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 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 ten voting members plus six non-voting members of the CRC's program staff. The Committee reports to the Principal Investigator, Martha Gray, Professor and Interim Director of Health Sciences and Technology (HST), and meets bimonthly 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 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.
The CRC received a grant award from the NIH for continuation of funds for the next four-year project period beginning in December 1996.
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 the current fiscal year, six postdoctoral fellows and four graduate students participated in research projects at the CRC. At the undergraduate level, thirteen Undergraduate Research Opportunities Program 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 five research staff positions became available. Five women were hired, two minorities. Eight Visiting Scientists were appointed, two women and one male. The Center will continue its efforts to increase the pool of qualified minority applicants as positions become available.
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), 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 multi disciplinary 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 486 inpatient days and 2,933 outpatient visits.
CLINICAL INVESTIGATOR TRAINING PROGRAM
This year, for the first time, graduates of the Clinical Investigator Training Program, a two year joint fellowship of HST and the Beth Israel-Deaconess Medical Center, received a Master of Science degree from Harvard Medical School. This unique program for clinicians, will, in the coming year, be joined by a parallel program for Ph.D.'s interested in applying their engineering, for this program, and the first Fellows will enter the program in the coming year.
CENTER FOR EXPERIMENTAL PHARMACOLOGY AND THERAPEUTICS
Research efforts have been centered in the application of quantitative measurements with such forms of technology as positron emission tomography, magnetic resonance imaging, and ultrasound to the process of drug development will be offered. This will be co-directed by Dr. Robert Rubin (HST), Dr. Stan Finkelstein (Sloan School), Dr. Tony Sinskey (Biology), and Dr. Charles Cooney (Chemical Engineering).
COMPUTER FACILITY
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.
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 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.
CORE LABORATORY/MASS SPECTROMETER FACILITY
The Core Laboratory 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, where stable isotope tracer analyses are performed. The Mass Spectrometer Facility 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 Core Laboratory. 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 catecholamine and cytidine.
RESEARCH HIGHLIGHTS
Suzanne Corkin, Ph.D. and her colleagues showed that in young normal subjects, the hippocampus, parahippocampal gyrus, an lingual and fusiform gyri, show increases in functional magnetic resonance imaging (fMRI) signal during novel picture encoding (Stern et al., 1996), while the left and right prefrontal cortices are activated selectively during picture recognition (Stern et al., 1994). Corkin's project predicted, therefore, that high-performing older normal subjects and high-performing Alzheimer's Disease subjects would show similar activations.
The imaging methods were: whole brain fMRI using BOLD contrast, 1.5 Tesla GE scanner with ANMR EPI upgrade, 3x3x7mm voxels, and twenty coronal slices. The encoding data were collected during two novel picture blocks and two familiar picture blocks per four minute run. The recognition data were collected during two picture recognition (old/new) blocks and two picture identification (indoor/outdoor) blocks per four minute run. Data analysis used the Kolmogorov-Smirnov test.
During encoding, activation in older normal subjects resembled that seen in young normal subjects, but the presence of activation was not as consistent across subjects. The pattern of signal change for the Alzheimer's Disease group resembled that for the older normal subjects. Hippocampal activation during encoding was associated with good recognition memory scores, further suggesting that the hippocampus is essential for encoding.
The older normal subject recognition data replicated the young normal subject data. Most Alzheimer's Disease subjects, however, failed to activate prefrontal cortex, and when they did, the activation was weak and diffuse. The similarity between the older normal subjects and Alzheimer's Disease groups in (a) patterns of activation during encoding, and (b) recognition scores suggests that the failure to activated prefrontal cortex constitutes an important difference. These data suggest that differing fMRI activation patterns distinguish early Alzheimer's Disease from older normal subjects, and indicate a potential clinical application for fMRI in the diagnosis of Alzheimer's Disease.
William H. Dietz, M.D., Ph.D. and his coworkers continue to study a large cohort of girls whose energy expenditure and activity levels were measured at study entry. At the time the girls entered the study they were ten years old. Their average age is now fifteen years. In the last year, the investigators demonstrated that reported vigorous activity appeared to be an important determinant of the serum levels of low density lipoprotein cholesterol (LDL-cholesterol). This finding suggests that although the total energy spent on activity may affect susceptibility to obesity, the type of activity may have a bigger impact on other risk factors for cardiovascular disease, such as LDL-cholesterol. In a separate series of studies, the investigators showed that as girls got older, the accuracy with which they reported their dietary intake increased. This finding demonstrates again that use of dietary intake to determine energy requirements may not be valid, although dietary records may be useful to understand patterns of food intake.
Paul A. Spiers, Ph.D., and Gail S. Hochanadel, Ph.D., ended their study on the effects of Citicoline in more chronic patients after ischemic stroke. The results from a pilot group of patients suggested that there is a positive effect of the drug in this population as well as in normal elderly. This pilot research is being prepared for submission to the 1998 joint meeting of the American Neuropsychiatric Association and behavioral Neurology Society.
Additional research projects examine the effects of Citicoline on memory in elderly patients with Age-Associated Memory Impairment, a condition which is widely considered to be a precursor of dementia, and the effects of phytoestrogen on the physical, emotional, and verbal memory disturbances associated with the menopause. (Phytoestrogen is the natural plant source of estrogen, and is abundant in soy.)
In June of this year, Drs. Spiers and Hochanadel had a poster presentation at the annual scientific symposium of the Massachusetts Neuropsychological Society. This poster, Citicoline Improves Recovery after Traumatic Brain Injury, dealt with two cases of high-functioning individuals who were treated with Citicoline on a compassionate use basis, under FDA guidelines, after they had suffered closed head injuries. In one case, the injury was mild but in the other (in fact, Dr. Spiers himself) the injury was extremely severe. Both cases had excellent recoveries, compatible with other European and American research using this drug with such patients. This report has also been submitted to the 1998 joint meeting of the American Neuropsychiatric Association and Behavioral Neurology Society.
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 obsessive compulsive disorder 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 twenty 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., was recently honored with a Doctor of Medicine (h.c.) from Uppsala University, Sweden.
Dr. Young and his colleagues earlier demonstrated the feasibility of using a whole body amino acid balance technique using 13C-labeled amino acid tracers to estimate human amino acid requirements. This novel approach opened the way for a reappraisal of the requirements for the nutritionally essential amino acids in human nutrition. Studies have been concerned with leucine, phenylalanine and lysine as the test amino acids. These studies by Young and coworkers have received international acclaim and have resulted in a profound change in concepts regarding the quantitative significance of the dietary amino acid intake level on human well-being. He is now initiating a collaborative study in Bangalore, India to assess the relevance of there findings from his MIT studies to healthy populations in the Third world.
Dr. Young was recently honored with a Doctor of Medicine (h.c.) from Uppsala University, Sweden.
Richard Wurtman
MIT Reports to the President 1996-97