march 2013 volume 9, issue 1 Advancing Biomedical Science, Education, and Health Care

Yale Cancer Center benefits doubly from generosity United Technologies supports “Smilow Cancer Hospital is now Easing suffering, ‘the power of innovation’ in delivering great service to the com- giving support munity, including utc employees,” Yale’s cancer care and research says Louis Chênevert, chairman and at the end of life ceo of United Technologies. “Our United Technologies Corporation company has a long history of sup- The Palliative Care (utc), a Hartford-based multinational porting leading organizations in our Program at Yale manufacturer and ’s largest communities, and Yale Cancer Center Cancer Center private employer, has donated $3 mil- is a proven leader.” (ycc) has received Jennifer Kapo lion to establish a new endowed profes- The new professorship, which a $1 million gift sorship at Yale Cancer Center (ycc). will support the full-time research from the Milbank Foundation for

The gift, which establishes the activities of a faculty member whose courtesy of united technologies corp Rehabilitation. United Technologies Corporation primary research focus is cancer, is (From left) Mark Reitsma, a utc employee Directed by Jennifer M. Kapo, Professorship in Cancer Research, also part of what Chênevert describes and patient at Smilow Cancer Center, and m.d., associate professor of internal stems from utc’s long-time commit- as utc’s “broader efforts of promot- Louis Chênevert, ceo of utc. medicine and chief of palliative medi- ment to supporting cancer care and ing employee wellness.” to live. And then, at his supervisor’s cine at Smilow Cancer Hospital at research, and represents a deepened Mark Reitsma, utc’s manager of recommendation, he sought a second Yale-New Haven, the Palliative Care commitment by utc to what its lead- Global Human Resources Support opinion at Smilow. Program focuses on managing symp- ers see as a track record of success at Operations, is one of many United Under the care of Scott N. Get- toms and quality of life issues for Yale. In July 2008, utc announced Technologies employees who have tinger, m.d., associate professor of adult patients with serious, chronic, a $1 million gift to Smilow Cancer been treated for cancer at Smilow. Di- medicine, Reitsma’s treatment has in- progressive, or terminal cancers at Hospital at Yale-New Haven, which agnosed with stage 4 lung cancer in cluded chemotherapy and new Phase the hospital. The donation will sup- was then under construction and 2010, Reitsma was initially told that I clinical trial drugs. Not only has his port the program’s services, research, which opened in 2009. he had only a few months or years disease been stable, but // utc (page 7) and palliative care // Milbank (page 7) New ceo will lead medical school’s clinical practice Executive arrives at a time of major in the breadth and depth of clinical programs. With growth in Yale’s practice, and change these developments has come the need for a more centralized and unified physician group practice. in American medicine as a whole On a national scale, the passage and implementa- tion of the Affordable Care Act represents a sea change Paul Taheri, m.d., m.b.a., has joined the School of for American medicine—particularly for academic Medicine as deputy dean and chief executive officer medical centers such as Yale’s—and the nation’s seri- of Yale Medical Group (ymg), following a nation- ous shortage of primary care physicians presents an wide search. Taheri began his new role at Yale in ongoing challenge. early March. “We know Obamacare is going to be here. We Taheri was the senior associate dean for clinical have to go with a very strong primary care base,” says affairs and president and ceo of the University of Taheri. “As long as we are data-driven, thoughtful, Vermont (uvm) Medical Group in Burlington as well and methodical, we can manage the changes and bal- as a professor of surgery at uvm. There, he was re- ance all the missions of the enterprise, and come out sponsible for overseeing and managing a 500­-member more able to bear risk.” multispecialty practice with more than 1,000 staff and Taheri has been charged with establishing a strong $250 million in annual revenue. Taheri has been cred- management structure for ymg and maintaining its ited with preparing the group, both financially and high-performing clinical operation. // ymg (page 6) operationally, for the future of health care reform. He comes to Yale at a pivotal time for the school’s This month, Paul Taheri joins the School of Medicine as ceo of clinical practice, which has expanded remarkably Yale Medical Group. Among other goals, Taheri aims to stan- over the past decade. The size of the clinical faculty dardize the operations of the clinical practice across its many sites, fully integrate electronic medical records, and oversee an has grown dramatically, clinical revenues have nearly expansion of Yale’s role in addressing the nation’s continuing doubled, and there has been a significant expansion shortage of primary care providers. rajan chawla

Non-Profit Org. inside this issue U. S. Postage 1 Church St., Suite 300, New Haven, CT 06510-3330 2 Lifelines www.medicineatyale.org paid Cardiologist Michael Simons is decoding New Haven, CT the signals that build new blood vessels. Permit No. 526 3 pet projects Researchers at Yale’s pet Center make the invisible visible. 5 A cellular mosaic Stem cells reveal unexpected genetic differences among healthy human cells also Advances, pp. 3, 5 Out & About, p. 4

@YaleMed f /YaleMed lifelines Medical student is ahead of the curve, and still under 30 Nicholas Down- ing, a student in the School of Michael Simons, a leading Medicine’s Class researcher on the role of of 2014, has been arteriogenesis in cardiovas- named one of cular diseases, directs the Forbes magazine’s Yale Cardiovascular Research Center (ycvrc). The ycvrc’s 30 most influen- collaborative spirit and Nicholas Downing tial people under unique scientific climate has the age of 30. In attracted top cardiovascular 2011, as a first-year student, Down- scientists to the School of ing began comparing the speed Medicine and has opened up new research directions and with which the U.S. Food and Drug avenues of funding. Administration (fda) approves new drugs to the speeds of drug approval by comparable agencies in Europe and Canada. His work, funded by the Pew

Michael Simons shapiro harold Foundation and published in 2012 in The New England Journal of Medicine (Downing is one of the youngest-ever first authors pub- Getting to the heart of disease lished in the prestigious journal) showed that, contrary to popular Scientist works toward After graduating, Simons went clusive. To better understand arterio- belief, the fda was faster than molecular therapies for to medical school at Yale, where he genesis, Simons studied the molecular regulators in other countries at ap- began to explore cardiology, crossing controls that determine blood vessel proving new medicines. cardiovascular diseases paths with influential figures in the growth. He continued this research The report concluded that field such as Barry L. Zaret, m.d., now for seven years as the A.G. Huber given the fda’s lead over its peer Born in Leningrad (now St. Petersburg), professor emeritus of medicine, and Professor of Medicine at Dartmouth institutions, criticisms about Russia, to Jewish parents before the fall S. Evans Downing, m.d., professor emer- Medical School, uncovering new and the inefficiency of the agency’s re- of the Soviet Union, Michael Simons, itus of pathology, an adviser for his unexpected mechanisms controlling view process for novel drugs may m.d., says a medical career was “sort of thesis research in coronary physiology. how the signals of growth factors are be unfounded. a default.” Anti-Semitism barred Jews In 1993 Simons joined the faculty at processed in their target cells. The idea for the fda study from many scientific pursuits, so his Harvard Medical School and Boston’s Returning to Yale in 2008, Simons emerged from the impending parents, both doctors, encouraged his Beth Israel Hospital (now Beth Israel succeeded Zaret as the Robert W. Ber- reauthorization of the Prescription interest in medicine as the basis for a Deaconess Medical Center), whose liner Professor of Medicine and chief Drug User Fee Act (pdufa), which strong natural science education. chief of cardiology was William Gross- of the medical school’s Section of Car- was first enacted in 1992 to allow Simons’ family immigrated to man, m.d., whose success in recruiting diovascular Medicine, and he launched the fda to collect fees from drug Boston in 1978. Simons had begun a leading molecular cardiologists soon the Yale Cardiovascular Research companies to fund the process of 6-year medical program immediately transformed the program into one of Center, which has become a research new drug approval. after high school in Russia, so he was the world’s best. “I never knew if it powerhouse under his direction. Downing says that his study admitted to Boston University School happened by design or by accident, Simons’ work holds great promise “injected some objective infor- of Medicine as a third-year student, but but we were able to do what nobody beyond the treatment of coronary mation into what had become a he chose instead to start anew, as an else could do,” Simons says. disease. “There are distinct signals relatively subjective debate.” undergraduate. “I thought, if I continue By that time, physicians were rou- that control cell fate and thus the type in a medical program, I’ll forever have tinely using procedures like balloon of vasculature that’s formed,” says correction In our September/Octo- an inadequate undergraduate educa- angioplasty and stenting to treat coro- Simons, also professor of cell biology. ber profile of Joan A. Steitz, ph.d., the tion,” he says, speaking with a mild nary artery disease, but Simons was By manipulating these signals, his description of the discovery of single- accent and an understated intensity. interested in doing so by stimulating work suggests, the growth of arter- nucleotide ribonuclear proteins Knowing nothing about the nearby the growth of new arteries, a process ies, veins, and lymphatic vessels can (snrnps) should have indicated that Massachusetts Institute of Technology known as arteriogenesis. To that end, be stimulated in a targeted way to this work was conducted with Michael Lerner, m.d., ph.d., then a student work- (mit), Simons walked inside and intro- he began studying whether recently treat arterial, venous, and lymphatic ing in Steitz’s lab. duced himself. “I figured it’s probably discovered angiogenic growth factors diseases—and he also believes that a state school, so it can’t be too expen- might be used to accomplish that goal. manipulating the vessels that supply sive,” he says, laughing. He applied and Animal research had shown promise, blood to tumors may one day lead to was offered a spot and a scholarship. but studies in humans were incon- new possibilities for treating cancer. Editor Peter Farley Associate Editor Charles Gershman Contributors Michael Fitzsousa, Daniel Jones, Colleen Shaddox, Sarah C.P. Williams Women’s Health Research at Yale celebrates 15 years of success Design Jennifer Stockwell Medicine@Yale is published five times each Women’s Health Research at Yale preventing tumor metastasis; smok- and psychology, year by the Office of Institutional Planning and Communications, , (whry), whose mission is to ensure ing and other addictive behaviors; and associate dean 1 Church St., Suite 300, New Haven, CT 06510-3330 that women are included in research cardiovascular disease; depression; for faculty affairs. Telephone: (203) 785-5824 Fax: (203) 785-4327 studies, gender differences in health osteoporosis; and adaptation of re- “More than half of E-mail [email protected] Website medicineatyale.org are examined, and health outcomes turning women combat veterans. the funded inves- Copyright ©2013 by . All rights reserved. are analyzed by gender, celebrated whry’s mission also includes tigators obtained If you have a change of address or do not wish to receive its 15th anniversary in February. building interdisciplinary research external funding future issues of Medicine@Yale, please write to us at the above address or via e-mail at [email protected]. Since its inception, whry has cores, training the next generation of using their pilot Postal permit held by Yale University, 155 Whitney Avenue, New Haven, CT 06520 awarded more than $4.4 million in researchers, and engaging the com- Carolyn Mazure results, at least five “seed” grants to more than 60 Yale munity through outreach. times the success investigators. Many of these scientists “Three-fourths of the pilot in- rate for new investigator-initiated Robert J. Alpern, m.d. used the results from whry-funded vestigators are junior and mid-level National Institutes of Health grant Dean and Ensign Professor of Medicine Jancy L. Houck studies to obtain a total of nearly $50 faculty who need initial funding to applications.” Associate Vice President for Development and million in grants that further their launch their research on women’s whry was founded in 1998 with Director of Medical Development (203) 436-8560 Mary Hu work in key areas of research. Some health and gender differences,” says funding from the Patrick and Cath- Director of Institutional Planning and Communications of these areas include developing new Carolyn M. Mazure, ph.d., direc- erine Weldon Donaghue Medical models for treating breast cancer and tor of whry, professor of psychiatry Research Foundation. Printed on recycled paper ♻

2 www.medicineatyale.org advances Health & Science News Mapmakers of the living human body Proteins folding badly: Positron emission tomography is a vital tool in schizophrenia that includes hallucinations and delu- for School of Medicine researchers studying sions—was a consequence of hyperactivity of the brain’s havoc ensues dopamine signaling system. “But until recently, we had no psychiatric diseases, diabetes, and cancer way to test that hypothesis,” Krystal says. This changed in the 1990s, when new research approaches in imaging made Imagine trying to develop a drug and being able to see how it possible to measure dopamine release noninvasively in a and where that drug acts inside the body of a living person. living person. “Now that we have pet,” Krystal says, “we’ve Just such a tool is provided by positron emission tomog- identified a number of pathological mechanisms that might raphy (pet), an imaging technology that is aiding drug be targeted with treatments for psychiatric disorders.” development and research on the mechanisms of disease at In the quest to find such treatments, brain imaging

istockphoto.com the School of Medicine’s state-of-the-art pet Center. has become essential. Single-photon emission computed When exposed to the antibiotic strep- Animal models are useful tomycin, bacterial cells begin making for many aspects of biological mistakes in protein production. The research, but when the aim is error-ridden proteins fold improperly translating research discover- and accumulate in the cell, clumping ies into applicable treatments into toxic aggregates that eventually for humans, particularly for kill the bacteria. brain disorders, research in Such aggregates are of broad living humans is critical. “It’s interest because they are also a only through imaging that hallmark of neurodegenerative condi- you can begin to understand Richard Carson tions such as Alzheimer’s disease. the complexity of the human A research group led by Dieter Söll, brain,” says Robert S. Sher- ph.d., of Molecu- win, m.d., the C.N.H. Long lar Biophysics and Biochemistry and Professor of Medicine and professor of chemistry, Jesse Rinehart, director of the Yale Center for ph.d., assistant professor of cellular Clinical Investigation (ycci). and molecular physiology, and Jiqiang It is precisely the inacces- Ling, ph.d., postdoctoral associate, sibility of the human brain have found that proteins misfolded that makes in vivo imaging Yiyun Henry Huang due to streptomycin are unusually technologies like pet so valu- prone to oxidation, a chemical state able. “If you suffer from an more likely to damage the bacterial illness of nearly any organ courtesy of richard carson cell. When the group amplified the of your body, it’s perfectly expression of certain genes related to acceptable to donate a piece An example of the Yale pet Center’s expansion of its research portfolio beyond neuro- of that organ for analysis” via science and psychiatry, these images were made using a tracer for insulin-producing oxidation and reduction, streptomy- pancreatic β-cells. (Top) In three views of a healthy subject there is robust uptake of the cin induced far less damage. biopsy, says John H. Krystal, tracer (red) in the pancreas, indicating a substantial population of β-cells. (Bottom) In The results, published in the m.d., Robert L. McNeil Jr. a patient with type 1 diabetes, cooler colors in the pancreatic region indicate a compro- December 14, 2012 issue of Molecular Professor of Translational Evan Morris mised population of insulin-producing cells. Cell, could shed light on protein ag- Research and chair of the gregates related to human disease. Department of Psychiatry. “But the preciousness of brain tomography, or spect, is a complementary imaging tool tissue has prohibited psychiatry from developing the kind of (often used during cardiac stress tests) that is more widely understanding of the organ that it studies relative to what is available than pet and does not require a cyclotron, because How bad timing possible in other areas of medicine.” spect tracers, often based on iodine or technetium, are befalls the brain In addition to the critical role it has played in neurosci- longer-lived and can be ordered from suppliers. But pet has In patients with Parkinson’s disease ence research at Yale, pet is now beginning to see wide use in become more popular thanks to the development of the pet (PD), carefully timed actions, such as research on diseases such as cancer and diabetes. isotope Fluorine-18, which has a longer half-life than most the coordinated behaviors that make Led by Richard E. Carson, ph.d., professor of diagnos- pet tracers and is widely used in clinical // pet Center (page 7) up body movements, can be severely tic radiology and biomedical engineering, the pet Center’s disrupted. The brain’s prefrontal mission—to provide the highest quality of nuclear imaging cor­tex, which is involved in planning to the medical school’s researchers—is embodied in numer- Scanning the horizon behavior, receives input from the ven- ous collaborations both on campus and off, all relying on There is no shortage of great ideas at Yale School of Medicine, as an intricate and well-choreographed network of technol- tral tegmental area (vta), a cluster of evidenced by the story on this page describing the number and neurons in the midbrain that produce ogy and personnel. variety of investigators using positron emission tomography (pet) the neurotransmitter dopamine. Since At the heart of the 22,000-square-foot facility is a to study psychiatric diseases, diabetes, and cancer. The strengths dopamine neurons are damaged in cyclotron, which accelerates atomic particles to produce of Yale’s basic science, translational, and clinical research continues PD, a team of Yale scientists wanted short-lived radioactive isotopes. A team of radiochemists to provide extraordinary opportunities to pioneer many promising to know whether vta neurons could led by Yiyun Henry Huang, ph.d., director of chemistry and crucial medical discoveries. We have invested strategically in play a role in temporal dysfunction. at the Center and associate professor of diagnostic radiol- technology and core equipment that assists many researchers in Ralph J. DiLeone, ph.d., associate ogy, uses these isotopes to synthesize radioactive versions their work, making the School of Medicine one of the largest and professor of psychiatry and neurobi- of drug molecules or other biologically active substances. most productive biomedical research institutions in the world. Medical school faculty are active in hundreds of fields, work- ology, and colleagues trained mice These radioactive molecules are called tracers: they trace ing to discover basic biological mechanisms, understand disease to press their noses against a wall the paths of molecules that are important in human processes, develop new diagnostic and therapeutic strategies, and physiology, such as glucose, and they’re administered to for food rewards, which would only analyze disease incidence and treatment outcomes across popula- be given if at least 20 seconds had research subjects in extremely small, trace amounts. tions. Our research enterprise is robust and highly collaborative elapsed since the last reward. Over A subject lies within a pet scanner (similar in appear- and it is among the top five recipients of funding from the National time, the mice learned to wait 20 ance to a CT scanner) while radiochemists, working under Institutes of Health. seconds before touching the wall. great time constraints due to the short half-life of pet The generosity of individual donors can accelerate Yale’s As reported in the December 11, isotopes, create the labeled compounds. When these com- groundbreaking research. With independent funds, Yale research- 2012 issue of Proceedings of the Na- pounds are injected into the subject’s body they navigate ers are able to harness the power of cutting-edge technology—like tional Academy of Sciences, when the and bind to specific organ sites. The pet scanner is able to pet imaging—and pursue tomorrow’s most significant biomedical team precisely targeted dopamine re- detect the accumulation of radioactivity at these various discoveries. There are many ways you can participate: ceptors in prefrontal neurons to alter sites and convert this data into color-coded maps. But pet Create a research fund to support new investigations $100,000 their activity, the mice were much less provides more than pretty pictures: the images are based Endow a Yale Scholar fund to support a young investigator $2.5 million accurate on the 20-second test—they on precise quantitative physiological and pharmacological (eligible for 100% matching funds from Yale University) frequently tried to get a reward after information that can be useful in its own right. Fund a professorship to assist a distinguished researcher $3 million only 10 or 15 seconds. The findings In psychiatry, imaging technologies like pet have For information about these and other ways to support could provide a new target for drugs enabled some of the most critical discoveries in recent the School of Medicine, contact Jancy Houck, associate vice to help PD patients who have dif- decades. Since the early 1960s, psychiatrists had hypoth- president for development and director, medical development, ficulty timing their behaviors. esized, for instance, that psychosis—a set of symptoms seen at (203) 436-8560 or [email protected]

Medicine@Yale March 2013 3 out & about

September 23 School of Medicine students and faculty 3 October 9 1. The Donaghue Foundation’s annual Andrews Lecture was took their talents to the courts at the Faculty-Student given by Sue Sheridan, m.b.a., deputy director of patient engagement Tennis Classic. 1. (From left) Medical students Anton at the Washington, D.C.-based Patient-Centered Outcomes Research Safonov ’15, Joel Winer ’15, Jia Liu ’15, and Michael Chang ’15. Institute. 2. Mark R. Mercurio, m.d., m.a., professor of pediatrics and 2. Alex Scherer ’18. 3. Robert Udelsman, m.d., m.b.a., director of the School of Medicine’s Program for 1 chair and William H. Carmalt Professor of Surgery and Biomedical Ethics (left), and Moreen Donahue, surgeon-in-chief at Yale-New Haven Hospital, attends d.np., r.n., senior vice president, patient care the baseline. 4. Jennifer A. Galvin, m.d., assistant services, and chief nursing officer, Western professor of ophthalmology and visual science and 4 Connecticut Health Network, take ques- pediatrics, keeps her eye on the ball. 5. Jordan Gruskay tions. 3. Raymond S. Andrews Jr., a trustee of ’15, gives it his all. foundation from 1993 to 2007 for whom the lectureship is named, enjoys a light moment. 1 2 2 3

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October 18 A reception was held in the medical school’s Histori- 1 2 cal Library honoring the appointment of George Lister, m.d., as chair of the Department of Pediatrics. Lister, seen here with a patient, Jonathan Narducci, is a 1973 graduate of the School of Medicine and former member of its pediatrics faculty. Lister is Jean McLean Wallace Professor of Pediatrics, professor of cellular and molecular physiology, and physician-in-chief at Yale-New Haven Children’s Hospital. gale zuker (3)

3 November 2 The Jane Coffin Childs Memorial Fund for Medical Research held a Symposium in honor of its 75th anniversary. 1. Huda Y. Zhogbi, m.d., of Baylor College of Medicine. 2. Members of the board include (front, from left) Stephen J. Elledge, ph.d., of Harvard Medical School; Randy W. Schekman, ph.d., of the University of California–Berkeley; Cynthia J. Kenyon, ph.d., of the University of California–San Francisco; and (back, from left) Haifan Lin, ph.d., professor of cell biology and genetics at the School of Medicine and director of the Yale Stem Cell Center; Richard M. Losick, ph.d., of Harvard University; Zhogbi; John Kuriyan, ph.d., of the University of Califorania–Berkeley; and Thomas D. Pollard, m.d., Sterling Professor of Molecular, Cellular and Developmental Biology, professor of molecular biophysics and biochemistry, and dean of the Yale Graduate School of Arts and Sciences. 3. (From left) Bronwen A. Childs, member of the Fund, and James E. Childs, sc.d., senior research scientist and

harold shapiro harold lecturer in epidemiology at the School of Public Health and chairman of the Fund’s board of managers.

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November 6 A celebration of the election of Marina Picciotto, ph.d., Charles B.G. Murphy Professor of Psychiatry and professor of neurobiology and pharmacology, to the Institute of Medicine was held in the medical school’s Historical Library. 1. Members of Picciotto’s lab (from left) include Mary Burke, Seth Taylor, Cali Calarco, john curtis (4) Emily Einstein, ph.d., Picciotto, Margreet Plantenga, Yann S. Mineur, ph.d., Yon Woo November 15 Yale students in the health professions came together to organize Jung , Samantha M. Sheppard, and Sam R.S. Blakeman. 2. (From left) John H. Krystal, the 20th Annual Hunger & Homelessness Auction. This year, more than $27,000 was m.d., chair of the Department of Psychiatry and Robert L. MacNeil Jr. Professor of raised for charities and service agencies in the New Haven area. 1. (From left) Linh Translational Research; Picciotto; Robert J. Alpern, m.d., dean and Ensign Professor Vu ’16, Richard Kim ’16, and Lucas Butler ’16, make a bid. 2. Amanda King ’15, one of of Medicine; and Pietro De Camilli, m.d., Eugene Higgins Professor of Cell Biology the auction’s co-organizers. 3. James J. Abrahams, m.d., professor of diagnostic ra- and professor of neurobiology. 3. Picciotto and her husband, Angus C. Nairn, ph.d., diology and surgery, with a friend. 4. Students in the Physician Associate program Charles B.G. Murphy Professor of Psychiatry and professor of pharmacology. with (in bow tie) William B. Stewart, ph.d., associate professor of surgery.

4 www.medicineatyale.org advances Health & Science News Stem cells reveal a long-hidden mosaic Cracking one of The cells that make up each human body Urban, ph.d., of Stanford University School of Medicine, are discovered to be surprisingly different thought more work was needed to show exactly what was Salmonella’s secrets causing these cnvs, so they launched a detailed genomic from one another at the level of the genome study of a group of ipsc cell lines that originated from skin cells of seven individuals. Whole-genome dna sequences Although the many cells in a human body have distinct were obtained from three ipsc lines from each donor and were functions and appearances, it’s generally been assumed that compared through several bioinformatic approaches to that of they all share the same genetic blueprint. So when adult cells the donor’s skin cells. are reprogrammed into their most basic, stem cell state, it’s “The first thing we found was that there was, in fact,

wikimedia commons wikimedia assumed that the resulting stem cells will all be the same. an alarming number of copy number variations, both Some Salmonella bacteria are flexible Such induced pluripotent stem cells —a mouse or a monkey is as good a (ipscs), the thinking goes, could then be host as a human. But Salmonella Typhi coaxed to develop into one of a number (S. Typhi), which causes typhoid fever, of different cell types that genetically is picky: it survives only in human match a donor. But a new discovery by a cells. In the November 16, 2012 issue team of Yale researchers has upended this of Science, Jorge E. Galán, chair and reasoning: cells accumulate so many ge- Lucille P. Markey Professor of Microbial netic changes during a human’s lifetime, Pathogenesis, and postdoctoral fellow they’ve found, that even a single tissue Stefania Spanò, ph.d., explain why S. can give rise to genetically diverse ipscs. Typhi dies off inside non-human cells. “These cells are increasingly used as In many types of Salmonella, a models for disease and potentially can protein called GtgE keeps a group be used as the basis for treatments,” says of enzymes away from the vacuole, Flora M. Vaccarino, m.d., Harris Professor a membrane that surrounds the in the Child Study Center and professor bacteria inside host cells. But S. Typhi of neurobiology, who led the new study. lacks GtgE, and in non-human cells “But there was evidence based on other ex- the membrane becomes studded with periments that there was genetic variation these enzymes, including one called among populations of ipscs, which could terry dagradi Rab32. In mouse immune cells Rab32 be bad news for the field.” Participants in a new study that used stem cells to reveal an unexpected delivers antimicrobial factors to the The variation had been spotted when other researchers degree of genetic mosaicism in human skin cells included (standing, S. Typhi-containing vacuole, but in compared the genomes of ipscs that they expected to be iden- from left) Livia Tomasini, Anna Szekely, Mike Wilson, Sherman Weiss- tical, since they’d all been reprogrammed from the same tissue man, Anita Huttner, Elena Grigorenko, and Ying Zhang. (Seated, from humans, “the immune system is still left) Alexej Abyzov and Flora Vaccarino, the study’s senior author. firing bullets, but this pathogen has in a single individual. Instead, when the ipsc genomes were learned how to dodge them,” Galán compared to one another, huge chunks of dna were found to duplications and deletions,” says Vaccarino. Each ipsc line had says. When the scientists blocked be duplicated or deleted—a phenomenon called copy-number an average of two cnvs, she says, though some had as many as Rab32 or added the GtgE gene to S. variation (cnv). Scientists began to fear that reprogramming five. “But we were still not convinced that this was due to the Typhi, the bacterium successfully in- creates unstable genomes and an increased ability to develop reprogramming.” Then they were surprised to notice that two fected mice for the first time, results mutations, which would undermine the promise of ipscs for different ipsc cell lines that originated from the same person that could lead to new treatments for both research and therapy. had an identical cnv. For both lines to have developed precise- typhoid fever. But Vaccarino and her collaborators, including first ly the same variation independently was highly unlikely, and author Alexej Abyzov, ph.d., associate research scientist, the observation suggested that the variation already existed in What’s behind a and co-senior authors Mark B. Gerstein, ph.d., the Albert L. the donor’s skin cells and was not due to the reprogramming Williams Professor of Biomedical Informatics, and Alexander used to make the ipscs. (page 7) risky cellular shift // Stem cells Yale scientists have pieced together a molecular program that sustains endo­thelial cells, which line blood ves- sels throughout the body. Research- Spine Center lets patients in pain get back on track ers had proposed only recently that Susan Cusano and Nina Kadan- S. Laurans, m.d., assistant profes- in a process called Endo-MT, these Lottick, m.d., share an unhappy sor of neurosurgery, and Associate cells transition into another type, distinction: Far too early, they felt like Professor of Neurosurgery Michael L. mesenchymal cells, which prompt the frail, elderly women. Cusano, 55, could DiLuna, m.d., are aiming to set up a buildup of scar tissue in vessel walls, barely walk. Kadan-Lottick, associate system that will allow a patient under heart valves, and other tissues. The professor of pediatrics, spent her early a surgeon’s care to be sent down the Endo-MT shift is suspected to play 40s gradually cutting back on activi- hall to a medical spine specialist or a role in many conditions, including ties until she was no longer playing some other caregiver. “We can send atherosclerosis and hypertension, but outside with her children. them to physical therapists whom it wasn’t fully understood how the Both women are patients at the we routinely communicate with,” change takes place. new Yale-New Haven Hospital Spine says Grauer. The center also plans to In the December 27, 2012 issue of Center in New Haven, where spine recruit a physiatrist—a clinician who Cell Reports, a team led by Michael surgeons Khalid M. Abbed, m.d., and specializes in treating pain and help- Simons, m.d., Robert W. Berliner Profes- Jonathan N. Grauer, m.d., stopped ing patients regain function. sor of Medicine and section chief of their debilitating pain and helped The new center, at One Long cardiovascular medicine, shows that them reclaim their lives. Abbed, as- Wharf, is located in a large suite a signaling molecule called fibroblast sistant professor of neurosurgery, complete with X-ray machines, and the growth factor (fgf) maintains levels and Grauer, associate professor of physical therapy gym has windows that robert lisak of let-7, a snippet of genetic material orthopaedics and rehabilitation and overlook Long Island Sound. Clinicians Donna Riccitelli, a registered technologist in known as a microrna. In turn, let-7 of pediatrics, are part of an interdisci- work in a hub surrounded by exam radiology, helps a patient prepare for an X-ray puts the brakes on expression of the plinary team at the Spine Center that rooms, so it is simple for providers to at the Spine Center. receptor for a signaling molecule called brings a variety of specialists under review a diagnostic scan together or for a physician who would spend the transforming growth factor beta (tgf- the same roof for optimal treatment collaborate on a treatment plan. time necessary to get to the root of b). When tgf-b binds to its receptor of any spinal ailment, surgical or not, Cusano and Kadan-Lottick were her complex problem. “I felt like I was it directly induces Endo-MT, so when in the most convenient and efficient treated with surgery, but they say 100,” remembers Cusano. Grauer rec- fgf expression was blocked, let-7 levels manner possible. they found it reassuring that they ommended surgical treatment known plummeted, and tgf-β did its damage. The Spine Center team, which were able to evaluate all their options. as decompression and fusion. Though “The loss of fgf signaling input also includes spine surgeons Peter G. Cusano came to Grauer with sig- Cusano didn’t relish having an opera- may be the root cause of a number Whang, m.d., and James J. Yue, m.d., nificant symptoms in her legs related tion, she is now happy with her deci- of the most common cardiovascular both associate professors of orthopae- to her lumbar spine. She had seen sion. “I’m raking. I’m shoveling snow. illnesses,” says Simons. dics and rehabilitation, and Maxwell other doctors, but was still looking I just lifted a // Spine Center (page 6)

Medicine@Yale March 2013 5 Grants and contracts awarded Interprofessional Education Services, 8 months, Gail McAvay, Universal American, The Prevalence $5,000 • Shawn Cowper, University of Pitts- and Impact of Depressive and Anxiety Disorders burgh (nih), University of Pittsburgh Clinical and in a Medicare Population, 2 months, $11,008 to Yale School of Medicine Translational Science Institute, 4 months, $4,478 Ruth Montgomery, Mayo Clinic of Rochester Sabrina Diano, American Diabetes Associa- (nih), High-Throughput Immunophenotypic November 2011–February 2012 tion, Inc., Minority Undergraduate Internship, Analyses of Humoral Responses to West Nile Virus, 1 year, $3,000 • Kyle Draheim, American Cancer 1 year, $74,475 • Gil Mor, Wayne State University Society, Inc., Elucidating the Significance of (nih), Services in Support of the Perinatology Federal ilk/Integrin Tail Interactions, 3 years, $150,000 Research Branch, 9 months, $138,606 • Adam Hervé Agaisse, nih, Mechanisms of Intracellular 1 year, $221,284 • Daniela Tirziu, nih, Molecular Marie Egan, Cystic Fibrosis Foundation, Cystic Naples, Autism Speaks, Brain Electrophysiology Pathogen Dissemination, 5 years, $2,078,958 Mechanisms of Arteriogenesis, 5 years, $139,108 Fibrosis Therapeutics Development Center, 1 year, of Interactive Social Stimuli, 2 years, $107,443 Hal Blumenfeld, nih, Functional Neuroimag- Christian Tschudi, nih, Transcriptome Analysis of $69,535 • John Elefteriades, Ministry of Educa- Don Nguyen, National Lung Cancer Partnership, ing in Childhood Absence Epilepsy, 5 years, Leishmania panamensis Developmental Stages, tion and Science of the Russian Federation, Identifying Metastasis-Propagating Cells and $1,819,456 • Titus Boggon, nih, The Mechanism 2 years, $166,042 • Tobias Walther, nih, Cellular MESRF Scholarship for Bulat Ziganshin, 8 months, Their Niche in Lung Adenocarcinoma Progres- of Arg Kinase Activation by Integrin B1, 4 years, Functions of Plasma Membrane Organization $30,415 • Elisabeth Erekson, American Urogy- sion, 2 years, $108,000 • Katerina Politi, Thomas $546,898 • Maria Diuk-Wasser, U.S. Environ- by Eisosomes, 3.9 years, $1,231,956 • Min Wang, necologic Society, Frailty and Functional Status G. Labrecque Foundation, A Translational Pilot mental Protection Agency, Novel Behavioral nih, Nicotinic Receptor Effects on Neurophysiol- in Older Women with Urinary Incontinence, Study on Serum Biomarkers of Lung Cancer Using Intervention for Prevention of Tick-Borne ogy of Dorsolateral Prefrontal Cortex, 3.8 years, 2.1 years, $25,000 • Irina Esterlis, Charles A. Transgenic Mouse Models of Lung Adenocarci- Infection on Block Island, 2 years, $150,296 $1,356,627 • Dianqing Wu, nih, Identification of Dana Foundation, Inc., Brain Imaging of the noma, 1 year, $70,000 • Scott Pope, American Peter Glazer, nih, Novel Triplex-Engineered, Novel Genes as Being Important for Neutrophil Glutamatergic System in Depression, 3 years, Cancer Society, Inc., Regulation of Inflammation brca1-Mutated Cell Lines for Research, 2 years, Functions, 2 years, $456,553 $200,000 • Terri Fried, Patrick and Catherine by Single Dependent Transcriptional Repression, $431,517 • Mark Hochstrasser, nih, Function and Weldon Donaghue Medical Research Founda- 3 years, $150,000 • Faye Rogers, Breast Cancer Assembly of Eukaryotic Proteasomes, 4 years, Non-federal tion, Development and Implementation of Alliance, Inc., Gene-Targeted Apoptosis as a Thera- $1,280,017 • Ellen Hoffman, nih, A Novel Zebra- Nancy Angoff, Arnold P. Gold Foundation for Patient-Centered Guidelines, 4 years, $880,000 peutic Strategy for her2-Positive Breast Cancer, fish Model for the Functional Analysis of Genes Humanism in Medicine, Arnold P. Gold Founda- Thomas Gill, University of Florida (nih), The life 1 year, $100,000 • Alessandro Santin, Honorable in Autism, 5 years, $752,967 • Susan Kaech, nih, tion 2012, 5 months, $2,000 • Baptiste Barbot, Study, 1.4 years, $1,899,930 • Peter Glazer, Doris Tina Brozman Foundation, Iron Oxide Nanoparti- The Role of stat3 in Effector and Memory CD8 T Spencer Foundation, Identity (re) Creation Duke Charitable Foundation, Nanoparticle- cles Complexed to cpe Peptide for the Early Detec- Cell Longevity and Metabolism, 2 years, $456,292 in Delinquent Adolescents, 1.5 years, $38,900 Mediated Correction of the Sickle Cell Disease tion and Treatment of Chemotherapy-Resistant Maria Kamenetska, nsf, Unwinding dna: Mea- Henry Binder, Flinders University, Development Mutation, 3 years, $486,000 • Andrew Ovarian Cancer Stem Cells, 2 years, $200,000 suring Mechanical Stiffness of a Single dna Mol- of New Strategies to Improve Zinc Status in Chil- Goodman, Crohn’s & Colitis Foundation of Lynn Selemon, Texas A&M University (U.S. Dept. ecule to Understand Histone Control over Gene dren with Environmental Enteropathy at Risk of America, Dissecting the Role of the Human Gut of Defense), The Root Cause of Post-traumatic Expression, 2 years, $113,000 • Anthony Koleske, Diarrhea, 3 years, $55,524 • Linda Bockenstedt, Microbiota in Aminosalicylate Metabolism, 1 year, and Developmental Stress Disorders, 1.4 years, nih, The Mechanism of Arg Kinase Activation by Nat’l Research Fund for Tick-Borne Diseases, $347,490 • Valentina Greco, American Cancer $324,987 • Mark Shlomchik, Merck KgaA, Integrin B1, 4 years, $739,728 • Miler Lee, nih, Inc., Regulation of Borrelia burgdorferi-induced Society, Inc., Stem Cell Deregulation during Autoimmunity and the Role of BLyS Signaling Characterizing Modes of Maternal rna Degrada- Inflammation by tam Receptors, 1 year, $60,000 Tumor Regression, 4 years, $720,000 • David Pathways, 2 years, $296,616 • Michael Simons, tion during Vertebrate Development, 3 years, Jonathan Bogan, American Diabetes Associa- Greer, University of Texas Health Science Center European Commission, Biodegradable Magnetic $161,802 • Nandakumar Narayanan, nih, Pre- tion, Inc., Diet-Induced Insulin Resistance in Adi- at Houston (nih), University of Texas Special- Stent for Coronary Artery Luminal Regenera- frontal Dopamine and Cognitive Symptoms of pocytes, 3 years, $339,250 • Elizabeth Bradley, ized Program in Acute Stroke, 1.3 years, $22,500 tion, 4 years, $641,567 • Matthew State, Simons Parkinson’s Disease, 5 years, $871,290 • Laura Commonwealth Fund, Hospital Strategies to Elena Grigorenko, Florida State University (nih), Foundation, Whole-Exome Sequencing of Simons Niklason, nih, Molecular Mechanisms of Arte- Reduce Risk-Standardized 30-Day Mortality for Genomic Sequence Pattern Analyses in African- Simplex Quads, 2 years, $2,646,852 • Asim riogenesis, 5 years, $122,888 • Polloneal Ocbina, Patients with Heart Attacks, 1.5 years, $194,931; American Families with Severe srd, 1 year, Tarabar, American Academy of Clinical Toxicol- nih, Investigating the Requirement of micrornas Management Sciences for Health, Sustainable $202,362 • Malini Harigopal, American Society ogy, Lily of the Valley Ingestion: Epidemiology, in vegf Signaling In Vivo, 1 year, $8,291 • Craig Leadership, Management, and Governance, of Cytopathology, hpv16 dna Methylation for Laboratory Diagnosis, and Treatment of Conval- Roy, nih, Deciphering Ubiquitin-Regulation 4.4 years, $86,016 • Jessica Brown, American Improved Triage of ascus, 2 years, $50,000 laria Toxicity, 1 year, $3,750 • Narendra Wajap- Host Responses to the Intracellular Pathogen Cancer Society, Inc., Do ene-like Structures Stabi- Kevan Herold, Benaroya Research Institute, eyee, Elsa U. Pardee Foundation, Pre-Clinical Legionella pneumophila, 2 years, $428,117 lize Cellular Noncoding rnas? 3 years, $150,000 jdrf/itn Partnership in Immune Tolerance, 1 year, Evaluation and Development of the Secreted Martin Schwartz, nih, Molecular Mechanisms of Jean-Marie Buerstedde, Nat’l University of $50,000 • Michael Higley, Epilepsy Founda- Tumor Suppressor igfmp as a Novel Lung Cancer Arteriogenesis, 5 years, $387,901 • William Sessa, Ireland, Galway, Locus Specificity of Immuno- tion of America, Inhibitory Control of Dendritic Therapeutic, 1 year, $100,000 • Sandra Wolin, nih, Molecular Mechanisms of Arteriogenesis, globulin Gene Diversification, 2 years, $31,032 Excitability in Epilepsy, 1 year, $50,000 • Martha Lupus Research Institute, Inc., The role of Ro60- 5 years, $485,877 • Gerald Shulman, nih, Mech- Jersey Chen, American Heart Association, Inci- Kaiser, Autism Speaks, Near-Infrared Spec- Bound rnas in scle, 3 years, $300,000 • Yanling anisms of Fat-Induced Insulin Resistance, 4 years, dence, Outcomes, and Treatment of Cardiotoxic- troscopy for Studies of Early Neural Signatures Wu, Genzyme Corp., Towards Cell Therapy $1,363,421 • Michael Simons, nih, Molecular ity After Breast Cancer, 3 years, $197,874 • Hyung of Autism, 3 years, $449,809 • Janghoo Lim, for Guacher’s Disease: Use of Triplex-Forming Mechanisms of Arteriogenesis, 5 years, $574,110 Chun, American Heart Association (Founders National Ataxia Foundation, Molecular Patho- Peptide Nucleic Acids to Correct Glucocerebro- Albert Sinusas, nih, Molecular Mechanisms Affiliate), Apelin-Targeted micrornas in Pulmo- genesis Studies of Spinocerebellar Ataxia sidase, 2 years, $211,179 • Luyang Yu, American of Arteriogenesis, 5 years, $147,208 • Richard nary Arterial Hypertension, 3 years, $198,000 Type 1, 1 year, $50,000 • Carolyn Mazure, Grace Heart Association, senp1-Mediated gata2 desu- Sutton, nih, Production of hiv Vector Super- Eve Colson, Association of American Medical J. Fippinger Foundation, Women’s Health moylation is Critical for Endothelial Activation in natant Using Helper-Dependent Adenovirus, Colleges, Identifying Beliefs About Barriers to Research at Yale: Research Cores, 1 year, $10,000 Graft Arteriosclerosis, 4 years, $308,000

// ymg (from page 1) Working with Dermatology, professor of surgery, // Spine Center (from page 5) dishwasher Most patients don’t need surgery, department chairs, faculty, and clinical and chief of the medical school’s with my daughter,” she says. so Abbed and Grauer always seek partners, he says, he plans to develop Section of Dermatologic Surgery and As for Kadan-Lottick’s symptoms, alternatives for those who can benefit and implement measures that improve Cutaneous Oncology. she says, “I really had to psych myself from them. “It used to be the hardest and standardize clinical operations, Leffell, who spearheaded the up to walk from my garage to my of- part of my job when I saw someone enhance revenues, and make the best branding of the clinical practice under fice” due to compression of her spinal who was hurting and they weren’t possible use of precious available space. the Yale Medical Group name, has cord that caused her severe pain. An candidates for surgery, so I couldn’t “There are huge benefits to stan- served in successive ymg leadership associate professor of pediatrics at the help them,” Abbed says. “Now we dardization. We could do better than positions since 1996. “Dr. Leffell is School of Medicine, Kaddan-Lottick have the ability to get them the non- we do now” across the many sites in the responsible for much of the transfor- says she was immediately impressed operative treatment they need.” Yale-New Haven Healthcare System, mation of Yale’s clinical practice over with Abbed, whose training includes The Spine Center’s physicians stay Taheri says. “Whether [patients] go to the past 15 years, while continuing to fellowships in orthopaedic and in close touch with physical therapists, New Haven or Bridgeport, it should be serve as an extraordinarily successful neuro­surgical spine surgery. Ulti- who routinely discuss the patient’s the same experience.” section chief,” says Robert J. Alpern, mately, she chose a surgical procedure progress with the surgeon and adjust Taheri is past chair of the Group m.d., dean and Ensign Professor of that drew on this specialized train- rehab techniques when necessary. on Faculty Practices for the Associa- Medicine. “His leadership has sig- ing—a multilevel, minimally invasive “Therapy is very specific to the tion of American Medical Colleges nificantly advanced ymg’s reputation decompression and stabilization pro- individual,” says Jhasson Brooks, and an examiner for the American for quality of care and service, and cedure that dramatically decreased lead physical therapist for the center. Board of Surgery. He has lectured he has spearheaded many initiatives, her recovery time, blood loss, muscle “We can bring them to a point where broadly on various business topics including the selection of the medi- injury, and hospital stay compared we reduce their pain, teach proper related to medicine, including the cal center’s first integrated electronic with conventional surgical options. body mechanics, and prevent further cost of care, physician leadership, health record system.” Kadan-Lottick was walking the injuries,” he says. and optimizing systems. He received Michael Berman, m.d., has over- day after surgery, and Abbed helped Cusano first saw the Spine Cen- his undergraduate degree from St. seen ymg’s operations as interim di- her craft a rehabilitation plan. ter’s new facility on a recent follow- Lawrence University and his medical rector and ceo during the past year, “I really feel like I had been living up visit, and she says she loved it. But degree from New York University, and he led the search process that the life of someone decades older,” the change she sees in herself is even then completed his general surgical recruited Taheri. During the transi- says Kadan-Lottick, now two years more impressive, she says. Of her first residency at Tulane University. tion to Taheri’s leadership, Berman out from her surgery. She says she is visit, she says, “I remember sitting Taheri succeeds David J. Leffell, is serving as a special advisor to the now hiking, skiing, and biking with there crying,” but today there are no m.d., the David P. Smith Professor of clinical practice. her family again. more tears.

6 www.medicineatyale.org // Stem cells (from page 5) So Vacca- dysregulation seen in cancer and other // pet Center (from page 3) cancer settings. mechanisms in the nervous system, rino and her collaborators—a multi- diseases. But significant genetic differ- pet instrumentation is expensive, but mice with spinal cord injury showed disciplinary team that included stem ences among cells in healthy individu- it offers a number of advantages over marked recovery, which Strittmatter’s cell biologists, bioinformaticians, and als were thought to be rare, especially spect: the cost per study is lower; team observed by using pet to measure geneticists—turned to a new, high­ among cells in a single tissue. spatial and temporal resolutions are the density of nerve fibers, using a tracer resolution technology called digital The new findings, which were higher; imaging is more sensitive and originally developed to study depres- pcr to scour the original skin cells for published in the December 20, 2012, contains less “noise”; and a greater sion. His work may lead to new treat- cnvs. Unlike older technologies, digi- issue of the journal Nature, suggest variety of tracers can be used. ments for spinal cord injury in humans. tal pcr is sensitive enough to detect that such variation has been “marked- Kelly P. Cosgrove, ph.d., assistant One of pet’s benefits is the un- variations present in only 0.1 percent ly underestimated,” write the authors. professor of psychiatry, uses pet to limited potential of radiochemistry to of the cells. The team discovered that “In the skin, this mosaicism is study the effects of nicotine-induced create and test new labeled com- around half of the cnvs they’d pin- extensive and at least 30 percent of dopamine release in the brain. In pounds. As in Strittmatter’s research, pointed in the ipsc lines could also be skin cells harbor different deletion or 2009, a team including Cosgrove, Irina often a compound will turn out to found in the fibroblasts. “It could be duplication of dna, each found in a Esterlis, ph.d., assistant professor of have important unexpected uses. In that even more than half are present,” small percentage of cells,” Vaccarino psychiatry and diagnostic radiology, recent studies led by Gary W. Cline, says Vaccarino, “but that’s what we explains. “This has far-reaching con- and the late Julie Staley-Gottschalk, ph.d., associate professor of medi- were able to detect with this method.” sequences for genetic analyses, which ph.d., published a study in Archives cine, Kitt Falk Petersen, m.d., profes- The study’s most intriguing twist currently use only blood samples. of General Psychiatry in which they sor of medicine, and Kevan Herold, is that the researchers found ipscs to When we look at the blood dna, it’s used spect imaging to demonstrate m.d., professor of immunobiology be remarkably stable—reprogramming not exactly reflecting the dna of other that, after quitting, smokers have an and medicine, researchers found that does not appear to significantly alter tissues such as the brain. There could increase in nicotine receptors that lasts a tracer originally designed to mea- the genomes of donor cells. Instead, it be mutations that we’re missing.” up to a month, and that this increase in sure neural activity in Parkinson’s is donor cells that show an unexpected The good news for researchers receptor availability is correlated with Disease could be used to measure the amount of variation. moving forward, says Vaccarino, is craving for cigarettes. mass of insulin-producing b-cells in Genomic variation in the cells of that ipsc cell lines provide a straight- Cosgrove, also assistant professor of the pancreas. “The ability to look at a single individual is called mosai­ forward way to reveal genetic diversity diagnostic radiology and neurobiology, and measure them in vivo in human cism, after the differently colored within individuals. “We can now use is building on that work, using pet beings over time is a hugely valuable tiles that make up a mosaic. Mosai­ the stem cells as a discovery tool to to study effects of variables like sex, tool” for diabetes research, Carson cism is known to result from the cell look at these rare events.” she says. psychiatric status, and genetic makeup says (see figure, page 3). on nicotine-induced dopamine release, As noted, pet is extremely valuable // utc (from page 1) Reitsma, a long- “In our businesses, we’ve seen how as well as cognitive changes that occur in drug design, and the ability of the time cyclist, has twice completed our investments in innovation can when a person stops smoking. pet Center’s radiochemistry team to Smilow’s annual 100-mile Closer to transform an industry and change Krystal has used pet to examine create a wide range of tracers underlies Free bicycle ride while in treatment. the world. We know the same is true the effects of post-traumatic stress dis- a mutually beneficial relationship the His care at Smilow, he says, “has in the fight against cancer.” order and early emotional trauma on Center enjoys with the pharmaceutical been fantastic. There’s an attitude of ycc Director Thomas J. Lynch, the brain. Others in the Department industry. Pfizer contributed $5 million optimism. You feel that there’s hope, m.d., sees utc as an important ally. of Psychiatry are using pet to study in 2007 to help establish the Center and not only because of the people you “utc’s continued support enables us to depression, schizophrenia, Tourette’s the company provides ongoing sup- interact with, but also knowing that broaden and deepen our reach in the syndrome, and various addictions. port for pet studies of its large library you have access to the latest treat- fight against cancer, so that we can con- Marc N. Potenza, m.d., ph.d., uses of compounds. The expertise of pet ments available.” tinue to help improve the lives of people pet to analyze brain reward circuits in Center scientists has now spurred col- According to Chênevert, United like Mark Reitsma,” says Lynch, the cocaine, alcohol, and gambling addic- laborations with more than 10 pharma- Technologies and ycc are linked by Richard Sackler and Jonathan Sackler tions. “pet offers distinct advantages ceutical companies. a spirit of innovation. “utc’s sup- Professor of Medicine and physician-in- over other widely used imaging mea- But the Center’s relationship with port of Yale Cancer Center reflects chief at Smilow Cancer Hospital. sures in that it allows for investigation industry is equally beneficial for Yale both the unfortunate fact that cancer utc has more than 215,000 em- of specific receptors,” which is “critical scientists. Having been designed to touches almost every utc employee ployees worldwide, about 26,000 of to understanding pathophysiology, accommodate industry studies—which in some form as well as our belief them in Connecticut. Its business units particularly with respect to developing typically occur at a faster pace and larg- in the power of innovation,” says produce Pratt & Whitney aircraft en- new pharmacotherapies,” says Potenza, er scale than federally funded academic Chênevert, the current chair of the gines, Sikorsky helicopters, Carrier air professor of psychiatry, neurobiology, studies—the Center has the advantage ycc Director’s Advisory Board and, conditioning and heating systems, Otis and in the Child Study Center. of high-quality instrumentation. along with his wife, Debbie, a long- elevators and escalators, utc aerospace Yale Cancer Center (ycc) is one The Center has a scanner able to time supporter of cancer research and systems, and Kidde fire safety and of the pet Center’s newest partners in image the human brain at a resolution treatment at the School of Medicine. detection systems. research applications outside psy- of 2.5 millimeters, for instance, one of chiatry. Like ycci, which has provided only 17 such scanners in the world. The // Milbank (from page 1) fellowships. physician-in-chief at Smilow Cancer significant funding and other resources scanner can also track and compensate “We are very grateful for the gener- Hospital. “The Milbank gift sets a to help initiate collaborative work, ycc for patients’ head movements 20 times ous support of the Milbank Foun- terrific example of supporting efforts has contributed pilot funding to facili- per second to eliminate blurring. dation and for their confidence in to help patients and families deal tate collaborations using pet. And the Center’s advanced chemis- our vision to build palliative care, with some of life’s hardest experi- One such project involves work try facilities mean that scans can often education, and research over the ences. With their support Yale will by Joseph N. Contessa, m.d., ph.d., be scheduled so closely that a tracer can coming years to benefit our patients be well on its way to establishing assistant professor of therapeutic radi- be produced and then quickly used in and their families,” Kapo says. “This one of the nation’s very top palliative ology, who is using pet to analyze the two or more scans. For that to happen, gift will ensure that we have the re- care units for patient care, education, actions of the anti-cancer drug erlotinib “there are a lot of different parts working sources needed to help train the next and research.” (Tarceva) in non-small cell lung cancer together,” says Evan D. Morris, ph.d., generation of palliative care physi- The Milbank Foundation for Re- by labeling erlotinib and using it as the co-director for imaging and associate cians, and to provide for the pallia- habilitation was created in 1995 to re- pet scan tracer. professor of diagnostic radiology, bio- tive care and end-of-life needs for all alize the vision of philanthropist Jer- Others at ycc—including David J. medical engineering, and psychiatry. of our patients.” emiah Milbank ( 1909) Carlson, ph.d., assistant professor of Since its 2007 opening, the Center Kapo came to Yale from the to integrate people with disabilities therapeutic radiology, and Sara Rock- has increased its capacity by acquiring University of Pennsylvania in 2012 into all aspects of American life. His well, ph.d., professor of therapeutic new pet scanners and growing its staff to build the Palliative Care Program grandson Jeremiah Bogert, of the radiology and pharmacology, and to more than 50, placing it among the into a model clinical service that Yale College Class of ’63, currently associate dean for scientific affairs—are largest, most active centers in the U.S. provides world-class, comprehen- serves as the Foundation’s chairman. using newly designed pet tracers to The Center’s abundance of re­ sive supportive and palliative care to Bogert’s father, brother, and son, study hypoxia (low levels of oxygen) in sources are not only of immediate ben- patients and their families who face Jeremiah Jr., are also Yale graduates the tumors of both humans and mice. efit for Yale research, but also enables cancer and other serious, life- (Classes of ’34, ’60, and ’89). pet has also proven valuable in as- School of Medicine scientists to make threatening illnesses. “My grandfather, Jeremiah Mil- sessing recovery from spinal cord injury. stronger cases when requesting grant “A commitment to care with bank, was one of the great philan- In 2011, Stephen M. Strittmatter, m.d., funding. Says Carson, “When you’re dignity at end of life says much about thropists of his time,” says Bogert. ph.d., the Vincent Coates Professor competing for grants in an always-dif- our humanity as a society,” says ycc “We are proud of our historic ties of Neurology and professor of neuro- ficult grant environment, it’s helpful to Director Thomas J. Lynch. m.d., to Yale and honored to follow in his biology, published a paper in Annals of be able to say, for instance, that we have the Richard Sackler and Jonathan philanthropic footsteps by support- Neurology showing that after treatment the highest-resolution pet scanners Sackler Professor of Medicine and ing the Yale Palliative Care Program.” with an agent that unlocks regeneration available in the world.”

Medicine@Yale March 2013 7 Researchers win prize honoring exceptional immigrant scientists

On February 5, the Vilcek Founda- Born in the United Kingdom, immunity was deemed unimportant tion announced that two immune- Flavell received his ph.d. in biochem- and received scant scientific attention, system researchers at the School istry in 1970 at the University of Hull but by 1997 Medzhitov, Janeway, and of Medicine will share one of the and came to Yale in 1988 to lead its colleagues identified an innate im- 2013 Vilcek Prizes, awards that re- immunobiology program. Flavell and mune system receptor in humans that cognize significant contributions colleagues have discovered several acts as a pathogen-detecting sentinel to American science and the arts important receptors of the innate im- and activates adaptive immunity. The made by immigrants. mune system, and he has made major study of innate immunity has since Richard A. Flavell, ph.d., chair contributions to our understand- seen explosive growth, and Medzhi- and Sterling Professor of Immuno- ing of how activation of the innate tov’s work continues to have signifi- biology, and Ruslan M. Medzhitov, system triggers the adaptive immune cant implications for autoimmune ph.d., David A. Wallace Professor of system’s more specialized responses. diseases, cancer, and other illnesses. Immunobiology, were honored for Medzhitov, a member of the “We are pleased to honor two their long-standing and influential Yale faculty since 1999, is a native truly outstanding scientists. The pio- work on the innate immune system, of Tashkent, Uzbekistan. He im- neering work of Ruslan Medzhitov the first line of defense against infec- migrated to the United States in the and Richard Flavell has led to impor- tion by bacteria and viruses. early 1990s, having been inspired tant insights into the mechanisms of This year’s Vilcek Prize in the by the then-controversial theories of the immune responses, which has im- shapiro harold arts and humanities will go to cello innate immunity championed by the plications for many fields of biomedi- Ruslan Medzhitov (left) and Richard Flavell are winners of a prize that honors significant virtuoso Yo-Yo Ma. The prizes carry late Yale immunobiologist Charles A. cal studies,” said Jan Vilcek, president contributions of foreign-born scientists and a cash award of $100,000. Janeway Jr., m.d. At the time, innate of the Vilcek Foundation. artists to American life.

Kent Professor’s research evaluates the Expert in vascular biology, inflammation, effectiveness of treatments for addiction and immunity is inaugural Bayer Professor

Kathleen M. Car- Psychotherapy Development Re- Jordan S. Pober, m.d., in innovative and collaborative re- roll, ph.d., recently search Center—the only National ph.d., recently ap- search, with the broader goal to deliver named Albert E. Kent Institute on Drug Abuse (nida) pointed as the inaugu- improved patient care. Professor of Psychia- center devoted to behavioral therapies ral Bayer Professor of Pober is director of the medical try, studies behavior- research—and of the New Eng- Translational Medi- school’s Human and Translational al, pharmacological, land node of nida’s Clinical Trials cine, is an authority Immunology Program and vice-chair and combined treat- Network. She received a merit on the interrelations of the Department of Immunobiology.­ ments for addiction, Award from the National Institutes of vascular endothelial He earned his m.d. at the School of with an emphasis on Kathleen Carroll of Health in 2003 for her research cells (which form the Jordan Pober Medicine in 1977 along with a ph.d. in improving the quality on computer-assisted training in lining of blood ves- molecular biophysics and biochemistry. of such therapies through rigorous cognitive-behavioral therapy. sels), inflammation, and immunity. His He returned to Yale in 1991 as profes- research on their clinical efficacy. Carroll has been designated as research aims to advance organ replace- sor of pathology and immunobiology, Carroll graduated summa cum a Highly Cited Researcher by isi ment therapy, tissue engineering, and and became professor of dermatology laude from Duke University, com­ Thompson, and she is the author of regeneration of injured tissues. in 1998. pleted predoctoral training in the more than 220 peer-reviewed research Bayer, a global enterprise in the Pober founded the Vascular Biology Yale Department of Psychiatry’s Divi- publications as well as numerous fields of health care, nutrition, and and Transplantation Program, the sion of Substance Abuse, and earned books and book chapters. high-tech materials, established the medical school’s first interdisciplinary her ph.d. in clinical psychology Carroll was president of the professorship to recognize its shared program in translational medicine, in from the University of Minnesota. American Psychological Association’s goals with the School of Medicine: to 1999. He has been honored as a Searle She joined the Yale faculty in 1990, Division 50 (Addictions) from 2002 to improve and speed up the translation Scholar, an Established Investigator of becoming full professor in 2002. 2005, when she received the Division’s and delivery of fundamental scientific the American Heart Association, and a Carroll is the principal inves- Distinguished Scientific Contributions discoveries in human health, from the merit awardee of the National Heart, tigator of the School of Medicine’s to Education and Training Award. laboratory into the clinic; and to engage Lung, and Blood Institute.

Ensign Professor has unveiled mechanisms Berliner Professor studies how blood flow shared by the vascular and nervous systems stimulates the formation of new arteries

Anne Eichmann, ph.d., newly desig- from 2001 to 2006 Martin A. Schwartz, ph.d., the Institute of Tech- nated Ensign Professor of Cardiology, and a research newly named Robert Berliner Profes- nology, and joined explores the factors that determine director for Inserm sor of Cardiology, is a noted cardio- the faculty of where the cells in blood vessels and since 2002. She vascular researcher whose studies Harvard Medical lymphatic vessels grow, as well as joined the Yale of cell adhesion and behavior have led School in 1983. In how the vascular and nervous sys- faculty in 2010. to new insights into atherosclerosis 1991, he moved to tems influence each other’s growth Her research and heart disease. the Scripps Re- and function. She has discovered has won her Professor of medicine and cell search Institute, that common molecular cues direct Anne Eichmann numerous honors, biology, Schwartz is affiliated with Martin Schwartz and then the Uni- growth of blood vessels and nerves, including a Lillian the Vascular Biology and Therapeutics versity of Virginia. opening new possibilities for direct- Bettencourt Prize for Life Sciences, Program. He is an expert on mechano­ He joined the Yale faculty in 2011. ing blood vessel growth toward the Chevalier de L’ordre National transduction—how cells respond Schwartz is part of a team at the infarcted tissue or away from grow- du Mérite, and the Jean Bernard to mechanical forces—and his lab’s Yale Cardiovascular Research Center ing tumors. Eichmann is currently Award from the Medical Research main focus is understanding how the that received a five-year, $9.5 million studying that link in diseases affect- Foundation. She has served on the friction of flowing blood against the grant from the National Heart, Lung, ing both systems, notably diabetes. Inserm Scientific Research Council, endothelial cells lining blood vessels and Blood Institute to study the mo- Eichmann obtained her m.sc. the European Research Council, and regulates the behavior of these cells, lecular basis of artery formation and at the Weizmann Institute in Israel, the Fondation Lefoulon Delalande including how increased flow leads to develop a new framework for thera- and a ph.d. in molecular and cell bi- fellowship board, and the editorial the growth of new arteries. peutic advances. ology from Université Paris 13. After boards of Physiology Reviews and Schwartz earned his ph.d. in The professorship is named for postdoctoral work, she moved to the Endothelium. She has been elected physical chemistry from Stanford Robert W. Berliner, m.d., a renowned Collège de France, where she was council member of the North Ameri- University. He conducted postdoc- kidney researcher and dean of the Inserm Avenir Young Investigator can Vascular Biology Organization. toral research at the Massachusetts School of Medicine from 1973 to 1983.

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