MIT Reports to the President 1998-99
The Whitaker College of Health Sciences and Technology (Whitaker College) is a major interdisciplinary academic and research entity at MIT. Several areas of research and teaching that are pertinent to health, both fundamental and applied, have been developed and been incorporated into Whitaker College.
Current activities in the Whitaker College include the Harvard/MIT Division of Health Sciences and Technology, the Clinical Research Center, the Center for Biomedical Engineering, Biomedical Imaging and Computation, and the Center for Environmental Health Sciences. Last year, the Division of Toxicology moved from the Whitaker College to join the Division of Bioengineering and Environmental Health in the School of Engineering.
More information about Whitaker College can be found on the World Wide Web at http://web.mit.edu/vpr/www/whitaker.html.
J. David Litster
The mission of the Center for Biomedical Engineering (CBE) is to combine engineering with molecular and cellular biology to develop new approaches to biomedical technology and foster research in Biological Engineering. Over 40 CBE faculty members (from departments in the MIT Schools of Engineering and Science, as well as the Whitehead institute, Harvard and Boston University Medical Schools and the Harvard-MIT Division of Health Sciences and Technology) carry out interdisciplinary, multi-investigator research programs within CBE. This faculty research provides a training environment for a new generation of graduate and undergraduate students at the Engineering/Biology interface.
While CBE has also been administratively responsible for certain bioengineering educational initiatives during the past several years, such as the new Undergraduate Minor in Biomedical Engineering, these educational activities have now been transfered to the new academic Division of Bioengineering and Environmental Health, which was formed within the School of Engineering last July, 1998.
Important new research directions, funded programs, and novel core facilities have been the central focus of this past year's activities.
New Programmatic Multi-Investigator Grants enabled the initiation of two new projects: Quantitative Microscopy and Imaging Network, funded by the NSF program in Instrument Development for Biological Research; and Vascular Tissue Sensors for Generic Toxin and Pathogen Detection, a DARPA-funded program involving 13
Co-PIs.
CBE's Engineering/Biology Seed Grant Program continues to act as a catalyst for multidisciplinary collaborations, funded by members of CBE's Industrial Advisory Board. The 1998—1999 Seed Grant awards funded projects on Subcellular Mechanotransduction in Vascular Smooth Muscle Cells (Professor Peter So, MIT, and Dr. Richard Lee, Brigham and Women's Hospital); Novel Bioengineering Approaches to Carbohydrate Synthesis (Professors Ram Sasisekharan and Peter Seeberger, MIT), and Semi-synthetic Extracellular Matrix Materials (Professors Linda Griffith and Frank Gertler, MIT). This Seed Grant Program has proven to be an important vehicle for funding new, highly innovative, but somewhat risky programs because they are new; awardees have had an excellent record of attracting follow-on funding from external sources based on their discoveries.
The annual meeting of CBE's Industrial Advisory Board (IAB) was held in May, 1999, and attended by representatives of over 15 member companies. IAB members attended an all-day Symposium at which 6 CBE Faculty gave oral presentations and 30 Posters were presented by CBE students and their faculty mentors. The Oral presentations further highlighted recent discoveries facilitated by CBE Seed Grants to faculty.
A new collaboration was initiated between CBE Faculty and members of the Partner's HealthCare System's Center for Innovative Minimally Invasive Therapy (CIMIT), focusing on liver and cartilage tissue engineering. Dr. Joseph Vacanti of the Massachusetts General Hospital (Partner's) became a member of CBE's Steering Committee representing CIMIT.
NEW FACILITIES
CBE has developed new multi-user core facilities this past year for use by undergraduate and graduate students, postdoctoral research associates, faculty and their collaborators at other institutions. A new Dual-Photon Microscopy Facility for 3-D Imaging of living tissues and cells has been constructed. A scanning probe Microscopy Facility has also been developed in newly renovated space, for imaging and intermolecular force measurements at atomic levels, using atomic force, scanning tunneling, and lateral force microscopy. Under the auspices of the NSF Imaging project, these and other microscopy facilities at selected locations across MIT are now being connected via a high speed network for applications in remote microscopy and analysis of images for real time image transmission and remote display.
For the last twenty years the Center for Environmental Health Sciences has tried to discover if the chemicals or radiation in our environment are responsible for causing the genetic changes which cause human diseases. The major hypothesis/dogma of this field was that environmental chemicals were metabolized to chemically reactive intermediates, reacted with the DNA and, failing the action of DNA repair systems, were miscopied at DNA replication to create heritable mutations. These mutations in turn included those necessary for human diseases such as cancer and atherosclerosis.
The preponderance of the available evidence now favors an interpretation that human genetic changes may not be caused by this pathway. It appears possible that the mutations in human tissues and germ cells did not arise as a reaction with environmental chemicals. A variation on this theme is that such reactions might begin the mutational process but that errors in filling in gaps after DNA lesions have been removed is the pathway of chemically-induced mutations.
It must also be acknowledged that only a small but growing fraction of professional scientists are of this opinion. The doubts about the previous paradigm are now understood and under active consideration by all MIT toxicology faculty.
Mutations inherited via germ cells in humans are chiefly G->A transitions (>70 percent) and small deletions at locally repetitive sequences (20 percent). A similar pattern is observed in mutations in cells in tissues as humans age or within tumors. These G->A transitions are also associated with patterns of spontaneous mutations in bacteria, yeast, rodent or human cells. They are also associated with reactions of the DNA with methylating agents, which could be of either endogenous or exogenous origin.
A major new observation was made this year that offers the first real indication of the source of human mutations. The mutational spectrum of an entire human gene, hprt, was studied in normal human cells in the absence and in the presence of very low concentrations of known mutagens. It was observed that the pattern of G->A transitions observed as human germinal and tissue mutations were recreated by treatment of the human cells by low concentrations of an agent which methylates the DNA. Calculations indicate that about 20 percent of human germinal and somatic mutations in this gene share the mutational pathway induced by low levels of methylating agent. The source of such reactive chemicals in humans could be either endogenous or exogenous. It could be that 20 percent of mutations in all humans follow this pathway or that this pathway represents the dominant mode of mutagenesis in 20 percent of all humans.
Already Steve Tannenbaum's laboratory has devised a means to measure methyl-DNA products and some 10,000 human blood samples have been acquired to chart variations in methyl-DNA levels among humans.
Last year CEHS published its findings that mitochondrial mutations are the same in number and kind in the lungs of smokers and nonsmokers. By the end of this year it will determine if the same thing is true of nuclear mutations. Work in progress indicates that any differences, if significant, are small. Analysis of human lifetime lung cancer mortality rates by CEHS researchers suggests that cigarette smoking is probably not particularly mutagenic but that it creates an environment in which many more precancerous adenomas survive than in nonsmokers' lungs.
These findings may be considered in terms of the natural progress of science inexorably discovering former error but they have also created a great deal of discomfort among MIT toxicology faculty and among scientific reviewers of CEHS proposals.
One important new initiative of CEHS is to develop a fine structural map of inherited mutations in the human genome. We believe that the disappearance of a subset of inherited alleles as a population ages is a clear indicator of which genes are important determinants of major causes of death, cancer and atherosclerosis. Based on its theoretical and technological lead in mutational spectrometry, CEHS looked to have a real opportunity in human genome studies. With its core laboratories CEHS researchers could pool as many as 100,000 blood samples and determine the number and kind of mutations inherited by the population sampled. However, the established human genome researchers successfully argued that sequencing large sections of DNA from a relatively small number of persons would reveal many important "single nucleotide polymorphisms" or SNPs coding for human disease. CEHS argue that important SNPs would have been reduced in number by adverse selective pressure such that it would be necessary to examine at least 10,000 persons' genes to discover such important inherited mutations as sets of mutations rather than as individual events. These ideas were not accepted by grant proposal reviewers. However, the observations from the national genome centers, including that at MIT/Whitehead have found that indeed much larger samples than (they) imagined are going to be required. CEHS has no intention of abandoning this area and is seeking research support from multiple sources.
Key to the success of the CEHS Center Grant renewal this year for five years of additional core funding was the MIT investment in the new facilities. But what earned the strongest praise of reviewers were the eleven junior faculty who joined the Center in the past seven years. The Center received a rating of Outstanding with enthusiasm, despite a recognition by the reviewers that observations were discordant with generally held beliefs. This is the highest rating the Center has received since its founding in 1978.
The Center Director, W.G. Thilly, continues as president of two organizations representing university environmental health and engineering researchers across the U.S.: Association of University Environmental Health Science Centers and the Association of Superfund Basic Research Programs. In these positions he continues 13 years work organizing some two hundred annual explanatory sessions in states and congressional districts regarding progress and limits of knowledge in the environmental health field as well as the research needs and opportunities.
William G. Thilly
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, and remains one of only two or three such centers. 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 (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 eleven voting members plus nine non-voting members of the CRC's program staff. The Committee reports to the Principal Investigator of the CRC's NIH Grant, Martha Gray, Professor and Co-director of Harvard/MIT Division of Health Sciences and Technology (HST); it 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 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 MIT's and all other CRCs, 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 the MIT CRC's 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, in order to increase their efficiency. The CRC would also use this networking as a platform from which to solicit additional NIH funds, perhaps as a part of a common grant.
Initially, the CRC extensively explored setting up a primary relationship with the CRC at the Beth Israel-Deaconess Medical Center (BIDMC). However, in spite of excellent intentions and a strong mutual desire that collaborations expand, no research protocols generated at that institution or MIT ever were implemented at the other center. The CRC then began to explore a more structured relationship with the CRC at the Massachusetts General Hospital (MGH), and this relationship has, in fact, been highly successful. To date (i.e., since July 1998) eleven MGH protocols have been approved and implemented at the MIT CRC, and three MIT protocols have been implemented at the MGH. (This includes for example, one, entitled "Positron Emission Tomography study," which studies very sick patients who couldn't be admitted to the MIT facility, for want of full-time medical coverage and imaging facilities). The senior program staffs at the two institutions have been meeting monthly to anticipate and solve potential problems related to the gradual 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. As evidence of the level of cooperation that exists between the two institutions - and the sanction of this activity by the NIH - the MGH CRC was authorized by the NIH to use $125,500 of its unexpended grant funds to purchase a Dual Energy X-Ray Absorptiometry (DEXA) instrument (for measuring body composition) which was installed in the MIT CRC, and is managed by the MIT staff.
The CRC's present NIH grant was supposed to terminate in December, 2000, while that of the MGH terminates two years later. In order that NIH funding for both institutions be considered at the same time, the CRC asked the NIH to extend the present grant - without a formal application or site visit - for a fifth year (the limit on such grants). The request has now been granted. With the MGH, MIT will request that the second additional year be funded–also without a site visit or full application–as a supplement to the MGH's grant, which will then be in its last year. Then the two institutions will submit a joint grant application for subsequent years, with the MIT funds provided as a subcontract of the MGH application. In that way, continued NIH funding of the MIT CRC will be obtained with no loss of "sovereignty". (Also, the CRC anticipates–based on discussions with the NIH–that absolute funding will increase, justified by the additional expenditures needed to coordinate the two administrations.)
Developing this type of "network" relationship with the MGH CRC allows the CRC to solve a 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 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 continues also 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 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.
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 candidates. The traditional means of locating them, by advertising and posting positions in local colleges, universities, medical institutions, and minority organizations, have not generated a significant response.
This past year three research staff positions became available. Three female candidates were hired. Twenty-one Visiting Scientists were appointed, thirteen female and eight males, three of whom were members of minority groups. The CRC 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 319 inpatient days and 1857 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
The HST Center of Experimental Pharmacology and Therapeutics (CEPT), based in the MIT CRC, has both an educational and research mission. This Center is directed by Dr. Robert Rubin, (HST), a member of the HST Academic Faculty. Educationally, each year 10 MD's who have completed their clinical training 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 the two years, 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 Ph.D. 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. Research-wise, the 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 efforts will be greatly facilitated, starting in the coming year.
COMPUTER FACILITY
The computer area continued the development of the CRC Operations System. This system uses an ORACLE relational database, and supports the day-to-day operations of the CRC. Researchers continue to make use of the SAS statistical software available on the CRC computer system. They also use 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.
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.
RESEARCH HIGHLIGHTS
Laurence Katznelson, M.D. and his colleagues conducted studies designed to investigate the utility of a long-acting somatostatin analogue for the management of patients with acromegaly. Acromegaly is caused by excessive secretion of growth hormone and is most commonly due to a pituitary adenoma. Acromegaly is a chronic, debilitating disease that is associated with a decreased life expectancy. It is also associated with medical morbidity, including sleep apnea syndrome, arthritis, hypertrophic cardiomyopathy, and cancer. Patients with acromegaly often describe severe joint pains and headaches, which may be debilitating in themselves. The current management for acromegaly includes surgery as the primary mode of therapy. However, surgery is effective in approximately 60 percent of patients and is a function of tumor size, tumor invasion, and skill of the surgeon. There is, therefore, significant need for adjuvant medical therapy. Currently, the mainstay of medical therapy includes the somatostatin analogue octreotide (Sandostatin). This is a chemical modification of the naturally occurring hypothalamic peptide somatostatin, which normally inhibits growth hormone and may be used to treat acromegaly. Sandostatin is administered in a subcutaneous fashion on a multi daily dose regimen, usually three times a day. It works immediately with regard to improving headaches and other pains. There have been several recent studies that have shown that long-term use of medical therapy with resultant biochemical remission may improve life expectancy. Therefore, there is an important role for medical therapy, both in immediate symptomatic relief and in prevention of long-term consequences of the disease.
The present studies investigate the utility of a longer-acting formulation of somatostatin, lanreotide, in the management of acromegaly. In these studies, lanreotide is joined to a micropolymer, which is injected in an intramuscular mode as a depot preparation. Administration of this drug allows for continuous release of lanreotide for up to two weeks. Therefore, this drug is a major advance in the treatment of acromegaly because it allows for a prolonged release formulation of the somatostatin analogue, which would lead to improved compliance of medication, quality of life, and ease of administration. These studies are part of a multi-center trial of the long-acting lanreotide analogue Ipstyl, for treatment of patients who have previously undergone some form of therapy for acromegaly.
Results from these trials will lead to further data that will be used by the scientific community and the FDA for consideration of marketing this drug in the United States. This drug is already marketed in Europe.
Judith Wurtman, Ph.D., studied the ability of a high-carbohydrate snack, which is known to increase amid serotonin levels, to promote weight gain. The initial intent of the most recent study was to see whether the efficacy of an anorectic agent, REDUX, could be prolonged by the concurrent daily administration of the carbohydrate-rich beverage. Patients treated with REDUX for twelve or more months fail to lose significant weight beyond the first six months. Since consumption of carbohydrate-rich, protein-poor food increases the synthesis of serotonin, the neurotransmitter whose activity is enhanced by REDUX, the investigator postulates that daily intake of a carbohydrate-rich beverage would extend weight loss in REDUX-treated volunteers. Unfortunately this study had to be curtailed, five months after its initiation, because of the voluntary withdrawal of the drug by its manufacturer. The inability to continue REDUX treatment was associated with the withdrawal of the majority of subjects from the study. However the investigator decided to continue the dietary intervention component of the study, with additional volunteers, to see whether a food-induced increase in serotonin synthesis might by itself have an affect on weight loss. Serotonin is involved in regulating two aspects of eating behavior that influence weight gain: satiety and overeating in response to stress. Thus the investigator anticipated that the carbohydrate intervention might make it easier for volunteers to adhere to a calorie deficient food plan, by increasing brain serotonin activity.
Obese females participated in a nine month weight loss program that included nutritional and behavioral counseling; an exercise program; and treatment with the experimental or placebo beverage. The drinks were consumed twice daily, an hour before lunch and between 4 and 5 PM. The drinks were isocaloric; the test beverage contained 45 grams of maltodextrin and the placebo beverage contained 15 grams of protein (casein) and 30 grams of maltodextrin. Blood tests carried out prior to the study demonstrated that the test beverage did increase the availability of tryptophan to the brain, and the placebo beverage lacked this effect. (Tryptophan is the amino acid precursor of serotonin. The uptake of tryptophan into the brain depends on its ratio in the plasma to that of five other neutral amino acids that compete with it for attachment to the uptake site. Measurements were made of tryptophan/large neutral amino acid ratios following intake of the carbohydrate-rich or protein-rich beverage.)
The study was completed in January, 1999 and the data are now being analyzed. One early finding form the study concerned the relationship between emotional disturbance and food intake. Applicants to the study were asked to complete a questionnaire on their eating behavior when experiencing stress. After noting that the majority of these 200 respondents described losing control over their food intake when experiencing negative moods, the questionnaire was also given to 93 normal weight volunteers selected at random from supermarket shoppers, health club members and women in a gynecology outpatient waiting room. There was a significant difference in the responses of the two groups; the normal weight respondents did not overeat in response to such mood states as anger, exhaustion, depression, frustration, tension, agitation and boredom, whereas 80 percent or more of the obese respondents claimed to snack excessively when experiencing these moods.
As this questionnaire made clear, the overeating that characterizes most of the study population was exacerbated by mood changes. Moreover, the obese respondents claimed to overeat only sweet and starchy (i.e., carbohydrate) snacks when feeling stressed. Although the study was not designed to test daily changes in mood and food intake, a questionnaire on the subject's cravings for carbohydrates was completed at every clinical center visit. It will be of interest to see whether those subjects consuming the carbohydrate-rich beverage were less likely to crave these foods than to those on placebo-treatment.
Dr. Richard Wurtman and his colleagues conducted a study on Phentermine, an old drug, was widely used in combination with fenfluramine to promote weight loss, and which in combination may have increased the incidence of cardiac valvular abnormalities and/or primary pulmonary hypertension in treated subjects. A few papers from the 1970's suggested that–based on in vitro data–phentermine was a monoamine oxidase (MAO) inhibitor, but this effect did not appear on the drug's label and was generally unrecognized. If it had been recognized, the phentermine never would have been combined with fenfluramine (or any other serotonin-uptake blocker), inasmuch as combining an uptake-blocker with an MAO inhibitor was known to be dangerous, and was specifically prohibited by the FDA. Studies were conducted to see whether the doses of phentermine generally used in the "phen-fen" combination inhibit MAO in people. The investigator observed that giving a low dose (15 mg), once, or a higher dose (30 mg) for five straight days, did indeed inhibit MAO in vivo, as shown by the increase in the levels of serotonin, an MAO substrate, within blood platelets.
Based on these findings, and on concurrent in vitro observations that numerous other widely-used drugs also are unrecognized MAO inhibitors (e.g., estrogen; pseudoephedrine; phenylpropanolamine), investigators at other institutions showed, in large-scale clinical studies, that virtually all of the cardiac valvular lesions that had appeared in patients taking REDUX, or Dexfenfluramine, occurred only if patients also took a recognized MAO inhibitor. These findings may lead to the re-emergence of drugs that act on brain serotonin to treat obesity. This seems desirable, inasmuch as brain serotonin normally controls both satiety and the proportions of macronutrients that people choose to eat.
Richard J. Wurtman, M.D. and Irina Zhdanova, M.D., Ph.D., and their coworkers continued studies on Melatonin, a primary hormone of the circadian system, which participates in the temporal coordination of multiple physiologic processes, including the alternating phases of sleep and alertness. The decline in melatonin secretion with advancing age, typical of humans, tends to attenuate the circadian synchronization of body rhythms and may contribute to the age-related decline in the amplitudes of such periodic physiologic functions as sleep, performance, cardiovascular adaptation, thermoregulation and the production of various endogenous agents. Melatonin deficiency may also contribute to the development of such age-associated pathologic conditions as chronic insomnia. They have previously showed that low doses of melatonin, that induce circulating concentrations of the hormone within the normal physiologic range, promote sleep onset in young healthy adults. They now have further studied this phenomenon in different populations and have demonstrated that:
Professor Vernon R. Young received the International Award for Modern Human Nutrition and presented the Rhoads Lecture to the American Society for Parenteral and Enteral Nutrition. Dr. Young and his colleagues have continued to explore quantitative aspects of amino acid metabolism in healthy adult humans, with particular reference to their nutritional corollaries. Studies have been completed on the nutritional interrelationships between dietary methionine and cystine, using 13C-labeled methionine and cysteine as tracers. These studies lead to the conclusion that the sparing effect of cystine on the methionine requirement is much less than has been previously assumed based on N balance experiments. Further investigations have also been completed on leucine kinetics and requirements, with reference to the impact of meal pattern and of the molecular form of the 13C-labeled intact protein). It is evident that while these experimental/metabolic factors affect the quantitative studies of leucine kinetics the results of these recent studies continue (a) to confirm the hypothesis that the current international requirement values for the indispensable (essential amino acids in healthy adults are far too low) and (b) to support that the tentative MIT amino acid requirement pattern as 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 for humans. In a related series of studies Dr. Young and his colleagues have begun to explore the nutritional regulation of glutathione (GSH) status in healthy adult. He is using a new gas chromatographic/mass spectrometric method for measurement of the stable isotopic content of intact GSH, following administration of labeled glycine and cystine as tracers. Preliminary estimates of GSH synthesis, using circulating erythrocytes as the sampled tissue, indicate that whole body GSH metabolism in highly compartmented and studies are planned to explore this aspect of GSH homeostasis using different labeled probes of the g-glutamyl cycle, including 5-[1-13C]oxoproline.
The Division of Comparative Medicine (DCM) provides animal husbandry and clinical care for all research animals on the MIT campus. From its inception in 1974, the Division has evolved into a comprehensive laboratory animal program that provides a full range of veterinary and surgical support. Additionally, the Division has a National Institutes of Health (NIH) grant for training veterinarians for careers in biomedical research. Total personnel in the Division now comprises 100 individuals. In March 1998 the Division moved its administrative, diagnostic and research laboratories to the newly renovated eighth floor of Building 16. This space is contiguous to the eighth floor of the newly renovated Building 56, which also houses quarantine, diagnostic and research space for DCM.
FACILITY MANAGEMENT AND ANIMAL CARE
The Division's state-of-the-art animal facilities include 30,000 gross square feet in Building 68, which has been occupied since November, 1994, a fully renovated E17/E18 facility (13,200 gsf), which has been occupied since March, 1995 and the renovated eighth floor of 56 which serves as a quarantine facility. Also, a new addition of 11,300 net square feet to the Whitehead facility along with renovations to the existing animal area were completed in 1997. These facilities support transgenic and gene "knockout" in vivo experiments. DCM now performs in vivo embryo transfer for rederivation of mice with endemic disease which have been imported to MIT from laboratories worldwide. The average daily census of laboratory animals was approximately 2 percent percent less in FY99 than in FY98. Mice remain the primary species used by MIT investigators and represent more than 97 percent of the animal population.
RESEARCH ACTIVITIES
Current NIH-funded grants support in vivo study of nitrite carcinogenesis, in vivo study of Helicobacter hepaticus and tumorigenesis, in vivo study of the pathogenesis of inflammatory bowel disease, in vivo studies of H. pylori pathogenesis and the role of Helicobacter felis and H. mustelae in inducing gastric cancer. A private pharmaceutical firm has provided funding for studies focusing on H. pylori pathogenesis. FY99 was the eleventh year of the Division's NIH postdoctoral training grant that has been funded through year 15. There are currently six postdoctoral trainees, one of whom is enrolled in the graduate programs in the Division of Bioengineering and Environmental Health. All 19 eligible postdoctoral fellows have now passed the board examination of the American College of Laboratory Animal Medicine.
DCM faculty and staff published five chapters, one book, 19 papers and 24 abstracts in FY99 and presented numerous research papers at national and international meetings.
ACADEMIC ACTIVITIES
Dr. James Versalovic joined the Division as a Research Scientist. He also holds an appointment at Massachusetts General Hospital. Dr. Versalovic has been named the Young Investigator of the Year by the American Academy of Microbiology. Dr. Fox received a merit award from the Massachusetts Veterinary Medical Association, was selected as the Distinguished Ramsey Lecturer at the University of Iowa and was the keynote Trexeler Lecturer at the National Gnotobiotic Association Meeting. Dr. Schauer was promoted to Associate Professor in the Division of Bioengineering and Environmental Health. Dr. Marisa Esteves, a former DCM postdoctoral fellow, completed her second year as a Research Scientist supported by a NIH research supplement for underrepresented minorities. DCM faculty and staff taught the graduate courses Toxicology 201 and 214.
COMMITTEE ON ANIMAL CARE ACTIVITIES
During the past year the Committee on Animal Care established a web site to better provide information to researchers. Required forms, information on the CAC's activities and schedules for training sessions are listed. DCM staff in conjunction with the Committee on Animal Care once again conducted didactic training sessions for Institute personnel on topics pertaining to the care and use of laboratory animals. The Committee continued to distribute to other institutions in the United States and abroad two instructional videos, one focusing on the role and responsibilities of Institutional Committees for the Care and Use of Animals and the other focusing on the use of anesthesia in laboratory animals. Both are available to MIT researchers at the Division or in the Schering-Plough Library.
James G. Fox
The mission of the Harvard-MIT Division of Health Sciences and Technology, established in 1970, is to develop and conduct educational and research programs across disciplinary lines within MIT, Harvard, and the teaching hospitals in order to combine the sciences and engineering in solving problems in biology and medicine. By uniting the great strengths of the two universities, HST trains students for research and leadership roles in medicine, biomedical sciences, and biomedical engineering. The program seeks to improve human health through its multi-disciplinary, multi-institutional research and educational activities.
Recognizing that the future requires leaders who can effectively bridge the cultures represented by medicine, science, and engineering, the Division accomplishes its mission by providing truly multi-disciplinary training to M.D., Ph.D. and M.S. candidates in six graduate degree programs:
The M.D. curriculum trains physicians who have a deep understanding of the underlying quantitative and molecular science of medicine and biomedical research. The Ph.D. programs combine rigorous scientific or engineering graduate training with an in-depth exposure to the biomedical sciences and clinical medicine. The masters degrees offered by the Medical Informatics Training Program and the Clinical Investigator Training Program are geared toward students and professionals who already have a terminal degree.
Today, HST is comprised of 320 post-baccalaureate graduate students, six full-time faculty (faculty with primary HST appointment), and 35 core faculty (faculty who have the functional-equivalent of 50 percent appointments in HST). We also have an affiliated faculty of nearly 200 scientists, engineers, and physicians drawn from MIT, Harvard University, and Harvard Medical School and its teaching hospitals.
The research programs for students and faculty similarly reflect the mixing of cultures in applying the appropriate tools of medicine, engineering, and science to address problems in human health and clinical medicine. They are focused on five main thematic areas: Medical Sciences and Molecular Medicine; Biomedical Engineering/Biological Physics; Imaging Sciences and Technology; Bioinformatics; and Clinical Therapeutic Discovery, Delivery, and Assessment.
Through these programs, HST seeks to explore the fundamental principles underlying disease, discover new pharmaceuticals and devices to ameliorate human suffering, and train the next generation of physicians, scientists, and engineers to do the same.
Because of its interdisciplinary and inter-institutional nature, HST's administrative home is the Whitaker College of Health Sciences and Technology at MIT. However, a manager and two administrative assistants are located at Harvard Medical School. The Division's two directors, Martha L. Gray for MIT and Joseph Bonventre for Harvard, report to Robert A. Brown, Provost at MIT; J. David Litster, Vice President for Research at MIT; Dennis Kasper, Executive Dean for Academic Programs at HMS; and Joseph Martin, Dean of Harvard Medical School at HMS. Richard Mitchell, Assistant Professor of Pathology at Harvard Medical School, serves as Associate Director of HST and Director of Student Affairs for HST-M.D. students. Frederick Schoen, Professor of Pathology at HMS, serves as HST Associate Director for Academic Programs.
HIGHLIGHTS OF THE YEAR
HST received a $20 million gift from Thanassis and Marina Martinos in March to create the Athinoula A. Martinos Center for Functional and Structural Biomedical Imaging. Named for the couple's late daughter, this Center will work to advance imaging science and technology at MIT, Harvard Medical School, and affiliated hospitals and institutions. The Center will be located on or near the MIT campus.
George N. Hatsopoulos (MIT Ph.D. '56) gave the keynote address at HST's Commencement Exercises on June 7, 1999. He is the Founder, Chairman of the Board, and former Chief Executive Officer of Thermo Electron Corporation, a world leader in products and services related to environmental quality, health, and safety.
The 12th annual HST Forum, held on March 4, 1999, "took off" this year with a focus on Space Medicine and Earthly Spin-offs. Sixty-four students presented their work at a poster session that afternoon, with topics ranging from Age Adjusting the Vestibulo-Ocular Reflex Time Constant to Visual Orientation in Unfamiliar Gravito-Inertial Environments. NASA Astronaut Richard M. Linnehan, DVM, was the keynote speaker. Following his talk was a panel discussion chaired by Laurence R. Young, Sc.D., director of the National Space Biomedical Research Institute (NSBRI). The event capped off with a gala dinner at The Marriott Hotel. HST's faculty members are very active in the United States' space endeavors. In October 1998, MIT Professors Laurence R. Young and Richard J. Cohen were among six NASA experts from around the country who advocated that former Senator John Glenn, who has been involved in many studies related to aging, be included on a space shuttle mission. They advocate his inclusion, because both the elderly and astronauts report similar symptoms of muscle atrophy. As Young noted, exploring the "deconditioning" that seems to occur in space could lead to potential new therapies for both groups.
For the past year, HST has been actively searching to hire more junior and senior-level candidates for tenure track positions, and the Division is now looking for a director of the new Martinos Imaging Center. Earlier this year Steve Massaquoi (HST ‘83), joined the MIT faculty with a joint appointment in HST and EECS. Betsy Tarlin, who has worked for the Division as a consultant for nearly a year, has also joined the staff as Director of Development.
OUTSTANDING STUDENTS
Eleven students graduated with Ph.D. degrees, 31 received M.D. degrees, and two received M.S. degrees. Of the 23 Harvard Medical School graduates who received special recognition, six cum laude awards and seven magna cum laude awards went to HST students. With the exception of those in internships and residencies, the majority of graduates have secured academic or industry jobs. For example, Sangeeta N. Bhatia is Assistant Professor of Bioengineering at UC San Diego, and Christopher Chen is Assistant Professor of Biomedical Engineering at Johns Hopkins Medical School.
Daniel J. DiLorenzo (HST M.D. and M.S. ‘99) won the $30,000 Lemelson-MIT Student Prize, one of MIT's most prestigious student honors. DiLorenzo, who began his neurosurgery residency in Utah after graduation, is currently working on developing prosthetic limbs that transmit neural messages to the brain.
Ngon Dao, a third-year MEMP student, and his partners won the grand prize in the 1999 MIT $50K Entrepreneurial Competition for their proposal to build software to screen drug compounds for side effects and efficacy. Anita Goel, a fifth year M.D./Ph.D. student, was on a semifinalist team.
Jennifer H. Elisseeff (MEMP ‘99) made national news for her research on polymers mixed with photoinitiators. This substance, when exposed to the right type of light, turns the liquid into a semi-solid called hydrogel. She is interested in using hydrogels to replace cartilage, a technique that would minimize or eliminate the need for surgery. Her research was conducted in the laboratories of Robert Langer.
FACULTY HONORS AND AWARDS
Three professors were appointed to named professorships. Richard J. Cohen is the new Whitaker Professor in Biomedical Engineering, a chair established by the late Uncas A. Whitaker who was a long-time member of the MIT Corporation. W. Eric L. Grimson, professor of computer science and engineering and also an HST affiliated faculty member, was named the first Benard Gordon Professor of Medical Engineering for a five-year term. Roger Mark was selected as the inaugural holder of the Distinguished Professorship in Health Science and Technology.
Two professors received the I. M. London Teaching Awards: William C. Quist, M.D., Ph.D., Assistant Professor of Pathology, and Thomas A. McMahon, PhD, who passed away in February 1999. Professor McMahon had been an HST faculty member since its inception and was the Gordon McKay Professor of Applied Mechnics and Professor of Biology at Harvard. To further honor his contributions, HST established the Thomas A. McMahon Award for Teaching and Mentoring. Next year will be the first year the award is granted.
Five HST faculty members received the third annual John F. and Virginia B. Taplin Awards, started in 1997 by John F. Taplin (S.B., 1935). These awards are intended to build infrastructure in biomedical engineering, physics, and chemistry. Each recipient receives $50,000 to use toward course development. This year's winners include Julie E. Greenberg, Dava J. Newman, Seth Teller, Jose G. Venegas, and Thomas F. Weiss.
HST Directors Martha L. Gray and Joseph V. Bonventre have been selected as 1999 Fellows of AIMBE, the American Institute for Medical and Biological Engineering.
Frederick J. Schoen, professor of pathology at HMS and a faculty member of HST, received the 1999 Founders Award of the Society For Biomaterials. Among the highest honors in the biomaterials community, the Founders Award is considered a lifetime achievement award for members who "have given much of themselves to research in biomaterials."
RESEARCH ACHIEVEMENTS
The research of the HST core faculty and research staff covers a wide spectrum of biomedical areas. In addition to labs at HST, MIT and Harvard, research links include a number of Harvard Medical School teaching hospitals (MGH, BWH, BIH, NEDH) and the Harvard Medical School quadrangle.
Biomedical Engineering/Biological Physics
Richard J. Cohen (HST ‘76) received permission from the US Food and Drug Administration on April 13, 1999, to market a test that can accurately predict the risk of heart arrhythmia. Professor Cohen, who studies the mechanical regulation and stability of the cardiovascular system, invented the T-Wave Alternans Test. One in seven Americans will eventually die of sudden cardiac death. Effective preventative treatment is available in the form of the implantable cardioverter defibrillator, but until recently it has not been possible to identify in advance the patients that require this therapy. This test, which is the only test that the FDA has approved for this indication, involves the analysis of microvolt level fluctuations in the electrocardiogram during exercise stress.
Elazer R. Edelman (HST ‘83) uses elements of continuum mechanics, digital signal processing, and polymeric controlled release technology to examine the cellular and molecular mechanisms that transform stable coronary-artery disease to unstable coronary syndromes. Tissue-engineered cells, for example, deliver growth factors and growth inhibitors for the study and potential treatment of accelerated arterial disease following angioplasty and bypass surgery. Professor Edelman is motivated by a tough clinical problem: more than half of blocked blood vessels that are cleared by a procedure called balloon angioplasty become blocked again. His discoveries have lead to patents for endovascular stents, drug-delivery devices, tissue-engineered implants, and new drug formulations.
Frederick J. Schoen has made major investigative contributions to understanding the problems of currently available prosthetic devices and patient management strategies. He has identified, elucidated the mechanisms of, and solved several of the critical problems associated with the biomaterials and devices used clinically. His approaches have used basic biology, evaluations of clinical implants that have failed, and industrial development studies of new and modified configurations and biomaterials.
Michael S. Feld heads the MIT Laser Biomedical Research Center, an NIH Biotechnology Resource Center housed in the MIT Spectroscopy Laboratory, which develops basic scientific understanding, new techniques, and technology for advanced biomedical applications of lasers. One area of research is the spectral diagnosis of disease using fluorescence, reflectance and Ramaan scattering. The techniques are implemented clinically by means of optical fiber catheters and imaging endoscopes. One example of progress over the past year is HST Ph.D. student Jason Motz's development of techniques for analyzing Ramaan scattered light from atherosclerotic plaques to extract information about the relative amounts of the morphological constituents present, such as necrotic core, smooth muscle cells, and calcification. Probes for collecting Ramaan spectra during clinical procedures are being developed.
Laurence Young continues actively as Director of the National Space Biomedical Research Institute (NSBRI). As the primary agency for NASA-sponsored space biomedical research, the consortium of seven universities including MIT, NSBRI has initiated forty-one research projects. With encouragement from NASA Headquarters, the Institute is implementing a broad-based plan for national and international expansion to prepare for eventual human exploration of Mars. In addition to his role as Director, Professor Young is an investigator on three NSBRI research projects. His NSBRI ground-based study of Principal Investigator-in-a-Box (also known as [PI]) tests the effectiveness of [PI] as an expert system designed to assist astronauts in the monitoring and troubleshooting of experiments conducted during space flight. His NASA Ames-sponsored [PI] project flew on the space shuttle twice during 1998: on Neurolab and with John Glenn on STS-95. His other two NSBRI projects are aimed ultimately at developing countermeasures to the postural instability and disorientation problems that result upon return to a gravity environment after long-duration space flight. One project examines the role of the otolith organs and the semicircular canals in head stabilization during horizontal acceleration and during tilt. The other uses short-arm centrifugation and yaw head movements to investigate humans' ability to learn and maintain simultaneous adaptation to rotating and stationary environments. Results from these projects will help define the limitations and benefits of various possible countermeasures, including artificial gravity.
Lisa E. Freed, Principal Research Scientist in HST, is studying cell and developmental biology using a model tissue engineering system based on isolated cells, three dimensional polymer scaffolds, and bioreactor culture vessels. Her NASA funded research grant, "Microgravity Tissue Engineering," focuses on engineering cartilage and cardiac tissues and evaluating them structurally and functionally, in vitro and in vivo. The goals are to improve basic understanding of tissue development through controlled in vitro studies and to generate clinically useful tissue equivalents.
Gordana Vunjak-Novakovic, Principal Research Scientist in HST and Adjunct Professor of Chemical Engineering at Tufts University, is supervising research teams working on engineered skeletal and cardiovascular tissues and biological research in microgravity. Her research interests include transport phenomena, tissue engineering and bioreactors, and in particular the integrated use of cells, biomaterials and bioreactors to model biological and engineering aspects of tissue development. She leads the science design and testing of the cell culture system for the International Space Station.
Imaging Sciences and Technology
Medical and biological imaging have grown explosively during the century since Roentgen's discovery of x-rays. The contribution of imaging technology to medical science promises to be even greater in the next century as imaging expands to demonstrate function as well as anatomy. The advance of structural and functional imaging includes imaging technology for disease, brain function, auditory and speech process, gene expression, and cardiac imaging. Revolutionary research has propelled imaging technology for active treatment planning and monitoring.
HST is launching the Harvard/MIT Imaging Center to house new faculty and their imaging and image processing teaching and research facilities and to create a critical link devoted to developing imaging technology.
Emery N. Brown devotes his research to statistical modeling of problems in neuroscience. Working jointly with colleagues in the Brain and Cognitive Sciences Department at MIT, he has been developing statistical signal processing techniques to analyze how neural systems encode information about relevant biological stimuli in their ensemble firing patterns. The techniques involve signal processing methods based on point process filtering and have been successfully applied to the study of how ensembles of pyramidal cells in the rat hippocampus encode the animal's representation of its spatial environment. In collaboration with members of the MGH NMR Center, Professor Brown has been developing statistical methods to characterize the dynamic properties of functional magnetic resonance imaging (fMRI) signals. A forthcoming application of these methods will be to study anesthesia-induced loss of consciousness monitored with fMRI. In collaboration with colleagues at the Brigham and Women's Hospital, Professor Brown has developed a statistical model to measure precisely the period of the human biological clock.
Martha L. Gray (HST '86), Director of HST, and collaborator Deborah Burstein (HST '86) use magnetic resonance for measuring composition and functional integrity of cartilage. Over the last century, clinicians and researchers have had to struggle to understand and treat diseases they couldn't see until significant cartilage destruction had occurred. This situation has the potential to improve dramatically with the method Professors Gray and Burstein have pioneered. In the past year this method has been used to nondestructively demonstrate biochemical alterations in intact human cartilage. In addition, pilot clinical studies have begun to demonstrate subtle alterations in cartilage, which may be amenable to early pharmacologic intervention.
Bruce Rosen (HST '84) is the Director of the NMR Center at the Massachusetts General Hospital. He is well known for his contributions in the area of "functional" imaging–that is, magnetic resonance images of the brain in which areas having some functional activity (e.g., visual cortex) are highlighted by receiving increased blood flow. The techniques he and his colleagues have developed are now being used by hospitals throughout the world in evaluating patients with stroke, brain tumors, dementia, and other mental illness. Recent work has focused on the fusion of functional MRI data with information from other modalities, including very high temporal resolution signal using magnetoencepholograpy (MEG) and non-invasive optical imaging.
Robert Lees and his colleagues have devised a noninvasive method for assessing atherosclerosis in the abdominal aorta, the site where the disease begins and is sometimes found even in children. They are using magnetic resonance imaging, with quantitative analysis, of the images. They plan to use this technique–along with the established method of quantitative carotid ultrasound–to determine the effects on the progression (or regression) of atherosclerosis with interventions such as the new cholesterol-lowering margarines (whose action may be slower, but more tolerable than that of cholesterol-lowering drugs). The new technique is one of a number of methods they have developed and brought into the clinic during their thirty years of cardiovascular imaging and diagnostic research at MIT.
Experimental Diagnostics/Therapeutics
One of the most visible and obvious arenas in which the bench-to-bedside transfer is a two-way bridge is with regard to therapeutics. Drugs and therapies not only may treat disease by serving as probes, but they can provide important insights into disease mechanisms and offer diagnostic opportunities. Most faculty in HST are involved at some point in clinical human studies. The support of a clinical research center at MIT and the teaching hospitals, and the recently launched Clinical Investigator Training program, have significantly enhanced the infrastructure, further enabling translational efforts.
Robert Kit Lee conducts research aimed at finding treatments for neurologic diseases, particularly Alzheimer's. Specifically, he is investigating the use of neurotransmitter-type drugs (e.g, beta-blockers, Prozac-type drugs) to prevent neurodegeration and the formation of amyloid plaques in Alzheimer's disease. He briefed the Prime Minister and cabinet ministers of Malaysia on the development of a biotechnology/pharmaceutical center to discover new drugs from indigenous plants found in the Malaysian tropical forests. His grant proposal to establish a partnership between MIT and Malaysia to investigate drugs from indigenous plants is being considered for funding by the Malaysian government. Professor Lee's most recent research suggests that nonsteroidal anti-inflammatory drugs, such as aspirin or ibuprofen, may be useful for preventing amyloid formation and for the treatment of Alzheimer's disease. He has initiated a collaboration with Merck & Co. to investigate the use of a class of new anti-inflammatory drugs–"super-aspirins"–as potential therapeutics for Alzheimer's disease.
Martin Yarmush and colleagues are making contributions to several fields, including tissue engineering, gene therapy and nucleic acid biotechnology, and metabolic engineering. Professors Yarmush, Mehmet Toner, and Ronald Tompkins are collaborating on one of the world's leading programs to establish a liver support device using hepatocytes and microfabrication techniques. Also in the area of tissue engineering, Professors Jeff Morgan and Yarmush are developing the next generation of skin substitutes using genetically modified cells. In the areas of gene therapy and nucleic acid biotechnology Professor Yarmush's lab, together with those of Professors Morgan and Charles Roth, are investigating rate limiting aspects of gene therapy and antisense therapy. Finally, Professors Yarmush and François Berthiaume are using the tools of metabolic engineering to investigate the complex metabolic changes that occur in chronic disease and major injury.
Richard J. Wurtman, M.D., program director of MIT's Clinical Research Center, also does research in Alzheimer's Disease. A generally held–if unproved–view of Alzheimer's is that dementia results from toxic effects of an abnormal protein, called amyloid, which is a polymer of small fragment (A-beta) of a protein (APP) that is produced normally in all cells. Hence, a major goal of researchers hoping to treat this disease is to find drugs that will decrease the formation of A-beta from APP, and increase the production of APP's other major metabolite APPs ("soluble APP"). Wurtman's laboratory has now shown that both the synthesis of the APP and the proportions of it that are broken down to A-beta or soluble APP are under the control of particular neurotransmitters and "second messengers" they generate. Thus, using drugs that act on these receptors, it should be possible to block the formation of APP and all its metabolites, or promote the formation of soluble APP and suppress A-beta. This has now been demonstrated in tissue culture and is in the process of being demonstrated in animal models of Alzheimer's. The next step, probably involving industry collaboration, involves devising a treatment to decrease the amount of amyloid in the Alzheimer's Disease brain. This treatment may conceivably ameliorate the dementia of the disease.
Robert H. Rubin has spent much of his clinical career studying and caring for transplant patients. Among his accomplishments are the development of new strategies for preventing the most important infections, particularly those due to viruses and fungi; the establishment of the link between certain viral infections and allograft injury and the development of certain malignancies; and the development of novel antimicrobial approaches that are effective not only in transplant patients but also in such other immunocompromised patient populations as those with AIDS and cancer. In 1999, he was named to the chairmanship of the Infectious Disease Section of the International Transplantation Society. As director of the HST Center for Experimental Pharmacology and Therapeutics, Dr. Rubin has pioneered in the application of positron emission tomography, magnetic resonance imaging and spectroscopy, and other measurement technologies to the development of new drugs, including those designed for the transplant patient. Professors Rubin and Alan C. Moses head a two-year Clinical Investigator Training Program, a joint effort of the Beth Israel Deaconess Hospital, HST and Pfizer, Inc. Trainees gain direct experience in clinical investigation and a strong foundation in the statistical and computational sciences, biomedical ethics, principles of clinical pharmacology, in vitro and in vivo measurement techniques, and aspects of the drug development process. After fulfillment of thesis requirements and successful performance on a qualifying exam, graduating trainees receive a M.M.Sc. degree in Clinical Investigation from HST.
Daniel Shannon is a founder of the field of pediatric intensive care and pulmonology. For more than two decades, he has been furthering his breakthrough studies into the rare condition of congenital central hypoventilation syndrome (CCHS). Professor Shannon and his colleagues have added incrementally to their framework of knowledge about the problem, using whatever new tool they could find to test specific hypotheses. One of his associates in these studies recently received an award from the NIH for discovering the first gene that controls respiration. Still, the clinical problems–like a child's failure to breathe adequately when asleep–continue to stump clinicians and researchers alike. His latest research reflects the use of technology to better serve patients.
Robert S. Langer, Jr., a pioneer in biomedical and chemical engineering, is studying new ways to deliver drugs, including a new microchip that can deliver drugs in a pulsable fashion. He is also researching tissue engineering and has created new approaches for creating blood vessels, cartilage, and many other tissues. He has also developed biomaterials for medicine, including plastic that slowly dissolves and releases therapeutic drugs directly to tumors. In 1996, this led to the first new treatment for brain cancer approved by the FDA in more than twenty years.
Medical Sciences and Molecular Medicine
Lee Gehrke studies the replication and assembly of viruses that use RNA as their genetic material. Key biochemical processes that allow viruses to replicate depend on docking interactions between RNA and protein molecules. Professor Gehrke's laboratory is focused on identifying these docking signals, an effort that will facilitate therapeutic approaches for blocking virus replication and assembly. The research has led to the molecular identification of amino acids and nucleotide sequences that are crucial for forming the RNA-protein interactions; moreover, the work also suggests the shape or conformation of the molecules changes upon binding. Another aspect of his work is learning how viruses are able to gain an advantage over the infected host cell in expressing their own genetic information. Nucleotide signals in a viral messenger RNA have been identified that give the virus a competitive advantage, and the lab is now working to elucidate the detailed mechanism.
Irving M. London, Founding Director of HST and Professor of Biology, Emeritus, is studying the regulation of hemoglobin synthesis at both transcriptional and translational levels. His laboratory has discovered and characterized the main enhancer elements that control the transcription of the human ß-globin. In collaboration with Professor Philippe Leboulch of the Harvard Medical School faculty, Dr. London is also focusing on novel gene transfer strategies for the gene therapy of human diseases, especially sickle cell anemia and thalassemia.
George Q. Daley (HST ‘91) is investigating the signaling pathways that allow the BCR/ABL oncoprotein to induce leukemia. His laboratory has demonstrated that a novel class of pharmaceutical agents called farnesyl transferase inhibitors have potent activity against BCR/ABL-induced leukemia, which will set the stage for clinical trials in humans. His lab has also demonstrated that hematopoietic stem cells develop from totipotent embryonic stem (ES) cells that are differentiated in culture, an important step towards using ES cells for cellular therapies.
Richard Mitchell researches the mechanisms underlying acute and chronic rejection in solid organ allografts, specifically in heart transplants. The work spans from mouse heart transplant models up to human hearts, and is focused on understanding the specific immunologic mediators that drive the rejection and failure of these allografts. His lab is particularly interested in the mechanisms that induce the process of "chronic vascular rejection," whereby the vessels in transplanted hearts become progressively more occluded until the grafts get starved for blood and die. The research may have much broader applicability, since the inflammatory mediators that drive the occlusive process in transplanted hearts may also be involved in mediating the vascular wall thickening that characterizes more "typical" atherosclerosis. Professor Mitchell's lab uses a number of genetically-engineered mice (so-called "knock-out" mice) that are either deficient in particular mediators (called "cytokines") or deficient in the receptors for those cytokines. In collaboration with other members of the HST community, such as Elazer Edelman, Professor Mitchell has been trying new interventions to prevent the chronic vascular pathology. They have also developed collaborations with a number of pharmaceutical firms like Schering-Plough and Bristol Myers-Squibb to evaluate new drugs that may reduce the vascular narrowing.
Jane-Jane Chen, Principal Research Scientist in HST, studies the regulation of hemoglobin synthesis by the heme-regulated eIF-2 alpha kinase (HRI) that is responsible for the translational regulation by heme of globin synthesis. Her group has identified the two heme-binding domains of HRI and the erythroid-specific promoter of HRI gene. These data have significance for further understanding the role of HRI in the production of hemoglobin, a vital oxygen-carrying protein.
Bioinformatics and Medical Informatics
Knowledge discovery and its dissemination in health care have been deeply influenced by recent advances in computer science and engineering. Medical and Biological Informatics (MBI) is the use of computer technology to extract, transport, and manage information from medical and biological data, and to model and support human decision-making in clinical and biological domains. The field is a scientific and engineering activity which is inherently multidisciplinary. Research challenges include: deducing and mapping genomic structure, predicting structure and function of proteins, representing medical knowledge for modeling diagnostic and prognostic decision-making processes, extracting new information from large clinical and biological datasets, building comprehensive electronic medical records (EMR) and clinical information systems, interfacing monitoring devices and the EMR, assuring privacy and confidentiality in medical transactions, analyzing and manipulating images, recognizing patterns of disease progression, analyzing costs and benefits related to medical use of information technology, computer-aided instruction, and utilizing the Internet for providing education and health care services.
Robert Greenes, M.D., Ph.D., Director of the Medical Informatics Training Program, established the Decision Systems Group (DSG) at Brigham and Women's Hospital in 1978 to pursue the application of information technology in physician education and decision making. Professor Greenes has had a 35-year history of work in the area of medical informatics. The DSG lab, which includes physicians, computer scientists, database experts, graphics and multimedia specialists has its primary focus on developing means to enhance decision support and education in medicine and for integrating these capabilities into clinical practice. For the past ten years, emphasis has been on the development of component-based, distributed, and Internet-based approaches to implementing applications that provide a framework for integration of diverse information resources in a cohesive manner.
Lucila Ohno-Machado investigates machine learning techniques to extract information from clinical databases, especially in the form of predictive models for prognosis. She has used special methods to predict survival for patients with AIDS, to assess the probability of myocardial infarction in certain populations, to predict ambulation for patients with specific kinds of spinal cord injuries, and to predict outcomes in other clinical domains. Her research is focused on the development and evaluation of models involving binary outcomes. She is interested in deploying practical models for direct use by patients, physicians, and health care managers, so that they can make more informed decisions. An example in this area is a project that uses artificial intelligence techniques for dealing with uncertainty to select suitable clinical trials for patients with certain types of breast cancer. Other areas of interest include decision support to help patients recognize early symptoms of a heart attack, patient education, and remote teaching using information technology.
Speech and Hearing
Dennis M. Freeman and colleagues seek to understand the mechanisms by which sounds stimulate the sensory cells in the inner ear. To that end, they have developed a three-dimensional imaging system that can resolve nanometer motions. Perhaps the most enigmatic structure in the inner ear is the tectorial membrane, a gelatinous structure into which the mechanically sensitive hair bundles of sensory cells protrude. They have developed methods to probe the electrical, mechanical, and osmotic properties of the tectorial membrane. They have applied the three-dimensional imaging system developed for research in hearing to measure motions of Microelectromechanical Systems (MEMS). With funding from DARPA, they are placing similar measurement systems at the University of California at Berkeley and at Carnegie Mellon University.
John J. Rosowski conducts research as a member of the Auditory Mechanics group at the Eaton-Peabody Laboratory. He and his colleagues strive to understand how the structures of the external and middle ear affect what we hear through measurements of normal function and structure in normal and pathological ears. In pursuing this goal, they make physiological and anatomical measurements in human ears and use the large patient population at the Massachusetts Eye and Ear Infirmary to test structure and function inferences. They also take advantage of the wide variations in ear structure by measuring function and structure in a variety of animal ears. In conjunction with the clinical staff in the Department of Otolaryngology of the Massachusetts Eye and Ear Infirmary, they investigated the relationships of ear pathology and post-surgical structure to hearing level. A correlational analysis between pathological stapes structure and hearing level in patients with otosclerosis (a disease marked by the proliferation of bone and bony fixation of the stapes) came to the surprising conclusion that pathological changes in the soft tissues that support the stapes are better correlated with hearing loss than the degree of bony fixation of the stapes. A second study demonstrated the prevalence and the degree of hearing loss after reconstructive surgery for otosclerosis. Several series of middle-ear measurements came to functional conclusions regarding middle-ear pathology and post-surgical hearing levels (1) Some preliminary computer-microvison measurements of three-dimensional stapes motion were performed to address the fundamental issue of whether the human stapes can be assumed to act as a translating piston. The present data set suggest that the piston assumption is valid below 1000 Hz but may not hold at higher frequencies. (2) A complete set of functional measurements and analyses of the effects of tympanic-membrane perforations on middle-ear function led to the first quantitative description of how ear-drum perforations of different sizes affect the frequency dependence and sensitivity of hearing function. (3) Measurements of the functional effects of different middle-ear surgical techniques came to the conclusion that two common techniques for reconstructing the middle-ear air spaces after disease lead to similar function. With continued analyses of other middle-ear surgical techniques, members of the Auditory Mechanics group contributed to papers that review various diagnostic and surgical procedures and make specific recommendations about surgical approaches and materials.
Charles M. Liberman studies the neurobiology of hearing and hearing loss in animals and humans. His work on normal hearing investigates the structure and function of the four major classes of afferent and efferent neurons connecting the inner ear with the brain. Notable recent progress includes the discoveries that sound-evoked activation of one of the efferent feedback pathways protects the inner ear from permanent acoustic injury and that inter-subject variation in the strength of this feedback reflex can predict susceptibility to hearing damage in noisy environments. His work on hearing loss is currently focusing on prevention of presbycusis, or age-related hearing loss. His laboratory has recently demonstrated a genetic manipulation in mice which dramatically minimizes age-related hearing loss as well as the age-related loss of sensory cells. The molecular mechanisms underlying this protective effect are now under investigation.
Bertrand Delgutte and his colleagues are investigating the neural mechanisms underlying the remarkable ability of normal-hearing people to hear out a sound of interest among competing noises. They recently found a class of neurons in the auditory midbrain that respond better to a sound signal in noise when the signal and the noise originate from different spatial locations. This research may lead to hearing aids and auditory implants that work better in the complex acoustic environments that cause great difficulties to hearing impaired listeners.
FUTURE PLANS
There is tremendous opportunity for growth in HST and for making MIT's contributions to the medical sciences much more substantial and visible. The Athinoula A. Martinos Center for Functional and Structural Biomedical Imaging provides a paradigm for this growth. It has already enhanced old collaborations and has begun to build new ones, both in the MIT community and the Boston area.
A major effort has been placed on rationalizing our faculty appointment process (for affiliated and joint faculty) and increasing the size of the faculty with primary HST appointments.
Partnerships with other departments, schools and industry are important to the growth and health of this Division. The creation of HST's new Advisory Council has brought new contacts and colleagues in the industrial sector. The goal is to develop new synergies with industry that offer a range of benefits for students, faculty, and professionals working in the private sector. Our recent partnership with the Harvard Dental School brings new perspectives and disciplines to our curricula. We have on-going partnerships with the National Space Biology Research Institute, which is comprised of members from HST, Johns Hopkins, Baylor, Rice, Moorhouse, and U Texas, and with the NSF Educational Research Center, which is comprised of members from Vanderbilt, Northwestern, U Texas at Austin, and HST. NASA has plans to double the number of participating universities.
As medicine and technology continue to change at a rapid pace, so too must curricula. Faculty members at HST continue to review the entire M.D. curriculum, build the biomedical imaging curriculum and biomaterials educational program, as well as develop a cell and molecular track for MEMP Ph.D. students, to name only a few. The Division also continues to work with new technologies to enhance our educational offerings and to offer new opportunities in distance learning and asynchronous networks.
More information about the Harvard-MIT Division of Health Sciences and Technology can be found on the World Wide Web at http://hst-hu-mit.mit.edu/.
Martha L. Gray
MIT Reports to the President 1998-99