MIT Reports to the President 1994-95

Clinical Research Center

The Clinical Research Center (CRC) was established in 1964, with grant support from the National Institutes of Health (NIH), to provide a facility in which Massachusetts Institute of Technology (MIT) investigators and their collaborators could apply the Institute's expertise in basic biochemical and biophysical mechanisms to the analysis of normal and pathologic processes in humans. MIT's CRC was the first federally supported clinical research center located in a university and not within a hospital. It was anticipated that in spite of its university venue, a large enough number of qualified physicians from MIT's faculty and staff would utilize the CRC to study normal volunteers, or patients with chronic diseases.

Scientists and physicians authorized to carry out research protocols using the CRC's facilities include: professors; research scientists who work exclusively at MIT; and those with primary appointments in local medical institutions whose research interests overlap extensively with those of MIT investigators. Research protocols must be approved by the MIT Committee on the Use of Humans as Experimental Subjects (COUHES) and the CRC Advisory Committee before they can be implemented. The CRC Advisory Committee, chaired by Dr. John Burke, Professor of Surgery at the Harvard Medical School, consists of 10 voting members plus six non-voting members of the CRC's program staff. The Committee reports to the Principal Investigator, Roger Mark, Professor and Co-Director of HST, and meets bi-monthly to evaluate protocols for their scientific quality, experimental design, statistical analysis and potential risk to human subjects. The Committee also sets general policies and reviews the operations of the CRC.


The CRC presently has a dual administrative locus within MIT. As a research unit, the CRC reports through Harvard-MIT Division of Health Sciences and Technology (HST) to the Vice President and Dean for Research, Professor David Litster. However, as a patient-care unit, the CRC is a part of the MIT Medical Department and reports to Dr. Arnold Weinberg, the Director of the Medical Department. Members of the CRC participate in the Medical Department activities; i.e., Quality Assurance, Pharmacy and Therapeutics, Medical Records, and Safety Committees.

On June 1, 1995, the CRC submitted a competing grant application to the NIH for renewal of funding for the next project period beginning in December, 1996.

In the past year MIT has undertaken a major analysis of space use and space needs in E17 & E18. After an architectural review of CRC space, a grant application was submitted to the National Center for Research Resources in March, 1995 requesting partial support for renovations directly related to the research needs of the Center.


The Core Laboratory (CL) specializes in assays that directly support the research efforts of CRC investigators. The most important and complex assays are undertaken by the Mass Spectrometer Facility (MSF), where stable isotope tracer analyses are performed. The MSF is a shared instrument facility that allows CRC investigators to conduct human metabolic studies using stable nuclide tracers. Principal areas of investigation concern the regulation of energy substrate metabolism in health and disease, and the regulation of whole body amino acid metabolism, with particular reference to the nutritional requirements for indispensable and conditionally indispensable amino acids. Research at the MIT CRC has made important contributions to the further development of national and international dietary standards and the establishment of sound food and nutrition policies and programs. Studies continue to examine the role of dietary arginine as a precursor of signal transducer nitric oxide. The novel doubly labelled water (2H218O) method is being used to define the energy requirements for adolescent and elderly subjects, and the factors which affect these needs. These various investigations offer new basic knowledge about the physiology of human energy substrate and amino acid metabolism and, additionally, make practical contributions to problems in human nutrition.

High performance liquid chromatography (HPLC) techniques are also utilized by the CL. A Beckman System Gold Amino Acid Analyzer HPLC provides resolution of up to 42 physiologic amino acids. Other HPLC assays include tests for choline, tryptophan, the catecholamines and cytidine.


The computer area focused on the development of the CRC Operations System. It is being developed using the ORACLE relational database, and supports the day-to-day operations of the Center. The delay we experienced due to a past staffing problem was resolved with the hiring of a new programmer/analyst with experience using ORACLE in the UNIX workstation environment.

Researchers continued to make use of the SAS statistical software available on the CRC computer system. They also began using the resources available on the Internet.


The CRC has continued to provide postdoctoral training for physicians who are participating in fellowship programs at MIT. These physicians have utilized the CRC's facilities to initiate research protocols and to participate in ongoing projects supervised by senior investigators and faculty. During 1994 - 95 six post-doctoral fellows and four graduate students participated in research projects at the CRC. At the undergraduate level, 13 Undergraduate Research Opportunities Program (UROP) students participated in clinical research projects with physician preceptors and faculty supervisors.

Clinical Investigator Training Program

A major new development central to the CRC's training function is the establishment of the Clinical Investigator Training Program (CITP). This two-year multidisciplinary training program, based in the MIT Clinical Research Center, is funded by an unrestricted five million dollar grant from Pfizer, Inc. Five physician Fellows a year, all of whom have completed their clinical training requirements for Board eligibility in their chosen specialty/subspecialty, are taken into the program for a period of two years. The goal of this Fellowship is to train physicians in techniques and processes relevant to patient-oriented research. The program's curriculum allows trainees direct, hands-on experience in performing technology- and basic science-based clinical investigation, and, concurrently, didactic course work designed to provide a strong foundation in the computational and statistical sciences, biomedical ethics, principles of clinical pharmacology, pharmacoeconomics, in vitro and in vivo measurement techniques, and various aspects of the device and drug development processes. In the past year three fellows participated in the program. There will be eight in 1995 - 1996.

Seminar Series

During this past year the CRC sponsored a well-attended monthly seminar series on the "Genetics of Human Behavior." Talks were given on "Genes & Human Sexuality" by Dean Hamer, Ph.D., Chief, Gene Structure & Regulation, NCI - NIH; "Genes & Obesity" by Jeffrey Friedman, M.D., Ph.D., Associate Professor / Investigator, Department of Genetics, Rockefeller University; and "Genes & Aggression" by Xandra O. Breakefield, Ph.D., Associate Geneticist / Professor of Neurology, Massachusetts General Hospital/Charlestown. The talks emphasized recent discoveries on genetic linkages or - in the case of obesity - mutations associated with particular types of behavior. They were well received and managed to skirt the controversies often associated with the field.


The hiring of women and minorities continues to be a high priority at the CRC; our primary problem in meeting affirmative action objectives has been attracting qualified minority candidates. The traditional means of advertising and posting positions in local colleges, universities, medical institutions, and minority organizations have not resulted in a significant response from qualified minorities.

This past year two research staff positions became available. Two women were hired. Six Visiting Scientists were appointed, two women (one minority) and three men. The Center will continue its efforts to increase the pool of qualified minority applicants as positions become available.


During the past year, most of the research activities of the CRC have continued to be associated with three clinical areas, and to involve three groups of scientists, each led by a senior professor. These areas are: Nutrition/ Metabolism (Vernon R. Young, professor, MIT School of Science) - an area in which the CRC constitutes the major locus of MIT's activity, and one that is a traditional component of clinical research centers; Neurochemistry/Neuropsychopharmacology (Richard J. Wurtman, Cecil H. Green Distinguished Professor and Program Director, MIT CRC) - studies on the effects of drugs, foods and hormones on brain composition and behavior; studies on melatonin and sleep, and on biologic rhythms in sleep and hormone secretion; studies on a set of diseases characterized by affective and appetitive symptoms (i.e., depression, premenstrual syndrome, smoking withdrawal, carbohydrate craving, obesity), which seem to relate to brain serotonin; and Behavioral Neuroscience (Suzanne Corkin, Professor of Brain of Brain and Cognitive Sciences) - focussing on the effects of diseases on cognitive and related brain functions and on genetic and other mechanisms causing neurodegenerative disorders (i.e., Alzheimer's disease). Groups collaborate on multidisciplinary projects, e.g., obesity; depression; Alzheimer's disease. Moreover, numerous CRC research collaborators involve both an MIT professor and investigators at an outside hospital or research laboratory.

This year the CRC patient census totaled 209 inpatient days and 3,009 outpatient visits.

Center For Experimental Pharmacology And Therapeutics

This year the Center for Experimental Pharmacology and Therapeutics (CEPT) was established within HST under Professor Robert Rubin, and located within the CRC. Its mission is to facilitate application of MIT-generated quantitative science and technology to the study of human physiology and the discovery of treatments for disease. The focus of the CEPT is on pathophysiologically oriented, patient centered, quantitative, and measurement based clinical research, as well as on the education of fellows and students in the performance of such research. Research programs relate to experimental therapies and to experimental measurement technologies. Both are viewed as probes for understanding normal physiology and for understanding and managing disease.

Research Highlights

Richard J. Cohen, M.D., Ph.D. and his associates demonstrated that analysis of beat-to-beat variability in hemodynamic signals provide a powerful, quantitative and noninvasive means of assessment of closed-loop hemodynamic regulation. They also demonstrated that system identification techniques can noninvasively quantify the baroreflex without the need to use pharmacologic agents.

Suzanne Corkin, Ph.D., and her colleagues showed that three learning systems exist, i.e., a "memory" system for cognitive learning, which acquires knowledge, and whose neural substrate is limbic circuits; a "habit" system for noncognitive learning, which forms automatic connections between a stimulus and a response, and whose neural substrate is the striatum; and a "priming" system mediated cortically. Event-fact learning corresponds to what Graf and Schacter term "explicit" memory, whereas skill learning and priming are instances of what the term "implicit" memory. Corkin's project tests predictions derived from Mishkin's model (extended to accommodate priming) against memory dissociations found in human subjects who have lesions that disrupt the reciprocal connections between limbic structures and cortex (in global amnesia), between striatum and cortex (in PD and HD), or within cortex (in AD and focal cortical lesions), in terms of three domains of performance: event-fact learning, skill learning, and priming.

William H. Dietz, M.D., Ph.D. and his co-workers demonstrated in a large cohort of non-obese pre-menarcheal girls, that components of energy expenditure include total daily energy expenditure, resting metabolic rate, the energy spent on non-basal energy expenditure, and VO2 max; that FAO/WHO/UNU equations provide the best estimate of metabolic rate in pre-menarcheal girls of different Tanner stages of sexual development. They also demonstrated that parent obesity seems to be unrelated to the components of energy expenditure that we have measured. In addition they showed that parent and daughter's reports of energy expenditure tend to be poorly correlated, except for leisure time activities, particularly for time spent viewing television, suggesting that family correlations of inactivity may be stronger than family patterns of activity. And they showed that the effect of television on susceptibility to obesity does not appear to be mediated by a reduction in metabolic rate.

Paul A. Spiers, Ph.D., and his associates demonstrated that low doses (1,000 mg. per day orally) of CDP-Choline raised plasma choline levels and was well tolerated and, in neuropsychological testing, exerted a positive effect on the verbal memory of some healthy, non-demented elderly men and women. This past year they also illustrated improvements in immediate and delayed recall of verbal material among subjects taking chronic high doses (2,000 mg. per day orally) of CDP-Choline. This suggests that the decline in memory associated with normal aging may be reversible with administration of choline and cytidine precursors. This could represent a significant savings in economic, social and health resources particularly given the "graying of America" with the 75 year and older age group becoming the fastest growing segment of the population.

Judith J. Wurtman, Ph.D. and her colleagues showed that weight gain among normal weight women undergoing a three month smoking withdrawal program can be minimized by treatment with dexfenfluramine although withdrawal of the drug following a three month treatment regimen causes weight to be gained. Fluoxetine treatment minimized weight gain for the first month of treatment; subsequently, weight gain among the fluoxetine treated group was similar to placebo and continued after the end of drug treatment. They also demonstrated that patients with obsessive compulsive disorder describe patterns of snack intake that include daily consumption of carbohydrate-rich snacks and self-reports of eating such foods when distressed. When their snacking habits were compared with a control population of patients attending a dermatology clinic, the snacking habits of both males and females with OCD were significantly different from the control group and was not related to either gender or weight status.

Richard J. Wurtman, M.D. and his co-workers demonstrated for the first time, that very low melatonin doses (0.1 or 0.3 mg), which raise daytime blood melatonin levels only to those which occur normally at night, make people sleepy and facilitate sleep initiation. The results obtained in 20 healthy people also suggest that the normal secretion of melatonin, each evening and night, is partly responsible for physiological sleep. In subsequent studies using low melatonin doses given later in the evening, using standard polysomnography, demonstrated that low melatonin doses at all of the time points tested cause sleep onset without disturbing the normal sleep structure. They additionally showed that melatonin administration causes no differences in mood and performance of people tested on the morning after melatonin or placebo. These preliminary results suggest that induction of melatonin concentrations close to normal physiological levels does not negatively affect humans' performance and mood the morning following treatment.

Vernon R. Young, Ph.D, D. Sc. and his colleagues demonstrated that it is feasible to estimate whole body leucine balance using 13C-leucine as a tracer. Through continuous 24h intravenous 1-13C-leucine tracer studies we have established the basis for a precise determination of daily leucine balance. This opens the way for a new approach for estimating the nutritional requirements for this amino acid in healthy subjects. It was also demonstrated that whole body leucine oxidation predicts total body amino acid catabolism as assessed from urea N excretion. This finding refutes the conclusion drawn by others that urea N salvage (via retention of N liberated urea hydrolysis of urea within the intestinal tract) plays a quantitatively significant role in body nitrogen (protein) homeostasis. They showed that daily whole body leucine oxidation is similar when the diet is taken as frequent small meals or as three discrete meals. This finding indicates that for leucine, at least, the 24h fed/fast tracer protocol used in our previous studies is a useful model for studying kinetics of leucine metabolism throughout the day. The latter is the unit of time of major interest with respect to nutritional and dietary issues.

Richard J. Wurtman, M.D.

MIT Reports to the President 1994-95