january/february 2010 volume 6, issue 1 Advancing Biomedical Science, Education, and Health Care

As science moves faster, the world gets smaller In a giant leap forward for personal- emerging technique to quickly and genetic scan. Moreover, it provided a ized medicine—one of the most highly completely map the “exome,” those re- preview of things to come from the anticipated benefits of the Human gions of the boy’s genome that contain ycga, a centerpiece of the School of Genome Project—Yale researchers have protein-coding genes and their associ- Medicine’s research expansion onto applied new technology to diagnose ated regulatory sequences. Yale’s West Campus. and recommend therapy for a rare in- In just 10 days, the Lifton team “We believe this heralds the dawn testinal disorder in a seriously ill baby was able to determine that the baby of a new era in genetics and person- half a world away. harbored a rare mutation in an intes- alized medicine,” says Lifton, also Doctors in Ankara, Turkey, were tinal protein which causes congenital professor of medicine and a Howard stumped as to the cause of chronic chloride diarrhea, a disorder in which Hughes Medical Institute investigator. dehydration in a 5-month-old baby the gastrointestinal tract fails to prop- “The results show that new technol- boy, and they called on the School of erly absorb chloride and water. Armed ogy can generate clinically useful Medicine’s Richard P. Lifton, M.D., with this information, the baby’s results quickly, bringing doctors and PH.D., chair and Sterling Professor doctors were able to tailor a successful patients closer to the day when com- of Genetics, for help. After obtaining treatment program. prehensive sequencing information jerry domian samples of the baby’s DNA from the The feat was a landmark in per- will be a routine part of medical care.” Turkish doctors, Lifton and colleagues sonal genetics, marking the first time Though the exome comprises (From left) Irina Tikhonova, Ute Scholl, Murim Choi, Shrikant Mane, and Richard Lifton used at the newly launched Yale Center that a patient has been diagnosed, and only 1 to 2 percent of the genome, the latest genomic techniques to diagnose an for Genome Analysis (ycga) used an treated, based on a comprehensive it includes crucial // Genes (page 7) illness in a baby 5,000 miles away in Turkey.

Medical school Fighting the fallout of childhood cancer mounts mission A personal encounter with a deadly cancer of mercy for Haiti inspires a $3 million contribution to advance On January 18, Martin Luther King psychosocial care, research for child survivors Day, people around the world were still struggling to grasp the extent Riva Ariella Ritvo, ph.d., has a favorite quote from Gandhi: of the devastation wrought in Haiti “The best way to find yourself is to lose yourself in the by a magnitude 7.0 earthquake, the service of others.” epicenter of which lay just 15 miles For much of her life, Ritvo, known to friends as “Ari,” from the nation’s densely populated has aimed to follow that maxim, treating and studying chil- capital, Port-au-Prince. dren with autism spectrum disorders at the Los Angeles– That day, David J. Leffell, m.d., area Ritvo Clinic and as a clinical instructor of long stand- the David Paige Smith Professor of ing at the Yale Child Study Center (ycsc). Ritvo’s husband, Dermatology and Surgery and depu- Alan B. Slifka, m.b.a., a 1951 alumnus of Yale College and ty dean for clinical affairs, conferred founder of New York–based Halcyon Asset Management, with Paul D. Cleary, ph.d., dean is similarly known for his public-spiritedness. In addition of the Yale School of Public Health to being the major donor to the Joseph Slifka Center for and Anna M.R. Lauder Professor of Jewish Life at Yale (named in honor of his father), Slifka Public Health, about the crisis. has been instrumental in advancing the cause of peaceful Leffell speedily convened a coexistence. Through the Alan B. Slifka Foundation, he meeting with Roberta L. Hines, launched The Abraham Fund, which promotes equality and m.d., chair and Nicholas M. Greene peace between Arabs and Jews in Israel, and he endowed the Professor of Anesthesiology; Mar- Alan B. Slifka Program in Intercommunal Coexistence, a tha C. Highsmith, ph.d., deputy master’s degree program in coexistence and conflict studies secretary of Yale University; Greg- at Brandeis University. ory Luke Larkin, m.d., m.s.p.h., “Alan is a visionary,” says Ritvo. “He likes to sponsor maggie heinzel-neel professor of emergency medicine; things that don’t exist yet. He was founding chairman of (Clockwise from left) Max Ritvo with his parents, Ariella Ritvo and Alan Linda C. Degutis, dr.p.h., m.s.n., Slifka. The Slifka Foundation has endowed a new professorship at the the Big Apple Circus. He was the first to release dolphins in Yale Child Study Center focused on the psychosocial needs of children associate professor of emergency captivity into the wild.” // Ritvo (page 5) who survive cancer. medicine and // Haiti (page 7)

Non-Profit Org. inside this issue 300 George St., Suite 773, New Haven, CT 06511 U. S. Postage www.medicineatyale.org 2 Lifelines paid Amy Arnsten explores the “molecular needs” New Haven, CT underlying mental illness Permit No. 526 3 A unified view of autoimmunity Yale researchers join together to understand the common roots of diverse diseases 5 When every second counts A new study finds significant improvement in hospitals’ approach to heart attack also Advances, pp. 3, 5 Out & About, p. 4 Grants and Contracts, p. 6 lifelines Radiotherapists honor Yale expert on tumor biology

“That’s what my mind looks Sara Rockwell, like,” says neurobiologist ph.d., professor Amy Arnsten of her office of therapeutic blackboard, where the data, sketches, and speculations radiology and that flow from her research pharmacology, on the prefrontal cortex of and associate the brain make up an ever- dean for scientific changing mural. Arnsten’s affairs, has been work has led to new treat- Sara Rockwell ments for attention-deficit named a fellow of hyperactivity disorder and the American Society for Radiation post-traumatic stress disorder. Oncology (astro). She received the award at astro’s 51st Annual Meet- ing, held in Chicago last November. Rockwell, who joined the medical school in 1974, is an expert on the biology of solid tumors. Many regions of these tumors are Amy Arnsten profoundly oxygen- and nutrient- terry dagradi deprived, factors that have diverse effects on their physiology and on their response to treatment with Keeping the brain in balance radiation and anticancer drugs. In over 200 scientific publications, A scientist’s lifelong quest California, San Diego (ucsd), to norepi- pfc neurotransmitters fluctuate, and Rockwell has described these nephrine (NE), a brain chemical released its function declines. In extreme situ- distinctive features and reported to make a difference in response to stress. She had arranged ations, or as a result of genetic factors, on approaches aimed at using these for the mentally ill a postdoctoral fellowship at the Univer- mental illness can result, and the list of features to improve cancer therapy. sity of Cambridge to continue this work, psychiatric disorders associated with pfc Rockwell, editor-in-chief of Ra- Amy F. T. Arnsten, ph.d., is one of those but a seminar given at ucsd by the late dysfunction — post-traumatic stress dis- diation Research, teaches in courses lucky souls who discover at a fairly young Patricia Goldman-Rakic, ph.d., a scientist order (ptsd), schizophrenia, obsessive- on radiation biology, pharmacol- age what their life’s work will be. While visiting from Yale, changed her plan, compulsive disorder, bipolar disorder, ogy, cancer biology, and ethics. a student at Columbia High School in and altered the course of her scientific attention-deficit hyperactivity disorder She directs the Tracking and Maplewood, N.J., in the early 1970s, career. “She talked about her research (adhd), anxiety disorders, and many Evaluation Program for the Yale Arnsten spent summers working with on the development of the prefrontal more — is long and varied. Center for Clinical Investigation children with mental illness, an interest cortex,” Arnsten recalls, “and I said to Arnsten has seen her research bear (ycci), and is a member of its ex- that was “crystallized,” she says, when she myself, ‘That’s what I have to know.’ ” fruit in medications that meet the pfc’s ecutive committee. Rockwell is the volunteered at the Greystone Park Psychi- In 1982, Arnsten began postdoc- “molecular needs.” Based on work in her medical school’s representative to atric Hospital in nearby Morris Plains. At toral studies at Yale. Under Goldman- lab, the generic compound prazosin is the American Association of Medi- Greystone, only two psychiatrists served Rakic’s tutelage, she began the explo- now used to treat ptsd. And last Septem- cal Colleges’ Group on Research a population of 2,000 patients, many of ration of the neurochemistry of the ber, for adhd, the Food and Drug Admin- and Development, and Yale Univer- whom, in an age of limited legal rights for prefrontal cortex (pfc) that has capti- istration approved Intuniv, a new formu- sity’s representative to the Federal psychiatric patients and relatively crude vated her ever since. lation of a compound that was inspired Demonstration Partnership. medications, had been institutionalized The pfc is a region at the front of by Arnsten’s research. Arnsten is now astro is the largest radiation for their entire adult lives. “It was like we the brain that is crucial to so-called working with Yale’s Office of Coopera- oncology society, with more than were still in the Middle Ages,” she says, executive functions — decision-making, tive Research to develop a plant-derived 10,000 members worldwide. A small “and I knew this was an area where one planning, predicting, and suppress- compound that has shown promise for number of long-standing astro could make — and needed to make — a ing distracting thoughts or socially treating schizophrenia, bipolar disorder, members who exemplify “excellence huge difference.” unacceptable behaviors. For such an ptsd, and related conditions. in research, patient care, education, As an undergraduate at Brown important structure, there is remark- “This is a tremendously collaborative and leadership/service” are chosen University, Arnsten largely designed ably little room for error in the pfc, says environment,” says Arnsten. “We are at as fellows each year. her own course of study in the “irre- Arnsten, who has playfully dubbed it a point of revolution in psychiatry and sistibly fascinating” field of neurosci- the brain’s Goldilocks: it functions best neuroscience, and Yale is a place where a ence. Having noted at Greystone that “when everything is just right.” When lot of that is happening.” even mild stress could greatly worsen we are fatigued or stressed, which can Yale Netcast patients’ symptoms, Arnsten devoted happen many times over the course “This Is Your Brain on Stress” her doctoral research at the University of of a single day, the relative levels of Available on iTunesU or at medicineatyale.org Managing Editor Peter Farley Assistant Editor Charles Gershman Contributors William Hathaway, Pat McCaffrey, Jill Max, Kara Nyberg, Karen Peart Design Jennifer Stockwell Medical historian lauded by Yale’s graduate school for mentorship Medicine@Yale is published five times each year by the Office of Institutional Planning and Communications, John Harley Warner, ph.d., chair and After receiving of Yale’s 10 largest majors) attracts Yale School of Medicine, 300 George St., Suite 773, New Haven, CT 06511 Avalon Professor of the History of his doctorate in about 40 new students per year. Telephone: (203) 785-5824 Fax: (203) 785-4327 Medicine and an expert on the cultural the history of sci- Warner is the author of numerous E-mail [email protected] and social history of medicine in the ence from Harvard scholarly articles and three books. Website medicineatyale.org United States during the 19th and 20th University in 1984, In 2009, Warner and James S. Ed- Copyright ©2010 by Yale School of Medicine. All rights reserved. centuries, is a recipient of a 2010 Gradu- Warner was a post- monson, ph.d., chief curator of Case If you have a change of address or do not wish ate Mentor Award in the humanities doctoral fellow at the Western Reserve University’s Dittrick to receive future issues of Medicine@Yale, please write to us at the above address or via e-mail at from Yale University’s Graduate School John Harley Wellcome Institute Medical History Center, published [email protected]. of Arts and Sciences. Warner for the History of Dissection: Photographs of a Rite in Postal permit held by Yale University, 155 Whitney Avenue, New Haven, CT 06520 The award, the university’s top Medicine in London. He joined the Passage in American Medicine, 1880– honor for teaching, advising, and medical school faculty as assistant pro- 1930, to wide critical acclaim. Yale School of Medicine Robert J. Alpern, m.d. mentoring, recognizes teachers and fessor of the history of medicine in 1986 Also receiving Graduate Mentor Dean and Ensign Professor of Medicine advisors for exceptional support of the and became chair of the section in 2002. Awards were Suzanne H. Alonzo, ph.d., Jancy L. Houck Associate Vice President for Development and professional, scholarly, and personal Under Warner’s leadership of assistant professor of ecology and Director of Medical Development 203 436-8560 development of their students. Warner the Program in the History of Sci- evolutionary biology, for the sciences, Mary Hu will be honored in February during the ence and Medicine, Yale College’s and Kelly D. Brownell, ph.d., profes- Director of Institutional Planning and Communications Michael Fitzsousa university’s Mentoring Week and at the undergraduate major in the History sor of psychology and epidemiology, Director of Communications Graduate School Convocation in May. of Science/History of Medicine (one for social sciences. ♻ Printed on recycled paper

2 www.medicineatyale.org advances Health & Science News Autoimmunity: finding common ground The shared biological mechanisms of diverse autoimmune disorders inspire a united research effort

Among researchers who study the adaptive immune sys- tem, generally speaking, you’re a T cell person or a B cell person. Kevan Herold, M.D., professor of immunobiology and medicine, studies T cells, so called because they ma- ture in the thymus. Herold’s colleague, Eric Meffre, PH.D., zhaoxia sun associate professor of immunobiology, studies B cells, Bending the curve: which mature in bone marrow. T cells play a central role in the immune responses mounted by cells themselves; the drug halts kidney cysts primary job of B cells, in contrast, is to produce antibod- About one-half of patients with the ies that target specific pathogens. Both play key roles in

most common form of polycystic kid- immunity, but Herold, an expert on type 1 diabetes, recalls li wen (2) ney disease (pkd), which affects about that when he was doing postgraduate work at the Univer- A pancreatic islet from a mouse with 600,000 Americans, will eventually sity of Chicago in the 1980s, “the T cell people were in one diabetes (above) shows extensive succumb to kidney failure requiring building, and the B cell people were in another building,” lymphocyte infiltration, compared to the islet seen in the pancreas of a transplant or dialysis. he says. “And we never talked to them.” healthy mouse (right). Islets contain Researchers studying zebrafish Thanks to Herold, at Yale, things are moving in the op- insulin-producing beta cells, which have noted that kidney cysts in these posite direction. He is a driving force behind the School of autoreactive lymphocytes attack. animals are often accompanied by a Medicine’s recent designation as an Autoimmunity Center distinctive body curvature (see photo). of Excellence (ACE) by the National Institutes of Health who explores why overactive immune T cells mistakenly Using this curve as a guide, Associate (nih), an achievement that Yale scientists see as a catalyst destroy the insulin-producing beta cells in the pancreas, Professor of Genetics Zhaoxia Sun, for a new burst of collaborative work on the dysfunctions causing type 1 diabetes. “But there hadn’t really been an ph.d., and colleagues report in the De- of the immune system that underlie diverse diseases such outlet” for translation into clinical trials that would “enable cember 22, 2009 issue of Proceedings as diabetes, lupus, and multiple sclerosis. the investigators to get more in depth into the clinically of the National Academy of Sciences “We’re extremely strong in basic immunology, and our relevant immunologic questions,” he says. “Hopefully this that kidney cysts could be suppressed immuno­biology department is one of the best in the coun- center will do it.” in the fish with valproic acid, a drug try,” says Robert J. Alpern, M.D., dean and Ensign Profes- Crucial to these efforts is the arrival in 2009 of David used for epilepsy and bipolar disorder sor of Medicine. “What we have focused on in the last five A. Hafler, M.D., chair of the medical school’s Department under the trade name Depakote. The years is to take advantage of our best basic science and use of Neurology and Gilbert H. Glaser Professor. Hafler, also effectiveness of the compound was that as a nidus to spin off translational research. And the chief of neurology at Yale-New Haven Hospital (YNHH), then confirmed in mice by pkd expert new emphasis on autoimmunity is an example of that.” came to Yale from Harvard Medical School, bringing a Stefan Somlo, m.d., the C.N.H. Long Autoimmune diseases vary greatly in symptoms, but in wealth of expertise in MS. Hafler is a leader in the effort to Professor of Internal Medicine. all cases the underlying cause is the failure of the immune define the molecular basis and causes of MS, and he was “This is exciting,” says Sun, “be- system to recognize one’s own normal cells and tissues as among the first to apply the technique of T cell cloning to cause valproic acid is also in clinical “self”; rather, the immune system mistakes these benign human disease, identifying the targets of activated im- trials as a potential cancer drug and cells and tissues as foreign, and attacks them, causing in- mune cells in MS patients. has a known safety profile.” flammation and cell death. Because these diseases affect a But in keeping with Yale’s focus on the commonalities wide range of organ systems, about 70 Yale Medical Group of autoimmune diseases, Hafler has also done extensive re- physicians in diverse specialties treat some form of autoim- search on the mechanisms of type 1 diabetes, and currently A good drug is better mune disease. However, the underlying mechanisms in has an NIH-funded grant to study that disease. “If you look apparently quite different diseases, such as diabetes and at the genetics of autoimmune disease, there’s a striking when parents can help multiple sclerosis (MS), are remarkably similar—a fact that commonality of genetic variants. Presumably there is also Children with pervasive developmental has great implications for further research (see sidebar, an underlying similarity in terms of the immune system,” disorders (pdds) — autism, Asperger page 7). Yale’s ACE will, Herold hopes, stimulate collabora- Hafler says. “We don’t truly understand the pathogenesis disorder, and related disorders — may be tive research and pave the way for a greater understanding of any of these diseases at the level that we want to, but impulsive and aggressive to an extent of common mechanisms of and potential treatments for they have a commonality in terms of treatment. Some that severely affects their daily lives. autoimmune diseases. treatments are different, some are very similar, and some In previous work with colleagues in The ACE program is a collaborative effort between the are paradoxical,” he says, citing as an example anti-TNF, the National Institute of Mental Health National Institute of Allergy and Infectious Diseases, the which improves rheumatoid arthritis symptoms but seems (nimh) Research Units on Pediatric lead institution funding ACE; the Office of Research on to worsen MS. “These curious paradoxes give us great Psychopharmacology (rupp) Autism Women’s Health; and the National Institute of Diabetes insight into these diseases. It’s not a luxury—it’s almost Network, Lawrence D. Scahill, m.s.n., and Digestive and Kidney Diseases, all agencies of the NIH. a requirement—to look to the mainstream // ace (page 7) ph.d., professor of nursing and child In late 2009, Herold and Insoo Kang, M.D., associate pro- psychiatry, has shown that the drug fessor of medicine, applied for and received the grant that risperidone can temper the “Richter- established Yale’s ACE, now one of nine such centers in the scale” tantrums of children with U.S., which conduct collaborative research among them- autism. But the drug does not improve selves under the auspices of a national steering committee. Campaign gifts can sustain the “stimulus package” the core symptoms of pdds, and it has The ACE grant, which is renewable at five-year intervals, As described on page 6, researchers at the School of Medicine side effects, including weight gain and enables the Yale scientists to participate in clinical trials landed over $100 million in grants from the American Recovery and its associated health effects. and to initiate trials at Yale. Yale’s ACE will be a center in Reinvestment Act of 2009 (arra) to fund their research for the next In the December 2009 issue of the a trial of a new immunologic in Sjögren’s syndrome—an two years. Journal of the American Academy of autoimmune disease of the tear ducts and salivary glands— These investigators will answer many important questions in Child and Adolescent Psychiatry, rupp for instance. And “we are looking into trials for sclero- areas like cancer, Alzheimer’s disease, autism, and heart disease, researchers report that supplement- derma,” says Herold. but they will also uncover mysteries and new opportunities for ing risperidone treatment with parent It is an auspicious time for a melding of efforts in auto­ further study. In three years’ time, when arra funds are no longer training allowed them to significantly immunity at Yale, says Herold, who came to the School of available, how will those new studies be funded? reduce the dose of the drug while Medicine three years ago to direct the autoimmunity re- Private gifts to create research endowments are a lasting retaining its benefits. search in the Department of Immunobiology’s Human and and satisfying answer. Endowed funds provide secure funding, in Scahill and rupp colleagues have a Translational Immunology (HTI) program. HTI, directed perpetuity, for research in areas of mutual interest to donors and new nimh grant to assess the efficacy by Jordan S. Pober, M.D., PH.D., professor of immunobiol- scientists. These gifts are invested in the Yale Endowment and of parent training alone in preschool- ogy, dermatology, and pathology, aims to move advances historically, have enjoyed both secure, annual income, and solid age children with pdds accompanied by in basic immunology into a clinical setting. growth of principal—a permanent stimulus for top science. disruptive, noncompliant behavior. The “It was very clear to me, when I came here, that scat- For more details, contact Jancy Houck at (203) 436-8560. study, the first of its kind, will enroll 180 tered across the campus there were outstanding people children through five medical centers. doing translational work in autoimmunity,” says Herold, Endow a research fund: $100,000 and up

Medicine@Yale January / February 2010 3 out & about

November 19 The 17th annual Hunger November 26 With his wife, Beth Balschi, John W. Blanton, m.d., assistant clinical and Homelessness Auction sponsored professor of pediatrics, hosted 10 School of Medicine students for Thanksgiving Dinner by the Yale Health Professional Schools at their home in New Haven. (Front, from left) Balschi, Blanton, Warren Perry, and Hao raised nearly $20,000 to benefit New Feng. (Back, from left) Timothy Law, Nyasha George, Debra Smith, Tammi Marie-Phillip, Haven–area charitable organizations. Charles Odonkor, Samrawit Goshu, Juliana Tolles, and Bing Zhang. A silent auction that began on Nov. 16 included offerings of clothing, din- ners, food, and lessons in language, arts, dance, and sports. The live auction featured such prizes as tarot card read- ings, a vintage Epiphone guitar, and a chance to challenge a team fielded by Dean Robert J. Alpern, m.d., in a softball game this spring. 1. Wade Brubacher, a professional auctioneer from Kansas and father of fourth-year medical student

Jake Brubacher, handled the bidding at courtesy of john blanton the live auction. 2. Nancy R. Angoff, 1 m.p.h., m.d., associate dean for student john curtis (6) affairs (right), and Margaret J. Bia, m.d., November 30 A reception celebrat- professor of medicine, raised $800 with ing the appointment of David A. their “Girls’ Night Out,” which promised Hafler, m.d., as the inaugural Gilbert “good food, great company, juicy gossip, H. Glaser Professor was held at the and worldly wisdom.” 3. Second-year Cushing/Whitney Medical Histori- medical students Kristina Liu (left) and cal Library. Hafler, chair of neurology Ferrin Ruiz displayed one of the auction at the School of Medicine and chief items, a rendering of the medical school’s 2 of neurology at Yale-New Haven official coat-of-arms. 4. Second-year Hospital, is a leader in the effort to medical students Amy Forrestel (left) and better understand the molecular basis Julia Lubsen (right) peruse offerings at

terry dagradi of multiple sclerosis (see related story, the silent auction. 5. First-year medi- page 3). The new professorship was cal students Bixiao “Brian” Zhao (left) established by friends and colleagues of Glaser, professor emeritus of neurology and and Michael Alpert (at piano) provided chair of the Department of Neurology from 1971 to 1986. A widely recognized pioneer musical entertainment during the silent in the field, Glaser led Yale’s epilepsy program to become one of the foremost in the auction. 6. First-year Physician Associ- world. (From left) Hafler, Glaser, and Stephen G. Waxman, m.d., ph.d., Bridget Marie ate Program student Jennifer Paeske 3 Flaherty Professor of Neurology, Neurobiology, and Pharmacology, and chair of the makes a bid. Department of Neurology from 1986 to 2009. harold shapiro

December 7 Officials from PepsiCo marked the opening of a new PepsiCo Research Laboratory at Yale with a visit to New Haven. Research at the new lab, at 25 Science Park, adjacent to the Yale campus, will focus on the development of healthier food and bever- age products. PepsiCo will also fund a graduate fellowship to support research related to nutritional science as part of the School of Medicine’s Medical Scientist Training 4 Program (mstp), known informally on campus as the m.d./ph.d. Program. The new lab is PepsiCo’s ninth global regional research center. (Front, from left) Carolyn W. Slayman, ph.d., Sterling Professor of Genetics, deputy dean for academic and scientific affairs, and professor of cellular and molecular physiology; Robert J. Alpern, m.d., dean and Ensign Professor of Medicine; Mehmood Khan, m.d., chief scientific officer, PepsiCo; Mark Pirner, m.d., ph.d., director, clinical and scientific development strategy, PepsiCo. (Back, from left) Mary Resseguie, ph.d., senior scientist, PepsiCo; Derek Yach, m.b.ch.b., m.p.h., senior vice president, global health policy, PepsiCo; George A. Mensah, m.d., director, heart health and global health policy, PepsiCo; Robert S. Sherwin, m.d., the c.n.h. Long Professor of Medicine; Kevan Herold, m.d., professor of immunobiology and medicine; Gregory Yep, ph.d., global vice president, long-term research, PepsiCo; Patricia E. Pedersen, ph.d., associ- ate vice president for development and university director of corporate and foundation relations at Yale; James D. Jamieson, m.d., ph.d., professor of cell biology and director of the mstp; Kenneth R. Williams, ph.d., adjunct professor of research in molecular biophys- ics and biochemistry, and director of the School of Medicine’s W.M. Keck Foundation Biotechnology Resource Laboratory, the Yale/nhlbi Proteomics Center, and the Yale/nida Neuroproteomics Center; Amy P. Rich, m.p.h., senior associate director of corporate and foundation relations in Yale’s Office of Development; Heidi Kleinbach-Sauter, ph.d., senior 5 6 vice president, research and development, global foods, PepsiCo.

4 www.medicineatyale.org advances Health & Science News Study finds improved heart attack care Using new guidelines, hospitals are unblocking arteries more quickly, and improving patients’ outcomes

Patients with heart disease have benefitted enormously from janice carr/corbis advances in cardiology over the last few decades, including cholesterol-lowering statin drugs and better blood pressure Sniffing out a strategy medications. And if a heart attack should occur, percutaneous to defeat malaria coronary intervention (pci; more commonly known as balloon Humans spend $10 billion per year angioplasty) can be a lifesaver, opening up blocked arteries to on deodorants, but to mosquitoes restore blood flow to the heart. — including Anopheles gambiae, But with pci, time is of the essence. In 2006, in order to terry dagradi minimize lasting damage to heart cells from oxygen depri- carriers of malaria in sub-Saharan In a study evaluating emergency heart attack care Africa (see photo) — our sweat is the vation, the American College of Cardiology and 38 partner at 831 U.S. hospitals, Elizabeth Bradley (above), sweetest perfume. organizations launched a national campaign known as the Harlan Krumholz (left), and colleagues found a In the February 3 online edition D2B Alliance. To shorten “door-to-balloon” (D2B) times— significant improvement in “door-to-balloon” (D2B) of Nature, John R. Carlson, ph.d., the the time from when a patient enters the hospital to the point times — the time period between arrival at the when blood flow is restored to the heart by opening a block- hospital and completion of angioplasty — following Eugene Higgins Professor of Molecular, the implementation of new D2B guidelines set by Cellular, and Developmental Biol- age with angioplasty—the alliance set a goal of 75 percent of the American College of Cardiology and 38 partner ogy, and colleagues report that they patients receiving this life-saving heart attack care within 90 organizations. expressed a variety of A. gambiae minutes of hospital arrival. odorant receptors in a neuron on the In 2005, less than half of hospitals studied met those Some examples of strategies to reduce D2B times include antennae of mutant fruit flies. First guidelines for D2B times. But in a study of the most recent having emergency department staff able to activate the author Allison Carey, a student in data from the National Cardiovascular Data Registry (ncdr) catheterization laboratory with a single call, taking steps to the School of Medicine’s m.d./ph.d. published by a Yale-led team in the December 15, 2009 issue of ensure that a catheterization team can be in the lab within program, then recorded over 27,000 the Journal of the American College of Cardiology, more than 80 20–30 minutes of being paged, and promptly reporting data responses to 110 different odors. percent of hospitals met the guidelines. on D2B times to staff. The team found that many A. The study team surveyed D2B times in 831 hospitals par- Bradley’s co-author Harlan M. Krumholz, m.d., the Har- gambiae receptors are precisely tuned ticipating in the ncdr’s Cathpci Registry from April 1, 2005 old H. Hines Jr. Professor of Medicine and Public Health, and highly sensitive to components of to March 31, 2008. The survey showed marked reductions in said patients are now being treated so rapidly that in some human body odors, which helps them unnecessary delays in treatment and widespread adoption of cases the heart attack is aborted, damage is avoided, and locate and infect the hundreds of mil- recommended strategies to improve care. The improvement patients rapidly experience a full recovery. “This remarkable lions of people afflicted with malaria was seen not just in select hospitals or certain states, but leap in performance is a tribute to the nation’s interventional each year. across the nation. cardiologists and other healthcare professionals who quickly “Compounds that jam these “The key is to have a leader and a team devoted to a single adopted effective systems that were developed by nih- receptors could impair the ability of goal and to be persistent, even in the face of setbacks,” says sponsored research,” he says. mosquitoes to find us,” says Carlson. senior author Elizabeth H. Bradley, ph.d., professor of public “Most of what we read about in health care reform is about “Compounds that excite some of these health at the Yale School of Public Health and associate clinical health care financing,” Bradley adds. “This effort shows that receptors could help lure mosquitoes professor of nursing. “This campaign has changed the way the way care is organized can have tremendous impact, and into traps or repel them.” heart attack care is delivered—for the benefit of patients.” with relatively little added resources.”

Appreciating rna // Ritvo (from page 1) bone and soft tissue that mainly af- “It’s a wonderful program, and I Late last year, the Slifka Founda- fects teenage boys. It is an insidious give Ari Ritvo and Alan Slifka tremen- in a whole new way tion built on its tradition of innovative disease: like ovarian cancer, Ewing dous credit for doing all of this. These Not so long ago, biology textbooks de- philanthropy with a $3 million gift to sarcoma generally has no definitive are children who have a tremendous picted proteins as the workhorses that the School of Medicine establishing symptoms until after it has metasta- range of mental health needs, and carry out most biochemical reactions in the Riva Ariella Ritvo Professorship sized. Because of his advanced illness, so do their families,” says Volkmar. cells, while pigeonholing rna as a mere in pediatric oncology psychosocial Max was flown to Sloan-Kettering. “We want to be there to help address middleman between dna and proteins. services at the ycsc. After several rounds of grueling pressing issues, but we can also help to But over the past twenty years, it has “In providing this gift to Yale, chemotherapy, Max’s cancer regressed prevent future problems. We want to become clear that rna can play far Ariella Ritvo and Alan Slifka are pro- to the point that he was eligible for be involved at all levels, and the vision more complex roles. viding essential help for children with surgical treatment. Finally, following behind this gift is to do just that.” In the December 3, 2009 issue of cancer,” says Robert J. Alpern, m.d., surgery and a subsequent course of With improvements in diagnosis Nature, scientists in the laboratory of dean of the medical school and Ensign radiotherapy, he was declared to be in and therapy, more children than ever Ronald R. Breaker, ph.d., the Henry Ford Professor of Medicine. “The psychoso- remission in June 2008. before survive cancer. But the psycho- II Professor of Molecular, Cellular, and cial challenges faced by young cancer Throughout his ordeal, Max and logical aftermath, which in addition Developmental Biology and Howard patients are an important problem, and his family relied heavily on the counsel to emotional distress can include Hughes Medical Institute Investigator, in great need of philanthropic support.” and support of Abraham S. Bartell, the development of serious learning describe a slew of previously unknown The new gift has very personal m.d., a psychiatrist and psychopharma- disabilities in children who undergo rna-based structures that may carry roots. In October 2007, Ritvo and cologist at Sloan-Kettering specializing chemotherapy, is often overlooked. out complex biochemical functions. Slifka’s world was turned upside- in the psychosocial needs of young “The world needs to accommo- First author Zasha Weinberg, ph.d., down when Ritvo’s 16-year-old son, people with cancer and their families. date” the ever-increasing number of and colleagues in Breaker’s lab report in Max, fell ill with mysterious symp- In one of Ari Ritvo’s frequent phone survivors, says Ritvo. “It’s going to detail on two large, intricate structures toms. Complaining of minor back calls with Fred R. Volkmar, m.d., the cost some money to do epidemiologic built entirely of rna in bacteria. One, pain, which he first attributed to a Irving B. Harris Professor of Child surveys and conduct research to de- golld, appears to help viruses that possible sports injury—he is a second- Psychiatry and director of the ycsc, termine who these kids are, and what infect bacteria to burst out of infected degree black belt in martial arts—Max Volkmar said that the ycsc had pro- their specific needs are during and after cells so that they can seek new targets. Ritvo soon developed a fever, which vided seed money for a Yale program treatment.” Another, hearo, might be a mobile ge- got steadily worse, and he was finally providing psychosocial services to Max Ritvo, now a Yale freshman netic element that causes sponta­neous raced to a Santa Monica, Calif., hospi- pediatric oncology patients. Because of in Jonathan Edwards College in the genetic change. tal for evaluation. the difference such services had made Directed Studies program, continues Breaker says the research helps us “Within a week,” recalls Ari Ritvo, in her family’s life, Ritvo encouraged to do well. He has joined the board of come to grips with how cells such as “I went from having a boy with a fever Volkmar to submit a pilot program pro- Kids Kicking Cancer, a Detroit-based our own really function. “Every time and a minor backache to admitting posal to the Slifka Foundation, which nonprofit organization that helps we feel as though we’re giving rna just him to the emergency room.” agreed to take over funding for the pediatric oncology patients manage about the right amount of credit,” he Max was ultimately diagnosed program. Then she and Slifka decided stress through meditation and the says, “we find more amazing rnas.” with Ewing sarcoma, a cancer of the to establish the new professorship. martial arts.

Medicine@Yale January / February 2010 5 Grants and contracts awarded Infection and Disease, 3 years, $300,000 • Sree- 1 year, $20,709 • Marc Potenza, Nat’l Center for ganga Chandra, W.M. Keck Foundation, Mecha- Responsible Gaming, The Yale Gambling core nisms of Synapse Maintenance: Role in Neurode- (Center of Research Excellence), 3 years, $402,498 to Yale School of Medicine generative Disorders, 1 year, $25,000 • Robert Yibing Qyang, Connecticut Innovations Inc., Deri- Collins, Jane Coffin Childs Memorial Fund for vation and Functional Characterization of Heart May/June 2009 Medical Research, Engineering of tpr Domains to Cells from Human Embryonic Stem Cells, 2 years, Recognize Cell-surface Receptors, 2 years, $94,583 $200,000 • Carrie Redlich, Center to Protect Federal Pietro De Camilli, Nat’l Alliance for Research on Workers’ Rights, Risk of Isocyanate Exposure in the Philip Askenase, nih, The Role of aids in Contact 2 years, $618,142 • Haiqun Lin, nih, Longitudinal Schizophrenia and Depression (narsad), Phos- Construction Industry, 1 year, $30,000 • David Sensitivity, 2 years, $455,125 • Sonia Caprio, nih, Study of Transitions in Disability and Death among phoinositide Metabolism and Psychiatric Diseases, Rimm, Associazione “Sandro Pitigliani” per la Metabolic Markers and Predictors of Childhood Older Persons, 3 years, $989,825 • James Mazer, 1 year, $99,999 • Clare Flannery, Endocrine Lotta Contro i Tumori, Evaluation of Topoisomer- Obesity, 5 years, $1,373,650 • Kelly Cosgrove, nih, nih, Allocation and Control of Visual Attention, Fellows Foundation, Effect of Hyperinsulinemia on ase IIa Protein by a Novel Approach (aqua, Auto- Dopaminergic and Endocannabinoid Interactions 2 years, $768,627 • Gil Mor, nih, Function of Toll- Endometrium, 1 year, $15,000 • Martín García- mated Quantitative Analysis), 1 year, $27,390; saic- in Nicotine Dependence, 1 year, $194,700 • Jared Like Receptors Throughout Gestation, 5 years, Castro, Connecticut Innovations Inc., Molecular Frederick, Inc., Intrinsic Controls for Formalin-Fixed, Davis, nih, Investigating the Mechanism of mrna $5,491,503 • Sukanya Narasimhan, nih, Tick Profiling and Cell Fate Potential of hesc Derived Paraffin-Embedded Tissue, 3 years, $569,643 Cleavage in the Ribosomal A-Site, 2 years, $96,856 Midgut Proteins Critical for Borrelia Transmission, Early Neural Crest Precursors, 2 years, $200,000 Craig Roy, Columbia University, Pathogenic Mech- Robin de Graaf, nih, Cerebral Metabolic Flux 2 years, $455,125 • Alexander Neumeister, nih, Nathan Hansen, Duke University, Brief Care-Based anisms of Coxiella burnetii, 10 months, $329,103 Mapping using Oxygen-17 nmr, 2 years, $903,284 Serotonin 1B Receptor Imaging in Major Depressive hiv Prevention for Newly Diagnosed Men, 1 year, Joseph Sarhan, American Heart Association— Ralph DiLeone, nih, Development of Neuronal Disorder, 2 years, $353,386 • Michael Nitabach, $2,483 • Kevan Herold, Duke University, Pilot, Founders Affiliate, hnrnps as MK2 Substrates in Tracers to Study Leptin Modulation of Dopamine nih, Novel Analgesics from Australian Funnel-Web Optimization and Testing of Nanoparticulate- Leukocyte Integrin-Induced Interferon-Gamma Circuits, 2 years, $389,125 • Maria Diuk-Wasser, Spider Venom, 2 years, $455,125 • Samuel Sathy- Based Non-Invasive Imaging in Autoimmune mrna Stabilization, 4 months, $5,000 • Masanori nih, Determining the Reservoir for Host-Targeted anesan, nih, Role of Transcription Factors in the Disease (ace), 1 year, $165,500; Connecticut Inno- Sasaki, Talecris Biotherapeutics, Inc., Combined Control Measures to Prevent Lyme Disease, 2 years, Action of Antipsychotic Drugs, 2 years, $389,125 vations Inc., Induction and Differentiation of Beta Intravenous Immunoglobulin and Cell Therapy for $165,500 • Robert Dubrow, nih, Framework Albert Sinusas, nih, Hybrid Volumetric spect/ct Cells from Human Embryonic Stem Cells, 2 years, Spinal Cord Injury, 2 years, $225,000 • Nenad Program for Global Health at Yale University, Imaging System, 1 year, $500,000 • Jeffrey Sklar, $200,000 • Yingqun Huang, Connecticut Innova- Sestan, March of Dimes, Molecular Control of 2 years, $270,000 • Barbara Ehrlich, nih, Regula- nih, Trans-Splicing of rna in Endometrial Stroma tions Inc., Molecular Function of Lin28 in Human Cortical Projection, Neuron Identity, and Connec- tion of Cholangiocytes by InsP3 Receptor Isoforms, and Other Tissues, 5 years, $1,665,114 • Thomas Embryonic Stems Cells, 4 years, $500,000 • Jeffery tivity, 3 years, $295,255 • Eva Sevcsik, Max Kade 4 years, $1,729,897 • Sorin Fedeles, nih, Molecular Steitz, nih, Structural Bases of the Functions of Kocsis, Connecticut Innovations Inc., Cellular Foundation, Inc., Role of Oxidative Stress in Aggre- Pathogenesis of Autosomal Dominant Polycystic rna-Protein Machines, 5 years, $7,732,270 Transplantation of Neural Progenitors Derived from gation and Membrane Interaction of Alpha- Liver Disease (adpld), 2 years, $50,988 • Erol Fikrig, Stephen Strittmatter, nih, Axonal Growth Cone Human Embryonic Stem Cells to Remyelinate the Synuclein, 1 year, $49,000 • Steven Southwick, nih, Circadian Regulation of Innate Immune Mech- Signal Transduction, 3 years, $1,422,273 • Scott Nonhuman Primate Spinal Cord, 4 years, $500,000 Mount Sinai School of Medicine, wtc rhc Data anisms of Viral Recognition, 2 years, $455,125 Strobel, Dept. of Defense (U.S.), Investigation of Graciela Krikun, Aniara Diagnostica, Detection of and Coordination Center, 1 year, $76,155 • David Jorge Galán, nih, Molecular Mechanisms of Sal- Diesel Producing Fungi as a Renewable Source of Plasma TF Expression and Activity in Women with Stern, Harry J. Lloyd Charitable Trust, Identifying monella typhi Pathogenicity, 2 years, $631,892 Fuel, 5 years, $4,175,381 • Joann Sweasy, nih, dna Endometriosis, 1 year, $5,000 • Harlan Krumholz, New Targets for Personalizing Melanoma Thera- Alison Galvani, nih, Impacts of Individual and Polymerase Beta and Mutagenesis, 5 years, National Bank of Egypt, Improving Healthcare in pies, 1 year, $120,000 • Stephen Strittmatter, Social Behavior on Influenza Dynamics and $1,628,932 • Cenk Tek, nih, Lifestyle Modification Egypt, 2 years, $534,492 • Maria Lara-Tejero, Wings for Life Spinal Cord Research Foundation, Control, 5 years, $2,986,225 • Kevan Herold, nih, to Reduce Weight and Related Morbidity in Mental Columbia University, The Interactions of Type III Imaging of Axonal Growth after Human Spinal Yale Autoimmunity Center of Excellence, 5 years, Illness, 2 years, $1,345,812 • Timur Yarovinsky, nih, Secretion Effector Proteins, 10 months, $82,750 Cord Injury, 1 year, $126,426 • Richard Sutton, $3,886,266 • Sohail Husain, nih, Ryanodine Recep- Type I Interferon-Induced Protection from Staphy- Qi Li, Connecticut Innovations Inc., Neural Stem Connecticut Innovations Inc., Genome-Wide tor in Pancreatitis, 5 years, $1,731,406 • Melinda lococcal Pore-Forming Toxins, 2 years, $443,892 Cell Responses to Hypoxia, 2 years, $200,000 Screen to Identify hesc-Specific dna Transcription Irwin, nih, Impact of Exercise on Ovarian Cancer Jun Lu, Connecticut Innovations Inc., Microrna Elements, 4 years, $500,000 • Oyebode Taiwo, Prognosis, 5 years, $3,375,064 • Akiko Iwasaki, nih, Non-Federal Regulation of hesc Fates, 4 years, $500,000 Stanford University, Disease, Disability and nlr Control of Antiviral Defense in the Respiratory Steven Bernstein, Montefiore Medical Center & Stephanie Massaro, Connecticut Innovations Inc., Death in an Aging Workforce, 1 year, $688,344 Mucosa, 2 years, $455,125 • Susan Kaech, nih, Hospital, Trial to Test the Efficacy of a Tailored The Influence of Aberrant Notch Signaling on RB Hugh Taylor, John B. Pierce Laboratory Inc., Determining How Adjuvants Alter Effector and Intensive Smoking Cessation Intervention in Mediated Cell Cycle Regulation in Acute Mega- Estrogen & Progesterone Effects on Orthostatic Memory T Cells during Vaccination, 2 years, Persons Living with aids, 1 year, $12,793 • Linda karyoblastic Leukemia, 2 years, $200,000 • Eric Tolerance, 2 years, $82,579 • Penghua Wang, $455,125; nih, Control of Effector and Memory T Bockenstedt, Nat’l Research Fund for Tick-Borne Meffre, Juvenile Diabetes Research Foundation Northeast Biodefense Center, Roles of Auto- Cell Development by Inflammatory Signals, 5 years, Diseases, Inc., Real-Time Imaging of Vector-Borne Int’l, Loss of B Cell Tolerance That is Common to RA, phagy in Flaviviral Immunity, 10 months, $2,060,662 • Barbara Kazmierczak, nih, Regula- Borrelia burgdorferi Infection in Mice, 1 year, sle and T1D, 7 months, $220,000 • Angus Nairn, $82,750 • Sandra Wolin, Connecticut Innova- tion of Motility and Organelle Assembly at the $60,000 • Mary Bogucki, Spectral Energetics, Inc., Michael Stern Parkinson’s Research Foundation, tions Inc., Investigating the Role of Nuclear rna Pseudomonas aeruginosa Pole, 2 years, $820,950 Non-Ionizing Radiation Vision for a New Army Identification of Neuron-Specific Protein Expression Surveillance in Embryonic Stem Cells, 2 years, David Kingery, nih, Exploring the Transition State (nirvana), 5 months, $27,234 • Angelique Bordey, and Post-Translational Modifications Involved in $200,000 • Tian Xu, Connecticut Innovations of Ribosomal Peptide Bond Catalysis, 2 years, Elsa U. Pardee Foundation, Control of Blood Flow Parkinson’s Disease, 1 year, $495,280 • Kevin Pel- Inc., piggyBac Transposon for Genetic Manipula- $41,176 • Anthony Koleske, nih, Regulation of in Glioma, 1 year, $123,963 • Michael Cappello, phrey, Duke University, Longitudinal Functional tion and Insertional Mutagenesis in Human Invadopodia Formation in Breast Cancer Cells, March of Dimes, Mucosal Immunity to Hookworm Imaging of Early Childhood Anxiety Disorders, Embryonic Stem Cells, 4 years, $500,000

‘Stimulus package’ grants saving jobs, building infrastructure, advancing research at Yale The $787 billion American Recov- Connecticut, Yale is a major contributor the brain and spinal cord. Strittmat- ery and Reinvestment Act of 2009 to the Connecticut economy. According ter recently helped to found Axerion, a (arra), colloquially known as “the to the Connecticut Center for Economic new company that is developing drugs stimulus package,” is helping to con- Analysis, salaries, wages, and benefits based on Strittmatter’s work. Within struct and repair roads and bridges, paid by Yale contributed $1.3 billion to the next six months, New Haven-based weatherize buildings, and create a the Connecticut economy in 2007. Axerion plans to hire as many as 20 new energy infrastructure based on Medical school scientists are already researchers and managers. renewable resources. putting arra funds—and Connecticut’s Likewise, a $331,000 arra grant to But arra is also helping to build citizens—to work, beefing up research Peter M. Glazer, m.d., ph.d., the Robert biomedical knowledge at Yale, and programs in areas as diverse as cancer, E. Hunter Professor of Therapeutic creating or saving American jobs in Alzheimer’s disease, autism, heart dis- Radiology and professor of genetics, the bargain. ease, multiple sclerosis, addiction, and will help him to pursue an exciting by the end of 2009 (see related story, At press time, Yale University as preventing suicide among adolescents. new approach to treating disease using page 1). a whole had received $121.6 million Moreover, in recent years, dis- a genetic “fix-it kit” that can provide “The medical school’s impressive in arra grants, $101.5 million of coveries by scientists at the School of a sustained cure for diseases such as success rate in arra applications is which was awarded to the School of Medicine have fueled a growing biotech sickle-cell anemia, hiv/aids, and many a testament to the very high caliber Medicine for research during the next industry in the New Haven area, which cancers. A local start-up company, Helix of science conducted at Yale,” says two fiscal years. itself employs approximately 1,400 peo- Therapeutics, has licensed patents for Dean Robert J. Alpern, m.d., “and During the spring and early summer ple. arra funding will provide further Glazer’s technology from Yale, and last also to the phenomenal energy of our of 2009, medical school faculty and staff momentum to this trend by helping Yale year secured its first $965,000 of seed investigators and their research and submitted more than 775 applications for researchers to commercialize technolo- capital from the state of Connecticut administrative teams.” arra grants, a full 25 percent of which gies and stimulate investments to start and other investors to hire scientists and were funded. In addition to 200 awards new companies by establishing “proofs begin research operations. already approved, another 41 proposals of concept” for early-stage treatments. Six of the largest grants, made correction In a story in our last issue about a new professor- totaling $52 million for construction For example, Stephen M. Strittmat- through the nih’s arra-funded ship established by Jonathan and Richard Sackler, projects and high-end instrumentation ter, ph.d., Vincent Coates Professor of Grand Opportunities (GO) program, we misprinted the first name of the Sacklers’ father, Raymond, and mistakenly stated that are still under review. Neurology and professor of neurobiol- are based around the Yale Center for Raymond and his wife, Beverly, had endowed the As the largest employer in New ogy, received $481,000 in arra funds Genome Analysis, which will be up Sackler Wing at the Royal Academy of Arts, rather than the Raymond and Beverly Sackler Galleries at Haven and the third largest employer in for his research on repairing injuries of and running on Yale’s West Campus the British Museum. We regret the errors.

6 www.medicineatyale.org // ace (from page 3) shares these samples with Kang, who // Genes (from page 1) sequencing tools would transform the science of immunology to explain studies T cells. “There’s a lot of overlap protein-coding regions where disease- work of researchers across the medical these things.” in our research,” Meffre says. causing mutations are most likely to school. They established the ycga, a Meffre, who joined the immuno- A push for contiguous labora- occur. The Lifton group—which in- core resource that will not only accom- biology faculty in 2008 and whose tory space is another aspect of Yale’s cluded ycga Director Shrikant Mane, modate a growing demand for genomic research is focused on B cell tolerance new collaborative research in auto- PH.D.; Postdoctoral Associates Murim sequencing, but also keep Yale research- (the extent to which these immune cells immunity. Though the particulars Choi, PH.D., and Ute I. Scholl, m.D.; ers at the forefront of human genetics. are reactive or nonreactive to self), has are yet to be determined, a group of and Research Associate Irina R. Tik- With support from the Ameri- uncovered similar functional abnor- principal investigators is slated to honova, PH.D., of the medical school’s can Recovery and Reinvestment Act malities in B lymphocytes from move this year into a single interdis- W.M. Keck Foundation Biotechnology (arra; see related story, page 6), 12 of patients with type 1 diabetes, rheuma- ciplinary auto­immunity lab dedicated Resource Laboratory—worked out an the latest-generation Illumina gene- toid arthritis, and lupus. For Meffre, exclusively to human studies. The exome sequencing method that com- sequencing machines, which will vastly the ace grant has already led to new centralized laboratory space bines gene-chip technology to isolate increase medical school researchers’ increased collaboration with other Yale will also house scientists working in the target DNA with the latest high- ability to perform high-throughput scientists. As part of one ace project, transplant and tumor immunology throughput sequencing techniques genomic analysis, are being installed for instance, a former colleague in Paris and in neurology. and hardware to decode it. at the ycga. sends Meffre samples from Sjögren’s “This new center for research on The approach yields a quick and The medical school’s early invest- syndrome patients, which he analyzes human autoimmunity,” Herold says, comprehensive view of an individual’s ment in this approach has already for B cell function. But Meffre also “will be a very exciting place.” genes for a few thousand dollars, or 10 jump-started a substantial amount to 20 times cheaper than sequencing of new research: of six major arra the entire genome. research grants the School of Medicine Autoimmunity: research on many fronts This “capture and sequence” received recently, five were based on method can be applied to virtually any this new sequencing technology. disease and will accelerate the pace of “This is an area where we are lead- discovery of new genes related to both ers,” Lifton says, “and we want to take abraham bothwell cho craft eynon fahmy flavell hafler herold kang rare and common conditions. advantage of that.” Even as they were developing the technology, Lifton and Mane could Yale Netcast: “Genes: You Are What You Inherit” kocsis mamula medzhitov meffre ruddle sherwin shlomchik waxman wen already envision how large-scale Available on iTunesU or at medicineatyale.org Inflammatory bowel disease (ibd) ibd is a group of inflammatory conditions of the colon and small intestine that includes Crohn’s disease and ulcerative colitis. // Haiti (from page 1) medical care. Wounds that would • Clara Abraham, m.d. Assistant professor of medicine director of the Yale Center for Pub- have been minor if treated early be- • Judy H. Cho, m.d. Associate professor of medicine and genetics lic Health Preparedness; and Maria came grossly infected, often requiring • Richard A. Flavell, ph.d. Chair and Sterling Professor of Immunobiology Bouffard, director of emergency man- amputation. “As horrible as something agement services at Yale University. like amputation is in this country, • Ruslan M. Medzhitov, ph.d. Professor of immunobiology A medical team was assembled, we have paved roads, we have public Lupus (sle) including Larkin; Nousheh Saidi, m.d., transportation, we have crutches and In this chronic disease, formally known as systemic lupus erythematosus, or sle, assistant professor of anesthesiology; wheelchairs and prostheses. These pa- the immune system attacks the skin, joints, blood, and kidneys. orthopaedic surgeon Peter Boone, m.d., tients don’t have any of those things,” • Joseph E. Craft, m.d. Professor of medicine and immunobiology of St. Vincent’s Hospital in Bridge- Larkin said at a February 1 press • Tarek Fahmy, ph.d. Associate professor of biomedical engineering port, Conn.; and physician assistant conference after the team’s return and chemical engineering Donald MacMillan, pa, and nurse to New Haven. “It’s hard enough to • Insoo Kang, m.d. Associate professor of medicine Tom Kimberly, aprn, of the Yale-New walk around on their dirt roads with • Mark J. Mamula, ph.d. Professor of medicine Haven Hospital (ynhh) emergency two working legs.” Saidi described • Eric Meffre, ph.d. Associate professor of immunobiology department. Ralph Jean-Mary, busi- the team’s work as a “drop of water in • Mark J. Shlomchik, m.d., ph.d. Professor of laboratory medicine and immunobiology ness manager for ynhh and a native of an ocean” of devastation, but she was Haiti, later joined the group to assist as glad to be able to help at least some of Multiple sclerosis (MS) an interpreter and with logistics. the victims. “If the team wasn’t there In MS, T cells (and probably also B cells) damage and scar the fatty myelin sheaths On January 26, a jet carrying the I don’t know when or if they would that insulate axons in the brain and spinal cord. Yale team and a donated, 1,500-lb. have had surgery,” she said. • David A. Hafler, m.d. Chair of Neurology and Gilbert H. Glaser Professor cargo of much-needed medical supplies The medical team’s efforts were co- • Nancy H. Ruddle, ph.d. John Rodman Paul Professor of Epidemiology touched down in the port city of Cap- ordinated in New Haven by Kimberly and professor of immunobiology Haïtien, Haiti. A small plane then took A. Davis, m.d., associate professor of • Stephen G. Waxman, m.d., ph.d. Bridget Marie Flaherty Professor of Neurology, them over mountainous terrain to the surgery, chief of the section of trauma, Neurobiology, and Pharmacology city of Hinche, about 50 miles north- surgical critical care and surgical emer- • Jeffery D. Kocsis, ph.d. Professor of neurology and neurobiology east of Port-au-Prince, where earth- gencies, and trauma director at ynnh. quake victims were being evacuated to “It should be a source of great pride Rheumatoid arthritis (RA) the Hôpital Sainte Thérèse, a hospital for our faculty and staff that, not only RA is a chronic autoimmune disorder that involves many tissues and organs — especially operated by the worldwide health care did key faculty leaders like Drs. Davis, the joints, where inflammation leads to pain, stiffness, and the destruction of cartilage. organization Partners in Health. Degutis, and Larkin, respond quickly • Eric Meffre, ph.d. Associate professor of immunology A small hotel in Hinche owned by to this tragedy, but we have such a Sjögren’s syndrome Jean-Mary’s parents provided lodg- broad range of talent that was eager to In Sjögren’s syndrome, immune cells attack the glands that produce saliva and tears. ing for the Yale team. For the next help,” says Leffell. “That’s what doctors Scientists believe that “misbehaving” B and T cells may be a cause. six days, they provided life-saving do. We help people in need.” • Insoo Kang, m.d. Associate professor of medicine medical, trauma, and surgical care at • Eric Meffre, ph.d. Associate professor of immunobiology the hospital for scores of children and (From left) Tom Kimberly, Nousheh Saidi, • Nancy H. Ruddle, ph.d. John Rodman Paul Professor of Epidemiology adults, and also instructed local doc- Rick Frechette, Gregory Luke Larkin, Donald and professor of immunobiology tors and nurses in the use of monitor- MacMillan, Peter Boone, and Ralph Jean-Mary ing and anesthesia equipment. in Hinche, Haiti, where they provided medical Type 1 diabetes The group treated fractures and care to earthquake victims. The team also delivered medical supplies to Frechette, a In Type 1 diabetes, T cells destroy insulin-producing beta cells in the pancreas. Some crush injuries, many of which were priest and physician who directs the St. Damien scientists implicate an autoimmune response meant to target virus-infected cells. worsened by the delay in obtaining Hospital in Port-au-Prince. • Alfred L.M. Bothwell, ph.d. Professor of immunobiology • Elizabeth E. Eynon, ph.d. Research scientist in immunobiology • Richard A. Flavell, ph.d. Chair and Sterling Professor of Immunobiology • David A. Hafler, m.d. Chair of Neurology and Gilbert H. Glaser Professor • Kevan Herold, m.d. Professor of immunobiology and medicine • Mark J. Mamula, ph.d., m.s. Professor of medicine • Eric Meffre, ph.d. Associate professor of immunobiology • Nancy H. Ruddle, ph.d. John Rodman Paul Professor of Epidemiology and professor of immunobiology • Robert S. Sherwin, m.d. C.N.H. Long Professor of Medicine

• Li Wen, m.d., ph.d. Senior research scientist in medicine donald macmillan

Medicine@Yale January / February 2010 7 Pioneer in studies of innate immunity wins Rosenstiel Award Ruslan Medzhitov, ph.d., the David W. and the late Yale in mammalian cells, and tlrs quickly of Molecular Biophysics and Biochem- Wallace Professor of Immunobiology immunobiologist recognize these patterns. Because istry, for her work with small nuclear and a Howard Hughes Medical Insti- Charles A. Janeway of their ability to potently stimulate ribonucleoproteins; (2001) Thomas A. tute investigator, has been awarded Jr., m.d., published adaptive immune responses, tlrs are Steitz, ph.d., Sterling Professor of Mo- the 2010 Lewis S. Rosenstiel Award for a seminal paper in promising drug targets. lecular Biophysics and Biochemistry and Distinguished Work in Basic Medical the journal Na- Sharing the award this year is Jules professor of chemistry and a winner of Science. ture showing that Hoffman, ph.d., of the National Center the 2009 Nobel Prize in Chemistry for The Rosenstiel Award, established proteins known as of Scientific Research in Strasbourg, contributions to determining the struc- Ruslan Medzhitov in 1972 by Brandeis University, has a Toll-like receptors France. Hoffman discovered the im- ture of the ribosome; (1996) Thomas long record of identifying and honoring (tlrs) performed a crucial role in sens- mune function of tlrs, which were D. Pollard, m.d., chair and Sterling pioneering scientists. Many winners of ing microbial infections and alerting previously thought to play only a devel- Professor of Molecular, Cellular, and the award have subsequently gone on the adaptive immune response to act opmental role, in the fruit flyDrosophila Developmental Biology and professor of to win other major prizes in biomedical against them. melanogaster. molecular biophysics and biochemistry, research, including the Nobel Prize. A tlrs work as a first line of defense Past Yale winners of the Rosen- for his contributions to the understand- $30,000 cash prize and a medal accom- against infection by detecting large stiel Award include: (2008) Arthur L. ing of molecular motors; and (1989) Sid- panies each award. molecules common to many patho- Horwich, m.d., Sterling Professor of ney Altman, ph.d., professor of biology, The award to Medzhitov is for gens. For example, the outer mem- Genetics and professor of pediatrics, for discovering the catalytic properties his “elucidation of the mechanisms of branes of many infectious bacteria for his work in protein folding; (2002) of rna. Altman won the Nobel Prize in innate immunity.” In 1997, Medzhitov contain structural elements not found Joan A. Steitz, ph.d., Sterling Professor Chemistry the same year.

Developer of new cancer drugs is honored with international award Joseph Schlessinger, ph.d., chair D.C., in April, and the 5th Annual U.S. Food and Drug Administration excitement because it appears to selec- and William H. Prusoff Professor of Stanley J. Korsmeyer Lecture in Padua, in January 2006 for advanced kidney tively target a cancer-causing muta- Pharmacology, has been named winner Italy, in May. Schlessinger will then cancer and for a stomach cancer known tion of a gene involved in metastatic of the 2010 Pezcoller Foundation–aacr receive the award—which includes a as gastrointestinal stromal tumor, or melanoma without affecting normal International Award prize of €75,000 and a commemorative gist. That drug, now marketed by versions of the gene, findings which for Cancer Research. plaque—at a ceremony in Trento, Italy, Pfizer as Sutent, and other drugs based suggest that other cancer-causing mu- The award, on May 7. on Schlessinger’s discoveries are being tations may also be precisely targeted. established in 1998, In a scientific career that has tested as treatments for more common The Pezcoller Foundation was recognizes a scientist spanned three decades, Schlessinger renal cancers, as well as breast and established in 1980 by Alessio Pezcol- “of international re- has discerned the mechanism of action other cancers. ler, an Italian medical professor and nown who has made of a family of surface receptors and The December 18, 2009 issue of the surgeon. In addition to sponsoring this a major scientific revealed their roles as critical drivers journal Science featured a news article award, the foundation also sponsors a Joseph discovery in basic of a variety of cancers. These studies on the remarkable clinical results series of symposia, publishes a journal, Schlessinger cancer research or provided the conceptual foundation obtained in metastatic melanoma with and supports awards for early-career who has made significant contribu- for the development of tyrosine kinase plx4032, a new compound developed scientists from Europe who have tions to translational cancer research.” inhibitors as successful new drugs for by Plexxikon, a biotech company submitted highly rated abstracts for As the winner of the award, Schles­ the treatment of many cancers. Schlessinger cofounded. In a Phase I presentation at the aacr’s annual singer will give two lectures on his Schlessinger has cofounded three trial, plx4032 had an unprecedented meeting. The aacr was founded by a work, one at the 101st annual meeting biotechnology companies and served 70 percent response rate in treating the group of 11 scientists in 1907, and now of the aacr (American Association as an advisor to several others—work disease. plx4032, which has moved has nearly 27,000 members in more for Cancer Research) in Washington, that led to a drug approved by the into Phase III trials, has generated than 60 countries.

Yale Cancer Center director is named inaugural Sackler Professor Thomas J. Lynch Jr., m.d., has been 136-acre West Cam- professor of genetics at Rockefeller wife, Beth, head the Richard and Beth named the inaugural Richard Sackler pus, for which he University, serves on ycc’s Advisory Sackler Foundation. Jonathan Sackler and Jonathan Sackler Professor of will recruit a direc- Board and the Yale School of Medi- and his wife, Mary Corson, lead the Medicine and Yale Cancer Center tor and senior and cine’s Dean’s Council. He and his Stamford-based Bouncer Foundation. Director. Lynch, who joined the Yale junior scientists faculty in 2009, is also physician-in- in the fields of cell chief at Smilow Cancer Hospital. signaling, cancer Lynch is renowned for his re- immunology, and Thomas Lynch steitz in stockholm search on the relationship between drug development. On December 10, in the elegant and festive genetic variations and the effective- Lynch received his undergraduate setting of the Stockholm Concert Hall, King ness of cancer therapies. An author- degree from Yale College in 1982 and Carl XVI Gustaf of Sweden presented the ity on lung cancer, he has conducted his medical degree from Yale School 2009 Nobel Prize in Chemistry to Thomas A. dozens of studies of “personalized” of Medicine in 1986. He completed Steitz, ph.d., Sterling Professor of Molecular cancer therapy—taking account his internship and residency at Mas- Biophysics and Biochemistry, for his semi- of small differences in patients’ sachusetts General Hospital (mgh), nal research in structural biology. genomes, or in the genetic makeup and after completing a fellowship in During the 1990s, Steitz, also profes- of their tumors, to tailor their treat- medical oncology at the Dana-Farber sor of chemistry and Howard Hughes ment with the most appropriate Cancer Institute, joined the mgh Medical Institute Investigator, and Yale anticancer agents. medical staff in 1993. At Harvard colleagues used X-ray crystallography to For example, in 2008, the Journal Medical School and mgh, he was determine the three-dimensional structure of Clinical Oncology published the professor of medicine and chief of of the large subunit of the ribosome at results of a multicenter clinical trial hematology/oncology. 2.4 angstroms — a resolution high enough led by Lynch that showed that lung Richard S. Sackler, m.d., and his for the researchers to model each of the cancer patients with mutations in brother, Jonathan Sackler, joined structure’s individual atoms. a gene known as egfr did twice as forces in 2009 to create a $3 million The ribosome is a cellular organelle that well after treatment with the drug endowment establishing the new is crucially involved in protein synthesis. gefenitib (Iressa) as do patients in professorship, expressly intended to Because many antibiotics work by target- the general population after standard be held by those appointed as director ing and shutting down the ribosomes of chemotherapy. of Yale Cancer Center (ycc). Richard bacteria, Steitz’s research is now guiding Lynch also oversees a new In- Sackler, co-chairman of Stamford- the development of new drugs for the stitute for Cancer Biology at Yale’s based Purdue Pharma and adjunct treatment of antibiotic-resistant infections. courtesy of the nobel foundation

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