The Connector
Fall 2008
newsletter for graduates, students, faculty and friends of the Harvard-MIT Division of Health Sciences and Technology
HST Founder reminds graduates of their responsibility to society
(continues on page 4)
Justin Knight
The 34th HST Graduation Exercises were held on June 4 at the Harvard Club in Boston. As master of ceremonies, Richard N. Mitchell, MD, PhD, Associate Director of HST, congratulated the 84 new graduates and welcomed faculty, parents and guests. He then introduced HST Director David E. Cohen, MD, PhD, who, in turn, introduced Irving M. London, MD, Founding Director of HST, who delivered the keynote address. Looking back over the almost four decades of HST, London gave an overview of the spectacular advances in the life sciences and in technology that characterize these years, highlighting the sequencing of the human genome, discovery of the genetic basis of many diseases, the therapeutic potential of RNA interference, the role of microRNAs in the regulation of gene expression, the growth of cells and tissues for the repair or replacement of body constituents, the development of materials for the controlled delivery of drugs, the advances in imaging technology, the exploration of the neurobiological basis of human behavior, and the prolongation of the human lifespan. These advances represent the joint efforts of medical and life scientists and physical and engineering scientists in solving the problems of human health. HST graduates are leaders in many of these fields, as well as in entrepreneurship — challenges for The HST Class of 2008
Faculty Poster Session
Lora Maurer
Fifty faculty members presented at the fifth annual HST Faculty Poster Session on September 25 in the Medical Education Center Atrium at HMS. This event is an integral part of the fall academic schedule, allowing faculty to showcase their research and attract HST students to their labs, while also introducing new HST students to the rich and varied research opportunities available to them. Eighty students joined the faculty to discuss their research and enjoy light refreshments. Myron Spector, PhD, Professor of Orthopedic Surgery (Biomaterials) at HMS and BWH, and HST affiliated faculty, presents his poster to students, including first-year MEMP student Daniel Macaya.
hst news Martinos Center’s new home debuts with new prototype hybrid scanner
2
Fall 2008
Justin Knight
Thanassis and Marina Martinos joined members of the HST community for the dedication of the new Athinoula A. Martinos Center building at 75 Thirteenth Street in Charlestown on May 20. Speakers included MIT President Susan Hockfield and MGH President Peter Slavin. In attendance as well was Dan Shannon, MD, a long-time friend of the Martinos family and the one who envisioned the Center and its programs in 1999 as a living memorial to their daughter, Athinoula. Bruce Rosen, Director of the Martinos Center, and Gregory Sorensen, Associate Director, remarked on the early days of the enterprise that has now been enlarged by the new facility in Charlestown. Thanassis and Marina Martinos both spoke to the assembled faculty, students and staff of their appreciation and commitment to the work, and to the many people involved in making the dream a reality. The Center’s new home welcomed a new addition: a prototype PET imaging system designed and built to be fully integrated with a Siemens Trio 3T MRI system. This unique technology, built by Siemens Medical Solutions, is a first-of-its-kind hybrid scanner that permits true simultaneous imaging of human brain structure and metabolic and molecular processes. Named BrainPET, this novel system promises to offer the benefits of fully spatially and temporally co-registered PET and MRI data, to synergistically harness the unique advantages of each modality for a more comprehensive view of tissue anatomy and physiology. The potential applications of this technology are abundant. Investigators interested in tumor imaging will be able to simultaneously measure glucose metabolism (via PET) and tumor angiogenesis (via MRI) in response to novel antiangiogenic treatments. Neurologists who study Alzheimer’s dementia will be able to acquire images of amyloid buildup (via PET) and quantify changes in cortical thickness, blood flow and resting state networks (via MRI). This technology also promises to engender entirely new classes of experiments. Dynamic MRI measurements of brain blood flow, blood volume or blood oxygenation might eventually be directly incorporated into dynamic modeling of PET tracer uptake curves, allowing researchers to measure — for the first time — the task induced activation of specific neurotransmitter systems. Alternatively, MRI measurements of arterial input functions could permit analysis of simultaneously derived PET brain uptake data to improve
(Front row) MIT President Susan Hockfield, Marina Martinos, Thanassis Martinos. (Back row) MIT Chancellor Phillip Clay, HST Faculty Director of Resource Development Daniel Shannon, HST Director Martha Gray, Martinos Center Associate Director Gregory Sorensen, and Martinos Center Director Bruce Rosen.
quantitative accuracy of tissue metabolism. The higher spatial resolution of MRI may also be utilized to aid reconstruction of PET data, and motion navigation methods for MRI data might be applied to help correct for motion within the PET image sessions — crucial for studies in elderly patients or children. Although this system is still quite new,
The Connector Editor Walter H. Abelmann, MD Managing Editor/Designer Becky Sun Editorial Assistant Fran Betlyon Contact Information Harvard-MIT Division of Health Sciences and Technology 77 Massachusetts Ave., E25-519 Cambridge, MA 02139-4307 P: (617) 253-4418 F: (617) 253-7498 E: hst@mit.edu http://hst.mit.edu
Martinos Center investigators have wasted no time exploring its capabilities and, in the process, making remarkable progress. Within only a few days of installation of the new system, investigators had acquired the first simultaneous PET and MRI phantom scans. Since these early experiments, they have also acquired the first-ever simultaneous (continues on page 3)
Volume 22 • Number 4 Editorial Board Sherene Aram Pavan Cheruvu (MD ’09) Patricia A. Cunningham Lisa E. Freed, MD, PhD ’88 Lora Maurer Catherine Modica Laurie Pass Arvind Ravi (MD ’10) Steven M. Stufflebeam, MD ’94 Peter I-Kung Wu (MEMP) Ex officio David E. Cohen, MD ’87, PhD
The Connector is a quarterly publication of the Harvard-MIT Division of Health Sciences and Technology. The staff and board of The Connector would like to thank the HST alumni, faculty, staff, and students who contributed to this issue. Please send reports of your recent activities and personal news to the above address or email. Previous issues of The Connector can be found at http://hst.mit.edu.
hst news
New Professorship M. Charles Liberman, PhD, Professor of Health Sciences and Technology, was appointed as the first incumbent of the Harold E. Schuknecht Professorship of Otology and Laryngology at HMS. Schuknecht, a world leader in otology research, was chair of otology and laryngology at HMS from 1961 to 1987. Liberman is the director of the Eaton-Peabody Laboratory at MEEI.
Awards and Honors David Nguyen, PhD ’08, has been selected as the 2007-08 Graduate Student Mentor of the Year by the MIT Office of Undergraduate Advisory and Academic Programming. MEMP student Riccardo Lattanzi has won the 2008 I.I. Rabi Young Investigator Award, given each year by the International Society for Magnetic Resonance in Medicine. The Rabi award recognizes achievements in original basic research in magnetic resonance; submissions all involve MR physics, chemistry or engineering. Jeffrey M. Karp, PhD, has been selected by the MIT Office of Undergraduate Advising and Academic Programming as their Faculty Mentor of the Year. He is Instructor in Medicine and HST at HMS and BWH, and Director of the Laboratory for Advanced Biomaterials and Stem-Cell-Based Therapeutics. He has also received Mass Tech Transfer Center seed funding for tissue adhesive tape development. His project, “Tissue Adhesive Tape Inspired by Nature,” is one of seven Massachusetts Technology Transfer Center Spring 2008 Investigation Awards, announced June 23. These grants of $40,000 each may be used to develop concepts, gather data that show proof of concept, or to demonstrate a technology’s competitive advantages over existing technologies. On June 11, Tarja Halonen, President of Finland, presented the prestigious Millennium Technology Prize of the Technology Academy Finland to Robert S. Langer, Jr., ScD, Professor of Health Sciences and Technology and MIT Institute Pro
of Colorado, Boulder. Elazer R. Edelman, MD ’83, PhD ’84, spoke on “Vascular Biology, Endovascular Stents, and Tissue Engineering: Robert Koch and the Dread Pirate Robert.” Edelman is Professor of Medicine of HMS and BWH, and the Thomas D. and Virginia W. Cabot Professor of Health Sciences and Technology.
fessor “for his inventions and development of innovative biomaterials for controlled drug release and tissue regeneration that have saved and improved the lives of millions of people.” The 800,000 euros award, seen as an unofficial Nobel Prize for Robert Langer technology, is given every other year for a technology that “significantly improves the quality of human life.” Valerie J. Pronio-Stelluto, MD, Instructor in Medicine at HMS and BIDMC, member of the HST affiliated faculty and Director of Medical Student Education at Mt. Auburn Hospital, is the recipient of the 2007 Grant V. Rodkey Award of the Massachusetts Medical Society, recognizing a Massachusetts physician for outstanding contributions to medical education and medical students. Pronio-Stelluto is Co-Director of HST 201M/202 M: Introduction to Clinical Medicine and Medical Engineering. HMS Dean Jeffrey Flier, MD, is the recipient of the American Diabetes Association’s Albert Renold Award, presented at the ADA’s annual scientific sessions. The award recognizes outstanding contributions to the training of diabetes research scientists and the facilitation of diabetes research. Flier elucidated the molecular mechanism of insulin action and also the molecular pathophysiology of obesity. He is the George C. Reisman Professor of Medicine and a member of the HST affiliated faculty. MEMP student Eliseo (Eli) Papa received the Poitras Pre-doctoral Research Fellowship, which is awarded annually to two MIT predoctoral students in Biomedical Engineering or Biophysics. Papa works at the Whitehead Institute on the evolution of immune responses to pathogens.
Three Alumni Speak at HMS Alumni Week Merit Cudkowicz, MD ’90, addressed the HMS Faculty Symposium on Neurodegenerative Disease. She spoke on “Advances in ALS Therapy: A Brave New World.” Cudkowicz is Associate Professor of Neurology at HMS and MGH. At the 25th Reunion Symposium, Gilad S. Gordon, MD ’83, MBA, gave a talk on “25 Years of Biotechnology: Has it Met its Promise?” Gordon is President of ORRA Group, LLC, and Clinical Assistant Professor of Medicine at the University
HST welcomes new staff
Fran Betlyon
HST affiliated faculty member Steven E. Locke, MD, was awarded the Ronnie Stangler Award for Innovation by the American Association of Technology in Psychiatry, an affiliate of the American Psychiatric Association, at its annual meeting in Washington, D.C., on May. The award is presented to “individuals who have shown creativity and innovation in applying technology to the practice of psychiatry and medicine,” and the award committee called the annual Summit on Behavioral Telehealth, organized by Locke, “an important venue to educate and generate discussion about important issues in psychiatry.” Locke is Associate Professor of Psychiatry at HMS and BIDMC.
photo courtesy of Millennium Technology Prize
Steve Locke Honored
Mercy Ameyaw is the new administrative assistant for the HST-India collaboration; she also supports Martha L. Gray. Ameyaw recently graduated from Northeastern University with a double major in political science and international affairs. She previously worked as an International Administrative Aide in the Secretary General’s office at the United Mercy Ameyaw Nations in New York City. She is currently serving her fifth year in the US Army National Guard Military Police Battalion.
Martinos (continued from page 2)
MR and PET images in a human patient. This accomplishment was possible due to a major team effort that involved many groups at MGH, including clinicians from the Stephen E. and Catherine Pappas Center for Neuro-Oncology, neuroradiologists from the Department of Radiology, and physicists and engineers from the Martinos Center. Given the potential importance of combined PET/MRI technology to the evolution of the molecular imaging, investigators at the Martinos Center are focusing on carefully studying and advancing this novel technology. Though much work remains, the prospects of this new system are truly exciting, and the progress made by our investigators within just a short span of time is impressive. BrainPET is a true example of the imaging innovation that is at the heart of Martinos Center’s research mission, and it holds enormous opportunities for both basic and translational research for HST PhD and MD students over the next decade. For more information, visit the Center’s website at nmr.mgh.harvard.edu/ martinos. —Nichole Eusemann, Martinos Center project manager
The Connector
3
hst graduation (continued from page 1)
which they are well qualified. London emphasized that leadership also requires a sense of responsibility to society. “Your views on social issues carry weight!” he said. London recommended advocating for high-quality universal healthcare, a healthy environment and a healthy lifestyle. He stressed the importance of collaborating with social and behavioral scientists in making a better world. He also gave full recognition to the key roles of past students and faculty, as well as the support of the leadership of Harvard and MIT, in the success of HST. The next speaker was HMS Dean Jeffrey S. Flier, MD, who expressed his pride in HST and his appreciation of having played a role in HST 060: Endocrinology. He then announced that the HST Society, to which all HST MD students belong, will be renamed the Irving M. London Society of the Harvard-MIT Division of Health Sciences and Technology in his honor. The other four societies are also named for pioneers in medical research and education: Walter B. Cannon, William B. Castle, Francis W. Peabody, and Oliver W. Holmes. MIT Chancellor Phillip Clay, PhD, and Jules L. Dienstag, MD, HMS Dean for Medical Education, also made brief remarks. Then, before the 2008 graduates received their degrees, former HST Director Joseph V. Bonventre, MD, PhD, delivered an appreciation of out-going Director Martha L. Gray, PhD, for her 12 years of exemplary leadership. After a reception and lunch, the assembly reconvened, first to hear from Joseph R. Madsen, MD ’81, President of the HST Alumni Association. He welcomed all new HST graduates to
the ranks of the Association, the goals of which include providing resources for career development, encouraging regional activities for alumni/ ae, having at least one HST event each year, fostering HST “brand recognition,” and facilitating alumni/student interaction. The presentations of faculty and student Awards followed. Henry Klapholz, MD, received the Irving M. London Teaching Award for his “long-term, outstanding teaching” in HST’s Human Reproductive Biology course. The Thomas A. McMahon Mentoring Award went to Elfar Adalsteinsson, PhD, “for his exceptional, caring mentoring as an academic and research advisor.” Teo Forcht Dagi, MD, received the Biomedical Enterprise Program Award for his teaching of Dynamics of Biomedical Technologies and for helping students “explore some of the most challenging issues facing the biomedical industry with his insight, tireless questioning, and lively repartee.” Next, Gray presented the HST Director’s Award to W. Hallowell Churchill, Jr., MD, Associate Professor of Medicine at HST, HMS, and BWH, and Director of HST 200: Introduction to Clinical Medicine, a course he has taught since 1973. Churchill has also been a lecturer in hematology and a member of key HST committees. Amanda S. Jenkins, SM ’08, received the Richard J. Thomas Outstanding Biomedical Engineering Program Thesis Award. Mohammed Saeed, MD ’08, was honored with the HMS Student Award for Multiculturalism and Diversity. Finally, Biju Parekkadan, PhD ’08, delivered the student address, sharing with the audience his academic journey as well as some wisdom gained
in the “most challenging program in the country.” He said HST was responsible for fortifying his commitment, providing guidance but preserving freedom, and dissolving the walls between engineering and medicine. “There is no box!” he exclaimed. Through HST he learned to think globally and to aim to make a difference in the world. “Try to help someone everyday,” he said. “We all have responsibility to ourselves and to others. So, go forth!”
Recipients of the MD Degree with Honors magna cum laude Steven Corsello Sonali Mukherjee Shah Yee-Ping Sun
cum laude Patrick Codd Paul Dieffenbach Felipe Jain Theodore Marentis Robert Ohgami Navid Redjal Jonathan Schoenfeld Monica Sircar Glenn Yiu Suzana Zorca
photos by Justin Knight
4
Fall 2008
hst graduation
(facing page, from left) HMS Dean Jeffrey Flier announces the renaming of the HST Academic Society to the Irving M. London Society of the Harvard-MIT Division of Health Sciences and Technology. London delivers the Keynote Address. (this page, clockwise from top) Drs. Richard Mitchell and Lee Gehrke hood Erika Brown Wagner, who is holding her one-week-old daughter, Sally Firestone Wagner. W. Hallowell Churchill, Jr., MD accepts the Director’s Award. Biju Parekkadan, PhD, delivers the student address.
The Connector
5
HST in the world
Finding the fine balance
by Jenny Mu
6
Fall 2008
photo courtesy of Jenny Mu
W
hen I was asked to contribute a perspective on finding balance in graduate school, I was intrigued. Here was a topic that was not often mentioned nor discussed in the student circles with which I was familiar, and was even nearly taboo in the presence of certain faculty members. It is often presumed that graduate students, in their pursuit of science, require a dedication to the exclusion of all else. But like so many other qualities associated with accomplishment, I have come to consider hard work to be a necessary but not sufficient condition for success. I began graduate school with the fervent desire to achieve all the conventional milestones of an extraordinary PhD experience. The research area I chose was particularly challenging, as it required the development and optimization of microelectromechanical systems (MEMS), biochemical probes for in vivo fluorescence imaging, and animal models of prostate cancer. Without lab precedence in this research area or a team of collaborators, I proceeded to learn and eventually hone characterization and chemical synthesis techniques, often through tedious trial and error. When not involved in classes, I was feverishly modifying synthesis routes for an array of biochemical probes to use in further experiments. Night and day mattered little during this period, as my schedule was dictated by the experiment or synthesis step planned for that day and the availability of necessary equipment. Experiment after experiment failed to produce the desired result. Even as a hint of success emerged, it was quickly quashed by negative outcomes at the next step. My confidence had begun to erode, quickly turning into a landslide as I learned that my graduate fellowship would not be renewed. The final blow came when senior advisors close to my project questioned my commitment to the research and challenged my integrity as a graduate student and scientist. As my personal life had essentially been sacrificed at the altar of my academic ambitions, this amounted to a cataclysmic personal crisis. I desperately wanted to quit graduate school. But I didn’t. Personal crises often have the unexpected effect of freeing you from shackles you never knew you had. My shackles bound me to the borrowed expectations and rhetoric of scientists and students in a highly competitive atmosphere. Clearly, the ethos of more days, longer hours, and total dedication over the long haul had not enabled me to succeed. After consulting with different faculty members, we agreed that a directed approach to the science with realizable intermediate goals and
Jenny Mu and her husband, David DiPaola, at the National Palace Museum in Taipei, Taiwan.
multiple interpretations of an acceptable outcome would yield a more tractable and rewarding research experience. As my academic and personal lives uncoupled, I discovered that I became more resilient; the sense of defeated purpose after a day of failed experiments was often easily overcome by indulging in a hobby or time with friends. Given more structured time constraints, I was also forced to be more focused and creative in managing my projects and experiments, and thus experienced a new level of personal and scientific maturity. Sports, service activities and travel gave me more perspective. The time spent away from the lab allowed me to define a vision for my life and to consider my strengths and weaknesses, methods of leveraging both to reach my desired goals, personal priorities, and the acceptable consequences of my life choices. I am now married to a wonderful man who had no idea what an academic life entailed when we first met. He has since been indoctrinated into this intense and often mysterious world by frequently accompanying me to lab on the weekends and picking me up when I have had to stay late. His unconditional support has been a source of strength, as I know he often graciously gives up our time together so that I may read, analyze data or write. However, when we do spend time together, he knows that I am fully present and ready to share in the day’s activities.
Lest this essay become a battle cry for reduced work days for graduate students, I should clarify that juggling the demands of a fulfilling life does not necessarily require or justify an institutionalized 40-hour work week. Structuring balance in one’s life is a means of directing one’s daily priorities, as they shift with respect to emerging needs or responsibilities, to align with the larger goal. I am still extremely passionate about my research and try to work as much as I reasonably can with some creativity and flexibility in structuring my lab schedule. For example, I spent long hours in lab every day for a month prior to a vacation so that my project would not be set back too much upon my return. Moreover, I continue to work on the weekends, but not every weekend. The compromise I make in not devoting all my time and energy to my research often raises the question of how I will be able to compete for academic jobs, specifically with those who have fully committed their time. The simple truth is that I don’t know. I would like to believe that my creativity and resourcefulness would more than compensate for the difference in designated research time. This is what I have come to realize: an academic job is not a requirement for a desirable outcome, if it comes at too high of a cost. Jenny Mu is in her 8th year in the MEMP program.
faculty profile
Shiv Pillai, Arvind Ravi
the Bard of HST by Arvind Ravi HST’s faculty are known for their cutting-edge research, interest in medicine and dedication to teaching. But what does it take to truly distinguish someone from the pack? How about having poetry published in Nature Immunology and a YouTube video with nearly 4,000 views? Enter: HST’s immunologist-cum-poet, HMS Associate Professor Shiv Pillai.
I
n the immunology world, Shiv Pillai, MD, PhD, is best known for pioneering work describing the development and fate of B cells. Ask any HST student, however, and one quickly discovers that he has also established himself as the consummate teacher-entertainer, fusing knowledge with a captivating lecture style. In retracing his youth, it’s not so surprising that he would eventually come to present both research and rhymes at scientific meetings. As a 15-year-old, he showed promise in science as a winner of India’s National Science Talent Search. At the same time, “I always had a slight literary bent,” he said, avidly reading books on science, such as Paul de Kruif ’s Microbe Hunters, which profiled leading personalities in microbiology. It was research that drew him to medicine, and at age 16 decided to begin his medical training in India at an old missionary hospital that had been converted into the well-known Christian Medical College, “the kind of place where people don’t work for money,” he recalled fondly. Even then, he was able to split his time among his many interests. “Writing and performing, those have always been there. In my medical school days I was a serious thespian. I was part of a drama group that produced some very wellknown actors in India; one had a lead role in Passage to India. I acted for many years, so I guess there was this thespian urge in me which was not fulfilled.” He also enjoyed serving as editor for his school magazine, where he would contribute “little rhymes” every now and again. In the summers, he pursued research on the immunology of leprosy, which was “very
interesting from an immunology perspective because of the polar forms of disease.” His mentor convinced him to begin a PhD after his medical internship. In spite of a successful research career at the time, friends who had moved to America began to convince him that by not following suit, his scientific training and exposure would suffer. “They told me I was setting my standards too low.” He remained unconvinced that he could seek a better opportunity abroad — until he attended one of the Gordon Conferences in the early ’80s. “I met David Baltimore, and I decided that I wanted to go and work with him,” Pillai said. “After being in his lab for about a year, I knew I wouldn’t be going back to India.” Pillai found the scientific transition to America a relatively easy one, as was the cultural transition, for the most part. “From my point of view, American culture was sitting in a fast car with a Coke in your hand. And when I came to America, I found out everything I thought was true!” he quipped. “I grew up in a slightly Westernized culture, listening to Crosby, Stills, Nash and Young and the Beatles, so there wasn’t a culture shock.” He jokes that the most difficult things he had to learn were how to use an ATM and to order a sandwich (“because of all of the options”). At the end of his postdoctoral training, Kurt Isselbacher recruited him to MGH, where he is today. Initially, his focus at the MGH Cancer Center was on allelic exclusion, the process by which self-reactive cells of the immune system are vetted. “I started looking at allelic exclusion, thinking that if you had defects in it, you would have autoimmunity. More recently, our work has taken a very strong clinical bent, as it is turning out to be very interesting in humans in terms of lymphomagenesis and autoimmunity.” During the course of his career, he has uncovered many facets of B cell development, from how cell fate decisions are made to detecting new sites of maturation. “Most B cells grow in follicles, but we discovered that there is a second niche in (continues on page 9)
LYMPHOCYTE RAP Pathogens lurking everywhere Go get them first, they never fight fair (Turn on EBF, then E2A Notch will make them go away) Thread that peptide into TAP Everybody do the lymphocyte rap Give me a D then give me a J Bring a V in frame so it’s A-OK Surrogate light chains or pre-TCR Kappa or Alpha can’t be too far [refrain] Thread that peptide into TAP Everybody do the lymphocyte rap Naïve cells dance from hall to hall Pining and hoping to get that call Looking for antigen below and above Many will die of unrequited love [refrain] DCs lurking everywhere They’ve got antigen — don’t despair CCL21 to CCR7 Come in, DC baby, make this lymphocyte heaven! [refrain] Wake up that T cell, turn on Zap T cell says you need two hands to clap Give me signal one, give me signal two I’ll make you a cytokine brew [refrain] Collectins, Complement, Macrophages That’s what you get in the early stages Then antibodies, cytokines and CTLs too Pathogen baby, that’s the end of you! (Thank you, Kees, thank you, Ellen, Dimitrios, THIS is lymphocyte heaven) [refrain] —Shiv Pillai
The Connector
7
the london society The Irving M. London Society was launched in the fall of 2000 to honor the founder of HST and to provide a new way for members of the HST community to contribute unrestricted financial support for the Division. The response to the Society has been outstanding. It is with great appreciation that we recognize the following contributions of $100 or more to the Society, made between July 1, 2007, and June 30, 2008. Those who are charter members of the Society are indicated with an asterisk. The Society took on a whole new meaning with the recent renaming of HST’s society at HMS (see page 4). As HST moves onward and upward, look for a newly named fundraising campaign this fall.
The Director’s Circle ($5,000+) Richard Anders Boston Heart Foundation Robert F. Higgins Debra Peattie, PhD, and Pedro E. Huertas, MD ’93, PhD* Infoscitex Corporation Kekst Family Foundation Gershon Kekst Dr. and Mrs. James Klingenstein NCIIA Norman C. Payson Revocable Trust* Dr. and Mrs. Norman C. Payson Laurent Perret Martin R. Prince, MD ’85, PhD ’88 Dr. and Mrs. Daniel C. Shannon* The Boston Foundation Anthony Williams
The 1970 Society ($2,500-$4,999) H. Frederick Bowman, PhD Edward J. Cheal, PhD ’86 Joseph A. Ciffolillo* Codman and Shurtleff Inc. Catherine F. Corrigan, PhD ’96* DBM Corporate Consulting Grp Driftwood Charitable Foundation Peter C. Farrell, PhD, DSc Peter Feinstein* Fidelity Investments Foley Hoag LLP Irwin Jack and Lena Pincus Foundation Proskauer Rose LLP John Romanelli, MD ’87 Mr. and Mrs. M. Joshua Tolkoff* Westfield Capital Management Co.
8
Fall 2008
The PhysicianScientist Association ($1,000-2,499) Claudia M. Alleyne, MD ’81 R. Rox Anderson, MD ’84 Marvin A. Asnes Hanne T. Beck Ching-Yen Joseph Chang, MD ’89 Dennis W. Choi, MD ’78, PhD David E. Cohen, MD ’87, PhD Natacha DePaola, PhD ’91 Jeffrey Drazen, MD David D. Fleming Martha L. Gray, PhD ’86* Dr. and Mrs. John J. Halperin, MD ’75 Norman Jacobs Mr. and Mrs. Howard W. Johnson* Richard J. Kitz, MD William M. Kettyle, MD Young-Jo Kim, MD ’94, PhD Bruce Lehman Irving M. London, MD* Joseph L. Loscalzo, MD, PhD Joseph Madsen, MD ’81, and Ilonna Rimm, MD Mathai Mammen, MD ’98* Bingham McCutchen, LLP Partners Healthcare System David Pincus, MD ’81 Dr. Elliot Riegelhaupt and Susan Steinberg, MD ’76 Rodman and Rodman, P.C. Swee Lian Tan, MD ’88 and Jonathan L. Weil Daniel C. Tosteson, MD Mr. and Mrs. Jeffrey M. Wiesen Debra Judelson, MD ’76, and A.J. Willmer Robert N. Wilson
Supporters ($100-$999) Mr. and Mrs. John E. Abele Walter H. Abelmann, MD* Ralph Gregory Allen Michael S. Aronow, MD ’89 Angel S. Bassa Pamela S. Becker, MD ’86 Camille L. Bedrosian, MD ’83* Jeffrey Behrens, SM ’07 Marie-Jose Belanger, PhD ’00 Paul S. Bernstein, MD ’88, PhD David A. Berry, MD ’06 Edward S. Bessman, MD ’81 Jonathan G. Bliss, PhD ’91 Charles R. Bridges, Jr., MD ’81 Gilbert Brodsky, MD ’77* Stephen K. Burley, MD ’87 and Ms. Sonia Espejon Reynes Deborah Burstein, PhD ’86 Dean E. Calcagni, MD Martin C. Carey, MD, DSc* Nicholas A. Cataldo, MD ’81 Raymond C. Chan, PhD ’01 Dr. Chwen-Yuan Ku and Hui Chao, PhD ’97 Andrew Chen, MD ’99 Vincent Chi-Kwan Cheung, PhD ’07 Hovig V. Chitilian, MD ’00 Gilbert Chu, MD ’80, PhD Paul Citron Columbia Tech Jorge Cesar Conde, SM ’07 Chester H. Conrad, MD ’77, PhD Mindy E. Cooper-Smith, MD ’75 Cooper-Smith/James Trust Douglas A. Cotanche, PhD
William Charles Crawford Merit E. Cudkowicz, MD ’90, MS (CITP) ’96 Patricia A. Cunningham Alan D. D’Andrea, MD ’83 Prajnan Das, MD ’99 Dr. and Mrs. Lawrence I. Deckelbaum, MD ’79 Joanne M. Donovan, MD ’84, PhD ’84* Toren Finkel, MD ’86 Dan J. Fintel, MD ’79 Stuart A. Forman, MD ’89, PhD Robert J. Fram, MD ’76 Dr. Theodore Sussman and Lisa Freed, MD ’88, PhD* Roger Freedman, MD ’78 Matthew P. Frosch, MD ’87, PhD Martha L. Gallagher Mr. Andrew Washabaugh and A. Minerva Garcia, PhD ’96 Drs. Mark and Paulette Gebhart Lee Gehrke, PhD Raymond J. Gibbons, MD ’76 Thomas Glaser, MD ’91 Mark Goldberg, MD ’81 John Gomori, MD ’76 Gilad Shalag Gordon, MD ’83* Oren Grad, MD ’84* Scot Cameron Graham, MD ’92 Scott D. Greenwald, PhD ’90 Anna Greka, MD ’04, PhD Leonard C. Groopman, MD ’81, PhD John J. Guinan, Jr., PhD Theresa A. Hadlock, MD ’94 Peter F. Hahn, MD, PhD ’81 Michael Helmus, PhD John Matthew Higgins, MD ’04 Arthur J. Hiller Chad Jackson Norman A. Jacobs*
Eugene H Kaji, MD ’94, PhD Professor and Ms. Tod Machover Vikram Sheel Kumar, MD ’04 Courtney C. Lane, PhD ’04 Juliette Larson Dr. and Mrs. Pui Ho W. Tsang Karen L. Lee, MD ’98 Rebecca J. Leong, MD ’88 Leann M. Lesperance, MD ’95, PhD ’93 Ming Lu, MD ’99, PhD Dr. and Mrs. Joshua Makower Stephen Malawista, MD Frederick L. Mansfield, MD ’76 Zhi-Hong Mao, PhD ’05 David Andrew Mark, MD ’99 Dr. and Mrs. Roger G. Mark Lawrence Marsh Cynthia Maxwell, MD ’97 Brian McGill John P. McGovern Dr. and Mrs. Robert C. McKinstry III, MD ’92, PhD Lucy Miller Richard N. Mitchell, MD, PhD* Michael Patrick Morrissey, PhD ’00 Joshua D. Moss, MD George Murakawa, MD ’92 Ira S. Nash, MD ’84* Ronald Richard Newman, MD ’78 Mark Nominee Trust Keiko F. Oh Kevin Ohashi, PhD, SM ’07 Annabelle A. Okada, MD ’88 John Healey and Dr. Paula Olsiewski Stephen Onesti, MD ’86* Scott Dewitt Packard, PhD David C. Page, MD ’84 Mark S. Pasternack, MD ’75
gifts & endowments Brian J. Pereira, MD Stephen J. Pfister, MD ’76 Wojciech H. Przylecki, MD ’05 Ellis L. Reinherz, MD ’75 Nina Restuccia Ivan C. Rokos, MD ’92 Carl Rosow, MD, PhD David A. Roth, MD ’87 Sam Rubinovitz Neal R. Satten, MD ’75 Jeremiah Matthew Scharf, MD ’01, PhD Joseph Hersh Schwartz, MD ’82 Michael Scott, MD Arnold Seto, MD ’01 Timothy D. Shafman, MD ’89 A. Shields, MD ’79, PhD and Ms. F. Yoshimura* Christine Tsien Silvers, MD ’01 Barry Sleckman, MD ’89 Joseph L. Smith, Jr. Charles W. Stearns, PhD ’90* Medtronic Foundation/ David M. Steinhaus, MD ’77, and Mrs. Meredith Steinhaus Eric Howard Stern, MD ’76 Kenneth N. Stevens, ScD* Nevin M. Summers, Jr. Benjamin Chih-An Sun, MD ’00 Drs. Neil D. Clarke and Cynthia Sung, PhD ’89 Jeffrey P. Sutton, MD, PhD* Dr. Herbert Tabor Thomas M. Talavage, PhD ’88 Nii A. Tetteh, MD ’02 K. Badizadegan, MD ’77, and Dr. K. Thompson Scott Bradley Vafai, MD ’07 Susan E. Voss, PhD ’98 Michael L. Wage, MD ’82 Bradford B. Walters, MD ’79 James C. Weaver, PhD Jesse Lynn Wei, MD ’01 Mark Eliot Whipple, MD ’01 Elizabeth Wise, MD ’78 and Mr. Robert M Young George R. Wodicka, PhD ’89 Greg Zaharchuk, MD ’00, PhD ’99*
Steven H. Zeisel, MD ’75, PhD Thomas E. Zewert, MD ’97 Ruilin Zhao, PhD ’02
Matching Gifts Johnson & Johnson Family of Companies Contribution Fund
We regret if we have inadvertently omitted any names from this list. If you note any omissions or corrections, please contact HST at (617) 253-4418 or hst@mit.edu.
Designated Gifts We are deeply grateful to the following contributors, who provided support of $100 or more for specific purposes within the Division between July 1, 2007 and June 30, 2008. American Heart Association Inc Robert D. Berkowitz Cambridge Science Fdn Inc. Joseph A. Ciffolillo Cooley’s Anemia Foundation Inc. Dr. and Mrs. Eric R. Cosman Driftwood Charitable Foundation Peter C. Farrell Bernadette C. Fendrock
Shai N. Gozani, MD ’94 Howard Hughes Medical Institute Jewish Community Foundation Mr. and Mrs. Lawrence Krakauer Dr. and Mrs. Jan S. Krouwer Les Laboratoires Servier Edward H. Mank Foundation Dr. and Mrs. Roger G. Mark
Mr. and Mrs. Thanassis Martinos Michael Edwin Mathaney Neurometrix Inc. Mark Nominee Trust Pervasis Therapeutics, Inc. Delin Shen, PhD’06 Steve Steinman Diana G. Thomas Rene and Ann Thomas Elaine Victor Suzanne Whitman Richard J. Zienowicz, MD
Bard of HST (continued from page 7)
the bone marrow around sinusoids, the perisinusoidal niche,” he said. While his successes in research are numerous, including identifying the function of the defective kinase involved in specific immune deficiency known as X-
entertainment as well.” His unique take on lectures has earned him distinction both at scientific meetings and in the classroom; he won the Irving M. London Teaching Award in 2001. More recently, he recited his famous “Lymphocyte Rap” at a meeting in Crete. (To see the video, go to
“I do [poetry] as much for the
students’ entertainment as mine. It’s also very entertaining for me on long flights.” linked agammaglobulinemia, he said the most exciting period in the lab has been the last year and a half, when the group made further progress in linking the regulation of B cell activation to autoimmunity. Pillai describes the shift as both “very clinical, and very satisfying.” While training the next generation of scientists has always been a part of his research career, his first formal foray into HST teaching came in 1997 with HST 175: Cellular and Molecular Immunology. Even then, Pillai remembers inserting the occasional rhyme into his course lecture. “I guess my use of rhyme evolved slowly,” he said. “In my first couple of years, I recited a poem I knew well, such as A.E. Housman’s ‘Terence, This is Stupid Stuff.’ For one year, when Hidde [Ploegh, the course co-director] was on sabbatical, I taught the undergrads, and I soon discovered that it was important to provide
YouTube.com and type in “Lymphocyte Rap” in the search box.) “I do it as much for the students’ entertainment as mine; I enjoy performing. I think it’s a device to help you learn,” Pillai said. “It’s also very entertaining for me on long flights.” In looking back at a career that has also allowed him to be part teacher and part performer, Pillai has been very satisfied with his choice to pursue research. “We are all fortunate that we live in an era where we actually can be funded to do research because it really is something we do for pleasure. To be prepared to do research, you should be prepared for failure and difficulties, but the rewards are so great that you ignore those.” Arvind Ravi is a member of the HST MD Class of 2010.
The Connector
9
research news A Potential Diagnostic Marker for Preeclampsia Raghu Kalluri, PhD, is senior author and the late Judah Folkman, MD, was co-author of “Deficiency in catechol-0-methyltransferase and 2-methoxyoestradiol is associated with preeclampsia.” The authors studied the genetic mouse model for pre-eclampsia COMT (-/-), deficient in catechol-o-methyltransferase (COMT), in which 2- methoxyoestradiol (2-ME), normally elevated during late pregnancy, is absent. 2-ME was found to eliminate all pre-eclampsia-like features in this model. Levels of COMT and 2ME were also found to be significantly lowered in women with severe pre-eclampsia. The authors suggest that 2M-E may be useful as a plasma and urine diagnostic marker for pre-eclampsia, and may also have therapeutic and/or preventative value (K Kanasaki et al., Nature 2008; 453: 1117-21). Both members of the HST affiliated faculty, Kalluri is Professor of Medicine at HMS and BIDMC, and Folkman was the Julia Dyckman Andrus Professor of Pediatric Surgery at HMS and CHB.
Transient Disruption of Blood-brain Barrier of Potential Clinical Value MEMP student Scott B. Raymond is first author, and Kullervo H. Hynynen, PhD, is co-author of “Ultrasound enhanced delivery of molecular imaging and therapeutic agents in Alzheimer’s disease mouse models.” The bloodbrain barrier has been an obstacle to many diagnostic and therapeutic approaches to the amyloid plaques of Alzheimer’s disease. Here, a method of low-intensity focused ultrasound comprising a microbubble contrast agent is introduced, which transiently disrupts the blood-brain barrier, permitting non-invasive, localized delivery of imaging fluorophores and immunotherapeutics directly to amyloid plaques. Trypan blue and anti-amyloid antibodies were administered to transgenic mouse models of Alzeimer’s disease. MRI guidance permitted selected treatment and monitoring of plaque-heavy anatomical regions such as the hippocampus. Treated regions of the brain showed significant increase in Trypan blue fluorescene and in anti-amyloid antibodies. Thus, ultrasound-mediated, transient interruption of the blood-brain barrier permits the delivery of both therapeutic and molecular imaging agents in this animal model (PLoS ONE 2008; 3: e2175). Hynynen is Professor of Radiology at HMS and BWH and member of the HST affiliated faculty.
Reprogramming of Murine Somatic Cells to Pluripotency MEMP student Tarjei S. Mikkelsen is first author of “Dissecting direct reprogramming through integrative genomic analysis.” Past efforts to reprogram mouse and human somatic cells to pluripotency through ectopic expression of defined transcription factors have involved a 10
Fall 2008
slow and inefficient process of low yields. This report presents an integrative, genomic analysis of reprogramming of mouse fibroblasts and B lymphocytes. Fully reprogrammed cells manifest gene expression and epigenetic states very similar to embryonic stem cells, whereas stable, partially reprogrammed cells showed reactivation of a distinctive subset of stem-cell-related genes, incomplete repression of lineage-specifying transcription factors and DNA hypermethylation at pluripotency-related loci. RNA inhibition of transcription factors facilitated reprogramming, and treatment with DNA methyltransferase inhibitors improved the overall efficiency of the reprogramming process (Nature 2008; 454: 49-55).
Combination of Photodynamic Therapy and Immunotherapy of a Murine Sarcoma Michael R. Hamblin, PhD, is senior author and Mei X. Wu, MD, PhD, is co-author of “Photodynamic therapy plus low-dose cyclophosphamide generates antitumor immunity in a mouse model.” Photodynamic therapy (PDT) uses a photoactivated dye in combination with visible light that produces reactive oxygen and destroys malignant tissue by direct cytotoxicity, destruction of tumor blood supply and activation of the immune system. In a mouse model of a highly metastatic reticulum cell sarcoma this study demonstrated the effectiveness of combining PDT with low-dose cyclophosphamide (CY), a cytotoxic cancer drug that damages tumor DNA and can potentiate antitumor immunity. PDT alone led to regression of the tumor, improved survival, but did not cure. PDT + CY led to 70% permanent cures. When cured animals were rechallenged with tumor cells, the tumors were rejected in 71% of mice. It was concluded that the effects of CY on this tumor “are caused by an immunostimulatory effect rather than by the traditional cytotoxic role of CY” (AP Castano et al., Proc Natl Acad Sci USA 2008; 105: 5495-500). Hamblin is Associate Professor of Dermatology at HMS and MGH; Wu is Assistant Professor of Dermatology at HMS and MGH. Both are members of the HST affiliated faculty.
Direct Observation of Diffusion of P53 Protein Leonid A. Mirny, PhD, Associate Professor of Health Sciences and Technology and of Physics at MIT, is co-author of “Tumor suppressor p53 slides on DNA with low friction and high stability.” The p53 protein is a transcription factor important in tumor genesis. It is thought to regulate gene activation both positively and negatively by diffusing along DNA via its C-terminal domain. Two processes have been proposed: sliding and keeping contact and “hopping,” breaking contact. This process, however, has not been observed directly. Using total internal reflection fluorescence microscopy, the authors were able to visualize the movement of human p53, fluorescently labeled, as
it moved along individual DNA molecules. They found that p53 is capable of sliding-moving along DNA while maintaining continuous contact. This report describes the first experimental observation of p53 sliding on DNA (A Tafvizi et al., Biophys J 2008; 95: LO 1-3).
Enhancing the Differentiation of Embryonic Stem Cells Jennifer H. Elisseeff, PhD ’99, is senior author of “Enhanced Chondrogenic Differentiation of Embryonic Stem Cells by Co-Culture with Hepatic Cells.” Authors’ Abstract: “Enhancing the specific differentiation of pluripotent embryonic stem (ES) cells has been a challenge in the field of tissue engineering. Previously, hepatic cells have been shown to secrete various soluble morphogenic factors to direct mesodermal differentiation of ES cells. In this study, we hypothesized that factors secreted by hepatic cells possess chondrogenic-differentiating effects, and, therefore, the co-culture of hepatic cells would enhance chondrogenesis of ES cells. ES-derived cells (ESDCs) were cocultured with hepatic cells (HEPA-1C1c7) in three-dimensional bilayered hydrogels. After 3 weeks culture, the histological and biochemical analysis of the HEPA-co-cultured ESDCs revealed a four-fold increase in glycosaminoglycan (GAG) compared to ESDCs cultured alone. This result was supported by real-time PCR analysis, which demonstrated an 80-fold increase in aggrecan expression in co-cultured ESDCs. Additionally, type IIB collagen expression was observed only with co-cultured ESDCs, and immunohistochemical analysis resulted in significantly more positive type II collagen staining with co-cultured ESDCs. Moreover, at day 21, gene expression of other lineages in HEPA-co-cultured ESDCs was either comparable to or lower than those of ESDCs cultured alone. These results indicated that coculture of ESdCs with hepatic cells significantly enhanced specific chondrogenic differentiation of ESDCs” (HJ Lee et al., Stem Cell Dev 2008; 17: 555-64). Elisseeff is Assistant Professor of Biomedical Engineering at the Whitney School of Engineering, Johns Hopkins University.
Fiber Optic Confocal Reflectance Microscope Permits Differentiation of Neoplastic From Normal Oral Mucosa Rebecca R. Richards-Kortum, PhD ’90, is senior author of “In vivo imaging of oral neoplasia using a miniaturized fiber optic confocal reflectance microscope.” Authors’ Abstract: “The purpose of this study was to determine whether in vivo images of oral mucosa obtained with a fiber optic confocal reflectance microscope could be used to differentiate normal and neoplastic tissues. We imaged 20 oral sites in eight patients undergoing surgery for squamous cell carcinoma. Normal and abnormal areas within the oral cavity were identified
research news clinically, and real-time videos of each site were obtained in vivo using a fiber optic confocal reflectance microscope. Following imaging, each site was biopsied and submitted for histopathologic examination. We identified distinct features, such as nuclear irregularity and spacing, which can be used to qualitatively differentiate between normal and abnormal tissue. Representative confocal images of normal, pre-neoplastic, and neoplastic oral tissue were presented. Previous work using much larger microscopes has demonstrated the ability of confocal reflectance microscopy to image cellular and tissue architecture in situ. New advances in technology have enabled miniaturization of imaging systems for in vivo use” (KC Maitland et al., Oral Oncol 2008; [E pub ahead of print]). Richards-Kortum is the Stanley C. Moore Professor of Bioengineering at Rice University.
Nasal Polyps Have Characteristic Transcriptional Signatures Konstantina M. Stankovic, PhD ’98, MD ’99, is first author of “Gene expression profiling of nasal polyps associated with chronic sinusitis and aspirin-sensitive asthma.” Author’s Abstract: “Objective: To identify genes whose expression is most characteristic of chronic rhinosinusitis and aspirin-sensitive asthma through genome-wide transcriptional profiling of nasal polyp tissue. Study Design: Prospective, controlled study conducted at a tertiary care institution. Methods: Thirty genome-wide expression microarrays were used to compare nasal polyp tissue from patients with chronic history of aspirinsensitive asthma (ASA, n = 10). Genes found to be most characteristic of each polyp phenotype, as determined from bioinformatics analyses, were validated using real-time quantitative polymerase chain reaction (RT-PCR) and immunohistochemistry in different patient sets. Results: The transcriptional signature of the control mucosa was distinctly different from that of either polyp phenotype. Genes most characteristic of the CRS phenotype included two up-regulated genes, met proto-oncogene (MET) and protein phosphatase 1 regulatory subunit 9B (PPP1R9B), and two down-regulated genes, prolactin-induced protein (PIP) and zinc alpha2-glycoprotein (AZGP1). The gene most characteristic of the ASA phenotype was periostin (POSTN), which was up-regulated relative to controls. Differences between the CRS and ASA phenotypes were associated with alterations in the 6p22, 22q13, and 1q23 chromosomal regions. Conclusions: Nasal polyps appear to have characteristic transcriptional signatures compared to normal sinonasal mucosa. The five genes identified in this study likely play roles in the pathogenesis of polyps associated with CRS and ASA, and are therefore attracted targets for novel medical therapies for these common debilitating diseases” (Laryngoscope 2008;118:881-9). Stankovic is a Clinical Fellow in Otology and Laryngology at HMS and MEEI.
New Renal Tubular Cell Biomarker for Acute Kidney Injury Robert A. Star, MD ’80, is senior author of “Urinary exosomal transcription factors, a new class of biomarkers for renal disease.”
Authors’ Abstract: “Urinary exosomes are excreted from all nephron segments and constitute a rich source of intracellular kidney injury biomarkers. To study whether they contain transcription (continues on page 12)
Epithelial Cells in Functional Control of Organ Injury and Fibrous Response Elazer R. Edelman, MD ’83, PhD ’84, the Thomas D. and Virginia W. Cabot Professor of Health Sciences and Technology at MIT, and Professor of Medicine at HMS and BWH, is senior author of “Tissue-engineered endothelial and epithelial implants differentially and synergistically regulate airway repair.” Authors’ Abstract: “The trilaminate vascular architecture provides biochemical regulation and mechanical integrity. Yet regulatory control can be regained after injury without recapitulating tertiary structure. Tissue-engineered (TE) endothelium controls repair even when placed in the perivascular space of injured vessels. It remains unclear from vascular repair studies whether endothelial implants recapitulate the vascular epithelial lining or expose injured tissues to endothelial cells (ECs) with unique healing potential because ECs line the vascular epithelium and the vasa vasorum. We examined this issue in a nonvascular tubular system, asking whether airway repair is controlled by bronchial epithelial cells (EPs) or by ECs of the perfusing bronchial vasculature. Localized bronchial denuding injury damaged epithelium, narrowed bronchial lumen, and led to mesenchymal cell hyperplasia, hypervascularity, and inflammatory cell infiltration. Peribronchial TE constructs embedded with EPs or ECs limited airway injury, although optimum repair was obtained when both cells were present in TE matrices. EC and EP expression of PGE (2), TGFbeta1, TGFbeta2, GM-CSF, IL-8, MCP-1, and soluble VCAM-1 and ICAM-1 was altered by matrix embedding, but expression was altered most significantly when both cells were present simultaneously. EPs may provide for functional control of organ injury and fibrous response, and ECs may provide for preservation of tissue perfusion and the epithelium in particular. Together the two cells optimize functional restoration and healing, suggesting that multiple cells of a tissue contribute to the differentiated biochemical function and repair of tissue, but need not assume a fixed, ordered architectural relationship, as in intact tissues, to achieve these effects” (BG Zani et al., Proc Natl Acad Sci USA 2008; 105: 7046-51).
Tracheal epithelial injury is localized in the airway injury model. (A and B) Trypan blue is excluded from deposition in the bronchial wall by an intact epithelium (A) but only in areas of remnant epithelium after localized nylon brush injury (B). Areas of epithelial denudation are demarcated by dark blue infiltration. (C and D) Histological cross-sections of rabbit trachea wrapped with a denatured collagen matrix 9 days after injury (C) were digitally reconstructed (D) for quantification of the areas of the lumen (L), epithelium (E), mesenchyme (M), cartilage (C), vascular (V), and injured tissue (I). (Magnification: C, x20.)
The Connector
11
research news factors, we collected urine from two acute kidney injury models (cisplatin or ischemia-reperfusion), two podocyte injury models (puromycin-treated rats or podocin-Vpr transgenic mice) and from patients with focal segmental glomerulosclerosis, acute kidney injury and matched controls. Exosomes were isolated by differential centrifugation and found to contain activating transcription factor 3 (ATF3) and Wilms Tumor 1 (WT-1) proteins detected by Western blot. These factors were found in the concentrated exosomal fraction, but not in whole urine. ATF3 was continuously present in urine exosomes of the rat models following acute injury at times earlier than the increase in serum creatinine. ATF3 was found in exosomes isolated from patients with acute kidney injury but not from patients with chronic kidney disease or controls. Urinary WT-1 was present in animal models before significant glomerular sclerosis and in 9/10 patients with focal segmental glomerulosclerosis but not in 8 controls. Our findings suggest that transcription factor ATF3 may provide a novel renal tubular cell biomarker for acute kidney injury while WT-1 may detect early podocyte injury. Measurement of urinary exosomal transcription factors may offer insight into cellular regulatory pathways” (H Zhou et al., Kidney Int 2008; 74(5):613-21). Star is the Director of the Division of Kidney, Urologic and Hematologic Diseases at NIDDK, NIH.
Biophysical Basis of Cognitive Dysfunction in Schizophrenia Steven Stufflebeam, MD ’94, is co-author of “Modeling GABA alterations in schizophrenia: a link between impaired inhibition and altered gamma and beta range auditory entrainment.” Authors’ Abstract: “The disorganized symptoms of schizophrenia, including severely disordered thought patterns, may be indicative of a problem with the construction and maintenance of cell assemblies during sensory processing and attention. The gamma and beta frequency bands (15-70 Hz) are believed relevant to such processing. This paper addresses the results of an experimental examination of the cortical response of 12 schizophrenia patients and 12 control subjects when presented with auditory click-train stimuli in the gamma/beta frequency band during measurement using magnetoencephalography (MEG), as well as earlier work by Kwon et al. These data indicate that control subjects show an increased 40Hz response to both 20- and 40-Hz stimulation as compared with patients, whereas schizophrenic subjects show a preference for 20-Hz response to the same driving frequencies. In this work, two computational models of the auditory cortex are constructed based on postmortem studies that indicate cortical interneurons in schizophrenic subjects have decreased GAT-1 (a GABA transporter) and GAD(67) (1 of 2 enzymes responsible
12
Fall 2008
for GABA synthesis). The models transition from control to schizophrenic frequency response when an extended inhibitory decay time is introduced; this change captures a possible effect of these GABA alterations. Modeling gamma/beta range auditory entrainment in schizophrenia provides insight into how biophysical mechanisms can impact cognitive function. In addition, the study of dynamics that underlie auditory entrainment in schizophrenia may contribute to the understanding of how gamma and beta rhythms impact cognition in general” (D Vierling-Claassen et al., J Neurophysiol 2008; 99: 2656-71). Stufflebeam is Instructor in Radiology at HMS and MGH, and member of the HST affiliated faculty.
tissue responses. The static group manifested up to four-fold increases in epidermal cellular proliferation after four days and an almost threefold increase in vascularity in the dermis. Using cyclical loading, comparable effects were evident in just eight hours. The authors concluded that “mechanical forces stimulate cell proliferation and vascular remodeling in living skin” and propose that “devices applying controlled mechanical loads to tissues may be a powerful therapy to treat tissue defects” (G Pietramaggiori et al., Ann Surg 2007; 246: 896-902). Orgill is Associate Professor of Surgery, at HMS and BWH. Ingber is the Judah Folkman Professor of Vascular Biology at HMS and BWH, and member of the HST affiliated faculty.
Transcription Factor XBP1 Is a Regulator of Lipogenesis
Value of Metabolic Profiling an Individual’s Response to Insulin
David E. Cohen, MD ’87, PhD, Associate Professor of Medicine at HST, HMS and BWH, Faculty Director of HST and Master of the Irving M. London Society, is co-author of “Regulation of hepatic lipogenesis by the transcription factor XBP1.” Excess ingested carbohydrates are converted into triglyceride in the liver and then transported to adipose tissue for energy storage. Malfunction of this process may lead to the metabolic syndrome, comprising obesity, dyslipidemia, hyperglycemia and hypertension. Several transcription factors, such as liver X receptor and sterol regulatory element-binding proteins, are known to play a role in the control of hepatic lipid metabolism. This research establishes the unexpected role in this process of the transcription factor X-box binding protein 1 (XBP1), known to control the expression of genes required for the unfolded protein response. XBP1 protein expression in mice was elevated after feeding carbohydrates and corresponded with the induction of critical genes involved in fatty acid synthesis. Inducible, selective deletion of XBP1 in the liver resulted in marked hypocholesterolemia and hypotriglyceridemia, secondary to a decreased production of lipids from the liver (AH Lee et al., Science 2008; 320: 1492-6).
MEMP student Oded Shaham is first author, Vamsi K. Mootha, MD ’98, is senior author, and Gregory D. Lewis, MD, SM (CITP) ’07 and Ravi Thadhani, MD, are co-authors of “Metabolic Profiling of the Human Responses to a Glucose Challenge reveals distinct axes of Insulin sensitivity.” Authors’ Abstract: “Glucose ingestion after an overnight fast triggers an insulin-dependent, homeostatic program that is altered in diabetes. The full spectrum of biochemical changes associated with this transition is currently unknown. We have developed a mass spectrometry-based strategy to simultaneously measure 191 metabolites following glucose ingestion. In two groups of healthy individuals (n=22 and 25), 18 plasma metabolites changed reproducibly, including bile acids, urea cycle intermediates, and purine degradation products, none of which were previously linked to glucose homeostasis. The metabolite dynamics also revealed insulin’s known actions along four key axes-proteolysis, lipolysis, ketogenesis, and glycolysis-reflecting a switch from catabolism to anabolism. In pre-diabetics (n=25), we observed a blunted response in all four axes that correlated with insulin resistance. Multivariate analysis revealed that declines in glycerol and leucine/ isoleucine (markers of lipolysis and proteolysis, respectively) jointly provide the strongest predictor of insulin sensitivity. This observation indicates that some humans are selectively resistant to insulin’s suppression of proteolysis, whereas others, to insulin’s suppression of lipolysis. Our findings lay the groundwork for using metabolic profiling to define an individual’s insulin response profile, which could have value in predicting diabetes, its complications, and in guiding therapy” (Mol SystBiol 2008; 4: 214-22). Mootha is Assistant Professor of Systems Biology at HMS, and Assistant Professor of Medicine at HMS and MGH. Thadhani is Associate Professor of Medicine at HMS and MGH and member of the HST Affiliated Faculty.
Role of Mechanics in Tissue Development and Wound Healing Dennis P. Orgill, PhD ’83, MD ’85, is senior author and Donald E. Ingber, MD, PhD, is co-author of “Tensile forces stimulate vascular remodeling and epidermal cell proliferation in living skin.” This work addresses the potential role of mechanical tension in development of tissue and in wound healing, relevant to the increasing number of cutaneous defects seen in the aging population, in diabetics and in obese patients. The ears of rats were mechanically loaded by applying tensile forces, either statically or cyclically, and then using in vivo microscopy, immunohistochemistry and corrosion casting to analyze
hst matriculants Medical Science Vineeta Agarwala Stanford University Biophysics
Alexander Francis Bagley
MIT Chemical Engineering; Biology
Yarl Balachandran
Columbia University Neuroscience and Behavior
Albert Sean Chiou Stanford University Chemistry
Katharine Rose Clapham Harvard University Biochemical Sciences
Yamicia Doyasi Connor
MIT Biology; Chemical Engineering
Michael Edward Coulter Harvard University History of Science
Mitra Dowlatshahi
Harvard University Physics and Mathematics
Gaurav Gulati
Harvard University Biology
Matthew Louis Hemming, PhD
U of California, San Diego Biochemistry and Cell Biology
Jonathan David Herman
Brown University Biochemistry and Molecular Biology
Grace Hsieh
University of Arizona East Asian Studies; Molecular Biology
William Liang Hwang, MS Duke University Electrical and Computer Engineering; Physics
Wui Ip
SUNY Binghamton Chemistry; Biology
Jeffrey Joseph Ishizuka, DPhil Williams College Chemistry
Laura A. Jacox (Dental)
MIT Biology; Earth, Atmosphere and Planetary Science
Divya Jayaraman
Harvard University Biochemical Sciences
Albert Hyukjae Kwon MIT Biology
Laurel Yong-Hwa Lee, PhD MIT Biology; Neuroscience
David Jing-Piao Lin
Stanford University Mathematical and Computational Sciences
Wendy Wing-Heng Liu
Daniel Joseph Macaya
J. Taylor Lloyd
Arjun Kumar Manrai
Princeton University Molecular Biology
Brown University Materials Engineering
Cornell University Materials Science and Engineering Harvard University Physics
Justin Han-Je Lo
Qunya Ong
Nina Mann
Carlos Pardo, SM
Khang Duy Nguyen, MS
Yin Ren
Derek Tilghman Peters
Huilin Shao
Rishi Venkata Puram
Jordan Matthew Spatz, SM
MIT Biological Engineering; Music MIT Chemical Engineering Yale University Molecular Biophysics and Biochemistry
U of Michigan, Ann Arbor Cellular and Molecular Biology MIT Biology; Chemistry
Ethan L. Sanford
University of Colorado, Boulder Biochemistry
Valeriy Shubinets
University of Chicago Biology; Chemistry
Adam Steven Was
MIT Mechanical Engineering
James Mead Wilkins, PhD Bowdoin College Biochemistry
Medical Engineering and Medical Physics Leah Christine Acker
Grove City College Electrical Engineering; Political Science
James Allen Ankrum
University of Iowa Biomedical Engineering
Jose Antonio Canseco Rice University Bioengineering
Ryan Mcomber Cooper
University of California, Berkeley Bioengineering
Rachel Ellman
MIT Aeronautics and Astronautics
Sharon Elizabeth Fox, MD Princeton University Art and Archeology; Neuroscience
Melanie Margarete Hoehl
Cambridge University Chemical Engineering; Natural Sciences
Chyan Ying Ke
Johns Hopkins University Biomedical Engineering
Teck Chuan Lim
Johns Hopkins University Biomedical Engineering
University of Michigan, Ann Arbor Biomedical Engineering U of Navarra, Pamplona, Spain Biomedical Engineering MIT Electrical Engineering and Computer Science Cornell University Biology; Physics University of Colorado, Boulder Aeronautics and Astronautics
Radiological Sciences Most Recent Position: Research Scientist/Medical Physicist, Xoran Technologies, Inc.
James Stewart Evans, MD*
Alan Ryan Braly
University of Vermont Hematology/Oncology
Johns Hopkins University Biomedical Engineering Most Recent Position: Senior Biomedical Engineer, Medtronic
Todd Vijay Dhavale
Vanderbilt University Biomedical & Electrical Engineering Most Recent Position: Senior Biomaterials Engineer, Kensey Nash Corporation
Joshua Gottlieb
Speech & Hearing Bioscience and Technology Maria Andrey Berezina
University of Massachusetts, Lowell Electrical Engineering
Yen-Fu Cheng, MD
Taipei Medical University Medicine
Gus Fizt Halwani
University of South Florida Psychology
Ann E. Hickox, MSc* Arizona State University French
Andrew Christopher Lysaght, SM University of Connecticut Mechanical Engineering
University of Texas, Austin Management Information Systems Most Recent Position: Project Manager: Consulting, Cerner Corporation
Andrew James Koert
University of Virginia Mechanical Engineering Most Recent Position: Development Eng./IT Eng., Pharos LLC/Levitronix LLC
Joseph Phillip Sterk
Harvard University Biochemical Sciences Most Recent Position: Consulting Associate, Clarion Healthcare LLC
John Alan Truesdell, Jr.
University of Colorado Biochemistry; Molecular Biology Most Recent Position: Lieutenant, US Navy
Alice Elizabeth Wagner, MA
University of Notre Dame Science Pre-professional Most Recent Position: Clinical Research Associate II, Genzyme Corporation
Sofia Martti Vallila, MA
U of North Carolina, Chapel Hill Dramatic Art; Romance Languages
Bo Zhu, MEng
MIT Electrical Engineering * June 2008 matriculant
Biomedical Enterprise Program (SM) Jonathan Douglas Alspaugh, MS University of Michigan Nuclear Engineering and
** February 2008 matriculant
Clinical Investigator Training Program (SM)
McMaster University, Michael G. DeGroote School of Medicine, Hamilton, Ontario Cardiology
Julie Lynn Hermann
University of Michigan, Ann Arbor Biomedical Engineering
University of Texas, SW Medical Center Internal Medicine
Meera S. Gupta
Adeeti Vedantham Ullal
Hongye Ye
Richard Lu, MD
Elizabeth Jane Brown, MD
Johns Hopkins University Biomedical Engineering; Mathematics University of California, Berkeley Biomedical Engineering
Gregg Daniel Fine, MD
Yeshiva University Computer Science Most Recent Position: Quantitative Research Associate, JP Morgan Chase MIT Mechanical Engineering Most Recent Position: Project Manager, Dynogen Pharmaceuticals, Inc.
Kartik Trehan, SM
Drexel University Internal Medicine
Biomedical Informatics Program (SM)
U of Pennsylvania School of Medicine Pediatric Nephrology
Susan Cheng, MD
Cristina R Ferrone, MD
Washington U School of Medicine Surgical Oncology
Yuchi Han, MD (HST ’00) Harvard Medical School Cardiology
Panagiotis Konstantinopoulos, MD, PhD
University of Patras School of Medicine, Patras, Greece Hematology/Oncology
Elizabeth Austen Lawson, MD Harvard Medical School Neuroendocrinology
Joshua L Roffman, MD
U of Maryland School of Medicine Psychiatry
Joseph H Schwab, MD
The Chicago Medical School Orthopedic Surgery
Ludy Chen Shih, MD
U of California, Los Angeles Neurology
Lisa Michelle Swartz, MD Harvard Medical School Pediatric Endocrinology
Marissa Beth Wilck, MD University of Cape Town Internal Medicine
Timothy Wei-Wen Yu, MD, PhD University of California, San Francisco Neurology
Leo Anthony G. Celi, MD*
University of the Philippines Internal Medicine/Critical Care
Penelope A. Cuevas, MD** Yeshiva University, New York Medicine
Guido Alejandro Davidzon, MD* Universidad Maimonides, Buenos Aires Medicine
Biomedical Engineering (SM) Sonal Sodha**
MIT Biological Engineering ** February 2008 matriculant
The Connector
13
alumnus profile
In p ursuit o f re sults .. . D
avid Berry is an impatient man. He doesn’t want to wait a lifetime before his medical and technology solutions have an impact on society. When it comes to novel therapies and clean fuel, the world can’t wait. While filling out medical school applications in 1999, he knew he wanted to be a physicianscientist who focused on research — the kind that would help alleviate the suffering he had witnessed in a childhood friend who was stricken with cancer, among his own family members, and in the patients at the VA and Valhalla Trauma hospitals, where he volunteered. He had narrowed his choices to the MDPhD program at Washington University Medical School and HST. While the former had a terrific program, the latter provided access to the research Berry wished to perform, with the role models with whom he wanted to work, and the excellent clinical training he needed to bridge the worlds of medicine and science. Decision made: He applied to and was accepted into the HST MD Class of 2004. Berry was initially introduced to HST while an undergraduate in the Brain and Cognitive Sciences department at MIT. His first advisor was Bobby Padera, a graduate of both the HST MD and MEMP programs as well as the Robert Langer Lab. Berry worked in the lab of Professor Ram Sasisekharan in the Department of Biological Engineering and HST as part of the MIT’s
Undergraduate Research Opportunities Program (UROP). Berry was attracted to the fact that HST’s MD program trained physician-scientists; he could go on to do the PhD — or not. Ultimately, he decided to continue the work he had begun with Sasisekharan and pursue a PhD in biological engineering as well as his MD degree. Possessing a restless intellect, Berry was excited by a number of projects during medical and graduate schools. His PhD research focused on the physiologic mechanisms involved in the regulation of cell function via the extracellular matrix. Specifically, he studied heparin, an anticoagulant, and fibroblast growth factor, a protein involved in the creation of new blood vessels, which eventually led to the development of a new protein called dimeric fibroblast growth factor (dFGF2). If used within 24 hours of a stroke, dFGF2 can limit the amount of brain tissue damaged in a stroke; if used after 24 hours, it can improve a patient’s rate of functional recovery — something current treatment does not do. He also applied his studies of heparin and dFGF2 to cancer treatment, developing a “cancer Band-Aid” that adheres to cancer cells and disrupts their function while preserving healthy tissue. Berry soon found that his passion for making an impact with his discoveries collided with the realities of research in a university setting. Berry said, “The academic environment is great for discovery, but it was hard to make a drug there.” Under the mentorship of Sasisekharan and Langer,
“HST not only helps you think
outside the box, it helps you think about the box in a different way.” 14
Fall 2008
photo courtesy David Berry
by Patricia A. Cunningham
now. David Berry and Yelena Dudochkin, his fiancée (wife since September 20), in Paris.
Berry discovered his entrepreneurial bent. He enjoyed taking his ideas to the marketplace, and, in fact, had a real talent for it. He was the runner-up in the MIT 50K Entrepreneurship Competition in 2005, and the winner of the Lemelson-MIT Student Prize for outstanding invention and innovation by an MIT student, also in 2005. Berry credits Sasisekharan for asking the truly pointed questions that took his work to the next level and beyond, and Langer for training him to think of the big concept. Langer advised, “Go big, even if you fail.” He received his PhD in biological engineering from MIT in June 2005. During the fall of that year, with one more year of medical school to go and time to think about applying for an internship and residency, Berry ruled out further clinical training. As he noted in an article written for the (continues on page 15)
alumni news 1970s
1990s
Raymond J. Gibbons, MD ’76, is Professor of Medicine and Co-Director of the Nuclear Cardiology Laboratory at Mayo Clinic. As President of the American Heart Association from 2006-2007, he issued a statement on June 25, 2008, deploring the “frozen funding for NIH heart disease and stroke research,” the 11 percent cut in NIH funding since 2003, and the failure to act on the Genetic Information Non Discrimination Act.
The 56 new Howard Hughes Medical Institute Investigators include two HST alumni/ae: Sangeeta N. Bhatia, PhD ’97, MD ’99, Associate Professor of Health Sciences and Technology and of Electrical Engineering and Computer Science at MIT; and David C. Chan, MD ’96, PhD, Associate Professor of Biology at the California Institute of Technology.
1980s Beth Karlan, MD ’82, has been appointed editor-in-chief of Gynecologic Oncology, the medical journal of the Society of Gynecologic Oncologists. She is director of the Cedars-Sinai Women’s Cancer Research Institute at the Samuel Oschin Comprehensive Cancer Institute, and Professor of Obstetrics and Gynecology at the Geffen School of Medicine at UCLA. Ira S. Nash, MD ’84, has been appointed vice-chairman of the department of Medicine at Mount Sinai Medical Center in New York and Chief of Medicine at the affiliated Bronx VA Medical Center.
Jack W. Tsao, MD ’97, and his wife, Joan Han, MD (HMS ’99), announce the arrival of Emmanuel Chi-Wang Tsao, born on August 21. Tsao is Associate Professor of Neurology at the Uniformed Services University of Health Sciences, Bethesda, Md.
2000s Erika B. Wagner, PhD ’08, and Andy Wagner announced the birth of Sally Firestone Wagner on May 28. Erika Wagner is the Executive Director of the Mars Gravity Biosatellite Program and the X Prize Laboratory in the Department of Aeronautics and Astronautics at MIT. Sally was introduced to HST at the 2008 graduation ceremony.
HST Alumni mix and mingle On May 28, the HST Alumni Association sponsored a HST Social Networking Mingle at Bertucci’s in the Longwood Medical Area. More than 30 current HST MD and PhD students networked with several Boston area alumni and faculty. This gathering was part of the Alumni Social and Networking Events that have been held since 2006. Joseph Madsen, MD ’81, President of the HST Alumni Association, says that the plan is to have several of these social events every year so that current students can create relationships with alumni and faculty. These Social Mingles are supplemented by HST Alumni Roundtables, which feature an alumnus or alumna and a small group of students, and are focused on a specific topic. Contact HST (hst@mit.edu) for more information on future Roundtables and Social Networking Mingles.
David Berry (continued from page 14)
Lemelson-MIT Prize Winner’s Circle, “What I appreciate most about science and research is that although you don’t aid people on a day-to-day basis as physicians do, you have the potential to impact society as a whole.” While pondering next steps — professorship? traditional academic programs? business school? — Flagship Ventures approached him. This Cambridge, Mass., venture capital firm focuses on creating, financing and building innovative companies in three major areas: Therapeutics, Life Science Tools & Diagnostics, and BioEnergy/Cleantech. Flagship’s clean-slate approach to technology was attractive, and Berry found irresistible the opportunity to create new entities that quickly translated science into the marketplace. He signed on as a Principal while finishing his MD degree, which he received in June 2006. He was recently made Partner. At Flagship Ventures, Berry has focused his energies on investing in and founding early stage life science and clean-technology ventures that have the potential to improve quality of life. One such clean-tech company is LS9, a California-based company created to market renewable, clean energy in the form of biologically manufactured petroleum. While biofuel in the form of ethanol has become a more popular
alternative to gasoline, people became concerned about its effects on the environment and world economies. Berry and colleagues brainstormed about alternatives, but arrived at the conclusion that the best alternative to petroleum was — petroleum! The infrastructure to use this type of fuel was already in place, after all. They wondered if they could they use biology to make it. Berry and his advisors put together a core team to work on the problem, and provided funding. They proved their concept, that microorganisms could be reengineered to produce petroleum, and this fuel is now in development. Their goal is to scale up production to pilot-level by 2010. It took only nine months to take this idea from development to proof of concept — a satisfying result for a self-described impatient man! For his work with LS9 and his other accomplishments, Berry was named one of Technology Review’s Young Innovators under 35 in 2007, as well as the magazine’s Innovator of the Year. Berry has developed ventures in the diagnostic/life sciences arena as well. These include BG Medicine, which “develops novel tools and technologies for systems biology applied to drug discovery and development,” and Epitome Biosystems, which develops “breakthrough protein biochip products for large-scale, high-throughput and standardized protein analysis.”
He credits the training and background he received in HST with making it possible for him to work in the life sciences, and for fostering his spirit of innovation. HST helped him develop the skills to think critically and speak the language of the clinical environment. Berry said, “HST not only helps you think outside the box, it helps you think about the box in a different way.” As a member of the MIT Corporation, Berry stays involved in the MIT community. He is on the Visiting Committees of the departments of Materials Science and Engineering, Chemistry and HST. He is interested in HST governance and vision, and admits engaging in passionate debates with colleagues about the future of HST. He has done some lecturing for the Biomedical Enterprise Program, a joint program of HST and the Sloan School of Management, and most recently for HST 939: Designing Technology Innovation for Global Health Practice. Berry is energized by the positive feedback he’s received from HST.939 students and from the successes of LS9. Most of all, he’s excited about how his various ventures impact the developing world. Berry is newly married (as of September 20) to Yelena Dudochkin, who runs the market analysis group at Factset by day and is an opera singer by night. They look forward to traveling together and enjoying their mutual love of music. The Connector
15
The Harvard-MIT Division of Health Sciences and Technology 77 Massachusetts Ave., E25-519 Cambridge, MA 02139 USA
Non-Profit Organization US Postage PAID Cambridge, MA Permit No. 54016
The White Coats are Coming Grace Hsieh (MD ’12)
During orientation, the HST MD Class of 2012 received their white coats, a symbol of the profession they are about to enter. The incoming class of the newly renamed London Society has 30 MD students and one DMD student. After the White Coat Ceremony, students went to Brigham and Women’s Hospital to attend a lecture and to meet their first patient as doctors-in-training. For a list of this year’s HST matriculants, see page 13.
16
Fall 2008