CLINICAL RESEARCH CENTER

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.

ADMINISTRATION

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. The CRC received its best priority score ever and anticipates funding of up to four years at a total of eight million dollars.

EDUCATION

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 1995 - 96 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.

AFFIRMATIVE ACTION

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 three research staff positions became available. Three women were hired, two minorities. Three Visiting Scientists were appointed, two women (one minority) and one male. The Center will continue its efforts to increase the pool of qualified minority applicants as positions become available.

Recently, Dr. Leticia Castillo, Visiting Scientist, was a recipient of a National Institutes of Health Research Supplement for Underrepresented Minorities award. This NIH program provides opportunities for minority scientists to gain further research experience and at the same time, allowing them to strengthen the pool of independent minority biomedical research investigators. Dr. Castillo is conducting studies on arginine metabolism.

RESEARCH ACTIVITIES

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) - focusing 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 352 inpatient days and 2,680 outpatient visits.

CLINICAL INVESTIGATOR TRAINING PROGRAM

The Clinical Investigator Training Program (CITP), which is based in the GCRC, was recognized by the Faculty Council of the Harvard Medical School in the following fashion: all Fellows successfully completing the program will receive a Master of Medical Science in Clinical Investigation from Harvard -- recognition of their unique training and experience. In the coming year, the diadactic material developed for the CITP will form the basis of an elective program for medical students and graduate students, as well as a training program for scholars in Latin America and Asia.

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.

COMPUTER FACILITY

The computer facility is now independent of both the Vax and PDPN systems. It provides administrative report support and statistical assistance to all researchers. Design of the system fully integrates web services with the local database. 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.

CORE LABORATORY/MASS SPECTROMETER FACILITY

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 labeled 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.

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 did not differ in girls whose parents were overweight. Self reported vigorous physical activity appears a better predictor of HDL-cholesterol and LDL cholesterol levels. In addition, ongoing studies of the accuracy of dietary intake demonstrate that young girls report their food intake more accurately than adolescents. Finally, comparisons of bioelectrical impedance (BIA) measurements of body composition showed that BIA provided accurate measurements of fat free mass but measurements of body fat were no more accurate than triceps skinfold.

• Paul A. Spiers, Ph.D., and Gail S. Hochanadel, Ph.D., this year published their research that Citicoline Improves Verbal Memory in Aging in the May, 1996 issue of the Archives of Neurology. After careful statistical analysis with the help of CRC Biostatistician Ray Gleason, Spiers and Hochanadel identified a subgroup of normal elderly who were most helped by Citicoline and which other studies have suggested may be those individuals who are the most at risk for developing some form of dementing illness. They also presented this research at the annual scientific symposium of the Massachusetts Neuropsychological Society in June. Spiers and Hochanadel have been helping to interpret the data from a national, multi-center trial of Citicoline given to patients acutely after cerebrovascular accident. At the same time, they are recruiting subjects for their own CRC protocol on the effects of Citicoline on memory after ischemic stroke which seeks to give this drug to patients who are chronic and may have had their stroke as much as five years earlier. This project is ongoing.

• 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 Dr. Irina Zhdanova 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., received two awards during this fiscal year: October 1995, Bristol Myers-Squibb Mead Johnson Award for Distinguished Achievement in Nutrition Research and, in May 1996, Roger J. Williams Award in Preventative Medicine. Dr. Young and his colleagues earlier 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 they established the basis for a precise determination of daily leucine balance. This opened the way for a new approach for estimating the nutritional requirements for this amino acid in healthy subjects. Recent studies have been expanded to include other nutritionally essential amino acids, such as phenylalanine and lysine. These studies by Young and co-workers have received international acclaim and have resulted in a profound change in concepts regarding the quantative significance of the dietary amino acid intake level on human well-being.

Richard J. Wurtman, M.D.

MIT Reports to the President 1995-96