MIT
Reports to the President 1994-95
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.
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.
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.
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.
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