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 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, and remains one of only two or three such centers. It was anticipated that in spite of its university venue, numerous 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 investigators 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. Daniel Shannon, professor of pediatrics at the Harvard Medical School and professor of health sciences at the Harvard/MIT Division of Health Sciences and Technology, consists of ten voting members plus nine nonvoting members from the CRC's program and operating staffs. The committee has reported to the principal investigator of the CRC's NIH Grant, Martha Gray, professor and codirector of the Harvard/MIT Division of Health Sciences and Technology (HST). With the CRC's administrative merger with the Massachusetts General Hospital's CRC, it now reports (for NIH grant purposes) to Peter L. Slavin, MD, principal investigator of the joint NIH grant and president of Massachusetts General Hospital, (MGH). The Advisory Committee meets bimonthly to evaluate protocols for their scientific quality, experimental design, ultimate statistical validity and potential risk to human subjects. The committee also sets general policies and reviews the operations of the CRC.
Administration
The CRC 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, Alice Gast. However as a patient-care unit, the CRC is a part of the MIT Medical Department and reports to Dr. William M. Kettyle, the director of the Medical Department. Members of the CRC participate in the Medical Department's activities; e.g., its Quality Improvement, Pharmacy and Therapeutics, Medical Records, and Safety Committees.
Several years ago the CRC was approached by the General Clinical Research Centers administration of the NIH, which funds this and all other CRC's, and asked to consider becoming a "Network" CRC. This would involve implementing at the MIT CRC some research projects generated at other local CRC's, and, conversely, implementing some of our projects (e.g., those involving very sick patients) at those other centers. Additionally, the CRC would, where possible, coordinate the activities of the core laboratories, nutrition programs, and nursing programs, with those of other local institutions, in order to increase their efficiency, and would use this networking as a platform from which to solicit additional common NIH grants. As a consequence, the CRC has successfully been developing a structured relationship with the CRC at the MGH, and in 2001 the MGH CRC and MIT CRC administratively merged. To date, 35 MGH protocols have been approved and implemented at the MIT CRC, and two MIT protocols are in the process of being accepted for implementation at the MGH. The senior program staffs at the two institutions meet monthly to anticipate and solve potential problems related to their integration and to streamline the protocol review process; COUHES and its MGH counterpart also work together to evaluate network protocols from the standpoint of safety. The MIT and MGH centers successfully collaborated on a joint NIH renewal grant application, for five years of support, which was funded by the NIH, starting in December 2002. The score, reflecting the reviewers' analysis of the joint application, was the best that MIT has received for its applications. MIT is now identified by the NIH as a "Satellite" to the MGH CRC, but is suffering no loss of "sovereignty" or autonomy nor any decrease in funding.
Developing this type of "network" relationship with the MGH CRC allows the CRC to solve a continuing chronic problem, i.e., the small and shrinking pool of medical doctors conducting clinical research in this facility, a consequence of the failure, during the last decade, of MIT's academic departments to appoint such people as professors. Most important, it guarantees the longevity of the CRC until such time as the pool again expands, and provides a source of physician scientists to collaborate with MIT biomedical scientists who hold doctoral degrees. The reputations of the two CRC's apparently are excellent, and the strengths of each institution complement those of the other. The CRC also continues to "network" with other Boston-area GCRC's (e.g., BIDMC) and all interested parties agree that the CRC should continue to do so in the future.
Education
The MIT CRC provides formal training in clinical investigation to advanced postdoctoral fellows taking a graduate degree (in clinical research) at Harvard Medical School, and to individual postdoctoral (medical) fellows working with CRC principal investigators and other researchers. These fellows and students utilize the CRC's facilities to initiate research protocols and participate in ongoing projects supervised by senior investigators and faculty. (See section on the Center for Experimental Pharmacology and Therapeutics). The MIT CRC also affords opportunities to MIT undergraduate and graduate students to participate in clinical research projects. In the spring semester of 2003, Ravi Thadhani, MD, assistant professor of medicine at the Harvard Medical School and an assistant program director, MIT CRC, again taught a formal undergraduate course in clinical investigation. The course was very well received and will be offered again in the spring semester of 2004.
Affirmative Action
The hiring of women and minorities continues to be a high priority commitment of the CRC. The CRC does have one continuing problem in meeting affirmative action objectives; i.e., in attracting qualified minority members. The traditional means of locating such personnel, by advertising and posting positions in local colleges, universities, medical institutions, and minority organizations, have not generated a significant response. Of the three visiting scientists and scholars appointed by the CRC in 2002–2003, two were women, but none were minorities. The CRC will continue its efforts to increase the pool of qualified minority applicants, as positions become available.
The CRC has, however, been highly successful in recruiting women and minorities as study subjects. During 2002–2003 approximately 72 percent of all study subjects were women and 23 percent of the total study population were minorities (17 percent black, 5 percent Asian, and 1 percent American Indian).
Research Activities
The CRC continues to maintain major commitments to the research activities associated with three clinical areas, each led by a senior professor. These areas are:
- Nutrition/ Metabolism. (Vernon R. Young, PhD, DSc, 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, MD., Cecil H. Green distinguished professor and program director, MIT CRC), which studies the effects of rugs, foods and hormones on brain composition and behavior, the effects of melatonin on sleep, and a set of diseases characterized by affective and appetitive symptoms (i.e., depression, premenstrual syndrome, smoking withdrawal, carbohydrate craving, obesity), which related to brain serotonin; and
- Behavioral Neuroscience. (Emilio Bizzi, MD, Eugene McDermott professor in the brain science and human behavior and Lee H. Schwamm, MD, associate professor of neurology at the Harvard Medical School and an assistant program director, MIT CRC) and Neuroendocrinology (Steven K. Grinspoon, M.D, associate professor of medicine at the Harvard Medical School and an assistant program director, MIT CRC and Anne Klibanski, MD, professor of medicine at the Harvard Medical School and codirector, MGH CRC). The behavioral neuroscience component now focuses on strategies for accelerating the return of various brain functions in people who have suffered strokes; the neuroendocrinology component focuses on neuroendocrine concomitants of AIDS, pituitary malfunction, and gender-dependent changes in calcium metabolism.
Groups collaborate on multi disciplinary projects, e.g., obesity; depression; Alzheimer's disease. The scope of the CRC's activities has expanded broadly: In the past year it also supported research protocols involving, for example, toxicology, pediatrics, psychopharmacology, women's health, HIV, biomedical engineering, and diabetes. Reflecting its evolving interactions with the MGH GCRC, 35 of these projects (out of a total of 78) were directed by investigators whose primary appointments are at the MGH.
During 2002–2003 the CRC patient census totaled 1,242 outpatient visits and 22 inpatient days. The CRC branch of the NIH had provided, based on prior year's activities, support for up to 2,437 outpatient visits and 30 inpatient days. The lower-than-anticipated census could be explained by the completion of the data-gathering portions of several large projects.
Center for Experimental Pharmacology and Therapeutics
The HST Center for Experimental Pharmacology and Therapeutics (CEPT), based at the MIT CRC, continues to have educational and research missions. This center, directed by Dr. Robert Rubin (HST), Osbourne professor of health sciences and technology, annually admits 10 MD's who have completed their clinical training. They enter a two-year program that provides both "hands-on" research experience and didactic training in clinical investigation and experimental pharmacology. At the end of this period, after passing a qualifying examination and fulfilling a thesis requirement, the graduates receive a master/medical science degree in clinical investigation from HST. A parallel program for PhD scientists is in the process of being established as well. This will involve HST, the Sloan School, the Department of Biology, and the School of Engineering, and will again be centered in the CRC. The research emphasis of the CEPT has been in the application of positron emission tomography, magnetic resonance imagery, ultrasound and other measurement technologies to the development of new drugs. With the development of imaging at MIT, these technologies will be greatly facilitated.
Computer Facility
The CRC computer facility provides hardware and software support for the CRC staff andinvestigators and statistical assistance to all researchers. The computer staff continues to develop and upgrade the CRC Operations System with the addition of computer systems for the CRC and investigators. These systems use an ORACLE relational database, and support the day-to-day operations of the CRC. During 2002–2003, changes in the CRC operations system included the addition of a method to track race and ethnicity data now required by the NIH and the development of a new comprehensive CRC staff database. The computer staff has also been working with their MGH counterparts to maintain and customize the Turbo software package, which has streamlined the protocol application process and NIH annual reporting requirement for both CRCs. In addition, considerable time and effort has been spent updating and improving the CRC web site by adding a link to the MGH CRC and information on the Research Subject Advocate Program, a new NIH required subject safety program. Researchers also continue to make use of the SAS statistical software available on the CRC computer system.
Core Laboratory/Mass Spectrometry Facility
The Core Laboratory specializes in assays that directly support the research efforts of CRC investigators and are not readily available commercially. 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 the 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.
The Core Laboratory also utilizes high performance liquid chromatography (HPLC) techniques. 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.
MIT Core Laboratory personnel are in frequent contact with their counterparts at MGH. This facilitates coordination of services and study planning (anticipating freezer space and reviewing core laboratory components of submitted protocols). During the past year and a half, four low temperature freezers were purchased with funds from MGH investigators replacing two non-functioning freezers. Also, in an effort to recruit more Core Lab users, the Core Lab actively networks with other GCRC labs. The MIT Core Lab posts a list of available assays on the National GCRC Core lab site and a core lab representative attends the GCRC National Annual Conference. This networking has generated a number of Core Lab Only protocols.
Research Highlights
Bandini, L.
Dr. Linda Bandini and her colleagues have concluded their longitudinal study of the effect of energy expenditure on growth and development in preadolescent girls. Subjects completed the study four years after menarche: at study completion the body composition and metabolic rate of the girls were measured in addition to their annual measures. As of June 30, 2003, 155 girls have completed the longitudinal study. This study will allow the investigators to determine whether reductions in daily energy expenditure or any component of energy expenditure is a risk factor for the development of obesity in adolescent girls. In 2002, an article, entitled "Relationship of Body Composition, Parental Overweight, Pubertal Stage, and Ethnicity to Energy Expenditure Among Premenarcheal Girls", was published in the American Journal of Clinical Nutrition.
Dr. Bandini also investigated the relationship of visceral fat to diet, activity, and hormonal changes in a subcohort of 40 girls. Abdominal scans were done at menarche to measure visceral fat. Visceral fat is again measured in these girls at study completion. These studies will provide information on variables that may influence visceral fat deposition. Determining what factors influence the deposition of visceral fat will provide useful information for the prevention of diabetes and heart disease.
A total of seven additional articles are submitted or in press concerning this study.
Bizzi, L. and Schwamm, L.
The Bizzi group including Drs. Emilio Bizzi, Lee Schwamm, Maureen Holden, and Karen Furie, has continued to develop and test new methods of treating upper extremity impairments. A novel computerized learning system, developed for these studies, is designed to facilitate motor re-training in patients with stroke. The system makes use of a virtual environment (VE) to provide augmented feedback to subjects about their performance. The system has been used to study motor learning and generalization in patients with stroke. Improvements were found in patients' upper extremity movements following the training on standard clinical tests of motor recovery, functional performance, and strength assessment. In addition, improvements were noted in the more quantitative kinematic measures developed to assess motor generalization. Many subjects not only improve on the movements they practice with VE system, but also improve on other movements or aspects of movements, that have not been specifically practiced. These findings were presented at the 2003 International Stroke Conference.
Also, recently, an NIH grant was received which will provide funding for a telemedicine enabled virtual environment. This system is designed to provide motor retraining of stroke patients in their homes. Patients are connected, via the Internet, to a remotely located therapist who then directs treatment sessions through software on the patient's home computer.
Grinspoon, S.
Dr. Grinspoon and his group have continued to investigate the pathogenesis, clinical phenotype, and treatment for related metabolic and body composition disorders associated with HIV disease. The HIV lipodystrophy syndrome is a novel metabolic syndrome, characterized by insulin resistance, dyslipidemia and significant changes in fat distribution. Over the course of the past year, substantial progress has been made by Dr. Grinspoon and his group to investigate the mechanisms and consequences of insulin resistance in HIV lipodystrophy. In collaboration with Dr. Vernon Young, using labeled isotopes, Dr. Grinspoon demonstrated increased rates of lipolysis among HIV-infected patients. In a corollary study, performed at MGH, he demonstrated that acute dosing with acipomox to block lipolysis resulted in significant improvement in insulin sensitivity. Also, continued collaboration with the Framingham Heart Study resulted in development of cardiovascular disease (CVD) prediction models for HIV-infected patients. CVD risk was significantly increased among such patients in association with fat redistribution. Furthermore, the long-term effects of metformin to reduce CVD indices tPA and PAI-1 were also demonstrated. Additional studies were undertaken to investigate the prevalence of hypogonadism among HIV-infected women. Novel data were produced suggesting that up to 50 percent of HIV-infected women had low testosterone levels. Also, novel studies using MR spect were initiated demonstrating reduced intravertebral bone marrow fat among HIV-infected patients withfat redistribution. In addition, ongoing MIT GCRC studies, in collaboration with Dr. Colleen Hadigan, are investigating the utility of dietary manipulation and exercise. Taken together, the studies of Dr. Grinspoon and his group have substantially advanced the understanding of mechanisms causing, and potential treatments, for insulin resistance in HIV lipodystrophy.
Wurtman, R.
Dr. Richard Wurtman and his colleagues have continued to examine the effects of drugs, foods, and hormones on brain composition and behavior. Three sets of pharmacokinetic studies have been performed on compounds, preliminary to using these compounds, to study behavioral or physiological mechanisms. These are: melatonin: an additional study was performed on both 0.3 and 0.6 mg doses, preparatory to a possible multicenter study on the hormone's sleep effects; 5-hydroxytryptophan (5HTP): studies were performed to confirm that this amino acid is normally found in the blood, and that administration of low doses without a decarboxylase inhibitor can produce dose-related increases in plasma 5HTP levels (The compound's effects on stress-induced eating will now be studied.); uridine monophosphate (UMP) studies were performed to determine whether its oral administration causes dose-related increases in plasma uridine levels. If so, we intend to determine whether it protects against age-related memory loss in humans as related compounds do in rats.
In other studies, this group examined the effects of normal meals rich in carbohydrate or proteins on the plasma tryptophan ratio. The delivery of circulating tryptophan to the brain and its conversion to serotonin vary directly with plasma tryptophan concentrations and inversely with those of other large neutral amino acids (LNAA). Although carbohydrate-rich, protein-free formula diets had been shown by us and by many other laboratories to elevate, and high-protein diets to depress, the tryptophan/LNAA ratio, few data were available about this ratio's responses to actual meals. Hence we conducted a study to determine whether carbohydrate-rich or protein-rich breakfasts, like those Americans normally eat, produce substantial differences in the plasma tryptophan/LNAA ratio. We also examined the effects of the meals on the corresponding ratio for tyrosine, the precursor of brain dopamine and norepinephrine.
Nine overnight-fasted subjects consumed, 3–7 days apart, a carbohydrate-rich (69.9g carbohydrate; 5.2g protein) and a protein-rich (15.4g carbohydrate; 46.8g protein) breakfast. Blood samples collected at baseline and after 40, 80, 120, or 240 minutes were assayed for tryptophan; tyrosine; the five other LNAA; and insulin.
We found that there were significantly different effects of the carbohydrate-rich and protein-rich breakfasts on both the plasma tryptophan/LNAA and tyrosine/LNAA ratios (each P<0.01). Among the eight subjects who completed both breakfasts, the median difference for tryptophan/LNAA was 54 percent (range: 36–88 percent). Rat studies indicate that such differences are quite sufficient to cause corresponding changes in brain serotoin synthesis. The median difference for tyrosine/LNAA was 28 percent (range: 10-64 percent). This is also sufficient to modulate dopamine synthesis in physiologically-active neurons. Insulin levels rose significantly after the carbohydrate but not protein meal.
Young, V.
Dr. Young and his colleagues have continued to explore the quantitative aspects of amino acid metabolism in healthy adult humans, with particular reference to their nutritional corollaries. Studies have been completed to the effects of a sulfur amino acid-free diet on whole blood glutathione (GSH) synthesis, showing that GSH production is regulated by the dietary availability of one of its precursors, cysteine. Studies have also been completed on the kinetics and urinary excretion of L-5-oxyoproline, an intermediate of the gamma-glutamyl cycle of GSH synthesis. Both sulfur amino acid-free and glycine-free diets alter the dynamics of oxoproline metabolism and increase the urinary excretion of this intermediate which may, therefore, serve as a potential probe of the status of GSH metabolism in human subjects. Studies have also continued on the kinetic aspects of amino acid metabolism in particular adults. Studies with lysine and threonine as the test amino acids again confirm the hypothesis that the current international requirements values for the indispensable (essential) amino acids in healthy adults are far too low and support that the tentative MIT amino acid requirement pattern is an appropriate one for use in practical considerations of adult human protein and amino acid nutrition. These findings and conclusions have major significance with respect to the planning of diets and an evaluation of diets for their amino acid adequacy worldwide. They also have important implications with respect to the planning of agricultural research programs that are directed toward improving the nutritional quality of foods in humans.
New CRC Investigator Initiated Programs
During the past year, three new investigator initiated programs have been established at the MIT CRC. In addition to fulfilling their scientific goals, these programs also provide opportunities for increased collaboration between the MIT and MGH CRC's.
The Program in Nutrition and Metabolism, directed by Steven Grinspoon, MD, is investigating the relationships among nutrition, body composition, and hormonal function. One of the program's chief therapeutic targets is HIV-lipodystrophy, which involves potentially unhealthy redistribution of body fat and changes in blood lipid levels that are often found in persons affected with the virus that causes AIDS.
The Program in Women's Health, directed by Judith Wurtman, PhD, has been established to study the psychological aspects of premenstrual syndrome (PMS) and of the menopause. This effort will hopefully identify promising leads for new treatments for the discomfort that may accompany these normal components of the human female life cycle. A first study, "Survey of Women with Premenstrual Discomfort" was recently conducted at the CRC. This study obtained information through the use of a daily diary on the association of mood and appetite changes during the luteal phase of the menstrual cycle that precedes menstruation, and their relationship to symptoms of pain and discomfort.
The Program in Applied Technology and Communications in Healthcare (PATCH), directed by Lee Schwamm, MD, seeks to develop new avenues for healthcare delivery through the strategic application of novel technologies. The program targets areas where barriers exist to the clinical implementation of evidence-based medicine, and seeks out technological solutions to overcome these barriers. Focus areas include low bandwidth transmission of medical multimedia content for education or decision-support, high bandwidth interactive medical evaluation or therapy, and wireless and handheld extensions of conventional bandwidth applications.
More information about the Clinical Research Center can be found on the web at http://web.mit.edu/crc/www/.