Eulogy for the clinical research center

David G. Nathan, David M. Nathan

J Clin Invest. 2016;126(7):2388-2391. https://doi.org/10.1172/JCI88381.

Op-Ed

The extramural General Clinical Research Center (GCRC) program has been funded for more than 50 years, first by the National Center for Research Resources, NIH, and more recently as part of the Clinical Translational Science Award (CTSA) program through the newly formed National Center for Advancing Translation Sciences (NCATS). The GCRCs represent the federally funded laboratories that employ a highly trained cadre of research nurses, dietitians, and other support staff and in which generations of clinical investigators trained and performed groundbreaking human studies that advanced medical science and improved clinical care. Without the opportunity for adequate discussion, NCATS has now stopped funding these Research Centers. In this “eulogy,” we review the origins and history of the GCRCs, their contributions to the advancement of medicine, and the recent events that have essentially defunded them. We mourn their loss.

Find the latest version: https://jci.me/88381/pdf OP-ED The Journal of Clinical Investigation Eulogy for the clinical research center

David G. Nathan1 and David M. Nathan2 1Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. 2Diabetes Center and Clinical Research Center, Massachusetts General Hospital (MGH), Harvard Medical School, Boston, Massachusetts, USA.

icans with a desire to learn the biomedical research technology of the early twentieth The extramural General Clinical Research Center (GCRC) program has been century were forced to travel to England, funded for more than 50 years, first by the National Center for Research France, Austria, or Germany. Resources, NIH, and more recently as part of the Clinical Translational The first American hospital entirely Science Award (CTSA) program through the newly formed National Center devoted to clinical research was created for Advancing Translation Sciences (NCATS). The GCRCs represent the at Rockefeller University in 1910, where federally funded laboratories that employ a highly trained cadre of research a score or so of beds were surrounded by nurses, dietitians, and other support staff and in which generations of basic research laboratories. The hope was clinical investigators trained and performed groundbreaking human studies that basic science would create new tech- that advanced medical science and improved clinical care. Without the nologies that would be explored at the opportunity for adequate discussion, NCATS has now stopped funding these bedside to understand and improve the Research Centers. In this “eulogy,” we review the origins and history of the prognosis of patients. Harvard Medical GCRCs, their contributions to the advancement of medicine, and the recent School copied the Rockefeller model when events that have essentially defunded them. We mourn their loss. the ten–research bed “Ward 4” opened at MGH in 1925 (6). It was in those beds that Fuller Albright, the father of endo- crinology in the US, studied hyperpara- Introduction Working Group report (5), although neither thyroidism and its effective treatment. In The Clinical Research Center (CRC) pro- report included any specific recommen- the same decade, Francis Weld Peabody, a gram, supported by NIH extramural fund- dations regarding the CRC program, and former MGH house officer, was recruited ing, is now dead (1). The CRCs included the several members of the IOM Committee by Harvard Medical School to lead a larger only federally supported beds (~600 nation- whom we contacted have denied any such clinical research enterprise, the Thorndike wide) and outpatient human research “lab- intent. The defunding of the CRCs, the Memorial Laboratory and the Thorndike oratories” in academic medical centers ded- home of federally funded clinical research Research Ward at the then Boston City icated to support all clinical investigators. for more than 50 years, including the space Hospital (7). He in turn recruited two other Until recently, the CRCs provided many that they occupy and their highly trained graduates of the MGH program, George services free of charge to federally funded research staff, has occurred with virtually Richards Minot and William Bosworth investigators. Industry-initiated studies no discussion in the scientific commu- Castle, to join him. Minot and others were charged for services provided. nity. As experienced CRC users and as the received a Nobel Prize for their contribu- Originally funded from the 1960s director of a GCRC/CRC for more than 25 tions to our understanding of the role of as the General Clinical Research Center years (D.M. Nathan), we mourn their loss vitamin B12 deficiency in pernicious ane- (GCRC) program through the National and here present our eulogy. mia. Castle is correctly considered one of Center for Research Resources (NCRR), the founders of modern hematology. support for CRCs became part of the Clin- The role of clinical center ical and Translational Science Awards investigation in Establishment of the (CTSA) program in 2006, which was sub- American medicine intramural and extramural sequently incorporated into the newly The history of research-oriented “beds” clinical research center established National Center for Advancing is actually the history of modern aca- programs by the NIH Translation Sciences (NCATS) in 2011 (2, demic medicine. Less than a century ago, Biomedical research success in the United 3). Funding support for the CRCs began American medical schools were largely States is the product of the interaction of to be restricted by NCATS within several trade schools. Laboratory-based academic three forces: the proper amalgam of basic years of its creation. The eventual total inquiry barely existed within them. Johns and clinical biological research effort, defunding of the CRCs was carried out Hopkins, the University of Michigan, together with advanced clinical care, purportedly on the basis of Institute of and the University of Pennsylvania had within the academic biomedical commu- Medicine (IOM) recommendations (4) and nascent academic programs that were nity; the continued effort of profit-moti- a subsequent NCATS Advisory Council carried out largely by pathologists. Amer- vated pharmaceutical and biotechnical companies; and the overall support of the enterprise by the NIH and other mem- Reference information: J Clin Invest. 2016;126(7):2388–2391. doi:10.1172/JCI88381. bers of the grant-making and donor com-

2388 jci.org Volume 126 Number 7 July 2016 The Journal of Clinical Investigation OP-ED munity. The directors of the NIH have Contributions of the GCRC and the uniform conduct of multicentered had a profound influence on biomedi- program NIH-sponsored studies have depended on cal research in the United States. Lewis The first extramural GCRC grants from the GCRC facilities and their expert staff. Thompson, the fifth director, secured the the NIH were awarded in 1963 to sev- Moreover, young investigators with insuf- present NIH campus and built its first six eral leading teaching hospitals around ficient funds to build facilities and recruit buildings including the National Cancer the country. The grants provided stable and train their own staff to conduct their Institute. , the sixth director, support for the necessary research space, early work found a “rent-free” home in planned the Clinical Center, the NIH’s beds, and equipment to carry out exper- the GCRCs, as most of the infrastructure central clinical research facility, and estab- imental measurements and therapeu- for clinical research was supported by the lished the National Heart Institute and tics in volunteer patients. The GCRCs institutional GCRC grants. the National Institute of Mental Health. included a highly trained, specialized staff James Shannon, the eighth director (1955– of research nurses, coordinators, statisti- The death of the CRC 1968), played a transformative role as he cians, research subject advocates, bioin- Increasing concern regarding the decline in presided over the massive growth and formaticians, and bionutritionists, who applications for NIH grants from aspiring influence of both the intra-and extramural reliably carried out complex research pro- research-oriented physicians during Wyn- programs of the NIH, including the initi- tocols from myriad investigators. gaarden’s and Varmus’ tenures led to the ation of the GCRC program. The GCRCs For the next 40 years, the contribu- 1995 formation of a Directors Committee aimed to provide medical scientists “who tions of the GCRCs to medical research on Clinical Research (17). The 1995 com- receive their primary research funding were outstanding. Although endocrinol- mittee (chaired by D.G. Nathan) advanced from the other components of the NIH” ogy, nephrology, and metabolism were a broad definition of clinical research that with “the resources which are necessary the major beneficiaries early on, as those included: (a) laboratory-based studies of for the conduct of clinical research” (3). fields particularly require careful measure- patients and their biosamples and tissues; Shannon’s regime produced the eleventh ments of body fluids that can only be well (b) studies in humans of mechanisms of (Donald Fredrickson), twelfth (James performed in a research environment, the disease, therapeutic interventions, and the Wyngaarden), and fourteenth (Harold GCRCs, and now CRCs, have served every development of new technologies; (c) clin- Varmus) directors. discipline in medical science. ical trials and epidemiologic and behav- The legendary transformation of bio- Physiologic and interventional stud- ioral studies; and (d) outcomes and health medical research by Rockefeller University ies and NIH-sponsored clinical trials that services research (17). had a major effect on the intra- and extra- were performed at GCRCs revolution- The 1995 committee concluded that mural programs of the NIH. The planners ized the understanding, prevention, and much of the aforementioned decline was of the original intramural NIH Clinical Cen- treatment of disease. A small number of based on both the financial and intellec- ter, which opened in 1953, reasoned that if examples emanating from the GCRCs tual insecurity of physician applicants. Rockefeller could be successful with twenty at Rockefeller University and MGH (the Educational debt relief programs and K research beds, the United States govern- first clinical research units in the country) awards were therefore urged as essential ment could be even more successful with include the following: advances in under- for the MD graduates and young investiga- ten times as many. Each of the several NIH standing the pathophysiology and treat- tors who hoped to pursue clinical research Institutes was assigned a proportional frac- ment of heroin addiction with methadone careers. The committee also strongly tion of the new beds, with the National Can- (8); the establishment of highly active advised the NIH to maintain the percent- cer Institute and what became the National antiretroviral therapy (HAART) for HIV age of extramural clinical research support Heart Lung and Blood Institute holding the (9); the treatment of precocious puberty in the NIH budget at least at the level that lion’s share. The beds were on one side of (10, 11) and bone disease associated with was extant in 1998. This combination of the modern building, and research labora- hyperprolactinemia, anorexia, and other initiatives would, the committee thought, tories for investigators studying the patients reproductive disorders (12, 13); and the produce higher success rates in R01 com- filled the other side. A massive recruiting revolutionary results of intensive treat- petitions, alleviate angst, and restore the program produced a spectacular clinical ment of type 1 diabetes (14, 15) and preven- physician clinical researcher pool of appli- and research faculty, and house staff to care tion of type 2 diabetes (16). Each of these cants. Importantly, the major recommen- for the patients came from the medical and studies, some of them multicentered with dation regarding the GCRCs was: “The surgical training programs of leading Amer- collaborations among GCRCs around the scope of the GCRCs should be broadened ican medical schools. When those residents country, relied on the resources supplied to enhance their leadership role in clinical returned to their home medical schools, by the GCRCs. During this period, the research and research training and NIH many became the academic division chiefs profile of GCRC research turned increas- should significantly increase its financial of the future, supported by a cornucopia of ingly to outpatient studies. While much support of these centers” (17). NIH-derived research and training grants. of the cardiology and oncology clinical , a radiologist with a In that golden age of the intramural NIH research could be conducted in the clin- strong interest in systems analysis, became program, the contributions of the NIH Clin- ical space, intensive phenotyping, the the fifteenth NIH Director in 2000. He ical Center to academic medicine could testing of new medications, other types believed that clinical researchers were dis- only be called extraordinary. of interventions and diagnostic methods, affected in part because they had inade-

jci.org Volume 126 Number 7 July 2016 2389 OP-ED The Journal of Clinical Investigation quate homes within the approximately 80 now essentially a training program and a even if the NIH reverses course and brings medical centers around the country with network of “hubs” that might interact on back the CRCs. GCRCs and that the onrushing molecular clinical trials of mutual interest. Gone are We fear that the decision to defund the revolution in medicine was rendering the the beds and research space, the patients CRCs, made without any public discourse, old GCRC model superfluous. Zerhouni in the beds, the novel ideas to be tested at will deeply damage clinical research and concluded that the GCRC program, as ini- the bedside and in outpatient CRCs, and demoralize the clinical research commu- tially constituted, needed to be “consoli- the brilliant nurses and other support team nity. As the CRCs slip away, we deeply dated” and more of its funds devoted to members who made it all happen. None mourn their loss. training, education, and collaboration (18). of the committees that have advised the Thus was born the Clinical and Transla- Director, not the original IOM Committee About the authors tion Science Award (CTSA) program. The (4), the Advisory Council reporting on the D.G. Nathan and D.M. Nathan have been GCRCs that survived were incorporated IOM report (5), or the Advisory Committee funded continually by NIH grants and clin- as one element in the CTSA “hubs” and to the Director (ACD) on NCATs chaired ical research centers since 1963 and 1980, were initially maintained. However, the by Maria Freire, PhD, which met three respectively. D.M. Nathan has also served most recent funding announcement (1) times in 2011 (20), has ever mentioned, as the Director of the Mallinckrodt GCRC prohibits any direct funding for the CRC much less suggested, defunding the CRCs. at MGH from 1990 to 2008 and as the space or for the actual conduct of research And yet, they are now effectively gone. Director of the MGH CRC, part of the Cat- studies and eliminates the vast majority The current narrative of clinical alyst Clinical Translational Science Center of research nursing, nutrition, and other research has been simplified into a dichot- at Harvard Medical School, since 2008. staff from the CRC, essentially destroying omy of large database exploration, such as the human research laboratories in which GWAS, or clinical trials that are largely left Acknowledgments thousands of investigators have performed to industry. However, the traditional role The authors are grateful to many col- their research. (The most recent request played by the GCRCs and CRCs, such as leagues, particularly Barry Coller, David for application [RFA] notes: “CTSA fund- the deep phenotyping necessary to under- Ginsburg, Garret Fitzgerald, and David ing can be used to support clinical research stand disease processes and complement Williams, for their incisive comments, staff only for oversight and quality assur- genetic, proteomic, metabolomic, and and for the continued support of the NIH ance, but not to support actual research imaging studies, is arguably more impor- throughout the authors’ careers. activities that are part of studies and trials tant than ever. Similarly, trials that are conducted at the CTSA hub . . . Space to important to the advancement of the pub- Address correspondence to: David G. conduct research cannot be charged to the lic health mission of the NIH, such as com- Nathan, Dana 1644, Dana-Farber Can- CTSA grant”) (1). parative effectiveness studies and other cer Institute 450 Brookline Avenue, Bos- Biomedical research is highly depen- patient-centered research not performed ton, Massachusetts 02215, USA. Phone: dent on technology, and advances in by pharmaceutical companies, also need a 617.632.2155; E-mail: david_nathan@dfci. molecular genetics, cell biology, and imag- home. Bench-to-bedside studies, first-in- harvard.edu. ing have become increasingly important. human trials that effectively join academic 1. National Center for Advancing Translational Sci- These advances have to some extent swept bench investigators and their clinical ences; NIH. Department of Health and Human the study of intact patients off center research colleagues, may be performed Services, Clinical and Translational Science stage. The changes that Zerhouni initiated, most effectively and efficiently in CRCs. Award (U54). https://grants.nih.gov/grants/ with the inclusion of the extramural GCRC Finally, young investigators who wish to guide/rfa-files/RFA-TR-14-009.html. Published September 12, 2014. Accessed May 13, 2016. program at CTSAs that were shifting their conduct clinical research projects during 2. CTSA Principal Investigators, et al. Preparedness emphasis to training and education, were their formative years continue to rely on of the CTSA’s structural and scientific assets to continued by , a genetics the CRCs for training opportunities. support the mission of the National Center for clinical investigator who became the six- We mourn the loss of the CRCs, Advancing Translational Sciences (NCATS). teenth Director of the NIH in 2008. To because we know how hard it is to create Clin Transl Sci. 2012;5(2):121–129. 3. Robertson D, Williams GH, eds. Clinical and deal with clinical research and the plight well-functioning research facilities. Only Translational Science Infrastructure in Clinical of physician-scientists, he established a highly trained nurses and other specialists and Translational Research: Principles of Human committee co-chaired by David Ginsburg have the skills and the interest to carry out Research. 1st ed. London, United Kingdom: Aca- and NIH staff. In 2014, that committee refined research procedures. The careful demic Press; 2009. confirmed the troubles of physician-sci- measurement of human physiology and 4. Committee to Review the Clinical Translational Science Awards Program at the National Center entists and made several valuable recom- disease processes and the implementation for Advancing Translational Sciences; Board on mendations. Like the 1995 committee, the of complex, novel interventions simply Health Sciences Policy; Institute of Medicine, Ginsburg committee made no suggestions cannot be performed well — or at all — in authors. Leshner AI, Terry SF, Schultz AM, to defund the CRCs (19). the inpatient or outpatient clinical setting. Liverman CT, eds. The CTSA Program At NIH. With little, if any, public discussion, Once the CRC research nurses and other Opportunities For Advancing Clinical And Trans- lational Research. Washington, DC, USA: The the Collins administration decided to research colleagues are gone and the facil- National Academies Press; 2013. eliminate any direct funding for the CRCs ities are “repurposed,” it will take years 5. Working Group of the NCATS Advisory Coun- and converted the CTSAs into what is to replace and rebuild them, respectively, cil to the Director. NCATS Advisory Council

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Working Group on the IOM Report: The CTSA hormone. A preliminary report. N Engl J Med. from the Diabetes Control and Complications Program at NIH. https://ncats.nih.gov/files/ 1981;305(26):1546–1550. Trial/Epidemiology of Diabetes Interventions CTSA-IOM-WG-draft-report.pdf. Published 11. Mansfield MJ, et al. Long-term treatment of cen- and Complications Study (DCCT/EDIC) study. May 16, 2014. Accessed May 13, 2016. tral precocious puberty with a long-acting ana- Circulation. 2013;127(2):180–187. 6. Means JH. Ward 4 — the Mallinckrodt Research logue of luteinizing hormone-releasing hormone. 16. Knowler WC, et al. Reduction in incidence of Ward of the Massachusetts General Hospital. Cam- Effects on somatic growth and skeletal matura- Type 2 diabetes with life-style intervention or bridge, Massachusetts, USA: Harvard University tion. N Engl J Med. 1983;309(21):1286–1290. metformin. N Engl J Med. 2002;346(6):393–403. Press; 1958. 12. Klibanski A, Neer RM, Beitins IZ, Ridgway EC, 17. Executive Summary — NIH Director’s Panel on 7. Elrod JM, Karnad AB. Boston City Hospital Zervas NT, McArthur JW. Decreased bone den- Clinical Research Report 12/97. http://grants. and the Thorndike Memorial Laboratory: the sity in hyperprolactinemic women. N Engl J Med. nih.gov/grants/NIH_Directors_Panel_Clinical_ birth of modern haematology. Br J Haematol. 1980;303(26):1511–1514. Research_Report_199712.pdf. Accessed 2003;121(3):383–389. 13. Klibanski A, Greenspan SL. Increase in bone May 13, 2016. 8. Dole VP, Nyswander M. A medical treatment for mass after treatment of hyperprolactinemic 18. Zerhouni EA. Translational and clinical sci- diacetylmorphine (heroin) addiction. A clinical amenorrhea. N Engl J Med. 1986;315(9):542–546. ence — time for a new vision. N Engl J Med. trial with methadone hydrochloride. JAMA. 14. [No authors listed]. The effect of intensive 2005;353(15):1621–1623. 1965;193:646–650. treatment of diabetes on the development and 19. NIH. Physician-Scientist Workforce Working 9. Markowitz M, et al. The effect of commencing progression of long-term complications in insu- Group Report. http://acd.od.nih.gov/reports/ combination antiretroviral therapy soon after lin-dependent diabetes mellitus. The Diabetes psw_report_acd_06042014.pdf. Published human immunodeficiency virus type 1 infec- Control and Complications Trial Research June 1, 2014. Accessed May 13, 2016. tion on viral replication and antiviral immune Group. N Engl J Med. 1993;329(14):977–986. 20. Freire M, et al. ACD Working Group Activities: responses. J Infect Dis. 1999;179(3):527–537. 15. Purnell JQ, Zinman B, Brunzell JD, DCCT/EDIC National Center for Advancing Translational 10. Comite F, Cutler GB, Rivier J, Vale WW, Loriaux Research Group. The effect of excess weight Sciences. Summary of Findings. http://acd. DL, Crowley WF. Short-term treatment of idio- gain with intensive diabetes mellitus treatment od.nih.gov/reports/ACD-NCATSWGR_ pathic precocious puberty with a long-acting on cardiovascular disease risk factors and ath- 09212011.pdf. Published September 21, 2011. analogue of luteinizing hormone-releasing erosclerosis in type 1 diabetes mellitus: results Accessed May 13, 2016.

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