Appendix C
Site Visit Reports, Telephone Interviews, and Letter Reports Lucille P. Markey Charitable Trust Small Research Program Grant Awards

BAYLOR UNIVERSITY SCHOOL OF MEDICINE PROGRAM IN DEVELOPMENTAL AND TUMOR BIOLOGY APRIL 2002

History and Background of Markey Funding

The request to Markey was to provide funding to help advance Baylor’s effort to become one of the nation’s pre-eminent biomedical research institutions. There was an extensive ongoing research effort in developmental biology and oncology, with emphasis on cell structure, oncogenes, growth factors, and tumor suppressor genes. Baylor now wanted to broaden graduate training to enable Ph.D. candidates to learn more about disease process in man. Specifically, the award was for $1.4 million to recruit two new senior faculty, two new junior faculty, and provide training stipends. Initial funding began in 1994 and continued until 1997.

Impact of Markey Funds

Markey funds were used to implement a new developmental biology program at Baylor College of Medicine, directed by Hugo Bellen. He has been able to recruit four developmental biologists: Kwang-Wook Choi from CalTech; Kathi Mahon from NIH; Anna Newman from CalTech; and Milan Jamrich, a senior scientist from Yale.



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Funding Biomedical Research Programs: Contributions of the Markey Trust Appendix C Site Visit Reports, Telephone Interviews, and Letter Reports Lucille P. Markey Charitable Trust Small Research Program Grant Awards BAYLOR UNIVERSITY SCHOOL OF MEDICINE PROGRAM IN DEVELOPMENTAL AND TUMOR BIOLOGY APRIL 2002 History and Background of Markey Funding The request to Markey was to provide funding to help advance Baylor’s effort to become one of the nation’s pre-eminent biomedical research institutions. There was an extensive ongoing research effort in developmental biology and oncology, with emphasis on cell structure, oncogenes, growth factors, and tumor suppressor genes. Baylor now wanted to broaden graduate training to enable Ph.D. candidates to learn more about disease process in man. Specifically, the award was for $1.4 million to recruit two new senior faculty, two new junior faculty, and provide training stipends. Initial funding began in 1994 and continued until 1997. Impact of Markey Funds Markey funds were used to implement a new developmental biology program at Baylor College of Medicine, directed by Hugo Bellen. He has been able to recruit four developmental biologists: Kwang-Wook Choi from CalTech; Kathi Mahon from NIH; Anna Newman from CalTech; and Milan Jamrich, a senior scientist from Yale.

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Funding Biomedical Research Programs: Contributions of the Markey Trust Perhaps the greatest impact of the $1.4 million Markey award was the leveraging of additional funding: a five-year training grant from NSF, which required matching funds for consideration; an NIH training grant; and a March of Dimes endowment of $5 million to support training and research. The Markey funds were the main stimulus to allow initiation of a new graduate program in Developmental Biology. From its beginning the program increased to 24 faculty and 16 graduate students at the end of Markey funding. Markey funding has been used to continue support of graduate students. In addition, funding has been used to establish a series of lectures by distinguished guest speakers. Finally, Markey funds supported part of the salary of a program administrator who coordinated the daily activities of the program in developmental biology. BRANDEIS UNIVERSITY PROGRAM IN STRUCTURAL BIOCHEMISTRY OCTOBER 2002 History and Background of Markey Funding Brandeis proposed establishing a protein crystallography laboratory to complement existing facilities for x-ray diffraction, electron microscopy, and computer graphics. Funds were required for spectroscopy, protein sequencing, and peptide synthesis. A particular feature of the new initiative was the incorporation of a postdoctoral exchange program between the Brandeis Laboratory and the Laboratory of Molecular Biology at the University of Cambridge. In 1998 Brandeis was awarded $2 million over five years, including approximately $1 million in salaries for three investigators. Funds totaling $500,000 were sought for technical personnel for the first three years and approximately $500,000 for crystallographic equipment. Brandeis was awarded supplemental awards of $500,000 in both 1990 and 1996. The former was directed to the activities of the structural biology and biochemistry group under the direction of Laura Davis; the latter supported the research of Lizabeth Hedstrom, a professor of biochemistry. Impact of Markey Funds Gregory Petsko was the principal investigator of the Markey award. The award, and the supplements, was used to fund the research of a number of investigators. Principal among them are Hugh Huxley, Laura Davis, and Lizabeth Hedstrom. Professor Hugh Huxley’s research focused on the use of x-ray syn-

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Funding Biomedical Research Programs: Contributions of the Markey Trust chrotron radiation to study changes in actin and myosin filament structure during tension development in muscle. Results of his work were reported at a number of international scientific meetings, including the symposium on actin structure sponsored by the United States, Australia, and Japan. Dr. Huxley also participated in a workshop on fibrous protein structure in Austria. Markey funds supported his participation at both of these meetings. Markey funds were used to support the modernization of the Rosentiel Center’s instrument shop and significant improvements in its computer network. In addition, the grant allowed the University to acquire an Orbital Sciences scanner, which was installed in the center’s electron microscope facility. Dr. Davis’s laboratory is devoted to the study of the transport at the cell nucleus. Access to and from the cell nucleus is governed by a large gate-like structure called the nuclear pore complex. The nuclear pore complex regulates entry and exit of protein and RNA over time. This regulation is crucial for turning specific genes on and off, and for controlling the time at which cells divide. Her laboratory is examining how the nuclear pore complex recognizes transport substrates and the mechanism by which transport can be regulated. Dr. Hedstrom investigated the mechanism of enzyme action. Her studies focus on three enzyme symptoms: trypsin, streptokinase/plasminogen, and inosine monophosphate dehydrogenase (MPDH). This research seeks to understand the structural basis of enzyme specifity. She has addressed the problem of identifying the structural features, which determine substrates specificity in the trypsin family of serine proteases. Another project underway focuses on structure-function styles of zymogen activation. The goal of this project is to use site-directed mutagens to analyze the conformation change that occurs when trypsinogen is active and inactive conformations of trypsinogen and trypsin are assessed on order to define the forces that govern protein conformational stability. BROWN UNIVERSITY PROGRAM IN MOLECULAR AND CELL BIOLOGY OCTOBER 2002 History and Background of Markey Funding In 1990 Brown began developing a program focused on Molecular and Cell Biology of Disease. In 1991, new faculty in Cell Biology, Pathology, and Molecular Genetics were added along with a graduate program in pathobiology, thus creating the Division of Biology and Medicine. This new Division is intended to facilitate interdisciplinary collaboration. Additionally, Brown increased the participation of faculty members from the

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Funding Biomedical Research Programs: Contributions of the Markey Trust clinical departments (all based in the medical school’s seven hospitals) in new investigative initiatives. The goal of the new program was to enhance opportunities to help translate findings of basic research to the care of patients. In 1992 Brown submitted a proposal to the Markey Trust for: (1) support for graduate students, M.D./Ph.D. students, and postdoctoral fellows; and (2) funding for new faculty positions as well as for equipment and renovation. In 1994 Brown was awarded $1.3 million for over five years. Subsequently, funds were extended through 2001 to support the molecular and cell biology of disease program. Agnes Kane was the principal investigator. Impact of Markey Funds The Markey grant helped the Division of Biology and Medicine to undergo at least 27 new research initiatives from cytokine networks in viral infections, to differential DNA replication in insect chromosomes, to studies on the mechanism of ribosomal translocation during protein synthesis. These new research initiatives attracted additional funding for 14 principal investigators. Overall the Markey grant supported 66 predoctoral students, 15 M.D./Ph.D. students, and 17 postdoctoral fellows who engaged in research in this program. Stipends and tuition were provided for an additional three M.D./Ph.D. students. In addition, Markey funding enabled faculty to renew nine grants and to prepare proposals that resulted in the funding of five new grants. A Fuji Phosphorimager was purchased with Markey funds and has been extensively used by faculty in the Division of Biology and Medicine, especially by Drs. Dahlberg, Gerbi, Hawrot, Hendrickson, Landy, Wessel, and Zarat. In addition, a Zeiss LSM410 confocal microscope was added to the core facilities. Drs. Bearer, Rioult, Wessel, Marshall, and Kane are the major users of this new equipment. They are working on collaborative research projects on emphysema, pulmonary hypertension, and breast cancer. This grant provided infrastructure support, which allowed the individual departments to co-exist without competition—all facilities are shared. Equally important, the Markey funds have provided seed money for renewal of NIH research grants for Drs. Dahlberg, Gerbi, Henderson, Landy, Mowry, Sedivy, Wessel, Wyche, and Zaret. Funding of new NIH research grants has been awarded to Drs. Henderson, Sedviy, Wharton, and Wyche.

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Funding Biomedical Research Programs: Contributions of the Markey Trust BURNHAM INSTITUTE STRUCTURAL BIOLOGY PROGRAM AUGUST 2002 History and Background of Markey Funding Burnham requested funding for major equipment in support of its cell recognition studies and the establishment of a structural biology program. Burnham proposed to use Markey funds to set up laboratories for three scientists. This grant request marked a policy change for the Markey Trust because they had never before granted an award in which the majority of the funds were to be used to purchase equipment. However, because of the excellent reputation of the Institute and its leadership, the Trust decided that the policy change was warranted. In 1991 the Markey Trust awarded $1.5 million over five years. Erkki Ruoslahti was the principal investigator. Impact of Markey Funds The Markey funds were used to establish the Structural Biology Program. Instrumentation was purchased to provide the structural studies by x-ray crystallography, nuclear magnetic resonance (NMR), and computer graphics modeling. Funds were also used to provide laboratory setup costs and partial salary support to recruit new scientists to the program. Burnham was able to recruit four new scientists, all of whom were able to obtain federal funding for their salaries and research. The NMR laboratory is now established and functional and is a shared facility in order to support the operational costs and service contracts. A 500 MHz spectrometer, manufactured by Varian, was installed in the newly developed NMR laboratory. Dr. Joseph Parello, relocated to La Jolla from the University of California, San Diego. His two postdocs—Francoise Roquet and Jean-Louis Baneres—joined with him in the new lab. They continued their structural studies of calcium-binding proteins (parvalbumins) and NMR analyses of fragments of the α5β1 integrin that bind the RGD site in fibronectin. Nuria Assa-Munt, a new spectroscopist, has been recruited to the Structural Biology Program. She will initiate NMR analyses of the PU.1 transcription factor and additional studies of the molecular structures of other DNA-binding proteins It is important to note that although the overall level of funding that the Burnham Institute received was not large compared to funding received by other recipients, it represented 10 percent of the total revenue for 1991. The Burnham staff stressed that the Markey funding was crucial for three reasons. First, the funding came during a period when federal

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Funding Biomedical Research Programs: Contributions of the Markey Trust funding had been severely reduced. Second, the Markey funding enabled the purchase of expensive equipment. Third, the Markey Trustees were flexible with the timing of the release of funds, allowing funds to be shepherded until they could be used efficiently. CARNEGIE MELLON UNIVERSITY DEPARTMENT OF BIOLOGICAL SCIENCES SEPTEMBER 2000 History and Background of Markey Funding In 1985 Carnegie Mellon submitted a proposal from the Department of Biological Sciences for two purposes: (1) to establish the Pittsburgh NMR Center for Biomedical Research, and (2) for an NMR spectrometer. Funds were also proposed for faculty development of both senior and junior scientists. Carnegie Mellon proposed to work in collaboration with the University of Pittsburgh and with additional funding support from the Richard King Mellon Foundation, the Commonwealth of Pennsylvania, and NIH. The principal investigator was Chien Ho. Impact of Markey Funds The Department received $1.925 million in September 1985. Funding was primarily used in infrastructure development and to provide support and start-up costs for investigators. The NMR Center was established and supported by a major grant from the National Center for Research Resources as a national biomedical facility on the application of magnetic resonance imaging and spectroscopy to biomedical sciences. It has become a major center on the application of MRI and MRS to biomedical sciences using animal models. They have developed novel MRI/MRS techniques and methodologies and have applied them to biomedical problems. During the past 15 years, the Center has also obtained grant funds from shared instrument grant programs of NSF and NIH to purchase new NMR instruments. In the area of infrastructure development, the Markey funding (commingled with other funding) was used to purchase a high-field NMR spectrometer. This spectrometer has led to additional extramural funding and the development of a specialized program in structural biology that investigates the structural determinations of biological macromolecules. In the 10 years since the Markey awards were made, 3 M.D./Ph.D. students, 8 graduate students, and 12 postdoctoral fellows received degrees or engaged in substantial research using Markey funded equipment. In

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Funding Biomedical Research Programs: Contributions of the Markey Trust addition, many undergraduates, graduate students, and postdocs have used this equipment as an ongoing part of their research activities. In the area of faculty development, the Markey award was used to provide salary support and start-up costs for four new faculty members in the Department of Biological Sciences. These include Drs. Koretsky, Pollock, Lopez, and Minden (who was also a Markey Scholar). The NMR Center remains a major center of the application of MRI/MRS to the biological sciences using animal models. In addition to the four faculty, the Center supports between six and eight graduate students each year. COLD SPRING HARBOR LABORATORY PROGRAM IN DEVELOPMENTAL NEUROBIOLOGY IN THE NEUROSCIENCE CENTER OCTOBER 2001 History and Background of Markey Funding During the tenure of James D. Watson, who was the director of Cold Spring Harbor Laboratory from 1968 until 1994, the programs of Cold Spring Harbor grew and prospered. Dr. Watson was an excellent recruiter of top-notch scientists and an effective fund-raiser. He renovated and expanded old facilities and began a major effort to create a Neuroscience Center, encompassing both research and education facilities accommodating a major initiative in the neurosciences. In 1990 the Lucille P. Markey Charitable Trust awarded Cold Spring Harbor $4.0 million, the largest of four Markey awards. In 1986 they received $150,000 to support advanced courses for neuroscientists during the summer. Also in 1986 Cold Spring Harbor received $863,500 from Markey Trust, which was seed money to begin a program in structural biology. They recruited two structural biologists and three crystallographers (and their respective equipment) with this grant. The $4.0 million grant was used as part of the capital campaign to begin the neuroscience program, including construction of a new facility. Finally, in 1996 the Markey Trust awarded an additional $500,000 for imaging equipment in the neuroscience program. In 1994 Bruce Stillman became the Director of Cold Spring Harbor Laboratory. He has since used some of the Markey grant money to pursue behavioral genetics. He has investigated DNA replication, chromatin assembly, biochemistry, yeast genetics, cancer, and the cell cycle. This area of study is somewhat controversial, and many advised against starting such a program. But Tim Tully was recruited to Cold Spring Harbor to begin the behavioral genetics program by studying fruit flies. The Markey grant enabled Dr. Tully to create mutant fruit flies to study memory and

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Funding Biomedical Research Programs: Contributions of the Markey Trust behavior, which led to a whole new pathway in memory research and the development of investigative drugs that can stimulate memory. Impact of Markey Funds According to Dr. Stillman, the greatest impact of the Markey funds was to enable Cold Spring Harbor to invest in good scientists early in their careers and give them the needed boost to get their research underway. Cold Spring Harbor used Markey funds to help support the salaries and operating expenses of new scientists until they were able to obtain sufficient research grants to maintain their own research programs. There are numerous examples at Cold Spring Harbor of scientists who successfully obtained funding from various institutes of the NIH. Dr. Hollis Cline received an award from the National Eye Institute, Dr. Roberto Malinow received an award from the National Institute of Neurological Disorders and Stroke, and Dr. Alcino Silva received an award from the National Institute of Aging’s Neuroscience and Neuropsychology of Aging Program. The current funding for the program of 11 faculty is $6.7 million (including all grants, post doctoral fellowships, gifts, and foundation funding). Since 1990, three buildings have been constructed totaling 53,000 sq. ft at a cost of $17.7 million (not adjusted for inflation). To date, the molecular neuroscience program has accumulated a total of $50.3 million in funding from 1991 to the present (excluding construction costs). One of the neuroscience faculty, Karel Svoboda, was selected as a Howard Hughes Medical Institute Assistant Investigator in the recent competition. Three faculty have received $1 million grants from the Harold Mathers Foundation and numerous NIH grants have been obtained by these faculty. The current number of faculty, students, and postdoctoral fellows are:   Faculty Postdoctorals Students Total since 1991 14a 76 34 Current 11 39 14 aIncludes faculty who have left for University positions (R. Davis, Baylor College of Medicine; H. Nawa, Niigata University, Japan; A. Silva, UCLA). Dr. Stillman believes that the Markey Trust was the first to emphasize the investment into the scientist rather than an institution. He also believes that a limited trust such as Markey can have greater vision for

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Funding Biomedical Research Programs: Contributions of the Markey Trust changes in direction by being able to award large grants that have huge impacts on institutions or programs. CORNELL UNIVERSITY PROGRAM FOR STRUCTURE-BASED DRUG DESIGN SEPTEMBER 2000 History and Background of Markey Funding In 1993 Cornell submitted a proposal, which was a revision of an earlier proposal, for $3.4 million to fund half of the salary of the Director of the Program for Structure-Based Drug Design, salaries for a Ph.D. program manager, postdoctoral trainees, and student assistants. Although the primary target of the project related to drug design, the technology is applicable to a multitude of biologic problems in molecular and cell biology. Cornell has one of the nation’s best veterinary medicine programs where there are active research collaborations between the veterinarian school faculty and the faculty in the biological sciences. The proposed research involved eight faculty members, four in chemistry, three in biochemistry, and one in the biotechnology program. Impact of Markey Funds In 1994 the Markey Trust awarded Cornell $1.2 million, which were often combined with other funds to accomplish the program’s goals. The Markey funds were used to partially support several major pieces of equipment, specifically a 600 MHz NMR spectrometer, and two X-ray detector systems and computers for the synchrotron beam lines at Cornell High Energy Synchrotron Source (CHESS). In the case of the NMR machine, about $160,000 of Markey funds were used to get a commitment from the Dean for another $300,000. These funds were used as matching funds to obtain about $700,000 from NSF, giving a total of more than $1 million for the purchase and operation of the NMR. In the case of the X-ray detectors, about $100,000 of Markey funds were combined with government funds and Keck Foundation funds to purchase two detectors at a total cost of about $800,000. The greatest accomplishment of the Markey grant was building Cornell’s presence in the field of structural biology. About 20 research papers also resulted. They were able to attract an NMR spectroscopist to the biochemistry department and to build infrastructure in X-ray crystallography. They trained several graduate students and postdoctoral fellows.

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Funding Biomedical Research Programs: Contributions of the Markey Trust Personal Observations Dr. Steven Ealick, Director of the Institute of Human Neuroscience, stated that the greatest benefit of the Markey program was to provide a flexible source of funding that often provided leverage for obtaining additional funds. He stated, “In my experience, most foundations want full ownership. The Markey funds were used to partially support several pieces of equipment.” ELEANOR ROOSEVELT INSTITUTE FOR CANCER RESEARCH STUDIES ON THE MOLECULAR GENETICS OF CELLULAR PHENOMENA SEPTEMBER 2001 History and Background of Markey Funding Although the Eleanor Roosevelt Institute is an independent entity under its own Board of Trustees, it is housed in the Department of Biophysics at the University of Colorado Medical School, with Dr. Theodore Puck as its director. Staff hold appointments on the University of Colorado Health Sciences Center faculty. The Eleanor Roosevelt Institute is organized into six basic science divisions: (1) Genetic and Metabolic Regulation, (2) Cell Regulation, (3) DNA Structure and Function, (4) Chromosomal Mapping, (5) Immunogenetics, and 6) Cell Membranes. These research programs are multidisciplinary and there is “crossover participation” by the investigators. In 1988 the Markey Trust funded Eleanor Roosevelt Institute $1,375,000 to support work on cyclic AMP and mutagenesis, to discover the basis of malignant change, and to seek ways in which to protect against such changes. Specifically, the Markey funds would be used for additional faculty members, both at the junior and senior levels; graduate student stipends, technical help, and equipment. In 1992, the Institute was awarded a supplemental award of $100,000. Impact of Markey Funds There were several scientific advances made possible with support from Markey, which are summarized below: Methods for measuring exposure of genes have been developed and applied to a variety of normal and pathologic cell systems, which have identified sites of genome exposure in the nucleus. These studies promise to provide new insight for a variety of diseases and particularly cancer.

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Funding Biomedical Research Programs: Contributions of the Markey Trust The use of cyclic AMP for treatment of specific cancers. For the prevention of cancer, development of a simple, rapid procedure that is capable of rapid detection of mutation sources in a fashion that is more than 200 times more sensitive than standard methodology. Development of human gene mapping—especially chromosome 21, which has resulted in the identification of specific genes whose mutation can lead to ALS. These mapping studies have resulted in new approaches that promise the possibility of improved diagnosis, treatment, and prevention of many diseases. Creation of microdissection libraries from many regions of the genome that are shared throughout the world. Thus, the contribution from Markey’s grant support has been useful both for the Institute’s research and for many other laboratories engaged in genome analysis and positional cloning of disease-related genes. A theoretical formulation proposing a new function of lipoproteins in cell metabolism. Scientists supported by the Markey grant have been appointed to key positions in the Cancer Center of U. Colorado School of Medicine and have been asked to advise this medical school about its future development in medical genetics. Trainees from Eleanor Roosevelt Institute laboratories have been appointed to professorships in distinguished universities throughout the world. FLORIDA STATE UNIVERSITY PROGRAM IN STRUCTURAL BIOLOGY APRIL 2002 History and Background of Markey Funding In 1988, Florida State University submitted a proposal to Markey to initiate a program in structural biology. The proposal included start-up funds for eight new faculty, capital equipment for ongoing research and for a new x-ray crystallography unit, initial support for research assistants, and construction funds to add 12,000 square feet of new research space. The new program, under the direction of Lee Makowski, was to have its administrative base in the Institute for Molecular Biophysics, which would change its name to the Institute of Molecular Biophysics and Structural Biology. The focus of the research was to be: x-ray crystallography and electron microscopy, nuclear magnetic resonance spectroscopy, laser spectroscopy, computational biochemistry, molecular endocrinology/neurobiology, and enzymology/protein chemistry. Ross Ellington is the current director of the Institute. In 1991, the Trustees

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Funding Biomedical Research Programs: Contributions of the Markey Trust The award became the base for leveraging other programmatic funding, and upon which the faculty associated with the Center attracts world-class research talent. UNIVERSITY OF CALIFORNIA, SANTA CRUZ CENTER FOR THE MOLECULAR BIOLOGY OF RNA SEPTEMBER 2002 History and Background of Markey Funding In 1988 University of California, Santa Cruz, requested funding to establish a Center for the Molecular Biology of RNA. Funds were to be used to recruit an additional structural biologist and an x-ray crystallographer interested in RNA structure. Additionally, funds were requested for equipment to support the crystallographer, salaries for postdoctoral fellows, several technicians, a computer programmer, a secretary, and for a major symposium on RNA structure and function. Impact of Markey Funds The Center for Molecular Biology of RNA, which received $2.5 million from the Markey Trust, was established in 1992 and has developed into a thriving research community with an international reputation for RNA research. The Center has grown from five to eight faculty, from the Departments of Biology, Chemistry & Biochemistry, and Computer Sciences. In addition to funding from individual grants to Center faculty, the Center itself obtained funding from the W.M. Keck Foundation and from the Agouron Institute. Among the Center’s accomplishments are hosting the first two international meetings on RNA Structure (1987 and 2000), which were widely acclaimed (reviews of the first meeting were published in Nature and Cell). The Center attracted eight faculty, spanning the areas of RNA structure and function, including X-ray crystallography, biochemistry, genetics, cell biology, computational biology, and genomics. One member has been elected to the National Academy of Sciences and another has been appointed as an HHMI investigator. In addition to the new faculty, 43 postdocs were brought into the program and many are university faculty at such institutions as Massachusetts Institute of Technology; Harvard Medical School; Johns Hopkins; University of California, San Diego; Iowa State; and the University of Illinois. Forty-seven graduate students were brought into the program. Most

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Funding Biomedical Research Programs: Contributions of the Markey Trust have gone on to do postdoctoral research at prestigious academic institutions, while others have taken positions in the biotechnology industry. UNIVERSITY OF CALIFORNIA, SAN DIEGO CHARACTERIZATION OF MACROMOLECULES REGULATING GROWTH AND ONCOGENESIS SEPTEMBER 2000 History and Background of Markey Funding In 1988, the University of California, San Diego requested funding to support a program involving biochemists, molecular biologists, crystallographers, and experts in site-directed mutagenesis and sophisticated computer graphic modeling to enhance understanding of cell growth and differentiation. The program was to focus on four regulatory proteins, and then broaden to other regulatory molecules. Of the funds requested, $550,000 was to be used to cover half the cost of completing laboratory space in a new building. Other expenditures proposed were: core equipment for the labs, salary support for faculty, pre-and-post doctoral stipends, technical staff, and laboratory supplies. Gordon Gill was the principal investigator. Impact of Markey Funds The University of California, San Diego, received $3.2 million from the Trust in 1988 through 1993. In 1994, the University received $500,000 in supplemental funds. The program was directed towards merging molecular and structural biology in an interactive program. Although this theme is widely accepted now, it was quite novel in the 1980s. The program consisted of eight investigators. The awarding of the Markey grant allowed the completion of shell space in the new Molecular and Cellular Medicine West Building into the Laboratory of Regulatory Biochemistry. Shared equipment relevant to the goals of the project was purchased and the Markey program became a paradigm of cooperation between the campus and the School of Medicine. It created interactions that have been strengthened and are ongoing. Although the program is no longer active, it has evolved and there are several sources of follow-up funding. One faculty member obtained NSF funding for the Center for Computational Crystallography at the San Diego Supercomputer Center. He and two other faculty members have garnered the cooperation of other institutions in the San Diego area including Scripps Research Institute, to create a center of biological computation at the San Diego Supercomputer Center. This is now the principal NSF-funded supercomputer center directed

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Funding Biomedical Research Programs: Contributions of the Markey Trust towards biological sciences, the home of the previous Brookhaven-sited protein data banks, and a pioneer in bioinformatics, including those relevant to structural biology and genomics. Much of this research arose out of the initial funding from the Markey Trust. It also evolved from the scientific success of the program. Each of the active investigators have well-funded, active research laboratories that continue the themes of the program. Training grants and a Burroughs Wellcome-funded program have been built on the foundation provided by the Markey program. Personal Observations Gordon Gill stated that his overall impression was that the Markey Trust is a unique experiment in philanthropy. By being limited in time and focused in programmatic giving, it had a profound catalytic effect on American biomedical sciences related to problems of human disease. It will, of course, be more difficult to measure this than programs which have spent less of their resources and have used their resources to sustain themselves over many, many years. The Markey Trust was always lean and mean with minimal administrative staff and maximal flexibility. They had unique leadership in the persons of Dr. Robert Glaser and Mr. Louis Hector whose wisdom I have not seen equaled before or after. It is my impression that a great many charitable foundations spend a large proportion of their resources on program officers and staff; they inevitably become bureaucratized and they dole out funds in small amounts which have minimal impact. The Markey Trust used an opposite philosophy, giving relatively large sums that truly made a difference in a concentrated way with minimal bureaucratic micromanaging. This is, I think, a reflection not only of the trustees and of the excellent staff, but of the outstanding and enlightened leadership of Bob Glaser and Louis Hector. UNIVERSITY OF COLORADO, BOULDER CENTER FOR MAMMALIAN BIOLOGY SEPTEMBER 2001 History and Background of Markey Funding The University of Colorado, Boulder, requested funding for a new Center for Mammalian Biology within the Department of Molecular, Cellular, and Developmental Biology. The newly formed center would focus on the biology of mammals, including humans, with emphasis on developmental and neurobiology. Leslie Lienwand is the chair of the depart-

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Funding Biomedical Research Programs: Contributions of the Markey Trust ment. The Department maintains active ties with the university’s Health Sciences Center in Denver, to which Markey also made a grant for $5.0 million in 1990. The 3-year Markey award of $1.5 million, made in 1994, was to provide laboratory space and equipment for six investigators, develop a mouse facility, and add a conference facility. Impact of Markey Funds The Department of Molecular, Cellular, and Developmental Biology is undergoing a doubling in size of faculty and research space. New construction began in 1995—prior to this no work was being done in mammalian research at Colorado. The Markey funds provided start-up packages, equipment, mouse eggs, etc. for the Center for Mammalian Biology and enabled Dr. Leinwand to hire five new faculty members. The new mouse facility was completed in 1996. Dr. Leslie Leinwand became the chair of the Center. She was recruited from Albert Einstein College of Medicine, where she was the Director of the Cardiovascular Research Institute and a Professor of Microbiology and Immunology. In addition to Dr. Leinwand, five other faculty were recruited. The department has grown to 27 faculty with plans to recruit an additional 14. The Center has 10 graduate students and 11 postdoctoral fellows. Recent accomplishments include: Development of a genetic mouse model for juvenile diabetes along with one for congenital deafness Development of conditional knock-outs of the mouse to study the central nervous systems and its response to injury Identification of new transcription factors that appear to function in heart and eye development Work on the genetics of antisocial behavior The Center is running well and is growing. The Center was able to leverage Markey funds with The William Keck Foundation, which provided an additional $1.5 million to set up a transgenic mouse facility. Additionally, all of the faculty members are well funded through NIH, MS, March of Dimes, or Burroughs Wellcome.

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Funding Biomedical Research Programs: Contributions of the Markey Trust UNIVERSITY OF OREGON CENTER FOR MACROMOLECULAR ASSEMBLIES IN CELL BIOLOGY JUNE 2001 Background of Markey Funding The Markey award was used to establish a new Center for Macromolecular Assemblies in Cell Biology, which builds on three fields of research: three-dimensional macromolecular structures, utilizing crystallographic techniques; macromolecular thermodynamics; and macromolecular interactions. This new Center permits an integrated attack on a central, but poorly understood problem, the intra and intermolecular interactions between proteins, nucleic acids, lipids, and carbohydrates. Such understanding is essential to the rational design of drugs, the definition of the genetic basis of many disease states, including metabolic disorders as well as malignancy, and the ultimate preparation of effective biological agents in useful quantities. At the time of the grant, the administrative responsibility of the Center was carried out by Dr. John Moseley, Vice President for Research, with an advisory board consisting of representatives from the biology, physics, and chemistry faculty. Brian Matthews was the Center director. The Markey $3.3 million award was a five-year award that began in 1988. The grant allowed the Center to upgrade existing research programs through the acquisition of an x-ray area detector facility, computing, graphics and NMR equipment, spectrophotometer, calorimeter, CD spectrophotometer, and freeze-quench apparatus. The Center also recruited three faculty members during the course of the funding and has recruited five more since funding has ended. According to Dr. Matthews, the Markey award was spent as follows: Major Equipment 40% Recruiting New Faculty 36% Core Facilities 12% Individual Labs 12% The Impact of Markey Funding The Center for Macromolecular Biology is now firmly established at the University of Oregon. Of the initial faculty recruited for the Center, two have since left the institution. After their departure, the Center experienced a bit of a decline during the search for new faculty. However, during the last year, five new faculty members have been recruited. Addi-

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Funding Biomedical Research Programs: Contributions of the Markey Trust tionally, NIH funding has increased to the point of sustainability for the Center. The impact of the Markey award was also monitored in terms of the number of graduate students and postdocs who were funded. Throughout the Institute of Molecular biology, 40 graduate students and 40 postdocs directly benefited from the award; an additional 80 graduate students and 80 postdocs indirectly benefited from the Markey award. Because of turnover in Center faculty, Markey funds were put on hold while the search for a replacement occurred. Consequently the last of the Markey funds were spent in 1996. The flexibility in disbursement of funds was crucial for the Center to be able to recruit the best replacement. In fact, this process took more than two years. By its very nature, the Center is interdisciplinary and students within the program are free to work in any of the labs (although their degrees are departmental, their research experiences cross the disciplines of chemistry, physics, and biology). Even though the University of Oregon is small (one of the smallest of the major public research universities), it enjoys an excellent reputation. Faculty members attribute the communal spirit and the continuity of good leadership to the success of the Center. Two of the Center faculty are HHMI investigators and one is a member of the National Academy of Sciences. Because the Markey award came at a time when NIH funding was at its lowest point, the Center Director emphasized that the award was one of the most important factors in allowing the Center to maintain, enhance, and expand its research program. UNIVERSITY OF ROCHESTER THE NEUROSCIENCES INSTITUTE OCTOBER 2001 History and Background of Markey Funding The Lucille P. Markey Charitable Trust awarded a 6-year grant of $4 million to the University of Rochester to help develop the Neurosciences Institute. In 1997, the strategic plan at the Institute decided to commit extensive resources to three major research initiatives in faculty hiring and strengthening of facilities: (1) Aging and development, (2) Cancer biology, and (3) Immunology and vaccine development. The Institute director was David Felten. The grant was used, in part, to recruit five new faculty, who all now have strong extramural funding, to support six investigators in pilot project research, and to support more senior investigators who wished to

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Funding Biomedical Research Programs: Contributions of the Markey Trust change the fundamental direction of their research and needed support to come up to speed in a new area before submitting an R01 request. Impact of Markey Funds The Neurosciences Institute has established itself as one of the core strengths for the University’s efforts for building research on aging. Because of this strength, the University’s medical center added core support in the form of a transgenic facility, an imaging facility, and other key faculty to strengthen collaborations (particularly in translational research). The Institute has established focuses of collaborative research for additional opportunities to further attract NIH center or program project support, pharmaceutical support, foundation support, or venture capital support. They are also putting together a business plan for a new biotech company. The Institute has developed a continuing research relationship with the National Institute on Aging in areas such as Alzheimer’s diseases, Parkinson’s disease gene therapy, neural-immune signaling and plasticity in aging, and neurotherapeutics. The four senior investigators hired with Markey funds—David Felton, Paul Coeman, Suzanne Haber, and Ira Shoulson—continue active research agendas. In addition, Markey funds were used to partially support an additional five investigators. These senior investigators continue to support the research efforts of many junior investigators and use a majority of their resources supporting projects that provide faculty development for these junior investigators to expand their research capacities and expand collaborative ties. Finally, the Institute has supported six pilot research programs utilizing Markey funds. This support for younger investigators is based on the likelihood that it will contribute to the successful application of extramural support. Moreover, pilot support was provided to senior investigators who wished to fundamentally change the direction of their research and needed pilot support to come up to speed in a new area before submitting an RO1 proposal. The faculty are encouraged to think in broader terms and programmatic efforts, to plan research activities as teams of collaborating investigators, and to explore non-traditional sources of support as well as standard NIH sources. The Chair has vigorously supported these efforts at the departmental level, and has recruited strong support for these interactions at the level of the Dean, the Vice President, Vice Provost for Health Affairs, and the President.

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Funding Biomedical Research Programs: Contributions of the Markey Trust UNIVERSITY OF UTAH CENTER FOR PROTEIN BIOPHYSICS SEPTEMBER 2001 History and Background of Markey Funding Martin Rechsteiner, of the department of biochemistry, requested funds in 1989 to establish a Center for Protein Biophysics. The proposed center would utilize the techniques of x-ray crystallography, nuclear magnetic resonance, and optical spectroscopy and be housed in the newly expanded basic science facilities of the medical school. Funds were to be used for two faculty members, graduate students, postdocs, major equipment, and remodeling of laboratory space. Impact of Markey Funds The Center received $2.5 million from the Markey Trust. Unfortunately, the Center is merely a shell at this time. The grant was significant in the history of the university because prior to Markey funding there was no structural biology. Equally important, the Markey funds were used to provide the salaries for support technicians, support that is generally unavailable from other extramural sources. The award provided 5-year support for both an x-ray technician and a peptide synthesis technician. In addition, the award provided 5-year support for graduate students and postdocs. Finally, the award was used for major equipment purchases and supplies. The grant allowed recruitment of three structural biologists, two of whom are still on faculty. In addition, Markey funds supported the research of three established scientists. Finally, the Markey grant supported the research of 17 postdoctoral fellows and three graduate students. The university could not commit to the long-term support of the Center, but did pick up two positions for technicians (mid-level) to run the crystallography equipment. Beginning in the mid 1980s, the level of extramural funding available from federal sources declined dramatically. Second tier schools were especially taxed by this decrease in federal funding. The Utah program in biochemistry was in desperate need of funding at the time of the Markey award and it enabled the program not only to retain talented faculty, but also to recruit new faculty.

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Funding Biomedical Research Programs: Contributions of the Markey Trust UNIVERSITY OF VERMONT THE MARKEY CENTER FOR MOLECULAR GENETICS OCTOBER 2001 History and Background of Markey Funding The University of Vermont, a small public university with a medical school, has created a joint department of microbiology to serve as a research center that serves both medicine and agriculture. Dr. Susan Wallace was recruited to direct the new center. In 1990, she submitted a request to the Lucille P. Markey Charitable Trust for a grant to study gene structure, function, and regulation. With considerable collaboration across disciplinary lines involving the Departments of Zoology, Botany, Biochemistry, Physiology/Biophysics, Cell Biology, and Pharmacology, the new joint program in microbiology explores fundamental processes by using plant cells. In 1991, the Department of Microbiology and Molecular Genetics was awarded 5-year support for $1.8 million. In 1996, the Department received a supplementary award of $500,000. With the Markey funds, Dr. Wallace has established a core group of molecular biologists and microbiologists who provide a basic science hub for applied medical and agricultural research. The grant provided the start-up costs, equipment, and technical assistance for these faculty. She also purchased sequencers, scanners, and other analytic instrumentation and computers. Approximately one half of the $1.8 million went to faculty development, one-third to the core research facility and equipment, and the balance for operational support. Impact of Markey Funds The Markey award was used to develop a Department of Microbiology and Molecular Biology headed by the newly recruited Susan Wallace. When she arrived, faculty, staff, and students totaled about 20. The department now has a faculty of 29 professionals, between 30 and 35 graduate students enrolling each year, and between 40 and 50 undergraduate majors. The program is still growing. In fact, it now brings in annual extramural funding of about $5 million. For the decade of the 1990s, extramural funding exceeded $42 million. Although the Markey funds were used in combination with other grants to develop the Center and its facilities, the impact of the Markey award appears to have been substantial. Not only is the Center name “The Markey Center for Molecular Genetics,” but Dr. Wallace is quite enthusiastic about the equipment purchased and faculty recruited with

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Funding Biomedical Research Programs: Contributions of the Markey Trust this grant. It is apparent that the University of Vermont nurtures the life sciences and invests in new and emerging technologies. Dr. Wallace believes that the lesson to be learned is that high quality teaching and research programs require investment and that the return on such investment is well worth the initial commitment. The Center is a lively research enterprise with enthusiasm and collegiality obvious even to untrained observers.

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