there are three critical elements that must be present in order for a program such as PIBS to be successful: An institutional vision from the top leadership is critically important in order to create and foster an atmosphere of collaboration and cooperation. Faculty collaboration among disciplines must be rewarded with prestige and funding. PIBS offers these rewards. A collaborative relationship between basic science departments and the medical school must permeate down from the deans, to the faculty, and finally to the students. Students need to know that they are welcome to enter anyone’s lab to ask questions or discuss problems or findings. All of the students that we talked with felt at ease talking with faculty from any of the PIBS disciplines. The physical proximity of the labs to each other is very important in fostering informal discussions among disciplines. In fact, although the new building at Mission Bay will offer much needed space, many of the students (particularly those in neuroscience) are concerned about losing these informal, spontaneous meetings with colleagues in the medical school. THE WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH MASSACHUSETTS INSTITUTE OF TECHNOLOGY PROGRAM IN BIOMEDICAL SCIENCES MARCH 2001 The site visit team had an informal dinner meeting with Gerald Fink, Director, Whitehead Institute; John Pratt, Associate Director, Whitehead Institute; and Eve Nichols, Director of Institutional Advancement. Whitehead representatives described the Whitehead Institute and Markey’s role in developing the careers of young faculty and promising scientists.
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Funding Biomedical Research Programs: Contributions of the Markey Trust Background of Markey Funding The 1988 award from the Lucille P. Markey Charitable Trust to the Whitehead Institute for Biomedical Research played a vital role in the development of the Institute. Seed money provided by the Markey Trust and other funding sources helped the Institute launch talented men and women into careers at the forefront of biology. The award was used by the Institute to support both junior faculty members and participants in the Institute’s Whitehead Fellows Program. The latter allows promising young scientists with exceptional research agendas to pursue independent research programs as an alternative to traditional post-doctoral positions. Every Whitehead Fellow who received Markey funds is now a prominent research scientist at a major university or research institute. Whitehead recipients of Markey funds included Dr. Eric Lander, now director of the Whitehead Center for Genome Research, the largest contributor of DNA sequence to the public Human Genome Project; Dr. Peter Kim, recently named Executive Vice President for Research and Development of Merck Research Laboratories; Dr. Terry Orr-Weaver, a Member of the Board of the Genetics Society of America; Dr. Ruth Lehmann of New York University and Dr. David Page of the Whitehead Institute, both Investigators of the Howard Hughes Medical Institute; Dr. Paul Matsudaira, a leading researcher at the interface of biology and engineering; and Dr. Hazel Sive, a pioneer in the study of vertebrate development. Seven of the eight junior faculty members supported by the Markey Trust at Whitehead became full Members of the Institute and received tenure in the Department of Biology at MIT. The eighth returned to Korea to head a new biomedical research institute. For the Whitehead faculty and Whitehead Fellows, seed money from the Markey Trust led the development of sophisticated research programs, which were subsequently supported by the NIH and other traditional funding sources. In addition to advancing the careers of exceptional young scientists, the Markey Trust award had an important impact on the evolution of the Whitehead Institute as a whole. In 1993, Whitehead Director, Dr. Gerald Fink and the Whitehead Board of Directors established a strategic plan for the future of the Institute. This plan called for major science-driven investment in three key research areas: structural biology, transgenic science (animal models of human disease), and infectious disease. Two of the three initiatives, structural biology and transgenic science, emerged from research programs supported at least in part by Markey funds. The strategic plan led to the construction of a new research wing—completed in the spring of 1996—and to the expansion of research and teaching programs that helped alter the course of biomedical science throughout the research community.
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Funding Biomedical Research Programs: Contributions of the Markey Trust The Markey Trust reinforced what is best about the Whitehead Institute—the ability to nurture outstanding young scientists in an environment that encourages creativity, collaboration, and technological innovation. Meetings with Markey-Funded Faculty and Fellow The site visit team had an opportunity to meet with four of the faculty who were funded by Markey: Paul Matsudaira, Terry Orr-Weaver, David Page, and Eric Lander. They also met with one of the Fellows, Bruce Tidor. Paul Matsudaira, who researches the interface of biology and engineering, had just completed a post-doc in England when he arrived at Whitehead in 1985. His Markey funding began in 1988, which was used to enhance his PEW innovator award. He has a joint appointment with MIT, teaches two courses a year and works in the project lab about two hours a day. Markey funding has allowed him to focus on his research without having to manage other projects at the same time. He has made significant advances in microscopy and protein chemistry, and has identified elements of the molecular cytoskeleton that play a central role in cell function and structure. He has also created microelectromechanical devices to track biomolecular interactions and enhance the identification of human disease genes. Terry Orr-Weaver was appointed as an assistant professor in 1987. Her six years of Markey support allowed her to start new projects in areas that were different from her original areas of research. She is researching how cells replicate their DNA (through the study of fruit flies), which has led to new information about two genes associated with cancer in humans. This research will help scientists understand the mechanisms responsible for this aberrant cell behavior and perhaps suggest new ways of blocking it. Her previous work, which focused on the mechanisms of chromosomal segregation in egg and sperm formation, was recognized in Discover magazine as one of the most important research achievements of 1995. David Page is studying the importance and complexity of the Y chromosome. His laboratory was the first to clone an entire human chromosome—the Y chromosome—and will soon report the entire sequence of the Y. In addition, he has revealed the genetic basis of some types of male infertility. Dr. Eric Lander arrived at Whitehead as a Markey Fellow and then was appointed to the faculty. This progression illustrates the critical role Markey funds played in the development of the Institute. Dr. Lander has a D. Phil. in Mathematics from Oxford University and spent five years
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Funding Biomedical Research Programs: Contributions of the Markey Trust teaching at Harvard Business School. During his years at Harvard, he became interested in the applications of mathematics and new informatics technologies to biology. He began studying molecular biology and genetics, first at Harvard and then at MIT, where the Director of the Whitehead Institute invited him to join the Fellows Program. The Fellows Program enabled him to test and refine new concepts in gene mapping, gene sequencing, and bioinformatics. Today, he heads the largest academic genome center in the world. Through his work in functional genomics, he is building a new framework for deciphering the origins of complex human diseases such as cancer, diabetes, and heart disease. The Markey Trust helped lay the foundation for this progression by providing partial support for the Lander laboratory for five years. Bruce Tidor was a Whitehead Fellow from 1990 to 1994 and is currently a member of the MIT faculty in the Department of Chemistry. The Fellows program is unique in that it offers the Fellows their own space and allows them to be the principal investigator for their research. The Markey funds enabled Whitehead to hire postdoctoral fellows for whom outside funding would be difficult. Visit to Genome Lab The site visit team had the opportunity to visit Eric Lander’s genome laboratory, which is one of the national labs for the Human Genome Project. Over the last few years Dr. Lander’s lab has developed methods and strategies applicable to high throughput genomic sequencing. The lab is a highly automated, scalable system that has all the necessary hardware and sofware to help in the worldwide effort to sequence the human genome. He has developed and implemented fully automated systems for production sequencing as well as developed software for information management and sample processing and analysis. He is now focused on completing the vision of creating a high throughput system capable of providing the community with low cost, accurate sequence data. Dr. Lander used $500,000 of Markey funding to progress from theoretical research to data-producing research, allowing his lab to produce markers and preliminary datat tha were used to garner NIH funds for the genomic lab. A concentrated “plug” of money was needed to get the lab started. It was not possible to get the NIH funding without preliminary data. Even though other funds were used to supplement the Markey award, Dr. Lander stated that, “Markey can take credit for building the genome center. This was high-risk research and money spread out does not allow for high-risk research.” He further stated that his Markey fellowship was “a chance to behave more as a scientist than as a careerist,”
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Funding Biomedical Research Programs: Contributions of the Markey Trust and that he had the freedom to explore his theoretical hypotheses without the risk of losing NIH funding. Conclusions The site visit team was very impressed with the Whitehead Institute. While the Markey funds certainly contributed to the success of this outstanding program, it is difficult to tease out Markey funds from the other sources of funding that were used to augment the Markey award. However, it is quite clear that both Markey funds and the other funds were used to create an atmosphere of cooperation and collaboration among the Institute’s scientists. The site team has identified four characteristics that appear to make the Whitehead Institute productive and effective. Because Whitehead was conceived and built as a separate entity from MIT, its founders were able to create a research environment that did not bring with it some of the departmental “baggage” that traditional institutions may bring to a new program. In addition, the Markey award (along with other funding) was used for developing the institute as a whole and not just one area or department. The Markey award (along with other funding) was used to fund new and promising researchers. These scientists were either undergoing a change in career directions or a change in research interest and probably would not have received adequate funding to make these changes without the Markey award. The funds were sufficiently generous so that these scientists were free to focus solely on their research projects without having to be burdened with conducting other research or administrative activities. The physical layout and the vision of the Whitehead Institute encouraged collaboration and communication across disciplines. There are no barriers between labs and there are plenty of open spaces for informal discussions. The atmosphere of the Institute is one of openness. The recruitment of faculty or fellows is very informal, which lends itself to greater flexibility and possibilities. Search committees are not constrained by institutional requirements, which might limit recruitment in some organizations.
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