For the last twenty years the Center for Environmental Health Sciences has been directed by Professor William Thilly, and during that time the faculty affiliated with this center has explored a broad range of questions relating to whether and how environmental agents are detrimental to human health. These questions have ranged from measuring chemical contaminants in river sediments and examining how these contaminants accumulate in the environment, to examining patterns of cancer induced mortality in population based epidemiological studies. In between these two extremes, the question of whether environmental agents have the potential to affect human health has been addressed using a wide variety of model biological systems. Such model biological systems are amenable to genetic, biochemical and other kinds of experimental manipulation, thus enabling the exploration of how environmental agents affect living organisms at many levels. In the last few years the endeavors of the center have become very focused upon the analysis of cancer mortality data and the measurement of mutations in human cells and tissues.
On September 1, 2001, Professor Leona Samson was appointed as director of the Center for Environmental Health Sciences with the charge of revitalizing and reorganizing the center. This presents a tremendous opportunity to assemble a diverse faculty to address issues of how environmental agents impact biological systems. For the past 25 years, Dr. Samson's own research has focused on how cells, tissues and animals respond to environmental toxicants, using a diverse set of approaches, including x-ray crystallography, biochemistry, microbial genetics, mammalian cell genetics, gene therapy, mouse knock out technology, genomics, and human population based studies. Professor Samson is joined by Professor Pete Dedon, a world-renowned expert in structural and biological aspects DNA damage and repair, as Deputy Director of the center. Their immediate plans are to establish at least five research cores within the center, plus three facilties cores. These are briefly described below.
The Research cores include the following:
- Professor Dedon will direct the Radiation Biology Research Core by bringing together a number of MIT faculty from several departments who are currently working in this area. This group plans to submit a Program Project Grant application in the Radiation Biology research area during the coming year.
- Professor John Essigmann will direct the Mutagenisis and Carcinogenesis Core, again bringing together a number of MIT faculty already working in this area. We expect significant synergy and new collaborations to emerge from bringing these faculty members together. Indeed we expect this to be the case for each one of the five research cores.
- Professor Linda Griffith will direct the Bioengineering for Toxicology Research Core, bringing an entirely new perspective to Environmental Health Sciences. Her bioengineering perspective will open up new avenues of research, and one of the goals of this core will be to explore possibilities for replacing animals with engineered tissues to test whether environmental agents are detrimental to biological systems.
- Professor Harry Hemond will direct the Environmental Chemistry and Microbiology Research Core, which will again involve faculty from several MIT departments. This represents a continuation of the quantitative assessment of environmental contaminants, but also extends to considering the role of various microbes in the environmental as spearheaded by Professor David Schauer.
- Professor Steven Tannenbaum will direct the Biomarkers Research Core, drawing on his extensive world-class research in this area. Once again this core will draw faculty from across the MIT campus, and in particular will engage a number Bioengineering faculty who are bringing a new perspective to this research. Finally, Professors Heidi Nepf and Patricia Culligan will continue to direct the Community Outreach Core.
The Facilities cores include the following:
- Drs. Art Lafleur and Peter Wishnok will direct a reorganized Mass Spectrometry and Analytical Core.
- Dr. Elena Gostjeva will direct a Cell and Molecular Imaging Core, and we plan to hire an experienced pathologist as co-director.
- Professors Samson and Sorger will direct a Genomics and Bioinformatics Core.
It should be noted that there has been a recent influx of new funding into the Center for Environmental Health Sciences. In particular, a very large program project that applies genomics approaches to exploring how cells, animals and humans respond to environmental agents was recently awarded. This represents an excellent beginning to launch the reorganization and revitalization of the MIT Center for Environmental Health Sciences.
More information about the Center for Environmental Health Sciences can be found online at http://mit.edu/cehs/.
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 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. Daniel Shannon, Professor of Pediatrics at the Harvard Medical School and Professor of Health Sciences at the Harvard/MIT Division of Health Sciences and Technology, consists of ten voting members plus nine non-voting members from the CRC's program and operating staffs. The committee has reported to the Principal Investigator of the CRC's NIH Grant, Martha Gray, Professor and Co-director of Harvard/MIT Division of Health Sciences and Technology (HST). With the CRC's administrative merger with the Massachusetts General Hospital's CRC, it now reports (for NIH grant purposes) to Dr. James Mongan, Principal Investigator of the joint NIH grant. 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 reports to Dr. William M. Kettyle, the Director of the Medical Department. Members of the CRC participate in the Medical Department's activities; e.g., its Quality Improvement, Pharmacy and Therapeutics, Medical Records, and Safety Committees.
Several years ago the CRC was approached by the General Clinical Research Centers administration of the NIH, which funds this and all other CRC's, and asked to consider becoming a "Network" CRC. This would involve implementing at the MIT CRC some research projects generated at other local CRC's, and, conversely, implementing some of the our projects (e.g. those involving very sick patients) at those other centers. Additionally, the CRC would, where possible, coordinate the activities of the core laboratories, nutrition programs, and nursing programs, with those of other local institutions, in order to increase their efficiency. 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. As a consequence, the CRC has forseveral years been developing 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 twenty-six 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 continue to meet 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.
The relationship between the two GCRCs will continue to be developed and expanded, and the two centers are currently collaborating on a joint NIH renewal grant application, for five years of support, to start funding in December of 2002, when the present MGH NIH grant expires. Meanwhile, since the present MIT grant expires a year earlier (2001), MGH and MIT have jointly submitted an application for one year of funding for the MIT CRC (December 2001 through November 2002) 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 discussions with the NIH, no decrease in funding. Recently, the NIH has notified MIT and MGH that they will fund the one year supplement.
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 CRC's apparently are excellent, and the strengths of each institution complement those of the other. The CRC also continues to "network" with other Boston-area GCRC's (e.g., BIDMC) and all interested parties agree that the CRC should continue to do so in the future.
The MIT CRC provides formal training in clinical investigation to advanced post-doctoral fellows taking a graduate degree (in clinical research) at Harvard Medical School, and to individual post-doctoral (medical) fellows working with CRC principal investigators and other researchers. It also affords opportunities to MIT undergraduate and graduate students to participate in clinical research projects, and will provide, in 2002-003, a formal undergraduate course in clinical investigation (taught by Dr. Ravi Thadhani, an Assistant Program Director). These fellows and students utilize the CRC's facilities to initiate research protocols and participate in ongoing projects supervised by senior investigators and faculty. (See section on the Centers 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 such personnel, by advertising and posting positions in local colleges, universities, medical institutions, and minority organizations, have not generated a significant response.
Of the six Visiting Scientists appointed by the CRC in 2000-2001 three were women and three were minorities. 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, 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), which studies the effects of drugs, foods and hormones on brain composition and behavior, the effects of melatonin on sleep, and a set of diseases characterized by affective and appetitive symptoms (i.e., depression, premenstrual syndrome, smoking withdrawal, carbohydrate craving, obesity), which seem to relate to brain serotonin; and Behavioral Neuroscience (Suzanne Corkin, Professor of Brain and Cognitive Sciences), which focuses 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. However, the scope of the CRC's activities has expanded broadly. In the past year it also supported research protocols involving, for example, toxicology, pediatrics, psychopharmacology, women's health, HIV, biomedical engineering, 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.
During 2000 the CRC patient census totaled 1604 outpatient visits and 54 inpatient days. The CRC branch of the NIH had provided, based on prior year's activities, support for up to 2500 outpatient visits and 253 inpatients. The decreased census could be explained by the completion of the data-gathering portions of several large projects.
Center for Experimental Pharmacology and Therapeutics
The HST Center 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), Osborne Professor of Health Sciences and Technology. Educationally, each year 10 M.D.'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 aqualifying 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 of Management, 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 technologies at MIT, these efforts will be greatly facilitated.
The CRC computer staff has continued to develop the CRC Operations System with the addition of systems for the Core Laboratory and the DEXA facility. These systems use an ORACLE relational database, and support the day-to-day operations of the CRC. The computer staff has also been working with their MGH counterparts to install and test the Turbo software package which will streamline the protocol application process and NIH annual reporting requirement for both CRCs. In addition, considerable time and effort has been spent on updating and improving the CRC website by instituting links to the MIT IRB protocol applications and establishing an interactive format for MIT and MGH investigators to complete their protocol applications on-line.
Researchers continue to make use of the SAS statistical software available on the CRC computer system. They also use resources available on the Internet. In addition, the computer facility provides hardware and software support for the CRC staff and investigators and statistical assistance to all researchers.
Core Laboratory/Mass Spectrometry Facility
The Core Laboratory specializes in assays that directly support the research efforts of CRC investigators and are not readily available commercially. The most important and complex assays are undertaken by the Mass Spectrometry Facility, where stable isotope tracer analyses are performed. The Mass Spectrometry Facility is a shared instrument facility that allows CRC investigators to conduct human metabolic studies using stable nuclide tracers. Principal areas of investigation concern the regulation of energy substrate metabolism in health and disease, and the regulation of whole body amino acid metabolism, with particular reference to the nutritional requirements for indispensable and conditionally indispensable amino acids. Research at the MIT CRC has made important contributions to the further development of national and international dietary standards and the establishment of sound food and nutrition policies and programs. Studies continue to examine the role of dietary arginine as a precursor of the signal transducer nitric oxide. The novel doubly labeled water (2H218O) method is being used to define the energy requirements for adolescent and elderly subjects, and the factors, which affect these needs. These various investigations offer new basic knowledge about the physiology of human energy substrate and amino acid metabolism and, additionally, make practical contributions to problems in human nutrition.
The Core Laboratory also utilizes high performance liquid chromatography (HPLC) techniques. A Beckman System Gold Amino Acid Analyzer HPLC provides resolution of up to 42 physiologic amino acids. Other HPLC assays include tests for choline, tryptophan, the catecholamines, cytidine and melatonin.
Dr. Linda Bandini
Dr. Linda Bandini and her colleagues have continued their 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 body composition and metabolic rate of the girls are measured in addition to their annual measures. As of December 2000, 136 girls had completed the longitudinal study and 20 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 provideinformation 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
Dr. Steven Grinspoon and his colleagues conducted studies to determine the effects of rhIGF-I (a nutritional-dependent anabolic hormone with potent effects on bone formation) and of estrogen on bone density in women with anorexia nervosa.
A fifty percent reduction in bone density is a common manifestation of anorexia nervosa (AN). Over 50 percent 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 mechanism responsible for decreased bone formation in anorexia nervosa, Dr. Grinspoon designed a double-blind randomized, placebocontrolled, trial of rhIGF-I. Short-term studies have shown a significant increase in bone formation in response to rhIGF-I. Recruitment for this study is ongoing and the data investigating specific predictive factors for regional bone loss in AN haverecently 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 over 130 patients with AN that have been screened.
Dr. Richard Wurtman
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 5 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 serotonin, 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's activity as an MAO inhibitor still is not mentioned on its label.
Dr. V. Young
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 to the effects of a sulfur amino acid-free diet on whole blood glutathione (GSH) synthesis, showing that GSH production is regulated by the dietary availability of one of its precursors, cysteine. Studies have also been completed on the kinetics and urinary excretion of L-5-oxyoproline, an intermediate of the gamma-glutamyl cycle of GSH synthesis. Both sulfur amino acid-free and glycine-free diets alter the dynamics of oxoproline metabolism and increase the urinary excretion of this intermediate which may, therefore, serve as a potential probe of the status of GSH metabolism of GSH metabolism in human subjects. Studies have also continued on the kinetic aspects of amino acid metabolism in particular adults. Studies with lysine and threonine as the test amino acids again confirm the hypothesis that the current international requirements values for the indispensable (essential) amino acids in healthy adults are far too low and support that the tentative MIT amino acid requirement pattern is an appropriate one for use in practical considerations of adult human protein and amino acid nutrition. These findings and conclusions have major significance with respect to the planning of diets and an evaluation of diets for their amino acid adequacy worldwide. They also have important implications with respect to the planning of agricultural research programs that are directed toward improving the nutritional quality of foods in humans.
More information about the Clinical Research Center can be found online 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 115 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 division now encompasses approximately 115,000 square feet devoted to animal research activities. In addition a new vivarium is being planned for the new neuroscience complex.
Facility Management and Animal Care
The average daily census of laboratory animals grew approximately six percent during FY2001. 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 a range of transgenic services including in vivo embryo transfer for rederivation of mice with endemic disease which have been imported to MIT from laboratories worldwide, in vitro fertilization, the provision of blastocysts, genotyping of mice and the making of transgenic mice. The division has begun to develop expertise in aquaculture and now provides veterinary support to the Sea Grant Program.
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 study of H. pylori pathogenesis, in vivo study of gastric cancer, and in vivo study of the pathogenesis of colitis. FY2001 was the thirteenth year of the division's 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-four trainees have completed our postdoctoral training program and 22 of them have now passed the board examination of the American College of Laboratory Animal Medicine.
DCM faculty and staff published six chapters, 25 papers and 32 abstracts in FY2001 and presented numerous research papers at national and international meetings. Dr. Fox is the senior editor of the second edition of Laboratory Animal Medicine which will be published in the winter of 2001 by Academic Press.
Dr. Barbara Sheppard earned board certification from the American College of Veterinary Pathologists. Dr. Arlin Rogers joined DCM as the division's second comparative pathologist in March. Dr. Melanie Ihrig was appointed Clinical Veterinarian for the animal resource program. She was formerly a postdoctoral trainee in DCM.
DCM faculty and staff taught two graduate courses in the division of Bioengineering and Environmental Health (BEH.202 and BEH.214).
Committee on Animal Care Activities
The web site for the Committee on Animal Care provides required forms, continuing education material and information on the CAC's activities. DCM staff in conjunction with the Committee on Animal Care has developed an on-line training program. Didactic training sessions for Institute personnel on topics pertaining to the care and use of laboratory animals are also offered. The CAC has also developed an occupational health screen for animal related occupational health issues and periodically sponsors seminars on health issues such as zoonotic diseases. 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.
More information about the Division of Comparative Medicine can be found online at http://web.mit.edu/comp-med/.
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 is 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 when diseases can be treated by "engineering" the phenotype of cells and tissues-when cell, tissue, and body functions can be manipulated using strategies that affect genes, cells, and their environment so they behave predictably. Advances in the diagnosis and prevention of disease are inexorably linked to these fundamental changes in our approach to disease management. Unquestionably, success in this area requires professionals with a broad range of skills that spans 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, conversely, clinical insights from the bedside to the bench. HST's programs are committed to exploring the fundamental principles underlying disease, to seeking new pharmaceuticals and devices that ameliorate human suffering, and to training the next generation of physicians, scientists, and engineers to do the same. Thus, HST trains physicians with a deep understanding of the underlying quantitative and molecular science of medicine and biomedical research. HST Ph.D. students similarly acquire a deep understanding of engineering and the physical and biological sciences. This unique training is complemented with hands-on experience in the clinic or in industry.
HST's administrative home is located at the Whitaker College of Health Sciences and Technology at MIT. As one of the five medical societies at Harvard Medical School, HST also maintains an office at the medical school's quadrangle campus in Boston. HST's two co-directors, Martha L. Gray for MIT and Joseph Bonventre for HMS, report to the provost and the vice president for research at MIT, as well as to the HMS executive dean for academic programs and the dean of HMS. Richard N. Mitchell, Assistant Professor of Pathology at Harvard Medical School, serves as the division's associate director and director of student affairs.
HST currently enrolls approximately 320 students who work with more than 200 faculty and affiliated faculty from the Harvard and MIT communities. Six multidisciplinary graduate degree options are offered, 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:
- Medical Sciences Program (M.D.)
- Medical Engineering and Medical Physics Program (MEMP)
- Speech and Hearing Sciences Doctoral Program (SHSP)
- Radiological Sciences Joint Program (RSJP)
- Medical Informatics Program (MI)
- Clinical Investigator Training Program (CITP)
HST's research programs involving its students, faculty, and staff reflect the mixing of cultures in applying the tools of medicine, engineering, and science to problems in human health and clinical medicine. Current research initiatives are conducted in these areas:
- Biomedical Engineering
- Functional and Structural Biomedical Imaging
- Informatics and Computational Biomedical Sciences
- Clinical Research
- Speech and Hearing Sciences
The VaNTH Engineering Research Center for Bioengineering Educational Technologies is a consortium of Vanderbilt University, Northwestern University, University of Texas at Austin, and HST. It is one of 24 engineering research centers (ERCs) funded by the National Science Foundation. The ERCs are charged with providing an integrated environment for academe and industry to focus on next-generation advances in complex engineered systems important for the nation's future. Unique among the ERCs, the VaNTH ERC focuses on the educational enterprise. Its mission is to develop the tools, curricula, and technologies that will educate future generations of bioengineers. Faculty and researchers in the VaNTH ERC are developing challenged-based learning modules that teach bioengineering content and provide an opportunity for the learner to explore the inter-connections and relationships of the selected concepts. Using the learning sciences philosophy articulated in How People Learn (Bransford, Brown, and Cocking, 2000), each bioengineering module is constructed to be knowledge-center, learner-centered, assessment-centered, and community-centered. All on equal footing, VaNTH focuses on four research thrusts: the bioengineering domain, learning sciences, learning technology, and evaluation and assessment. Through its educational thrust, VaNTH stresses involvement in research and educational outreach program.
BioMATRIX, a new mentoring and advising program sponsored by HST, was launched in February 2001. The program is aimed at individuals with common interests in the biological and medical sciences and engineering. Headed by HST affiliated faculty David A. Roth (M.D. '87), its goal is to foster meaningful mentoring relationships among undergraduate students, graduate students, and practitioners who include HST faculty and staff. Funded by the Alex and Brit d'Arbeloff Fund for Excellence in MIT Education, BioMATRIX is an acronym for bio/medical science and biomedical engineering, MIT mentoring, advising and tutoring in real-life issues extended over time. BioMATRIX is not intended to replace traditional academic advising, but rather to be a means of giving students the broadest possible set of contacts with basic and clinical research scientists, academic physicians, clinicians, health economists and health policy faculty, and biologists in both academia and industry. Mentors and students are introduced via faculty profiles posted on the BioMATRIX web site. Meetings are then arranged between faculty and students with common interests, ideally in the setting of the hospital or laboratory. Since its inception, BioMATRIX has held several on-campus events, and it enjoys close ties with the undergraduate dean's office at MIT.
Highlights of the Year
The opening of the MGH/MIT/HMS Athinoula A. Martinos Center for Functional and Structural Biomedical Imaging was celebrated on November 3, 2000, at the MGH-East NMR facility in Charlestown, the center's temporary home. HST established this state-of-the-art imaging center to foster biomedical imaging research that spans scientific disciplines from basic research to clinical investigation, and to develop medical applications for these new technologies. This new biomedical imaging center, made possible through the generosity of Marina and Thanassis Martinos, is a partnership between the HST and MGH. Its mission is to build the build the next generation of functional imaging tools; and to apply these tools to biologically, neurologically, and clinically relevant problems; to train physical, biological, and clinical scientists; and to provide a hub for interdisciplinary collaborations between MIT, Harvard, and other institutions worldwide. Facilities include low- and high-field MRI for human and animal imaging. Systems-level imaging, high-field human MRI, high-spatial and temporal functional mapping of the brain and heart, optical imaging and pharmacological imaging are some initial research areas under investigation.
In fall of 2000, the HST student body ratified the constitution of the HST Student Council, making the HST student government the students ' official representative body. The newly formed HST student government aims to foster a sense of community within the diverse HST student body and to provide a transparent and efficient mode of student representation within and outside of HST. It consists of an M.D. Council, a Ph.D. Council, and a Joint Student Council. While the M.D. and Ph.D. councils address matters pertaining to their respective HST educational branches, the Joint Student Council addresses issues of concern to all students. Council leadership works closely with the HST administration. Elected student officials sit on HST, MIT, and HMS committees to ensure student input into almost all aspects of the HST experience.
The first meeting of HST's new advisory council was held in November 2000. The council was created to assist HST in achieving its strategic goals as well as to enhance the impact of the division's activities, forge new relationships, and identify potential sources of support. Joseph Ciffolillo, retired COO of Boston Scientific Corporation, Inc., and BSC's current director, serves as chair of the council.
Greg Koski (Ph.D. '77, M.D. '78) delivered the keynote address at HST's commencement exercises on June 6, 2001. Koski was appointed in June 2000 as the first director of the Office of Human Research Protections, a new office within the Department of Health and Human Services that leads efforts to protect human subjects in biomedical and behavioral research. Fourteen students graduated with Ph.D. degrees; twenty-nine students received the M.D. degree, six students received M.D. and Ph.D. degrees, and eight students received the S.M. degree. Special recognition also went to three students who graduated cum laude and three who were recognized with magna cum laude.
The 14th annual HST Forum was celebrated on March 11 at The Westin Hotel, Copley Square, Boston. This year's forum marked the 20th anniversary of HST's first graduating class in Medical Engineering/Medical Physics (MEMP). Preceding the forum events, an HST alumnae professional development workshop featured a talk by Dr. Joyce K. Fletcher, Professor of Management at Simmons College Graduate School of Management. An alumni panel that discussed "There is Life After MEMP," was led by Deborah Burstein (Ph.D. '86), Associate Professor of Radiology at Harvard Medical School/Beth Israel Deaconess Medical Center and current MEMP student Mark D. Price. Panelists Dr. Edward Cheal (Ph.D. '86) Managing Director of Apex Surgical LLC, Lakeville, MA; Dr. Catherine M. Ford (Ph.D. '96), Managing Engineer at Exponent Failure Analysis Associates, Inc., Philadelphia, PA; Dr. Cynthia Sung (Ph.D. '88) head of the Pharmacokinetics Group at Human Genome Services, Inc., Rockville, M.D.; and Dr. Mehmet Toner (Ph.D. '89), Associate Professor of Surgery and Bioengineering at HMS/MGH made brief presentations describing their lives after graduation.
On March 12 and 13, HST presented a hands-on learning experience for participants in its symposium Experiencing the Frontiers of Biomedical Technology. This unique symposium brought together a diverse group of clinicians, biotech workers, lawyers, venture capitalists, and science reporters to explore techniques used in state-of-the-art biomedical technologies and to see what it takes for these techniques to have an impact on healthcare delivery. Hands-on workshops introduced participants to tissue engineering, drug delivery systems, human-machine systems, and informatics. Interactive discussions also addressed regulatory and legal issues related to biotechnology research. A plenary session, held on day two, summarized the results uncovered by the workshop's participants. Leaders in the field also discussed the art and science of biotechnology research and the outlook for possible innovations. In a talk on drug delivery systems, Dr. Robert S. Langer, the Germeshausen Professor of Chemical and Biomedical Engineering, detailed the many challenges faced by the researchers who successfully developed a chemotherapy wafer for brain cancer treatment. Addressing the future of tissue engineering, Dr. Mehmet Toner, a faculty member in HST, Harvard Medical School, and Massachusetts General Hospital, told the audience that innovations hinge on the development of a groundbreaking therapy, possibly in the area of replacement tissue for the liver or in bone. Faculty members Dr. Emilio Bizzi and Dr. George M. Church addressed the state of biotechnology in human-machine systems and in informatics, respectively. Because of the overwhelming response, plans are underway for a second symposium in March 2002. Symposium director, Dr. Elazer Edelman, will expand the range of workshops and vary the format to enable participants to attend more than one workshop.
During 2000-2001, HST encouraged the development of regional alumni chapters in Boston and New York City. New York's meeting in April was well attended and included a talk by HST alumnus David D. Ho, (M.D. '78), director and CEO of the Aaron Diamond Research Center. Additional chapters are planned for Washington, DC, Baltimore, and San Francisco.
A five-day conference to explore the characteristics and challenges of medical care in China and the US was held at MIT in June 2001. Health Care East and West, Moving into the 21st Century was a significant event that will strengthen the relationships between the two countries through improved understanding, professional relationships, and collaborations. HST was well represented at the conference as Nelson Y.-S. Kiang, the Eaton-Peabody Professor Emeritus of HST, chaired the conference. HST co-director Martha L. Gray (Ph.D. '86) served on the conference program committee and delivered a talk on the next generation of medical investigators and how HST has pioneered medical education for physician-scientists. Co-director Joseph V. Bonventre served on the organizing committee. Many HST faculty and affiliated faculty not only served on various planning committees, but also participated in panel discussions and session leaders. HST students also served as conference ambassadors.
Several new courses were added during the academic year 2000-2001 to enhance HST's curriculum. They include: HST.502 Survival Skills for Emerging Researchers: Responsible Conduct of Research; HST.505 Laboratory in Molecular and Cellular Sciences; HST.515J Aerospace Biomedical and Life Support Engineering; HST.588 Biomaterials and Tissue Engineering in Medical Devices and Artificial Organ; HST.935 Narrative Ethics: Literary Texts and Moral Issues in Medicine; and HST.960 Creative Writing for Physicians.
The following HST students and graduates were award recipients in the last year:
- Alexandre R. Carter, seventh-year M.D.-Ph.D. student—National Medical Association's 2000-2001 Award for Medical Journalism, recognizing journalistic excellence and overall academic achievement and leadership.
- Jason L. Gaglia, M.D., magna cum laude—Harvard Medical School's Leon Reznick Memorial Prize.
- Neil S. Ghiso, M.D.—NBI Humanism in Medicine Award, given to a graduating student who consistently demonstrates compassion and empathy in the delivery of care to patients.
- Thomas Heldt, fourth-year Medical Engineering/Medical Physics student—MIT's Hugh Hampton Young Memorial Fund Fellowship, which recognizes broad interdisciplinary interests, strong character, and leadership skills.
- Diego E. Marra, M.D., magna cum laude—Harvard Medical School's James Tolbert Shipley Prize, awarded for research carried out by a medical student, the results of which have been published or accepted for publication.
- Eric M. Morrow, M.D., magna cum laude—Harvard Medical School's Harold Lamport Biomedical Research Prize for the best paper reporting original research in the biomedical sciences.
- David O 'Gorman, Speech and Hearing Sciences student—MIT's Poitras Predoctoral Fellowship for biomedical engineering and/or biophysics research.
- Shunmugavelu D. Sokka, fifth-year Medical Engineering/Medical Physics student—MIT's William L. Stewart, Jr., Award, presented to students who have made outstanding contributions to co-curricular activities and events at MIT.
- Ryuji Suzuki, first-year Medical Engineering/Medical Physics student—Howard Hughes Medical Institute predoctoral fellowship in neuroscience and physiology.
- Xun Clare Zhou, M.D.—Harvard Medical School's Multiculturalism and Diversity Award given to students who have done the most to exemplify and/or promote the spirit and practice of multiculturalism and diversity at HMS.
Faculty Honors and Awards
- Louis D. Braida, Warren Professor of Electrical Engineering and Director, HST Speech and Hearing Sciences Program—co-recipient of HST's Thomas A. McMahon Mentoring Award, presented to a faculty member who not only provides scientific guidance to students, but also inspires personal growth.
- Bertrand Delgutte, HST affiliated faculty and principal research scientist in MIT's Research Laboratory of Electronics—HST's John F. and Virginia B. Taplin Award to develop laboratory exercises in neural modeling for HST's Speech and Hearing Sciences program.
- Lee Gehrke, Professor of Health Sciences and Technology—mentoring award from the Biological and Biomedical Sciences Ph.D. Program at Harvard University.
- Martha L. Gray, HST co-director and the Edward Hood Taplin Professor of Medical and Electrical Engineering at MIT—elected to board of directors of the National Space Biomedical Research Institute.
- W. Eric L. Grimson, HST affiliated faculty and professor in MIT Department of Electrical Engineering and Computer Science—MIT Bose Award for Excellence in Teaching, recognizing faculty in the School of Engineering for outstanding contributions to undergraduate education.
- Donald E. Ingber, HST affiliated faculty and HMS professor of pathology—HST's John F. and Virginia B. Taplin Award to work on creating a new biocomplexity initiative in HST. Also chosen as the Mayo Clinic's Distinguished Lecturer in Medicine for 2001.
- Isaac S. Kohane, director of HST's Program in Bioinformatics and Functional Genomics and HMS associate professor of pediatrics, and Gregory Stephanopoulos, HST affiliated faculty and MIT professor of chemical engineering, received an HST John F. and Virginia B. Taplin Award to develop a multi-institutional, HST-based training grant in functional genomics and bioinformatics.
- Roger G. Mark, Distinguished Professor of Health Sciences and Technology—MIT's Frank E. Perkins Award for excellence I graduate advising and mentoring. Also co-recipient of HST's Thomas A. McMahon Mentoring Award, presented to an HST faculty member who not only provides scientific guidance to students, but also inspires personal growth.
- Richard N. Mitchell, Associate Director (Master) of HST at HMS and HMS associate professor of pathology—HMS Faculty Prize for Excellence in Teaching, recognizing exemplary teaching in either HMS' preclinical or clinical curricula.
- Lucila Ohno-Machado, HST affiliated faculty and HMS assistant professor of radiology—HST's John F. and Virginia B. Taplin Award to build an HST curriculum in biomedical informatics.
- Valerie Pronio-Stelluto, HST affiliated faculty and HMS instructor in medicine—co-recipient of HST's Irving M. London Teaching Award, which recognizes teaching faculty who have made outstanding contributions to the training of HST students.
- Shiv S. Pillai, HST affiliated faculty and HMS assistant professor of medicine—co-recipient of HST's Irving M. London Teaching Award, which recognizes teaching faculty who have made outstanding contributions to the training of HST students.
- Jeffrey P. Sutton, HST affiliated faculty and HMS associate professor of psychiatry—named team leader of new Smart Medical Systems Team of the National Space Biomedical Research Institute.
- Steven E. Weinberger, HST affiliated faculty and HMS professor of medicine—HMS 2001 Class Day Preclinical Teaching Prize.
The research of the HST core faculty and research staff covers a wide spectrum of biomedical areas. In addition to laboratories at HST, MIT, Harvard University, and the Harvard Medical School, research collaborations include several HMS teaching hospitals in the Boston area (including Massachusetts General Hospital, Brigham and Women's Hospital, Beth-Israel Deaconess Medical Center, Dana Farber Cancer Institute, and Children's Hospital).
The objective of HST's effort in biomedical engineering is cost-effective replacement of cell, tissue, and organ function. Toward this end, HST researchers apply the rigors of physical sciences to problems in medicine and biology. In particular, this work seeks to understand, harness, and engineer tissues, cells, and molecules. A principle site of this effort is the Harvard-MIT Biomedical Engineering Center, located on the MIT campus. There, seven resident faculty members supervise a scientific staff of 90. An additional 70 affiliated faculty at MIT and HMS use the center's extensive facilities and resources, which support work in a broad range of integrated sciences from molecular and cell biology to animal physiology.
Elazer R. Edelman (HST '83) is the Thomas D. and Virginia W. Cabot Associate Professor of HST and Director of the Harvard-MIT Biomedical Engineering Center. Professor Edelman and colleagues in his laboratory use elements of continuum mechanics, digital signal processing, molecular biology, and polymeric controlled release technology to examine the cellular and molecular mechanisms that transform stable coronary-artery disease to unstable coronary syndromes. Tissue-generated cells, for example, deliver growth factors and growth inhibitors for the study and potential treatment of accelerated arterial disease following angioplasty and bypass surgery. The laboratory holds patents for drug-delivery devices, tissue-engineered implants, and new drug formulations.
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. Fluorescence, reflectance, near-IR Raman, light-scattering spectroscopy, and low-coherence interferometry are being used for histological and biochemical analysis of tissues, diagnosis and imaging of disease, and cell biology applications. Clinical studies are conducted with researchers from the Cleveland Clinic Foundation, Medical University of South Carolina, Brigham and Women's Hospital, Metrowest Hospital, Beth Israel Hospital and New England Medical Center. Clinical studies using trimodal spectroscopy, the combined application of intrinsic fluorescence, diffuse reflectance, and light-scattering spectroscopies, have demonstrated successful diagnosis of dysplasia in Barrett's esophagus, the urinary bladder, adenomatous polyps, the oral cavity and the uterine cervix. Light-scattering spectroscopy was used to measure and image subcellular structures much smaller than an optical wavelength. Novel low-coherence interferometry techniques, which use two harmonically related wavelengths to measure optical phase, have been developed. Exceedingly small refractive index and length changes, tomographically mapped, were used to study structure and dynamics of cellular organelles. Raman spectroscopy was used to measure blood analytes with clinical accuracy and identify morphology of breast lesions. The experimental and theoretical work of this program is advancing new laser diagnostic technologies in the fields of medicine and cell biology.
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, Distinguished Professor of Health Sciences and Technology, together with colleagues at Beth Israel-Deaconess Medical Center, Boston University, and McGill University, continue to develop 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 (http://www.physionet.org). Professor Mark's 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.
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. Ongoing investigations are focusing on cell-extracellular matrix interactions in the mechanisms of native heart valve degeneration and as determinants of the structure-function-quality correlations in heart valves fabricated by tissue engineering methods.
Martin L. Yarmush and colleagues are contributing to several fields, including tissue engineering, gene therapy and nucleic acid biotechnology, genomic and proteomic technology, and metabolic engineering. Professors Yarmush, Mehmet Toner, and Ronald G. Tompkins are collaborating on one of the world's leading programs to establish a liver support device using hepatocytes and microfabrication techniques. In addition, in the area of tissue engineering, Professors Jeffrey R. 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 laboratory, together with those of Professors Morgan and Arul Jayaraman, are investigating rate-limiting aspects of gene therapy and antisense therapy. Professors Yarmush, Toner, Morgan, and Jayaraman are also collaborating on a new platform for monitoring real-time gene expression using a living cell microarray, which can provide minute-by-minute information in a massively parallel format. 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.
MIT is one of the seven original institutions participating in the National Space Biomedical Research Institute (NSBRI), the primary agency for NASA-sponsored space biomedical research. Under the direction of Professor Laurence R. Young, the NSBRI has nearly doubled in size, expanding the number of consortium members from seven to twelve, and the number of research teams from eight to twelve. In his role as an NSBRI investigator, Professor Young is 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 (Professors Young and Dava Newman and Dr. Charles Oman). Professor Young has also worked successfully with NSBRI and HST toward developing a new graduate program in space life sciences. His translation of Ernst Mach's Fundamentals of the Theory of Movement Perception will appear in fall 2001.
James C. Weaver, HST Senior Research Scientist, and his research group, have completed the initial development of a computer simulation method to transport molecules, heat, and electricity in multicellular biological systems, with potential applications in transdermal drug delivery and in understanding the response of human tissue to electromagnetic fields.
Lisa E. Freed, HST Principal Research Scientist, 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, three-dimensional scaffolds, and bioreactors to engineer functional skeletal and cardiovascular tissues. The goals are to improve basic understanding of tissue development through controlled in vitro studies and to generate clinically useful tissue equivalents. She also participated in teaching HST.588 Biomaterials and Tissue Engineering in Medical Devices and Artificial Organs.
Chi-Sang Poon, HST Principal Research Scientist, was co-organizer (with HST affiliated faculty Dr. Homayoun Kazemi at Harvard Medical School) of the international Conference on "Frontiers in Modeling and Control of Breathing," held on October 11-15, 2000 in North Falmouth, Massachusetts. Jointly sponsored by the Whitaker Foundation, the American Physiological Society, the Physiology Society in the UK and other sources, this triennial event extends an acclaimed tradition that began at Oxford University more than two decades ago. Drs. Poon and Kazemi were also co-editors for a pre-conference special issue of the journal Respiration Physiology on a similar topic, and a post-conference book published by Kluwer Scientific/Plenum Publishers based on the conference proceedings. In a paper published in the Proceedings of the National Academy of Science, Dr. Poon and a former associate introduced a novel numerical titration technique, whereby the intensity of chaos can be measured by its so-called titration strength against added noise. This finding confirmed their previous findings that subtle heart-rate variabilities are not simply random fluctuations, but are complex yet deterministic patterns that are probably chaotic. This technique may find wide applications, including the identification and control of cardiac arrhythmia, epileptic seizures, or other biomedical variables.
Gordana Vunjak-Novakovic, HST Principal Research Scientist and Adjunct Professor of Chemical Engineering at Tufts University, is supervising research teams working on tissue engineering of skeletal and cardiac tissues, and biological research in space. Her research interests include tissue engineering, bioreactors, and transport phenomena in living systems, and in particular the integrated use of cells, biomaterials and bioreactors in quantitative studies of cell function and tissue development. She is serving as the science lead of the design and testing of the cell culture system for the International Space Station. Her teaching responsibilities include Biomaterials and Tissue Engineering for Medical Devices (HST.588, course co-director), Quantitative Physiology of Cells and Tissues (6.021J, recitation instructor), and Biomaterials and Tissue Engineering (ChE 164 at Tufts University, lecturer).
Functional and Structural Biomedical Imaging
Biomedical imaging is a relatively young field that enables physicians and scientists to "see" and better understand tissue and organ function. It provides investigators with the ability to visualize the structure of tissues and to capture their function on film. One type of biomedical imaging is magnetic resonance imaging (MRI), also known as nuclear magnetic resonance (NMR). Using electromagnetic fields and radio waves to read minute shifts in the magnetic alignment of protons in soft tissue such as the brain, it involves the collaboration of engineers, computer scientists, neuroscientists, and physicians. An important advance called functional MRI (fMRI) shows how living tissues are functioning in real time. For example, fMRI can make a 100-millisecond scan every few seconds to detect variations in regional blood flow within the brain to signal sight, hearing, thinking, or feeling. Combining many fMRI scans makes a real-time "movie" of functioning organs, a technique that has been especially useful in cognitive neuroscience and psychology.
Emery N. Brown devotes his research to statistical modeling of problems in neuroscience. Working jointly with colleagues in MIT's Brain and Cognitive Sciences Department, he is 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 is 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 statistical models to measure precisely the period of the human biological clock and to characterize the properties of circadian and neuroendocrine rhythms.
Martha L. Gray (HST '86), HST co-director, and collaborator Deborah Burstein (HST '86) use magnetic resonance to measure the composition and functional integrity of cartilage. Over the last century, little progress has been made in developing effective preventative and therapeutic strategies for arthritis, other than total joint replacement. among the challenges limiting progress has been the fact that there were no nondestructive means to visualize cartilage. Pioneering work by this team has yielded a clinically feasible method that is now employed in pilot studies. Work with Genzyme's Carticel(tm) product revealed an apparent improvement by 18 months after surgery. An evaluation of dysplastic hips revealed composition correlates with pain. These are examples of information that were previously unavailable. Clinicians and researchers have had to struggle to understand and treat diseases they could not 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 demonstrate nondestructively 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 R. Rosen (HST '84) is director of the NMR Center at the Massachusetts General Hospital and the new Athinoula A. Martinos Center for Functional and Structural Biomedical Imaging. 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 being used by hospitals throughout the world to evaluate 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 signals using magnetoencephalography (MEG) and noninvasive optical imaging.
One of the most visible arenas in which the bench-to-bedside transfer is a two-way bridge is therapeutics. Drugs and therapies not only treat disease by serving as probes, but they also can provide important insights into disease mechanisms and offer diagnostic opportunities. Many HST investigators are involved in clinical human studies at some point in their research. The opportunities available through MIT's Clinical Research Center, the Harvard Medical School teaching hospitals, and the Clinical Investigator Training Program, significantly enhance HST's research and educational programs, further enabling translational efforts from bench to bedside.
Robert H. Rubin, the Gordon and Marjorie Osborne Associate Professor of HST, 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 and assumed the position of editor-in-chief of the journal, Transplant Infectious Disease. As director of HST's Center for Experimental Pharmacology and Therapeutics, Professor Rubin has pioneered 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. In addition to his other responsibilities, Dr. Rubin is associate director of the Division of Infectious Diseases at the Brigham and Women's Hospital, charged with the responsibility of directing the clinical service and the clinical research program.
Professors Rubin and Alan C. Moses head the 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 MMSc degree in clinical investigation from HST.
Richard J. Wurtman, program director of MIT's Clinical Research Center, also conducts research into 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) produced normally in all cells. Hence, a major goal of researchers working 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"). Professor Wurtman's laboratory has 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 the particular neurotransmitters and "second messengers" they generate. Thus, by 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 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.
With medicine and biology undergoing a fundamental shift, new approaches to engineering, mathematics, and computer science will have to be developed concurrently with genetics and molecular cell biology. Existing scientific disciplines will have to give way to increased communication and collaboration. Scientists typically found only in the engineering, physics, materials science, or mathematics departments will need to become immersed in the biomedical community. In turn, the biomedical community will need to transform itself into a nurturing environment for physical scientists. Through the success of the Human Genome Project, functional genomics, proteomics, and chemical microanalysis, an almost inconceivable amount of data is being generated that is related to individual molecular components comprising living cells and tissues. At the same time, the application of live cell imaging techniques, engineering approaches, and microfabrication are leading us to recognize the importance of spatial position, structure, and mechanics for cell regulation. The scientific challenge is to understand biological complexity: how life and cellular function emerge from the interactions of these different components. HST's work in this area is to develop entirely new analytical tools and computational models needed to describe the nonlinear emergent behavior of complex biological systems.
Joseph V. Bonventre (HST '76), HST 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, KIM-1, 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. This molecule is shed from the cell membrane, and it appears in the urine of patients with kidney injury at an early stage of the disease process. Using PCR-based subtraction techniques and bioinformatics, a many 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. Bone marrow derived stem cells have differentiated to epithelial cells replacing injured kidney cells. Approaches are being explored to facilitate this process and potentially regenerate the tubular epithelium and restore function to a failing kidney. 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 associates 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.
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 active clinical testing of these agents are underway. His lab has also demonstrated that hematopoietic stem cells develop from pluripotent embryonic stem (ES) cells that are differentiated in culture, an important step towards using ES cells for cellular therapies.
Lee Gehrke, Professor of Health Sciences and Technology, studies the replication and assembly of viruses that use RNA as their genetic material. Important 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.
Richard N. Mitchell, HST's associate director, researches the mechanisms underlying acute and chronic rejection in solid organ allografts, with specific emphasis on heart transplants. His 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 Mitchell's laboratory uses several genetically engineered mice (so-called "knock-out" mice), which are either deficient in cell surface molecules that promote the cellular cross-talk necessary to promote rejection, or which lack particular "cytokine" mediators or their receptors. In collaboration with other members of the HST community, such as Professors 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 several pharmaceutical firms such as Schering-Plough, Bristol Myers-Squibb, and Novartis.
Jane-Jane Chen, HST Principal Research Scientist, studies the regulation of hemoglobin synthesis and erythropoiesis by the heme-regulated eIF-2 alpha kinase (HRI). Her group has knockout the HRI gene in mice, and established that HRI, which is expressed predominantly in erythroid cells, regulates the synthesis of both a and b globins in red blood cell precursors by inhibiting the general translation initiation factor eIF2. This inhibition occurs when the intracellular concentration of heme declines, thereby preventing the precipitation of excess globin polypeptides. In iron deficient HRI-/- mice, globins devoid of heme aggregated within erythrocyte and its precursors, resulting in a hyperchromic, normocytic anemia with decreased red blood cell count, compensatory erythroid hyperplasia and accelerated apoptosis in the bone marrow and spleen. Thus, HRI is a physiological regulator of gene expression and cell survival in the erythroid lineage. These data have significance for further understanding the physiological role of HRI in the production of not only hemoglobin, but also red blood cells upon stress.
Informatics and Computational Biomedical Sciences
Knowledge discovery and its dissemination in health care have been deeply influenced by recent advances in computer science and engineering. Medical and biological informatics 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 that 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 data sets, 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 A. Greenes, director of HST's 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 a 37-year history of work in the area of medical informatics. The DSG lab, which includes physicians, computer scientists, database experts, and specialists in graphics and educational technology, has a major focus on developing means to enhance decision support and education in medicine and for integrating these capabilities into clinical practice. Primary technologies involve knowledge representation, machine learning, decision science, and information retrieval. The DSG is also is working in the area of bioinformatics, particularly in the development and application of machine learning, classification, and prediction methods, for analysis of DNA microarray data, and of flow cytometry data characterizing cellular proteins.
Isaac S. Kohane, director of HST's Program in Bioinformatics and Functional Genomics, is involved in leading multiple collaborators in bioinformatics as well as tumorigenesis, neurodevelopment, neuroendocrinology, and transplantation biology. He also created the World Wide Web Electronic Medical Record System (W3-EMRS), which has served as the foundation for several multi-institutional implementations and collaborations.
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 decisions that are more informed. 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 Sciences
In a world with increasingly complex societal interaction, there is an imperative need to understand how humans communicate, and what can be done to assist those with impaired abilities to produce speech or to perceive auditory signals. HST's Speech and Hearing Sciences research focuses on the biological and physical mechanisms underlying human communication by spoken language. The processes addressed by these sciences include the physical acoustics of sound and the perceptual and neurophysiological bases of hearing, as well as the cognitive and linguistic levels of processing by talkers and listeners. This research and its application to human needs is inherently an interdisciplinary activity.
Understanding the process of receiving and translating speech sounds has been the focus of several HST researchers, including Dennis M. Freeman. Via a bundle of microscopic hairs, sensory cells in the inner-ear sense sound-induced motions of inner-ear structures, which trigger neural messages that relay information about sound to the brain. Professor Freeman and his colleagues have measured the motions of a lizard's inner-ear sensory cells in response to sound stimulation. They have also measured mechanical properties of the tectorial membrane, an essential tissue that mechanically stimulates hair cells. In this work, they have obtained the first quantitative measurements of the bulk modulus, fixed charge concentration, and point impedance of the tectorial membrane. In their related microelectromechanical systems (MEMS) work, his group developed a Mirau interferometric imaging system to characterize MEMS motions and used it to measure dynamic profiles of flexible MEMS (optical gratings). This dynamic profilometer for MEMS is likely to have important applications in many MEMS labs. In the area of synthetic aperture optics, in addition to building a 50-beam synthetic aperture light projector using 488 nm light, his group also built a surface-acoustic-wave (SAW) light modulator and used it to break a single incident beam at 193 nm into hundreds of output beams with controlled amplitudes and phases. The SAW optical modulator is likely to have wide application as a general light modulator.
M. Charles Liberman, director of the Eaton-Peabody Laboratory at the Massachusetts Eye and Ear Infirmary, 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.
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 by measuring the function and structure in normal and pathological ears. On the order of one percent of the human population suffers from some form of chronic middle-ear disease, and thousands of surgeries are performed annually at the Massachusetts Eye and Ear Infirmary alone to control these diseases and restore hearing. The Wallace unit is investigating the clinical utility of laser-Doppler measurements of sound-induced middle-ear velocity in patients and human subjects in order to diagnose middle-ear disease and evaluate 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 be determined by this procedure.
Bertrand Delgutte and his colleagues seek to understand the neural mechanisms for perception of sounds. In the past year, Martin McKinney (a graduate student in HST's Speech and Hearing Sciences program) and Dr. Delgutte focused on how auditory neurons respond to musical sounds. The universality of many aspects of music, such as octave relationships and the use of dissonance and consonance to create harmonic tension and resolution, suggests that they may have fundamental neurophysiological bases. Thus, music provides a natural set of stimuli and associated percepts with which the auditory system can be studied. They found that most neurons in the auditory midbrain respond preferentially to pairs of tones forming dissonant musical intervals (such as a minor second) than to pairs of tones forming consonant intervals such as a fifth or a fourth. Their findings show that percepts generally considered cognitive, such as the dissonance of musical intervals, have direct correlates in the responses of auditory neurons. In general, a better understanding of how the auditory system processes musical sounds may help design hearing aids and cochlear implants that would improve the quality of life of the hearing-impaired by providing them with a more enjoyable musical experience.
HST's cardiopulmonary research is dedicated to developing innovative diagnostic and therapeutic technologies and medications that will have an impact on clinical care within a ten-year period. Traditionally, academic institutions have focused on long-term basic research, whereas the research efforts of pharmaceutical companies, as well device and equipment manufacturers, have focused on development. HST's cardiopulmonary investigations focus on novel ideas that bridge this gap between basic research and applied development. In order to achieve translational research and to train new investigators in this field, HST builds on its strong ties to academic and clinical laboratories, including the Boston Heart Foundation, and develops new ties with industry. In cooperation with these partners, HST's cardiopulmonary effort will be able to provide products designed for a patient's specific phenotype when developing new technologies and drugs.
The laboratory of Richard J. Cohen (HST '76), Whitaker Professor of Biomedical Engineering, is involved in the development of cardiovascular diagnostic and therapeutic technologies. One of the technologies developed in his laboratory is the noninvasive measurement of microvolt level fluctuations in electrocardiographic signals to identify individuals at risk for sudden cardiac death from heart rhythm disturbances. This technology, called the measurement of microvolt T-wave alternans, has been commercialized by a company that Dr. Cohen helped found--Cambridge Heart, Inc. This past year, the technology has been successfully tested in a wide range of international clinical trials and is currently being introduced into widespread clinical practice. Under sponsorship of the National Space Biomedical Research Institute, Dr. Cohen is using this technology to determine whether long duration space flight increases the risk of life threatening heart rhythm disturbances. Dr. Cohen's laboratory was also involved in demonstrating the effectiveness of a new pharmacologic countermeasure to another adverse effect of space flight on the cardiovascular system. After long duration space flight, astronauts develop orthostatic hypotension; meaning that their blood pressure drops when they attempt to sit or stand. This effect may be so severe as to cause syncope or fainting. Dr. Cohen's laboratory collaborated in studies demonstrating that a single oral dose of the sympathetic alpha-agonist midodrine taken at the end of simulated space flight is effective in markedly reducing the development of orthostatic hypotension. Plans to test this drug in astronauts are in progress.
Robert S. Lees, Professor of Health Sciences and Technology, and his colleagues have devised a noninvasive method for assessing atherosclerosis in the abdominal aorta, the site where the disease begins and where it 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 several methods they have developed and brought into the clinic during their thirty years of cardiovascular imaging and diagnostic research at MIT.
Daniel C. 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). Dr. 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 serve patients better.
HST was awarded an NIH grant to fund a new predoctoral training program in life sciences and genomics disciplines. The program's new doctoral track will train a new generation of quantitative scientists who are expert in the biology, engineering, and information science of genomics. The program will be launched in spring 2002 with the admission of three students. Seven students will be admitted annually thereafter. It will function under the auspices of HST's Medical Engineering and Medical Physics program, sharing structural elements such as: simultaneous admission to HST and to a collaborating MIT department; participation in preclinical subjects at HMS; the opportunity to participate in clinical subjects; a seminar series; access to laboratories at MIT, Harvard, the Harvard teaching hospitals; and a community of student peers with shared interests in the intersection of the biological and computational-engineering sciences.
Medical innovations gleaned through laboratory research and clinical care can only have societal benefit when translated into commercial products and services. Yet, leaders in industry rarely bring together the three disciplines of medicine, science-engineering, and business. HST is working with MIT's Sloan School of Management to develop a program that will prepare an extraordinary group of students to lead the development of new technologies from concept through product development to clinical adoption. The two-year program is being designed for students with both business experience and a strong grounding in quantitative science. The curriculum will leverage the unique strength of both HST and Sloan. Students will take preclinical and engineering courses alongside HST M.D. and Ph.D. students, and Sloan business courses with other MOT and MBA students. Courses designed specifically for this program by HST and Sloan faculty will address the particular challenges and issues involved with the commercialization of health care products. HST and Sloan plan to offer this program beginning in the fall of 2002.
HST and MIT's Division of Bioengineering and Environmental Health (BEH) are working to broaden the program leading to a Master of Engineering in Biomedical Engineering (MEBE). Designed to further the education of MIT undergraduates at the interface of engineering and biology or medicine, the MEBE program was created in response to the growing interest in the fields of bioengineering and medical engineering. Through the MEBE program, HST and BEH seek to educate and prepare students for leadership positions in the medical products, pharmaceutical, and biotech industries. The current bioengineering track (BE), which emphasizes the unification of engineering and biology, was introduced in September 2000, under the auspices of BEH. A new medical engineering track (ME), which will emphasize applications of engineering in systems physiology, biomedicine, and health sciences will be launched in fall 2002 under the auspices of HST.
The MGH/MIT/HMS Athinoula A. Martinos Center for Functional and Structural Biomedical Imaging is a paradigm for this growth. A survey course of functional imaging techniques, offered in the fall 2001, will be open to students in HST, other MIT and Harvard departments, and students of investigators conducting research at the center. In addition to its powerful magnetic resonance facilities, the installation of a 306-channel magnetoencephalography (MEG) system is underway. Plans are underway to bring position emission tomography (PET) imaging capabilities to the center.
HST's charter membership in the National Space Biomedical Research Institute (NSBRI) has brought considerable money to MIT and has served as a focus for research in manned space flight. The membership of the NSBRI has grown beyond the initial charter group of HST, Johns Hopkins University, Baylor College of Medicine, Rice University, Morehouse School of Medicine, and Texas A&M University to include the University of Washington, University of Arkansas for Medical Sciences, Brookhaven National Laboratory, University of Pennsylvania Health System, and the Mount Sinai School of Medicine. The number of research teams has also been expanded from eight to twelve. HST faculty represents a significant number of investigators within these programs. Large growth in funding is projected for NSBRI programs.
More information about the Harvard-MIT Division of Health Sciences and Technology can be found online at http://harvard-mit-hst.edu/.