MIT Reports to the President 1997-98
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 and clinical scientists 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 eleven voting members plus nine non-voting members of the CRC's program staff. The Committee reports to the Principal Investigator, Martha Gray, Associate Professor and Co-director of Harvard/MIT Division 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 the 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.
Based on discussions with the Program Directors at the Massachusetts General Hospital (MGH) and the Beth Israel Deaconess Medical Center (BI/DMC) and the NIH staff, the MIT CRC has been designated a "network" facility, which encourages a closer collaboration with these and other CRC's. For example, MGH investigators are implementing relevant outpatient protocols at MIT; and conversely MIT CRC Investigators will be initiating studies on inpatients at MGH. Similarly, the MIT CRC uses the biostatistical services of the BI/DMC and together they direct the Clinical Research Training Program under the auspices of the Center for Experimental Pharmacology and Therapeutics (CEPT).
EDUCATION
The CRC provides postdoctoral training for physicians who are participating in fellowship programs at MIT. These physicians utilize 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 such research projects. At the undergraduate level, nine Undergraduate Research Opportunities Program students participated in clinical research projects with physician preceptors and faculty supervisors.
On June 9, 1998, the CRC organized a major symposium on Neuroprotection in Stroke for the benefit of both the MIT and the broader Boston biomedical community. The program consisted of eight presentations by academic clinical neuroscientists on the development of clinically useful neuroprotective strategies in acute ischemic stroke. This was followed by a panel discussion including representatives of five pharmaceutical companies involved in neuroprotective drug research and development.
AFFIRMATIVE ACTION
The hiring of women and minorities continues to be a high priority at the CRC; our continuing problem in meeting affirmative action objectives is 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. One male and one female were hired. Eight Visiting Scienists were appointed, two female and six males, two of whom were members of minority groups. 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 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 and Cognitive Sciences), focusing on the effects of diseases on cognitive and related brain functions and on genetic and other mechanisms causing neurodegenerative disorders (e.g., 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 307 inpatient days and 2,985 outpatient visits. The CRC branch of the NIH provided support for up to 295 inpatients and 3906 outpatient visits.
CENTER FOR EXPERIMENTAL PHARMACOLOGY AND THERAPEUTICS
Research efforts have been centered in the application of quantitative measurements to the process of drug development with such forms of technology as positron emission tomography, magnetic resonance imaging, and ultrasound. This Center is directed by Dr. Robert Rubin (HST), a member of the HST Academic Faculty.
COMPUTER FACILITY
The computer area continued 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 continue to make use of the SAS statistical software available on the CRC computer system. They also use the resources available on the Internet.
The computer facility 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 SPECTROMETRY 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 Spectrometry Facility, where stable isotope tracer analyses are performed. The Mass Spectrometry 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 catecholamines, cytidine and melatonin.
RESEARCH HIGHLIGHTS
Suzanne Corkin, Ph.D. and her colleagues conducted studies designed to identify brain regions involved in somatosensory perception and to determine whether they are similar to those of non-human primates, in which somatosensory maps have been identified with the post central gyrus.
Several distinct somatosensory maps exist within the nonhuman primate postcentral gyrus (PCG). Brodmann area 3a, located in the depth of the central sulcus, contains a map of proprioceptive and deep receptor input. Areas 3b and 1, located on the crest of the PCG, each possess separate maps of predominantly tactile information. These maps have been shown to have distinct anatomical connectivity and dissociable perceptual functions. Given their importance in the nonhuman primate for somatosensory perception, we have used fMRI and inflated brain analysis techniques to define areas 3a and 3b/1 functionally in human subjects.
Subjects (N = 6, 27-32 yr) were scanned in either a 1.5 T scanner with a 5" circular surface coil, or in a 3 T scanner with a GE birdcage head coil. In both scanners, 16 coronal oblique slices (4x3x3mm voxel size) were taken during 4:16min scans (TR = 2.0s). To activate the 3b/1 and 3a maps, subjects were scanned while they performed a tactile and a proprioceptive/motor task. In the tactile task, subjects received 3 Hz stimulation of the right palm, administered with a 5.88 log10mg von Frey filament. In the proprioceptive/motor task, subjects opened and closed the fingers of the right hand at 3 Hz without touching the digits to the palm (to avoid additional tactile input). Both tasks consisted of 16s epochs of stimulation alternated with 16s epochs of no stimulation. Data were analyzed using a Fourier transform with a Bonferroni correction for multiple tests. Data were displayed on an inflated brain to visualize distinct maps within the PCG.
The tactile and proprioceptive/motor tasks activated distinct maps around the central sulcus. In both the tactile and the proprioceptive/motor task, the precentral gyrus (area 4, the locus of primary motor cortex) was activated. In the tactile task, the crest of the PCG (areas 3b and 1) was also activated, but the depth of the central sulcus (area 3a) was not (N=5/6). Conversely, in the proprioceptive/motor task, the depth of the central sulcus (area 3a) was activated (N=6/6) in addition to area 4.
Their results demonstrate multiple maps within the human PCG that code for separate submodalities of somatosensory perception. The segregation of these neighboring maps suggest parallel processing streams for somatosensory perception. They are currently investigating the activation of area 2, located on the posterior bank of the PCG, which integrates these two types of information in nonhuman primates.
Linda Bandini and William Dietz continue to follow girls annually to examine the relationship of energy expenditure to growth and development. Girls are being studied annually until four years post menarche. They have completed four years of follow-up data in the entire cohort, and some girls gave completed five and six years of follow-up. At each annual visit anthropometric measures, and bioelectrical impedance are done. Girls are also asked to fill out questionnaires regarding diet and activity, and bloods are drawn for the measurement of insulin, and sex hormones. At the subjects last visit (four years post menarche) body composition is measured by isotopic dilution of O18 water and basal metabolic rate is measured by indirect calorimetry.
Forty six girls (approximately twenty-five percent of the original cohort) have now completed the study. In a subset of girls daily energy expenditure was repeated at age twelve and again at age fifteen to examine the changes in activity level with age and development. Twenty-eight girls were studied at age twelve, and twenty-three have been studied at age fifteen. In another subset of girls body composition and visceral fat are measured at menarche and four years post menarche. The first phase of this analysis has been completed. Forty-four girls are enrolled in this part of the study. They will examine the relationship of several factors including diet, activity, and hormone levels to the distribution of body fat at puberty and four years post menarche.
In a cross-sectional analysis they examined the validity of anthropometry and bioelectrical impedance to predict fat-free mass and body fatness in pre-menarcheal girls. Their findings suggest that bioelectrical impedance was a reliable measure of fat-free mass but is no better than triceps skin-fold thickness in the predication of body fat in pre-menarchael girls. Preliminary analysis of the change in activity level from age ten to fifteen years suggests a decrease with age, however the findings were not statistically significant. Although the decrease in activity level was not significant, it was lower than in previously published data for thirteen to seventeen year olds.
Paul A. Spiers, Ph.D., and Gail S. Hochanadel, Ph.D., continued their study on the effects of Citicoline in patients treated a month after an 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 the normal elderly. This pilot research was presented at the 1998 joint meeting of the American Neuropsychiatric Association and Behavioral Neurology Society.
Additional research projects examined 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.
William Thilly, Ph.D. and his coworkers detected mutations at the level seen in normal healthy humans. They have developed the means to measure point mutations in certain DNA sequences at mutant fractions as low as 10-6 without reference to phenotypic changes. The specificity of mutations allowed researchers to construct a mutational spectrum which is characterized by a reproducible set of predominant point mutations.
Mutational spectra show what mutates DNA in humans. Specifically, they have examined mitochondrial sequences as the source of mutations. In the development of constant denaturant capillary gel electrophoresis (CDCE) it was necessary to discover an appropriate mtDNA sequence. In this process they had to characterize human mtDNA for polymorphisms (1). An appropriate mtDNA sequence was discovered, which now allows examination of mutations in human organ tissue samples. From these studies they have determined that there is a similarity of hotspot sets in vivo and in vitro for mtDNA (2). Thus, they have concluded that human mitochondrial point mutations in the sequence studied are primarily spontaneous in origin and arise either from DNA replication error or reactions of DNA with endogenous metabolites.
Richard J. Wurtman, M.D. and his coworkers 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., recently received the first Danone International Prize for Nutrition (France) and he has been made recipient of the 1998 International Award for Modern Nutrition (Switzerland).
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 has initiated a collaborative study in Bangalore, India to assess the relevance of their findings from his MIT studies to healthy populations in the Third world. Their early observations confirm the applicability of the MIT findings to populations worldwide.
Richard J. Wurtman