MIT Reports to the President 1999–2000
The Division of Bioengineering and Environmental Health (BEH) officially began operation in July of 1998, with the mission of fostering MIT education and research fusing engineering with biology, and the two ensuing years have been extraordinarily exciting and productive. Our formal Institute mission statement is "To organize education and research at the interface of engineering with biology, with special emphasis on biomedical engineering, pharmacology, and toxicology." The central premise of BEH is that the science of biology will be as important to technology and society in the next century as physics and chemistry have been in the one now ending — especially for application to the field of human health. Therefore, to translate the revolution in modern biology into a corresponding revolution in biology-based technologies, a new biology-based discipline of bioengineering must be established. We must educate engineers and scientists who can: apply their measurement and modeling perspectives to understanding how biological systems operate, especially when perturbed by genetic, chemical, mechanical, or materials interventions, or subjected to pathogens or toxins; and apply their design perspective to creating innovative biology-based technologies in medical diagnostic, therapeutic, and device industries (as well as in non-health-related industrial sectors such as agriculture, environment, materials, manufacturing, and defense). That is, we must educate a new generation of people who can solve problems using modern biotechnology, emphasizing an ability to measure, model, and rationally manipulate biological systems. Hence, a key function of BEH is to create and support curricula in which biology and engineering are taught as synergistically as possible.
BEH has already increased from its initial number of 22 faculty to a current number of 25, with 10 holding primary appointments in the division, 9 holding dual appointments in the division, and 6 holding joint appointments in the division. During the past year, we have hired 2 new dual faculty members, 1 faculty member has moved from joint to dual status, and we have added 1 new joint faculty member. Dual appointments will grow into the major mode as the division continues its increase in size, though new faculty will also be added in the joint and primary categories; our strategic plans calls for the BEH faculty size to approach a total of approximately 35 (with approximately 18—20 "full-time-equivalents") in the coming 5—7 years.
The current primary faculty members are Peter Dedon, Bevin Engelward, John Essigmann (joint appointment in Chemistry), James Fox, Ram Sasisekharan, David Schauer, James Sherley, Steve Tannenbaum (joint appointment in Chemistry), William Thilly, and Gerald Wogan. The current dual faculty members, with their shared appointments noted in parentheses, are William Deen (Chemical Engineering), Linda Griffith (Chemical Engineering), Alan Grodzinsky (Electrical Engineering and Computer Science), Roger Kamm (Mechanical Engineering), Douglas Lauffenburger (Chemical Engineering), Paul Matsudaira (Biology), Dane Wittrup (Chemical Engineering; hired this past year), and Ioannis Yannas (Mechanical Engineering; transferred this past year); in addition, Darrell Irvine (Materials Science and Engineering; hired this past year) will join the dual faculty upon completion of his postdoctoral work (at Stanford University Medical School in the Department of Immunology). The current joint faculty members are Forbes Dewey (Mechanical Engineering), Neville Hogan (Mechanical Engineering), Ian Hunter (Mechanical Engineering), Alex Klibanov (Chemistry; joined this past year), Robert Langer (Chemical Engineering), and Harvey Lodish (Biology).
Regarding undergraduate education, BEH administers SB Minor programs in Biomedical Engineering and in Toxicology and Environmental Health, along with a newly-established 5-year M.Eng. program in Biomedical Engineering. Regarding graduate education, BEH runs SM and PhD programs in Bioengineering and in Toxicology.
Research activity by BEH faculty is conducted under the auspices of a variety of major inter-departmental laboratories and centers, including four headed by BEH faculty: the Center for Biomedical Engineering (Alan Grodzinsky, Director), the Center for Environmental Health Sciences (William Thilly, Director), the Division of Comparative Medicine (James Fox, Director), and the Biotechnology Process Engineering Center (Douglas Lauffenburger, Director). Even outside these formal laboratory/center administrative units, much of the research led by BEH faculty involves multi-disciplinary collaborations with investigators in other MIT academic units as well as in industry and academia elsewhere. As we continue to grow our BEH faculty and facilities, we are placing strategic emphasis on four research areas that permit innovative application of our unique fusion of biology and engineering: cell and tissue engineering; molecular therapeutics (including protein and nucleic acid) discovery, design, and delivery; new tools for pharmacological, toxicological, and genomic studies; and biological imaging, measurement and modeling.
Finally, in April 2000 we held the inaugural meeting of the BEH Visiting Committee. Under the superb leadership of Committee Chair Susan Whitehead, this two-day event provided a wonderful opportunity to have our aims, activities, and plans assessed critically by a diverse group of external experts. We were gratified by the enthusiastic response of this Committee to the presentations by and meetings with BEH faculty and students, and our efforts in the coming years will be guided very beneficially by the thoughtful advice offered by the Committee members.
During fiscal year 2000, the sponsored research volume for BEH was $4.3 million. This represents only those sponsored projects assigned to the division. Many BEH faculty members have sponsored research projects assigned to other departments, labs and centers.
With the formation of BEH in July of 1998, there was created an appropriate academic "home" for the Minor degree program in Biomedical Engineering (BME). This program had been overseen by Professor Roger Kamm via the Center for Biomedical Engineering since the Minor’s inception in 1995. Immediately upon the establishment of the new division, however, the administration of the BME Minor was transferred permanently to the BEH Academic Office.
Moving the BME Minor to a central departmental office has proven to be beneficial. Debra Luchanin, Academic Administrator for BEH, now oversees the administration of the program, and keeps formal records on student enrollment, withdrawal, and completion. In addition, program information has been revised and redesigned.
The BME Minor continues to attract a steady number of undergraduates. Eighty-four students were enrolled in the program during 1999—2000 and 28 seniors were awarded the Minor degree at Commencement. Most of the students are drawn from Chemical Engineering, Biology, Electrical Engineering, or Mechanical Engineering.
Generous funding from the Whitaker Foundation has enabled us to establish several Bioengineering Undergraduate Research Awards to be distributed each year, beginning in 1999—2000. Students enrolled in the BME minor receive preference for these awards, which were given to support bioengineering UROP projects. Thirteen students each received $1,200 of research support during the academic year; additional six students were each awarded $4,400 of support for their summer 2000-research projects. BMES members continued to be active; among other activities, they assisted with the Academic Midway and the Pre-Frosh Preview, and organized a Career Fair.
One concern about the BME minor has been the relatively high withdrawal rate from the program. Between 25—30% of those who enroll in the Minor do not complete the requirements. We are now beginning to track formally the reasons given for withdrawal. The program is certainly one of the most rigorous, and students often site a lack of time to complete all of the courses as being the primary reason for dropping the Program. In order to help alleviate the heavy course load, the required Science Core and Bioengineering Core courses were recently modified to allow for more flexibility. The BEH Academic Administrator will continue to monitor the withdrawal rate and to collect information from those who drop the program to determine if there are additional future modifications to be implemented in order to improve the program’s retention rate.
A new BEH-administered undergraduate Minor degree program–in Toxicology and Environmental Health (TEH) –began accepting formal enrollment in Fall 1999. The goal of this new Minor is to meet the growing demand for Undergraduates to acquire the intellectual tools needed to understand and assess the impact of new products and processes on human health, and to provide a perspective on the risks of human exposure to synthetic and natural chemicals, physical agents, and microorganisms. Given the importance of environmental education at MIT, the program is designed to be accessible to any MIT Undergraduate. Requirements include three didactic core subjects, a newly created laboratory subject "Laboratory Fundamentals in Biological Engineering," and one restricted elective. Eight students, mostly Biology majors, enrolled in the TEH minor; three of those completed the program and graduated in June, 2000. An informational Open House about the TEH minor was held in April and attracted more than 60 interested students. We eagerly anticipate future enrollment of 20—25 students per class as more students become aware of this program.
The existing Toxicology Graduate Program was placed under the auspices of the BEH in July 1998 with minimal disruption. Forty-two students were enrolled in 1999—00; five graduated during the year (2 PhD; 3 SM). Zachary Shriver received the Whitaker Health Sciences Fund Fellowship, a competitive MIT fellowship awarded by the Graduate Dean's Office. Three students received Fellowships from sponsors outside of MIT: Marita Barth and Carrie Hendricks are supported on Department of Defense Fellowships, and Cecilia Fernandez continued to receive a Ford Foundation Fellowship for Minorities. Nishla Keiser has been selected to receive a NSF Fellowship in 2000—2001. Toxicology admissions appeared not to have been affected by the move to BEH. We received 40 applications for admission in 2000, which is similar to the number received in previous years. Of the 12 admitted to the program for September 2000, eight have accepted our offer to join the Toxicology Ph.D. program.
Completely independent of the move to BEH, a revised TOX Ph.D. curriculum was implemented in Fall, 1999. Most significant was the introduction of a half-term format for several required subjects. The revised curriculum allows for focus on fewer problems in greater depth and the incorporation of new disciplines (e.g., cell kinetics, extracellular matrix) into the curriculum. In addition, students are introduced to the primary literature earlier and more often. Structured in several two-week sessions in which students apply basic facts/concepts/methods to problems in toxicology, the new BEH.203 course addresses students' possible need for remediation in organic chemistry, molecular biology, cell biology, physical chemistry, mathematics or other areas.
The new Ph.D. program in Bioengineering was introduced in Fall, 1999 with a class of eleven students. The outstanding caliber of this inaugural group was confirmed by the fact that three from this group were awarded the prestigious Whitaker Foundation Fellowships to support their work in bioengineering. The students’ first-year curriculum included four common core bioengineering courses and additional electives. All eleven students passed the Written Qualifying Exams in May and have subsequently joined research lab groups. Applications to the Bioengineering program in 1999—2000 were nearly double (128) that received for the first year (67) of the program. Seventeen applicants were offered admission, nine of whom accepted our offer. In addition, two students who previously deferred enrollment will be joining the class entering in September, 2000 for a total of eleven new students. Among that group, four have been awarded Whitaker Foundation Fellowships, and one has been awarded an NSF Fellowship.
Of the entire pool of 1999—2000 applicants to BEH, ten were members of under-represented minority groups: African American (6), Mexican American (2), Puerto Rican (2). Three minority applicants were offered admission; two accepted the offer to join the BEH Ph.D. program and one chose, instead, to enroll in the Department of Electrical Engineering and Computer Science Ph.D. program at MIT. One of the minority students who accepted our offer of admission has been awarded a Leventhal Fellowship by the MIT Graduate Deans’ Office; the other newly admitted student has been selected for as a recipient of a very prestigious GEM (Graduate Degrees for Minorities in Engineering/Science) Fellowship.
Professor Peter C. Dedon–Edgerly Science Partnership Award with Professor Peter So.
Professor Bevin P. Engelward–Burroughs Wellcome Fund New Investigators Award in the Toxicological Sciences (2000).
Professor John M. Essigmann–Award for Scientific Excellence in Mutation Research. He was nominated for this award by the American Chemical Society.
Professor James G. Fox–1999 AALAS N.R. Brewer Scientific Achievement Award.
Professor Robert S. Langer–Honorary Doctorate (The Catholic University
of Louvain, Belgium); Glaxo Wellcome Award (Royal Pharmaceutical Society of
Great Britain); Millenial Pharmaceutical Scientist Award (Millenial World Congress
of Pharmaceutical Sciences); First Pierre Galletti Award (American Institute
of Medicine and Biological Engineering); Wallace Carothers Award (American Chemical
Society, Delaware Section).
Professor Douglas A. Lauffenburger–Elected Chair of the College of Fellows,
American Institute of Medical and Biological Engineering; Amgen Award in Biochemical
Engineering from the Engineering Foundation.
Professor L. Mahadevan–Honors: Office of Naval Research Young Investigator
Award; Society of Engineering Science Young Investigator Medal; Edgerton Award
for Faculty Achievement, MIT
Professor James L. Sherley–Charles E. Reed Faculty Initiatives Fund Recipient; Samuel A. Goldblith Career Development Professorship.
Professor K. Dane Wittrup–Fellow in the American Institute of Medical and Biological Engineers; the University of New Mexico College of Engineering Distinguished Young Alumnus for 1999.
Professor Peter C. Dedon organized and chaired a symposium, "Mechanisms of Action of Cytotoxic Agents," at the 201st meeting of the American Chemical Society, San Francisco, 3/29/00. The symposium will be featured in an upcoming issue of Chemical Research in Toxicology as a "symposium-in-print."
The past year has seen major research accomplishments in three areas. First, in our studies of novel DNA adducts arising from oxidative DNA damage, we have identified a novel cytosine adduct formed by cis-2-butene-1,4-dial, a product of 5’-oxidation of deoxyribose. We have also defined the mechanism by which glyoxal adducts in DNA arise, namely by a phosphonate-release from the phosphoglycoaldehyde residue arising from 3’-deoxyribose hydrogen atom abstraction. The goal for the coming year is to quantify both adducts in cells exposed to oxidative stress.
In a second avenue of study, we have identified a bacterial enzyme, alkA, that repairs deoxyxanthosine, the deamination product of deoxyguanosine in DNA. This is a critical step in our efforts to distinguish base deamination caused by nitric oxide from base oxidation caused by peroxynitrite, two related and genotoxic chemicals produced by macrophages.
Finally, Professors So and Dedon were awarded an Edgerly Science Partnership Award to study the effects of positive DNA supercoiling on DNA structure and protein interactions. We have determined that positive supercoiling, which is produced during DNA transcription and replication, increases the reactivity of DNA bases toward genotoxic chemicals. This is consistent with flipping of the bases out of the DNA helix as the DNA becomes overwound. We are currently investigating the effects of positive supercoiling on DNA-directed enzymes that rely on base flip-out to perform their catalytic activity.
Professor William M. Deen was an invited speaker at a symposium on membrane science at the AIChE Annual Meeting in Dallas, Texas on November 2, 1999. He was also an invited speaker at a symposium on the kidney microcirculation at the meeting of the European Society for Microcirculation in Stockholm, Sweden, on June 5, 2000. His laboratory continued its investigations in the areas of hindered transport in fibrous media, water and macromolecule filtration in kidney capillaries, and physico-chemical aspects of nitric oxide toxicity and carcinogenicity.
Professor Bevin P. Engelward–Research Accomplishments: Although we know that homologous recombination events promote tumorigenesis, we know almost nothing about what causes these events in mammals. One of our major goals is to engineer a system for detecting homologous recombination events in mammals. This year, we have genetically engineered a substrate for detecting recombination in mammals, we have demonstrated that recombination of our engineered substrate yields a strong fluorescent signal, and we are currently doing experiments to establish transgenic animals in which recombination events can be detected by a fluorescence in situ.
Innovative tools to detect homologous recombination can ultimately be used
to help reveal the genetic and environmental factors that promote genetic changes
that lead to cancer. Alongside tool development, we are also studying the interplay
of DNA damage, repair and recombination in model systems. We are particularly
interested in endogenous and environmental agents that cause genetic changes.
Nitric oxide is an endogenously produced DNA damaging agent that is associated
with chronic inflammation. Despite a tremendous amount of research directed
at understanding the biological effects of nitric oxide exposure, almost nothing
was previously
known about the mechanisms that cells use to prevent nitric oxide induced toxicity.
We have discovered that mitotic recombination is a pivotal defense against nitric
oxide induced toxicity. In addition, we found that a side effect of recombinational
repair is that nitric oxide can cause aberrant homologous recombination. The
discovery that nitric oxide is as potent a recombinogen as is UV light introduces
a novel potential mechanism for the well established association of inflammation
and tumorigenesis.
Professor John M. Essigmann–This year the Essigmann group made progress in the following areas. First, they reported the first system by which the mutagenic activity of a DNA adduct could be determined in all possible sequence contexts. Results showed that DNA repair proteins selectively repair adducts in some contexts in vivo. Second, they showed that nearly all known recombination systems play a critical role in helping E. coli defend against the anticancer drug cisplatin. They proposed a model whereby the interplay of mismatch repair and recombination systems selectively sensitizes germ line tissues to cisplatin. Third, they have designed an improved selective toxin for tumor cells that express the estrogen receptor. They showed that the receptor binds to the adducts and shields them from repair. They are now in the process of linking other DNA damaging agents to the receptor ligand and are at mid-course in a series of animal studies aimed at establishing antitumor efficacy in vivo.
Professor James G. Fox–Distinguished Veterinary Medicine Sesquicentennial Lecturer, University of Wisconsin, Madison WI; Appointed to Editorial Board of Journal of Experimental Medicine and Biology; Appointed to Board of Trustees Association of Accreditation and Assessment of Laboratory Animal Care; Presented 24 invited lectures at various national and international meetings and academic institutions; list available on request —Published 15 papers and 7 chapters
Professor Linda Griffith–Linda Griffith continues to serve as PI on a DARPA project to develop tissue-based sensors for biological warfare agents. She also continues work in the area of new polymers for tissue engineering and cell biology. She chaired a NIH workshop on Tissuegenesis and Organogenesis for the National Heart, Lung, and Blood Institute, and was elected to serve on the Surgery and Bioengineering Study section. She gave several invited talks at conferences, other universities, and government panels. At MIT, she continues to serve as the Associate Director of Education for BPEC and as head of the Biotech Student Leadership Council.
Professor Neville Hogan–In the past year our ongoing studies have confirmed
the lasting benefit of using robots for neurologic rehabilitation. Robot sensory-motor
therapy improved the motor ability of stroke patients’ treated limbs twice
as much as conventional (manual) therapy alone; and this advantage was sustained
for at least three years. (Neurology 53:1874—1876, 1999; Neurology 54:1938—1944,
2000; see also brief media coverage in US News and World Report,
6/26/00 and http://web.mit.edu/newsoffice/rd/2000/jul.html).
Professor Roger D. Kamm–Major research accomplishments include: Have identified using AFM the process of filament formation and structure in the development of a network with various biomaterial applications. Developed computational models for deformations of neutrophils or epithelial cells subjected to a variety of mechanical forces. Obtained industrial funding (2 yrs, $250K/yr) to study the stimulation of angiogenesis by means of external compression of the lower extremities.
Professor Robert S. Langer–Herman Beerman Lecturer (Society of Investigative Dematology); Bayer Lecture (University of Massachusetts at Amherst); William G. Lowrie Lectureship (The Ohio State University); Frank T. Gucker Lecturer (Indiana University); First pattern Distinguished Lectureship (University of Colorado at Boulder);
Professor Douglas A. Lauffenburger–elected as Chair-Elect of the College of Fellows of the American Institute of Medical & Biological Engineering. He was also appointed to serve on the Advisory Committee of the Burroughs-Wellcome Program on Interfaces Between the Physical, Chemical, and Computational Sciences. In addition to being Co-Director of BEH and the Biotechnology Process Engineering Center (BPEC), he was appointed Associate Director of the MIT-DuPont Alliance in Bio-Based Materials.
Professor L. Mahadevan–My research continues in two directions: the physics of interfaces and thin solid and liquid films, and molecular and cellular biomechanics. In the past year, my group has made some advances in understanding the structure and formation of singularities in elasticity and hydrodynamics, and has begun to work on problems associated with motility in biological machines, such as the acrosomal process in Limulus and polymerization-driven motion in Listeria.
Professor David B. Schauer–Received tenure at MIT and has become an Adjunct Associate Professor at the Tufts University School of Veterinary Medicine. Research Accomplishments: In the past year his lab has identified and characterized cytolethal distending toxin as a candidate virulence determinant in Helicobacter species. His lab has also successfully generated isogenic mutants of Helicobacter that they are using to test the role of this and other candidate virulence determinants in cell culture and in vivo.
Professor James L. Sherley–New York University School of Medicine, Cellular and Molecular Biology Training Program Retreat, Keynote Speaker, "Back to the Future p53 Gene Function in Healthy Cells"; Tennessee State University, 22nd Annual University-Wide Research Symposium Keynote Speaker, "Informing the Public in Environmental Health Science: Who, How, and Why?"; Editor, Journal of Biomedicine and Biotechnology. Major Research Accomplishments:
Professor Steven R. Tannenbaum–Invited Lectures: U.S.-Japan Program, "Chronic Inflammation and Cancer"; University of Pennsylvania, "DNA Damage via Peroxynitrite"; Texas A & M, "Nitric Oxide and DNA Damage"; Oregon State/Linus Pauling Institute, "Nitric Oxide and DNA Damage." Committees: Steering Committee — New England Drug Metabolism Discussion Group; U.S. Air Force — Scientific Advisory Board (ad hoc); NAS/NRC — Stockpile Committee; Institute of Medicine — Vice Chair of Section 1 and Membership Committee.
Our research group continues to make progress along several fronts:
Professor K. Dane Wittrup joined the faculty as a two-key Professor in the Department of Chemical Engineering and the Division of Bioengineering and Environmental Health in August 1999. He was invited to present the Colburn Lectureship at the University of Delaware, as well as ten other invited talks, including the NAE German-American Frontiers of Engineering, University of Connecticut and University of Wisconsin/Madison. He currently serves on the national Awards Committee of AIChE.
Professor Gerald N. Wogan–Professor Gerald N. Wogan received appointments as: Princess Takamatsu Cancer Research Fund Lecturer in Japan; Scientific Advisor to the Laboratory of Human Carcinogenesis at the National Cancer Institute; and Visiting Professor in the Department of Environmental Health Sciences at the Johns Hopkins University School of Hygiene and Public Health. He was elected Chairman of the Division of Chemical Toxicology of the American Chemical Society. He serves as a member of the National Advisory Environmental Health Council of NIH and the Operating Board of Directors of the Chemical Industries Institute of Toxicology. He also holds memberships in the External Science Advisory Committees for the Comprehensive Cancer Centers of the University of Colorado and the University of Minnesota, as well as the Center for Research on Environmental Disease of the University of Texas, MD Anderson Cancer Center.
Professor Ioannis V. Yannas–Dinner Lecturer at Royal College of Engineering, London, UK, "The Future of Tissue Engineering."
Peripheral nerve regeneration studies based on several tubular devices have yielded long-term (60-week) data on axonal structure at near-terminal locations. These devices were used to bridge a 10-mm gap in the transected rat sciatic nerve. One device, a collagen tube filled with a highly porous ECM analog (the nerve regeneration template) led to formation of axonal structure at near-termainal locations which was significantly closer to normal structure than that obtained using autograft controls, the current "golden standard" of peripheral nerve repair (Chamberlain et al., J. Neurosci. Res. 60, in press).
A new theory for peripheral nerve regeneration has been proposed based on the recent discovery of a tight capsule of contractile cells (differentiated fibroblasts) around neuromas (stumps that have been allowed to heal without tubulation treatment) or around the small-diameter nerves which are known to regenerate when a gap in the nerve has been bridged with a silicone tube. In contrast, a very thin contractile cell capsule formed around nerve regenerated inside a collagen tube. The novel theory described nerve regeneration across a gap in the transected nerve as resulting from a balance between two competitive mechanical forces: the axial forces generated by the outgrowth of axons and non-neuronal cells from the proximal stump and the constrictive forces imposed by the contractile cell capsule that promote wound closure at the stump site (Chamberlain et al., 2000, J. Comp. Neurol., 417: 415—430).
More information about the division can be found on the World Wide Web at http://web.mit.edu/beh/.
Douglas A. Lauffenburger, Steven R. Tannenbaum
MIT Reports to the President 1999–2000