MIT Reports to the President 19992000
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 Environmental Health Sciences, and the Division of Comparative Medicine.
More information about this organization 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 to foster research in the rapidly growing discipline of Biological Engineering. With five new members this past year, over 45 CBE faculty (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 in Bioengineering, at the interface between Engineering and Biology.
To accomplish this mission, a major focus this past year has been the further development of state-of-the-art core facilities, and a novel Engineering/Biology Seed Grant Program in collaboration with CBEs Industrial Advisory Board. The Core Facilities have been crucial in establishing new multi-investigator collaborations with Harvard Medical School affiliated Hospitals, including a Core Center in Musculoskeletal Diseases focusing on Orthopaedic Gene Therapy and Tissue Engineering, involving 35 investigators from MIT and Harvard, and a collaborative Program in Mechanotransduction In Cardiovascular Cells, focusing on basic research in mechanical regulation of cellular response, with direct application to cardiovascular disease.
Among the many outstanding research accomplishments by CBE faculty this past year, new developments in neural tissue engineering have emerged based on a novel self assembling peptide scaffold biomaterial. This emerging technology has resulted in a broad spectrum of biocompatible materials through molecular engineering, which have been used to encapsulate cells such as neurons and chondrocytes. The ongoing DARPA Program in Vascular Tissue Sensors for Generic Toxin and Pathogen Detection, involving 13 Co-Pis, has produced critical advances which have been leveraged, in part, by CBEs Multi-Photon Microscopy facility.
CBEs Engineering/Biology Seed Grant Program continues to act as a catalyst for such multidisciplinary collaborations, funded by members of CBE's Industrial Advisory Board. CBEs next Industrial Advisory Board meeting will occur this coming Fall 2000, at which students and faculty will present oral and poster presentations summarizing their latest research.
The 19992000 Seed Grant awards funded projects on:
This past year, CBE has developed additional state-of-the-art multi-user core facilities for use by undergraduate and graduate students and faculty. In addition to Multi-Photon Imaging and Atomic force Microscopy, a new Cryofixation, Freeze-Fracture/Deep Etch facility is now housed in Room 56-367, comprising two devices: a Leica EM-CPC plunge slam freezer and a Cressington CFE-60 Freeze Fracture System. The combination of these two pieces of equipment will allow users to bring tissue specimens, cell cultures, cell-seeded scaffolds, or other hydrated biomaterials to the facility and take away a dimensionally stable platinum/carbon replica of the cryopreserved ultrastructure as revealed by the fracture plane (etched or unetched). The replica will be suitable for viewing on high-resolution transmission electron microscopy. Applications include resolving ultrastructural details of extracellular matrix, scaffold and gel matrices, cell membranes, and intracellular ultrastructure, and can be extended to include histochemical identification of individual matrix/cellular components if combined with techniques such as immunogold labelling. These methods will enable microstructural characterization of tissue engineering matrices and scaffold materials at the submicron level, which is critical to understanding cell-material interactions.
More information about this Center can be found on the World Wide Web at http://web.mit.edu/cbe/www/.
Alan J. Grodzinsky
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 especially cancers. 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 environmentallyinduced mutations included those necessary for human diseases such as cancer and atherosclerosis.
However, research in our Center has produced observations that directly challenge the importance of environmentally induced mutations. Three separate studies have yielded observations comparing smokers and nonsmokers lungs which are wholly inconsistent with the idea that cigarette smoking increase risk of lung cancer by increasing the rate of point mutations in the bronchial epithelium from which most lung tumors arise.
One major CEHS program grant, the Superfund Basic Research Program has been studying the nearby Aberjona River Basin and its residents for some fifteen years. A second is the program grant, "Mutagenic effects of Air-borne Toxicants," in which we sought to test the hypothesis that urban air pollution represented an increased risk for lung cancer. Both have been funded via the National Institute of Environmental Health Sciences (NIEHS). Our new approach to analysis of public health records led us to re-examine the widely held assumptions that the town of Woburn, MA, home to two Superfund Sites, had a statistically higher experience of pediatric leukemia and that this was due to exposure to a contaminated public water supply. We organized the age-specific mortality data for all towns and cities in Massachusetts and created a model for the expected distribution of deaths from each major disease observed in the past thirty years. We discovered that the distribution of deaths from pediatric leukemia was consistent with variations among communities due to chance alone. The town of Woburn was fifth highest among Massachusetts communities lying well within the distribution expected for chance variation. We further found that the distribution of death rates for all diseases save lung cancer was consistent with differences due to chance alone. The statistically significant difference for lung cancer was explained by the significantly higher measured prevalence of cigarette smoking in cities as compared to towns and villages.
We next compared mortality rates among towns comprising or immediately downstream from Superfund Sites with all other towns without any known local cache of chemical contaminants. There were no differences between these two groups of towns for any form of mortality. These studies are now being extended to the populations of Pennsylvania, New York, Illinois, California, Texas and Florida comprising some 44% of all deaths in the United States since 1968.
These findings, both by direct measurements of genetic change in human organs or by organizing and analyzing public mortality data, may be considered positively in terms of the natural progress of science inexorably discovering former error. But they have also created a great deal of discomfort among scientific reviewers of CEHS proposals and even the committee that decides whether or not we can submit program proposals to NIEHS. This discomfort is acute and has created an immediate hiatus in CEHS funding. For instance, after we reported our basic findings regarding urban pollution, cigarette smoking and lung cancer to NIEHS we were refused permission to submit a competitive renewal proposal after 22 years of funding and the enthusiasm of five successive site visit teams for peer review. The total rejection of our analyses of the leukemia situation in Woburn and our conclusion that the presence of Superfund Sites had no effect on mortality rates in Massachusetts led to rejection of our competitive renewal proposal for the Superfund Basic Research Program. These two programs comprised more than 2/3 of CEHS research support.
To overcome the funding problems and build upon the solid accomplishments of our faculty we have reorganized to create a Center in which faculty explore various organs in the human body to discover what biological changes could be affected by environmental agents and create higher cancer risks.
Importantly the defunct NIEHS research program has been accepted as a new program grant proposal by the National Cancer Institute where our novel findings have struck a responsive chord. Both NCI and we believe that smoking is the clearest case of an environmental factor increasing cancer rates and that an orderly series of hypotheses such as we have presented should be tested.
CEHS is in the midst of hard times with respect to research funding but is also experiencing an exciting scientific renewal possibly defining its worth as an MIT level organization. Let us hope financial recovery precedes our institutional demise.
More information about this center can be found on the the World Wide Web at http://web.mit.edu/cehs/index.html.
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 Institutes expertise in basic biochemical and biophysical mechanisms to the analysis of normal and pathologic processes in humans. MITs 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 number of qualified physicians and clinical scientists from MITs 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 CRCs 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. 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 eleven voting members plus nine non-voting members from the CRCs program staff. The Committee reports to the Principal Investigator of the CRCs 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, ultimate statistical validity, and potential risk to human subjects. The Committee also sets general policies and reviews the operations of the CRC.
The CRC presently has a dual administrative locus within MIT. As a research unit, the CRC reports through 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 reported to Dr. Arnold Weinberg, the Director of the Medical Department. Members of the CRC participate in the Medical Department 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 CRCs, and asked to consider becoming a "Network" CRC. This would involve implementing at the MIT CRC some research projects generated at other local CRCs, and, conversely, implementing some of the projects (e.g., those involving very sick patients) at those other centers. Additi onally, 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. 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 expanding relationship has, in fact, been highly successful. To date fifteen MGH protocols have been approved and implemented at the MIT CRC, and three MIT protocols have been implemented at the MGH. The senior program staffs at the two institutions have been meeting monthly to anticipate and solve potential problems related to their 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.
To date, 15 MGH projects have been approved and initiated at MIT; three projects conducted by MIT investigators are being conducted at both sites. The relationship between the two CRCs will continue to be developed and expanded, and the two centers will formally submit a joint NIH renewal grant application, for five years of support, to start funding in December 2002, when the present NIH grant expires. Meanwhile, since the present MIT grant expires a year earlier (2001), the MGH and we will, in the next year, jointly submit an application for year of funding for the MIT CRC as a dedicated supplement to the MGH grant. We will thereafter be identified as a "Satellite" to the MGH CRC, but will suffer no loss of "sovereignty" or autonomy nor, based on discussion with the NIH, no decrease in funding.
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 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 CRCs apparently are excellent, and the strengths of each institution complement those of the other. The CRC also continues to "network" with other Boston-area GCRCs (e.g., BIDMC) and all interested parties agree that the CRC should continue to do so in the future.
The CRC provides opportunities for training in clinical research to regular MIT and HST students and fellows. These fellows and students utilize the CRCs facilities to initiate research protocols and to participate in ongoing projects supervised by senior investigators and faculty. (See section on the Center for Experimental Pharmacology and Therapeutics)
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 them, by advertising and posting positions in local colleges, universities, medical institutions, and minority organizations have not generated a significant response.
This past year one research staff position became available; a male minority was hired. All four Visiting Scientists appointed in 1999-2000 were women. The CRC will continue its efforts to increase the pool of qualified minority applicants, as positions become available.
The CRC continues to maintain major commitments to the research activities 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 MITs 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., Alzheimers disease). Groups collaborate on multi disciplinary projects, e.g., obesity; depression; Alzheimers disease. However, the scope of its 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, diabetes, and neuroendocrinology. Reflecting its evolving interactions with the MGH GCRC, 15 of these projects (out of a total of 45) were directed by investigators whose primary appointments are at the MGH.
This year the CRC patient census totaled 100 inpatient days and 1181 outpatient visits. The CRC branch of the NIH had provided, based on prior years activities, support for up to 295 inpatients and 3906 outpatient visits. The decreased census could be explained by the completion of the data-gathering portions of several large projects.
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), Osbourne Professor of Health Sciences and Technology. Educationally, each year 10 MDs 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.
The CRC computer staff continued to develop the CRC Operations System with the addition of systems for the Core Laboratory and the Dual Energy X-ray Absortiometry facility (DEXA). These systems use an ORACLE relational database, and support 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 hardware and software support for the CRC staff and investigators and statistical assistance to all researchers.
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 metabolisms in health and disease, and the regulation of whole body amino acid metabolisms, 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 effect these needs. These various investigations offer new basic knowledge about the physiology of a 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.
Dr. Linda Bandini and her colleagues have continued to follow-up girls in the longitudinal study of the effect of energy expenditure on growth and development in pre-adolescent girls.
Annually, subjects visit the CRC for measures of height, weight, and anthropometric measures. In addition they complete questionnaires regarding their activity and dietary patterns. Girls complete the study four years after menarche. At study completion the girls body composition and metabolic rates are measured in addition to their annual measures. As of November 30,1999, 107 girls had completed the longitudinal study and 52 remained active in the study. In a subcohort of 40 girls, abdominal scans were done at menarche to measure visceral fat. In these girls, visceral fat is again measured at study completion.
Because this is a longitudinal study, the results of the study will not be available until study completion. 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.
Dr. Bandini is also investigating the relationship of visceral fat to diet, activity, and hormonal changes in a subcohort of girls. These studies will provide information on variable 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.
Dr. Steven Grinspoon and his colleagues conducted studies to determine the effects of rh IGF-I ( a nutritional-dependent anabolic hormone with potent effects on bone formation) and of estrogen on bone density in women with anorexia nervosa.
Fifty-percent reduced bone density is a common manifestation of anorexia nervosa (AN). More than 50% women with AN will have significant bone loss. Bone loss in AN occurs at a young age, and is often resistant to improvement with existing therapies such as estrogen. Bone formation is significantly reduced in women with AN, in association with increased bone resorption. To address the issue of low bone formation in anorexia nervosa, Dr. Grinspoon designed a double-blind randomized, placebo controlled, trial of rh IGF-I. Short-term studies have shown a significant increase in bone formation in response to rh IGF-I. Recruitment for this study is ongoing and the data investigating specific predictive factors for regional bone loss in AN have recently been submitted for publication. Studies have shown that nutritional factors, more than indices of estrogen deficiency or other estrogen-related parameters, determine regional bone loss in a cohort of more than 130 patients with AN that have been screened.
Dr. Richard Wurtman and his colleagues examined the effects of giving a single dose of phentermine (15 or 30 mg, N=17), or daily doses (30 mg) for five days (N=8), on levels of dopamine and serotonin in platelet-rich plasma, examined at various time points (0-4 hr) after drug administration.
They found that phentermine caused significant elevations in platelet serotonin without increasing those of plasma serotonin. Inasmuch as platelets are unable to synthesize this amine, its increase must have reflected diminished metabolism - by the enzyme monoamine oxidase (MAO). This confirmed older in vitro data showing that phentermine is an MAO inhibitor.
The demonstration that, in humans, phentermine is an MAO inhibitor probably explains why some individuals who took "fen/phen" (fenfluramine - a serotonin releaser and uptake blocker - and phentermine) developed cardiac valvular lesions. The fenfluramine blocked the ability of platelets to take up plasma serotonin, and the MAO inhibition by phentermine blocked the only other pathway available for getting rid of the plasma serotonin, i.e., enzymatic degradation in liver, kidney, etc. The transient, but repeated, elevations in plasma serotonin levels that followed probably caused damage to the heart valves, and such damage probably would not have occurred (nor has it been seen) in patients just taking fenfluramine or phentermine alone. Unfortunately, phentermine activity as an MAO inhibitor still is not mentioned on its label.
Professor Vernon R. Young gave the 5th Annual Fisher Lecture at Rutgers University and the keynote address at the 8th Asian Congress of Nutrition.
Dr. Young and his colleagues have continued to explore quantitative aspects of amino acid metabolisms 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 oxyoproline metabolism and increase the urinary excretion of this intermediate which may, therefore, serve as a potential probe of the status of GSH metabolism of GSH metabolism in human subjects. Studies have also continued on the kinetic aspects of amino acid metabolisms in particular adults. Studies with lysine and threonine as the test amino acids again confirm the hypothesis that the current international requirement 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.
More information about this department can be found on the World Wide Web at http://web.mit.edu/crc/www/.
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 105 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.
The Divisions state-of-the-art rodent facilities are either new or have been renovated during the past five years. The average daily census of laboratory animals grew approximately 9 percent during FY00. Mice remain the primary species used by MIT investigators and represent more than 97 percent of the animal population. The animal 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 Division has begun to develop expertise in aquaculture and now provides veterinary support to the Sea Grant Program and Woods Hole Biomedical Institute.
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. FY00 was the twelfth year of the Divisions NIH postdoctoral training grant that has been funded through year 15. There are currently six postdoctoral trainees, two of whom are enrolled in the graduate programs in the Division of Bioengineering and Environmental Health. Twenty-two trainees have completed our postdoctoral training program and 21 of them have now passed the board examination of the American College of Laboratory Animal Medicine.
DCM faculty and staff published five chapters, 15 papers and 35 abstracts in FY00 and presented numerous research papers at national and international meetings.
Dr. Barbara Sheppard joined the joined the Division as a Comparative Pathologist. Recruitment is underway for an additional pathologist and a clinical veterinarian. Dr. James Fox received the Foundation Award for Excellence in Research from the American Veterinary Medical Association. He also received the Nathan R. Brewer Scientific Achievement Award from the American Association of Laboratory Animal Medicine for identifying, naming and describing diseases associated with Helicobacter species. Dr. David Schauer earned tenure as an Associate Professor in the Division of Bioengineering and Environmental Health. DCM faculty and staff taught graduate courses Toxicology 201 and 214.
The web site for the Committee on Animal Care provides required forms, continuing education material, information on the CACs activities and schedules for training sessions. 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 CAC has also increased efforts in screening animal users for occupational health issues. The CAC 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 Harvard-MIT Division of Health Sciences and Technology (HST) brings engineering, science, technology and medicine to the solution of problems in biology and human health. A successful 30-year collaboration of the Massachusetts Institute of Technology (MIT), Harvard University, Harvard Medical School (HMS), area teaching hospitals, and research centers, HST has been a pioneer in interdisciplinary educational and research programs designed to educate outstanding minds, cultivate leaders, create knowledge, and generate cost-effective preventive, diagnostic and therapeutic innovations. It is among the largest biomedical engineering and physician-scientist training programs in the United States.
Advances in biology and technology are bringing us to an era where disease can be treated by "engineering" the phenotype of cells and tissueswhere cell, tissue, and body functions can be manipulated using strategies affecting genes, cells, and their environment so that they behave in predictable ways. Inexorably linked to these fundamental changes in the approach to disease management are advances in our ability to diagnose and prevent disease. There is no question that success demands individuals with a broad range of skills spanning the domains of science, engineering and medicine.
HST is dedicated to integrating these disciplines into an educational program that carries engineering and the physical and biological sciences from the laboratory bench to the bedside, and clinical insight from the bedside to the bench. Our programs are committed to exploring the fundamental principles underlying diseases, seeking new pharmaceuticals and devices to ameliorate human suffering, and training the next generation of physicians, scientists, and engineers to do the same. Thus HST trains physicians to have a deep understanding of the underlying quantitative and molecular science of medicine and biomedical research. HST Ph.D. students similarly are trained to have a deep understanding of engineering, physical sciences and the biological sciences, complemented with hands-on experience in the clinic or in industry.
Today HST is composed of 320 students who work with more than 200 faculty and affiliated faculty members drawn from throughout the Harvard and MIT communities. HST offers six multidisciplinary graduate degree options, each targeted at students with different backgrounds and goals, each requiring a focused educational and research program, and each offering a different level of clinical training.
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. HST Research initiatives fall into four major interdisciplinary areas and presently two major disease-focused areas:
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, HSTs administrative home is the Whitaker College of Health Sciences and Technology at MIT. However, a manager and an administrative assistant are located at Harvard Medical School. The Divisions 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..
Thanks to a $20 million gift in 1999, HST will establish the Athinoula A. Martinos Center for Functional and Structural Biomedical Imaging. The Martinos Center will be a state-of-the-art imaging center established specifically to bring together the extraordinary strengths in science, engineering and technology found at MIT, coupled with the equally powerful strengths of the medical and clinical sciences found at Harvard Medical School and its affiliated hospitals. Under one roof, HST will bring together engineering and the physical sciences, computational sciences and informatics, basic and applied biological sciences, imaging and radiological sciences and clinical sciences. The mission of the Martinos Center is to design and build the next generation of functional imaging tools and to apply these tools to biologically and clinically relevant problems; to provide training for physical, biological and clinical scientists and to serve as a hub for interdisciplinary collaborations across Harvard and MIT. The Martinos Center will house low and high-field MRI for human and animal imaging, magneto-encephalography (MEG), optical imaging, and PET. The initial areas of focus will include: systems-level imaging, high-field human MRI, high spatial and temporal functional mapping of the brain and heart, optical imaging and pharmacological imaging.
Kenneth I. Shine, M.D. gave the keynote address at HSTs Commencement Exercises in June, 2000. Dr. Shine is the President of the Institute of Medicine of the National Academy of Science, and Professor of Medicine Emeritus, UCLA School of Medicine, where he is also past Dean and Provost for Medical Sciences.
The 13th annual HST Forum, entitled "The Speech Chain", was held on March 9, 2000. Forty-seven students presented their work at the afternoon poster session, and three faculty spoke at the plenary session. Dr. Kenneth Stevens, Clarence J. Lebel Professor of Electrical Engineering at M.I.T. presented a seminar entitled "Toward Models for Human and Machine Recognition of Speech". Dr. Donald K .Eddington, Associate Professor of Otology and Laryngology at Harvard Medical School and Principal Research Scientist at M.I.T. spoke on "The Cochlear Implant: A Neural Prosthesis for the Deaf". Dr. Jennifer Melcher, Assistant Professor of Otology and Laryngology at Harvard Medical School and the Massachusetts Eye and Ear Institute delivered a presentation entitled "Imaging the Human Central Auditory system: Function and Dysfunction." The evening was capped by a reception and dinner at the Cambridge Marriott Hotel.
For almost 10 years, the Boston Heart Foundation (BHF), located in Kendall Square, Cambridge, has been a clinical research affiliate of the Harvard/MIT division of Health Sciences and Technology (HST). The BHF was founded by Dr. Robert S. Lees, an HST professor with more than 30 years of service to MIT. This past spring, the Co-Directors of the HST Program, Drs. Joseph Bonventre and Martha Gray, invited the BHF to become the HST Cardiovascular Genomics Center. The BHF has a large and loyal multi-generational outpatient population which includes families with the more common precursors of heart disease such as familial hypercholesterolemia, and also rarer ones such as the hypoalphalipoproteinemias and sitosterolemia. The BHF medical staff provide inpatient care, when needed, at the Massachusetts General Hospital. The BHF has an international reputation for providing outstanding, personalized medical care for both common and rare diseases of the heart and blood vessels. Its research programs in the causes, diagnosis, and treatment of heart disease, which involve MIT undergraduate and graduate students, as well as HST medical and medical engineering students, are equally well recognized. In a world in which genomicsthe study of the role of genes in the cause and treatment of diseaseis becoming central to medical science, the formal affiliation of the BHF and HST promises to bring better understanding of the causes, treatment, and prevention of heart disease. It will continue to provide exciting research opportunities to our students and increased benefits to patients. At its May 2000 meeting, the formal affiliation between HST and the BHF was proposed by HST Co-Director Joseph V. Bonventre to the BHF Board of Directors. The latter approved unanimously.
Thirteen students graduated with Ph.D. degrees; thirty-five students received the M.D. degree, nine students received M.D. and Ph.D. degrees, and two students received the M.S. degree. Special recognition also went to five students who graduated cum laude and five who were recognized with magna cum laude.
The following HST students received awards at the June 2000 Commencement ceremonies:
Amy E. Adams, M.D., Ph.D. received the Kurt Isselbacher Prize (Harvard Medical School) for the student demonstrating humanitarian values and dedication to science.
Howard Y. Chang, M.D., Ph.D. received the Leon Reznick Memorial Prize (Harvard Medical School) for excellence and accomplishment in research.
Anthony Chen, M.D. received the Multiculturalism Award (Harvard Medical School), awarded to the student who has done the most to exemplify and/or promote the spirit and practice of multiculturalism and diversity.
Rose Du, M.D., Ph.D. (Physics, MIT), received the James Tolbert Shipley Prize (Harvard Medical School) for Excellence and Accomplishment in Research.
Whitney B. Edmister, M.D., Ph.D. (Medical Engineering/Medical Physics, MIT) received the Dr. Sirgay Sanger Award for excellence and accomplishment in research, clinical investigation or scholarship in psychiatry.
Marcus Ware, M.D., Ph.D. received the Harold Lamport Biomedical Research Prize (Harvard Medical School) for the best paper reporting original research in the biomedical sciences.
Shunmugavelu D. Sokka received the Student Leadership award in the HST Medical Engineering and Medical Physics Program.
Dr. Martha Gray, HST co-director, was appointed Edward Hood Taplin Professor of Medical Engineering and Electrical Engineering. Dr. Elazer Edelman, Thomas Cabot Associate Professor of HST, received the inagural Thomas A. McMahon award for mentoring in the Harvard-MIT Division of Health Sciences and Technology. Dr. Lee Gehrke, L.J. Henderson Professor of HST received the mentoring award from the Program in Biological and Biomedical Sciences at Harvard Medical School. Dr. Richard H. Masland and Dr. David N. Louis received the 2000 Irving M. London Teaching awards presented by the Harvard-MIT Division of Health Sciences and Technology.
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.
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 Motzs 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), the primary agency for NASA-sponsored space biomedical research. Since its founding in June 1997, the Institute has nearly doubled in size, expanding the number of consortium members from 7 to 12, and the number of research teams from 8 to 12. In his role as NSBRI investigator, Professor Young directs two 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. Prof. Young is also leading a major new research initiative in artificial gravity. Results from these efforts will help define the limitations and benefits of various possible countermeasures to the postural instability and disorientation problems that result upon a return to gravity after long-duration space flight. He is collaborating on other research being prepared for the International Space Station, including the MICRO-G project to provide advanced force and moment sensors, and a virtual reality experiment informed by Neurolab experience (Profs. L.Young and D. Newman, Dr. C. Oman). Profs. Dava Neuman and Young have also worked with NSBRI and HST toward developing a new graduate program in Space Life Sciences.
Lisa E. Freed, Principal Research Scientist in HST, supervises a research team working on tissue engineering. Her research interests include cell and developmental biology, biomaterials, and biomedical engineering, and in particular the integrated use of cells, 3-dimensional scaffolds, and bioreactors to engineer functional skeletal and cardiovascular tissues. The goals are to improve our 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
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 animals 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 Womens 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 couldnt 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" imagingthat 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 techniquealong with the established method of quantitative carotid ultrasoundto 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.
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.
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 worlds 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 Yarmushs 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 MITs Clinical Research Center, also does research in Alzheimers Disease. A generally heldif unprovedview of Alzheimers 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 APPs other major metabolite APPs ("soluble APP"). Wurtmans 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 Alzheimers. The next step, probably involving industry collaboration, involves devising a treatment to decrease the amount of amyloid in the Alzheimers 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 problemslike a childs failure to breathe adequately when asleepcontinue 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.
Roger G. Mark, together with colleagues at HMS, Boston University, and McGill University launched the new NIH-funded Research Resource for Complex Physiologic Signals. The Resource investigates cutting-edge physiologic signal processing techniques, and freely distributes extensive archives of annotated physiologic data and signal processing software to the international research community via the internet (www.physionet.org). Professor Marks group also is developing computational cardiovascular models to better understand orthostatic intolerance induced by space flight, and is exploring innovative approaches to intelligent patient monitoring.
Dr. Chi-Sang Poon, Principal Research Scientist, reported that newborn mice lacking the gene for a key subunit of the NMDA receptor developed abnormal depression of neurotransmission in a brain region important for vital physiological functions and subsequently died of respiratory failure prematurely within the first day of life. This finding raised concerns about the exposure of pregnant women to certain common anesthetic and illicit drugs, and such caution received attention in major biomedical publications including the British medical journal Lancet. A graduate student in Dr. Poons lab, Daniel L. Young, received an individual predoctoral fellowship award from the National Institute of Mental Health for his proposed thesis research in neuroengineering. This was the only award of this kind that had been won by a MIT graduate student in recent years.
Stephen Burns is interested in medical instruments in the developing world. He and his students are using inexpensive personal computer technology to implement devices characterized by intensive signal processing. They have developed an electrocardiogram machine and are currently working on several ophthalmic instruments for screening for glaucoma including a through-the-eyelid tonometer.
James C. Weaver, Senior Research Scientist, and colleagues at MIT and Chicago are carrying fundamental theoretical studies of the conditions under which weak electric and magnetic fields (EMF) can alter biochemical processes. Their recent paper in Nature shows that biological sensing based on magnetically sensitive chemical reactions should be possible, and could allow detection of remarkably small magnetic field difference.
Jane-Jane Chen, Principal Research Scientist in HST, studies the regulation of hemoglobin synthesis and erythropoiesis by the heme-regulated eIF-2 alpha kinase (HRI) that is responsible for the translational regulation by heme of globin synthesis. Her group has knockout the HRI gene in mice. In iron-deficiency, HRI null mice maintain the nomal cell size and hemoglobin content of the red blood cells, in contrast to the hypochromic and microcytic red blood cells of wild type mice. In addition, there is a structural alteration in the red cells and a decrease in toatl red blood cell number in the HRI null mice under these conditions. Thus, HRI is required for the well being of the mice in iron deficiency. These data have significance for further understanding the physiological role of HRI in the production of not only hemoglobin, but also red cells
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 Gehrkes 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, and plans are underway 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, with specific emphasis on heart transplants. The work runs the gamut from mouse transplant models to human clinical transplantation, and is focused on understanding the specific immunologic pathways that drive rejection and ultimately graft failure. His lab is particularly interested in the mechanisms that induce the process of "chronic 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 Mitchells lab uses a number of genetically-engineered mice (so-called "knock-out" mice) that are either deficient in cell surface molecules that promote the cellular cross-talk necessary to promote rejection, or that lack particular "cytokine" mediators or their receptors. In collaboration with other members of the HST community, such as Elazer Edelman and Andrew Lichtman, Professor Mitchell has been evaluating new interventions to prevent the chronic vascular pathology. His group has also developed collaborations with a number of pharmaceutical firms such as Schering-Plough, Bristol Myers-Squibb, and Novartis
Joseph V. Bonventre (HST 76), co-director. studies the mechanisms of cellular and tissue injury and repair, particularly as related to ischemic injury to the kidney. Recent studies have focused on the role of inflammation and adhesion in the pathophysiology of acute renal failure. A novel adhesion molecule has been cloned that is expressed at very high levels during the recovery phase of acute renal failure and in models of chronic renal disease as well as in a number of human kidney diseases including polycystic kidney disease. Using PCR based subtraction techniques and bioinformatics a large number of additional genes whose regulation is altered during repair have been identified. Many of these represent potential targets for therapeutic interventions to prevent or treat kidney injury. Transcription factors are important determinants of the cellular repair processes after an ischemic insult to the kidney. A novel kidney-specific zinc finger transcriptional repressor, Kid-1, whose expression is regulated in renal ontogeny and by ischemia/ reperfusion was cloned and characterized. The Kruppel Associated Box-A (KRAB-A) motif of this and other zinc finger proteins was identified as a common repressor motif. A transcriptional repressor, KRIP-1, that interacts with KRAB-A has been cloned. A new family of proteins that associate with KRIP-1 (Trip-Br family) have been characterized which interact with E2F/DP1, two critical proteins for cell cycle regulation. A second major focus of the lab is phospholipase A2 (PLA2) and the role of this family of enzymes on acute tissue injury, apoptosis, signal transduction and nuclear events including transcription. Using the yeast two- hybrid system a nuclear protein that interacts with the cytosolic 85 kDa cPLA2 has been identified. A cPLA2 knock-out mouse has been created to study the function of PLA2s in signal transduction and renal, respiratory, gastrointestinal and neurological disease. Gene therapy approaches with adenovirus are being used.
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 Womens 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.
John J. Rosowski is co-director of the Wallace Middle-Ear Research Unit of the Eaton-Peabody Laboratory at the Massachusetts Eye and Ear Infirmary. 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. On the order of 1% of the human population suffers from some form of chronic middle-ear disease, and thousands of surgeries are performed each year at the Massachusetts Eye and Ear Infirmary alone to control these diseases and restore hearing. The Wallace unit is currently investigating the clinical utility of laser-Doppler measurements of sound-induced middle-ear velocity in patients and human subjects in the diagnosis of middle-ear disease and the evaluation of post-surgical results. Preliminary results indicate certain hard-to-diagnose ossicular abnormalities can be differentiated by vibrometry and that the reasons for a large percentage of middle-ear surgical failures can also be determined by this procedure.
Dennis Freeman has improved imaging of sound-induced motions of sensory cells in the inner ear so that it now possible to reslice the images to view motions from arbitrary perspectives. The ability is similar to tomographic reconstructions done in magnetic resonance imaging (KRI) but at a micrometer scale. Dr. Freeman has also developed novel probes for measuring mechanical properties of the tectorial membrane (a gelatinous structure that plays a key role in mechanically stimulating the sensory cells in the inner ear) based on MEMS (microelectromechanical systems) technology. His laboratory is using the new probes to characterize mechanical coupling of sensory cells through the tectorial membrane.
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.
There is tremendous opportunity for growth in HST and for making MITs 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. It will be temporarily located in the Charlestown research facility of the MGH until it can be permanently located on the MIT campus. This is an exciting collaboration in the Imaging sciences and education among MIT, Harvard and the MGH and we fully expect that this Center will be the leading education and research venue in biomedical imaging.
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.
Additional partnerships have been developed with other departments, schools, Teaching hospitals and industry are important to the growth and health of this Division.
The creation of HSTs 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. For the first time it will be possible to have Dental students, who are committed to a career as Dental science investigators, enrolled in HST.
HSTs charter membership in the National Space Biology Research Institute has brought a considerable amount of money to MIT and has served as a focus for research in manned flight in space. The membership of the NSBRI has been expanded beyond the initial charter group of HST, Johns Hopkins, Baylor, Rice, Moorhouse, and Texas A and M to include the University of Washington, University of Arkansas, Brookhaven labs, University of Pennsylvania, and Mount Sinai Medical School. Additional research programs within the NSBRI have been established with a significant represention of HST faculty within these programs. There is a projected large growth in the funding support for all the NSBRI programs.
The NSF Educational Research Center, which is comprised of faculty from Vanderbilt, Northwestern, U Texas at Austin, and HST, has proven to be an outstanding forum for development of curricula in biomedical engineering. This NSF funded ERC brings together engineers, scientists, and educators including learning scientists in a rich collaboration which approaches the field of biomedical engineering education in a completely novel way.
As medicine and technology continue to change at a rapid pace, so too must curricula. Faculty members at HST 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. We have introduced new course directors in Endocrinology, Renal Pathophysiology, and Biochemistry and have initiated a new course on Creative Writing for physicians that will be taught by Diane Klingenstein of the MIT Writing program.
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://harvard-mit-hst.org/.
Martha L. Gray
MIT Reports to the President 19992000