0013-7227/91/1285-2209S03.00/0 Endocrinology Copyright © 1991 by The Endocrine Society

Vol. 128, No. 5 Printed in U.S.A.

Editorial: The Howard Hughes Medical Institute Today Although the Howard Hughes Medical Institute (HHMI) was founded in 1953, in the past 6 yr there have been extensive changes in the size and scope of the Institute's activities that I shall describe briefly here. Any discussion of HHMI must begin with the explanation that it is not a foundation but an operating medical research organization (MRO). As an MRO it, in the language of the Treasury regulations which govern such organizations, must be primarily involved in the "direct, active conduct of research in conjunction with a hospital." This means that there is an employer-employee relationship between the Institute and the scientists, investigators in Institute terminology, who carry out the research supported by it, not a grantor-grantee relationship. (Since 1987 HHMI has had the ability to expend a certain portion of funds in a grant mode, a point to which I shall return below; however, over 80% of its expenditures remain in the MRO mode.) Though employees of the Institute, these investigators retain faculty appointments in their host institutions. The rapidity of the recent expansion of HHMI is indicated by the fact that in the past 4 yr the numbers of investigators and of host institutions where they are located have more than doubled, and it is anticipated that approximately 20 additional investigators will be added in the coming year. The purpose of this article is to describe the current activities of HHMI; however, a few comments about its early development will serve to put recent events in perspective. The Institute was founded in 1953 by the aviator-industrialist Howard R. Hughes. Mr. Hughes had a long-standing interest in medical research and as early as 1926 contemplated the establishment of a research institute, and planning for such an endeavor was underway by 1949. It is of interest that Hughes himself indicated that he was interested in basic research, "research that probed into the genesis of life processes." Accordingly, when the Institute was founded in 1953, the charter indicated that its objective was "the promotion of human knowledge within the field of the basic sciences (principally the field of medical research and education) and the effective application thereof for the benefit of mankind." This remains the primary objective of the HHMI today. Received January 7,1991. Purnell W. Choppin, M.D., author of this editorial, is the President of the Howard Hughes Medical Institute.

The Howard Hughes Medical Institute was founded on December 17, 1953 at the same time as the Hughes Aircraft Company, which was spun off from the Hughes Tool Company. The Aircraft Company was given to the Institute and remained its sole asset and source of operating funds until its sale in 1985. The Institute began its research operations under the guidance of a Medical Advisory Board whose first chairman was Dr. Verne R. Mason, a professor at the University of Southern California School of Medicine and Hughes' physician. Dr. Mason was succeeded by Dr. George Thorn, a founding member of the board and also the first Director of Research for the Institute. Dr. Thorn has remained associated with the Institute until today as a Trustee, and he served as chairman of the Trustees from 19841990. From 1953 until 1976 HHMI supported research in a variety of different fields conducted by investigators located in a small number of medical schools. These early awards were usually for periods of about 5 yr and provided predominantly salary support. In 1976, the Institute adopted a programmatic approach and three areas of emphasis were established: genetics, immunology, and metabolic regulation (subsequently changed to cell biology and regulation). The number of institutions where investigators were located also began to increase, and the annual budget grew from approximately $7 million in 1976 to $36.2 million by 1984, with funds provided for supplies and equipment in addition to salaries. The year 1984 was a major turning point for HHMI. In that year, after prolonged litigation over the manner in which Trustees of the Institute were to be appointed after the death of Mr. Hughes who had been the sole Trustee, the Court of Chancery of Delaware, where the Institute is incorporated, ruled that the Court would appoint a self-perpetuating group of Trustees. The Chancellor of that Court named eight outstanding leaders in the fields of medicine, law, business, and academia and instructed that group to elect a ninth Trustee. (The current Trustees are listed in Table 1 and the senior administrative and scientific officers of the Institute are listed in Table 2.) An early act of the Trustees was the decision to sell the Hughes Aircraft Company. The sale to General Motors was completed in December 1985 at a purchase price of approximately $5.2 billion, thus creating the largest private philanthropy in the United

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TABLE 1. Trustees

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Alexander G. Beam, M.D. Adjunct Professor The Rockefeller University Former Senior Vice President Merck Sharp & Dohme, International Helen K. Copley Chairman of the Corporation and Chief Executive Officer The Copley Press, Inc. Frank William Gay Former President and Chief Executive Officer SUMMA Corporation James H. Gilliam, Jr., Esq. Executive Vice President Beneficial Corporation

William R. Lummis, Esq. Chairman of the Board of Directors SUMMA Corporation Irving S. Shapiro, Esq., Chairman Of Counsel Skadden, Arps, Slate, Meagher & Flom Former Chairman and Chief Executive Officer E. I. du Pont de Nemours and Company George W. Thorn, M.D., Chairman Emeritus Professor Emeritus Harvard Medical School James D. Wolfensohn President James D. Wolfensohn, Incorporated

Hanna H. Gray, Ph.D. President The University of Chicago

TABLE 2. Senior administrative and scientific officers President Vice President and Chief Scientific W. Maxwell Cowan, M.D., Ph.D. Officer Vice President and Chief Investment Graham 0. Harrison Officer Vice President for Grants and Special Joseph G. Perpich, M.D., J.D. Programs Vice President and General Counsel William T. Quillen, Esq. Vice President and Chief Financial Robert C. White Officer Senior Scientific Officer Donald H. Harter, M.D. Senior Scientific Officer David W. Kingsbury, M.D. Senior Research Program Administrator Claire H. Winestock, Ph.D. Purnell W. Choppin, M.D.

States. In August of 1990 the endowment of the Institute was approximately $5.9 billion. The creation of this large endowment provided both an opportunity and the responsibility for a rapid expansion of the HHMI's activities. As an MRO the Institute must spend 3.5% of the net worth of the endowment in the conduct of research. Before the sale, the value of the endowment was in dispute because the Institute was the sole owner of Hughes Aircraft Company, and there was therefore no publicly traded stock on which to base an evaluation. The sale in 1985 provided both an evaluation and the liquidity with which to rapidly increase the Institute's investment in research, including research facilities. As shown in Fig. 1, there was a striking rise in the Institute's budget in 1986 followed by a more gradual, continued increase. The budget for fiscal year 1991 beginning September 1990, is $322.5 million. The remarkable changes in the Institute's activities have included the construction of research facilities, a large increase in the number of investigators, addition of new research programs, and the initiation of a grants program emphasizing education. It is widely recognized that the construction of needed

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50 1980 '81 '82 '83 '84 '85 '86 '87 '88 '89 '90 '91

FIG. 1. Annual expenditures of HHMI in fiscal years 1980-1991. The 1991 value is a budgeted amount.

biomedical research facilities has lagged to an alarming degree in recent years, and during this period the federal government has not made a major investment in laboratory construction. The creation of the HHMI endowment through the sale of the Hughes Aircraft Company enabled the Institute to make a major contribution in this area, at a crucial time. Since 1986 the Institute has made commitments for over $120 million for construction of new research laboratories, and each year substantial expenditures are made for renovation of existing laboratories. Similar large investments have been made in scientific personnel. There are currently approximately 218 investigators located in 52 leading medical schools, universities, and research institutes in 22 states. They are assisted by a support staff of over 1600. This represents an increase of about 2.5-fold in the past 5 yr. In addition to the large increase in the number of investigators, an important new type of appointment was initiated in 1986. Previously, the Institute's scientists were based in units with 6-15 investigators associated with about 20 medical schools. It was decided that a major route of future expansion of the HHMI should be through the appointment of investigators as individuals rather than members of an existing large unit. In this way the Institute can support the best scientists where we find them, and extend its resources to a larger number of institutions. This program has been very successful, and to date more than 50 outstanding scientists have been appointed through this mechanism. As an MRO the Institute employs its investigators, providing their full salaries and fringe benefits, as well as funds for supporting personnel, equipment, and supplies. However, the investigators retain faculty appointments at their host institutions where they are based and are expected to be good institutional citizens, participating in teaching and other faculty activities. In addition to expansion in laboratory facilities and scientists, two new research program areas have also been added in recent years. Research by Institute scien-

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EDITORIAL

tists is now conducted in the following five areas which are broadly interpreted: cell biology and regulation, genetics, immunology, neuroscience, and structural biology. As a part of its program in structural biology, the newest area of interest, HHMI is funding the construction of a beam line on the synchrotron at the Brookhaven National Laboratory which when completed will be available not only to HHMI investigators but the structural biology community in general. An extremely important feature of the HHMI mode of operation is that the Institute supports the research careers of its investigators rather than specific research projects. Thus although they are identified with one of the Institute's five program areas, they are free to pursue research of their choosing and may even change program areas if they so desire. Scientists are appointed at three levels within HHMI, Assistant Investigator, Associate Investigator, and Investigator, which correspond to the Assistant Professor, Associate Professor, and Professor ranks at universities. The terms of the initial appointment at these ranks are 3, 5, and 7 yr, respectively. Appointments are renewable in 3-5 yr increments. We at HHMI are keenly aware that young scientists are vitally important to the vigor and continued success of the research enterprise, and that these are very difficult times for those beginning their independent research careers. Accordingly, the most rapidly growing category of HHMI scientists is that of Assistant Investigator. In the past year 21 new scientists were appointed at this level, including 7 that were identified in a national competition in which over 200 institutions where there were currently no HHMI investigators were invited to nominate Assistant Professors for appointment. As an operating medical research organization the magnitude of the contributions of HHMI must be largely measured by the quality of its investigators and the research that they conduct. Thus the procedures by which scientists are appointed as HHMI investigators and their progress is reviewed are extremely important. Nominations of candidates for HHMI investigator positions come to the Institute in several ways. At each institution where there is an HHMI unit, there is a faculty liaison committee that can make nominations on behalf of that institution. Institutions that do not have an HHMI presence make nominations through an appropriate official, e.g. Dean of the Medical School or President of the University. In addition, the Institute has two levels of advisory groups that may at times identify outstanding scientists for consideration. Applications from individual scientists are not accepted. The two peer review groups that advise HHMI on appointments, promotions, and renewal of appointments are the Scientific Review Board (SRB) and the Medical Advisory Board (MAB). The members of these boards

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are distinguished scientists with expertise in the areas of Institute activities who are appointed for 3- or 4-yr terms on a rotating basis. The current members of these boards are listed in Tables 3 and 4. The SRB, organized on the basis of scientific fields, consists of a panel of four to six outstanding scientists in each of the five HHMI program areas. The MAB is a multidisciplinary group of 10 distinguished scientists and a chairman, with representation from each of the program areas. When a nomination is received from a host institution it is accompanied by a curriculum vitae and supporting documentation. This material is submitted for review and evaluation to the appropriate panel of the SRB and usually to several ad hoc members in the scientific field of the candidate. These evaluations are then assembled and submitted to the MAB at one of its quarterly meetings. The MAB reviews the material and recommends to the Institute the appointment of those scientists who meet the high standards required of HHMI investigators. The SRB and MAB are also involved in a careful review process to evaluate investigators for reappointment after their initial terms. One or 2 yr before the end of their current terms, investigators are reviewed. They submit in advance a brief description of past research accomplishments, their plans for the future, and copies of their recent publications. They then come to Bethesda, where HHMI has its headquarters, to meet with a group of reviewers consisting of members of the appropriate SRB panel, the MAB, ad hoc reviewers if needed in certain fields, and the scientific management of the Institute. The investigators present their work and plans in a 1-h talk followed by a discussion session. On the basis of both the submitted material and this presentation, the review group makes a recommendation regarding renewal or nonrenewal of the appointment. This recommendation, subject to review by the MAB, is submitted to the Institute scientific management for final action. If an appointment is not to be renewed, the investigators will receive at least 1 or 2 yr notice, depending on their rank, during which time they can seek alternate support. The quality of a large group of scientists is difficult to quantify; however, the Institute is extremely pleased with the overall excellence of our current group of scientists, 29 of whom are members of the National Academy of Sciences, and 4 hold the Nobel Prize, including 1 winner in each of the 3 yr 1987 through 1989. HHMI investigators are also holders of many other awards and prizes, e.g. the National Medal of Science, Lasker Award, Horowitz Award, Gairdner Award, etc. Perusal of any of the leading journals covering the fields in which the Institute has an interest will reveal many important publications by Institute scientists. In addition to the research conducted by its investi-

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EDITORIAL

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TABLE 3. Scientific review board Genetics

Cell biology and regulation Alfred G. Gilman, M.D., Ph.D. Professor of Pharmacology University of Texas Southwestern Medical Center at Dallas Tony Hunter, Ph.D. Professor of Molecular Biology and Virology The Salk Institute Marc W. Kirschner, Ph.D. Professor of Biochemistry and Biophysics University of California, San Francisco, School of Medicine Stuart Kornfeld, M.D. Professor of Medicine Washington University School of Medicine David J. L. Luck, M.D., Ph.D. Professor of Cell Biology The Rockefeller University Lucille Shapiro, Ph.D. Professor of Developmental Biology Stanford University School of Medicine

David Botstein, Ph.D. Professor of Genetics Stanford University School of Medicine Ira Herskowitz, Ph.D. Professor of Biochemistry and Biophysics University of California, San Francisco, School of Medicine Anthony P. Mahowald, Ph.D. Professor of Molecular Genetics and Cell Biology University of Chicago Thomas P. Maniatis, Ph.D. Professor of Biochemistry and Molecular Biology Harvard University Malcolm A. Martin, M.D. Chief, Laboratory of Molecular Microbiology National Institute of Allergy and Infectious Diseases National Institutes of Health Harold E. Varmus, M.D. Professor of Molecular Virology University of California, San Francisco, School of Medicine Structural biology

Immunology Joseph M. Davie, M.D. President G. D. Searle and Company

David R. Davies, Ph.D. Chief, Section on Molecular Structure, Laboratory of Molecular Biology National Institute of Diabetes, Digestive, and Kidney Diseases National Institutes of Health

William E. Paul, M.D. Chief, Laboratory of Immunology National Institute of Allergy and Infectious Diseases National Institutes of Health

Michael N. G. James, D. Phil. Professor of Biochemistry University of Alberta

Matthew D. Scharff, M.D. Professor of Cell Biology Albert Einstein College of Medicine

Dinshaw Patel, Ph.D. Professor of Biochemistry and Molecular Biophysics Columbia University College of Physicians and Surgeons

John D. Stobo, M.D. Professor of Medicine The Johns Hopkins University School of Medicine

Michael G. Rossmann, Ph.D. Professor of Biological Sciences Purdue University

Emil R. Unanue, M.D. Professor of Pathology Washington University School of Medicine Neuroscience Floyd E. Bloom, M.D. Chairman, Department of Neuropharmacology Member, Scripps Clinic and Research Foundation Arthur M. Brown, M.D., Ph.D. Professor of Molecular Physiology and Biophysics Baylor College of Medicine

William A. Catterall, Ph.D. Professor of Pharmacology University of Washington School of Medicine Melvin I. Simon, Ph.D. Professor of Biology California Institute of Technology

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TABLE 4. Medical advisory board Michael S. Brown, M.D. Professor of Medicine and Genetics University of Texas Southwestern Medical Center at Dallas John E. Dowling, Ph.D. Professor of Natural Sciences Harvard University Gerald D. Fischbach, M.D. Professor of Neurobiology Harvard Medical School Hugh 0. McDevitt, M.D. Professor of Microbiology, Immunology and Medicine Stanford University School of Medicine Frederic M. Richards, Ph.D. Professor of Molecular Biophysics and Biochemistry Yale University

David D. Sabatini, M.D., Ph.D. Professor of Cell Biology New York University School of Medicine Phillip A. Sharp, Ph.D. Professor of Biology Massachusetts Institute of Technology William S. Sly, M.D. Professor of Biochemistry and Molecular Biology St. Louis University School of Medicine Lloyd H. Smith, Jr., M.D. Professor of Medicine University of California, San Francisco, School of Medicine Thomas A. Waldmann, M.D. Chief, Metabolism Branch, National Cancer Institute National Institutes of Health

Janet S. Rowley, M.D. Professor of Medicine, Molecular Genetics and Cell Biology University of Chicago

gators, HHMI is currently involved in other important activities. One of these is a joint program with the NIH in Bethesda, MD, in which 40-50 medical students from schools across the country take a year or two out of medical school and come to Bethesda to do fundamental research in an NIH laboratory. This program (which has come to be known as the Cloister Program because it is housed in the former home of an order of cloistered nuns on the NIH campus) was begun with Dr. George Cahill as Director; he was succeeded in 1989 by Dr. Donald Harter. It has been extremely successful and is highly valued by the students and the NIH, as well as the Institute. In March 1987 an extremely important agreement was reached with the Internal Revenue Service that enabled the Institute to expand its activities with a certain portion of its expenditures. Among the important points in this agreement was the decision that after the Institute had expended 3.5% of its endowment in the course of any year in the direct active conduct of research by its scientist employees, it could spend funds above that amount in any tax-exempt fashion consistent with its charter. This meant that for the first time HHMI could give grants, scholarships, and fellowships to institutions or individuals, activities that had been precluded before. A very important and happy consequence of this decision was that the Institute could begin to have a major initiative in science education, a role that was envisioned in its charter (cited above) but which had been limited to postdoctoral research associate training by the prior

interpretation of the regulations. This increased flexibility in spending could not have come at a better time, because of numerous studies indicating that interest in careers in science and the quality of education in science, particularly at the precollege level, are declining. The Trustees, with the enthusiastic concurrence of the management of the Institute, have decided that the bulk of the expenditures possible under the new ruling, i.e. those above 3.5% of the endowment, would go into science education across a broad front. Since 1987 HHMI has initiated several programs that extend from precollege to postdoctoral education. These include the following: 1) A predoctoral fellowship program for students pursuing Ph.D. degrees in the biomedical sciences, providing a stipend and an institution allowance for a 3-yr period, renewable for an additional 2 yr depending on progress. Sixty-six new fellowships are to be awarded each year. At its maximum this program will have about 330 fellows in training. 2) A medical student research training program, complementing the above-mentioned Cloister Program at the NIH, in which up to 60 students may take a year out of medical school to spend a year in basic research in their own or another medical school. A small number of these students may spend a second year in research, and a few on a competitive application basis may receive scholarship aid from the Institute for up to two remaining years of medical school. 3) A postdoctoral fellowship program for physicians with at least 2 yr of clinical training beyond the M.D. degree who wish to receive 3 yr of training in basic research. It is anticipated

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EDITORIAL

that 25-35 fellows will be appointed each year, with a total of 75-100 in training when the program is at full strength. This program was created because of a well recognized decrease in the number of physician scientists well trained in both clinical medicine and in basic research. 4) A college undergraduate biomedical science education program. This is the largest component of the grants program, with $30.5 million committed in each of the past 4 yr. This program is designed to enhance biological and related sciences education at the college level, but includes components such as outreach programs to high school students and teachers and undergraduate student research experience. To date $122 million has been committed; 44 liberal arts colleges and historically black institutions and 51 research and doctoral granting universities have received awards and a second round of applications has begun. To our knowledge this is the largest initiative ever mounted by a private philanthropy in support of undergraduate science education. 5) Other major grants have been awarded to the Cold Spring Harbor Laboratory and the Marine Biological Laboratory for support of the specialized scientific courses that they conduct, to the Jackson Laboratory, an international resource for laboratory mice, and to the Institute of Laboratory Animal Resources of the National Research Council. The Institute of Medicine has been awarded a special endowment grant to support studies and program activities on a spectrum of health science policy topics. HHMI has also supported the computer data bases that comprise the human genome mapping library, first at New Haven and currently at The Johns Hopkins University School of Medicine. The Institute recently awarded a grant for the support of the international Human Genome Organization. In addition to these activities that are already underway, the Institute has a strong interest in precollege science education. It funded a study by the Commission on Life Sciences of the National Research Council on this subject. The report of that study, "Fulfilling the Promise: Biology Education in the Nation's Schools," has recently been published. Based on that study and other investigations carried out by our own staff and consultants, the Institute is planning additional initiatives in the area of precollege science education. Until this year, the involvement of HHMI in the international arena was limited to its fellowship programs under which foreign students may apply to work in laboratories in the United States and U.S. citizens may apply to work abroad. Recognizing the international nature of science, the Institute is beginning this year on a pilot experimental basis the awarding of grants through a peer review process to a small number of scientists outside the United States, beginning with our immediate neighbors, Canada and Mexico. Depending on the expe-

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rience with this initial phase, the international program may be expanded on a limited basis to other countries. The grants program budget for this fiscal year is $50.2 million, and it is anticipated that HHMI will continue to have a major grants program with emphasis on biomedical science education and training. Another exciting and significant new venture for the Institute is the construction of a new headquarters and conference center complex on a beautiful 22.4-acre plot of land in Chevy Chase, MD, about a mile from the NIH campus. Work has recently begun on this project with completion scheduled for September 1992. This installation will not only provide the Institute with its own permanent headquarters to replace existing inadequate rented space, but the conference center will become the heart of our research programs. Because the HHMI is indeed an institute without walls, with scientists spread across the nation, it is critical to our scientific effectiveness that our many investigators be brought together periodically to exchange ideas and provide a level of intellectual and scientific cross-fertilization that the Institute is uniquely organized to provide. To inform interested parties about the growing activities of HHMI, the Institute publishes several communications on a regular basis. These include: a general "Annual Report" describing various programs of the Institute and a brief financial report; a formal "Annual Scientific Report" including reports by all investigators with bibliographies; "Research in Progress," describing in language intended for the nonexpert in the field the work of each investigator; and "Grants for Science Education," a brochure describing the grants programs of the Institute. In addition, from time to time special reports for a general audience are published on biomedical topics of interest. For example, a recent report entitled "Finding the Critical Shapes," describing recent exciting developments being done in structural biology, was widely distributed and extremely well received, particularly by science teachers. HHMI, and indeed the biomedical enterprise in the United States, is fortunate that the endowment generated by the sale of the Hughes Aircraft Company in 1985 made possible great increases in expenditures by the Institute for biomedical research and education and for construction of laboratory facilities at a time when stresses on funding of research by the federal system, particularly NIH, were increasing. These problems in federal funding are paradoxically occurring when the time is ripe to exploit the rapid progress in the biological sciences for the benefit of humanity. It seems highly appropriate that the recently enlarged resources of HHMI could be dedicated to biomedical research and education at this critical time. The importance of the Institute's role in this arena is illustrated by the fact that

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EDITORIAL

according to the "NIH Databook for 1989," in 1988 HHMI accounted for 24% of the nation's private nonprofit support for biomedical research and development (total $744 million), and this figure does not include the approximately $40 million in grants awarded by the Institute in that year. As significant as the Institute activities are in the private nonprofit sector of support, it must be emphasized that this sector provides only a small portion (4%) of the total support for biomedical R & D, and even if expenditures by industry are removed, private nonprofit support is less than 10% of that of the federal government. Thus, although the laudable pluralism of support has created in the United States the finest biomedical research enterprise in the world, and although private philanthropy still has a vital role to play at this critical time of revolutionary advances in our knowledge of life processes and disease mechanisms, the health of that biomedical research enterprise is irrevocably tied to the health of the NIH. Similarly, the state of basic research

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in non-medical areas is inseparable from the support of the National Science Foundation and other federal agencies. These great federal scientific agencies must remain robust. They have done a truly remarkable job in fulfilling the promise of science. In summary, the Howard Hughes Medical Institute is the nation's largest private philanthropy with a budget for the current year of $322.5 million. The Institute is dedicated to biomedical research and education. Its goals are to support research of the highest quality by its investigators today and, through research training in Institute laboratories and its grants programs in education, to do its part in guaranteeing that there will be future generations of well trained biomedical scientists to do the research of tomorrow, thereby continuing the extraordinary revolution in medicine that we are now witnessing. Purnell W. Choppin, M.D. President The Howard Hughes Medical Institute Bethesda, Maryland

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The Howard Hughes Medical Institute today.

0013-7227/91/1285-2209S03.00/0 Endocrinology Copyright © 1991 by The Endocrine Society Vol. 128, No. 5 Printed in U.S.A. Editorial: The Howard Hughe...
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