New Alliance with Gilead Sciences Is 'Transformative'

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May/June 2011 volume 7, issue 2 Advancing Biomedical Science, Education, and Health Care New alliance with Gilead Sciences is ‘transformative’ Research collaboration pairs Yale experts To begin to bend this troubling curve, some phar- maceutical companies have been building scientific with industry scientists to accelerate the alliances with universities, a trend that has picked up development of new drugs to treat cancer steam during the past few years. In March, President Richard C. Levin announced that Yale University When Robert J. Alpern, m.d., dean of the School had forged a multi-year research alliance with Gilead of Medicine, was asked recently to prepare a brief Sciences, Inc., a biopharmaceutical company based overview of the current state of drug discovery for a in Foster City, Calif., to accelerate the discovery and symposium at Yale’s West Campus, a familiar phrase development of new drugs to treat cancer. came quickly to mind: “It was the best of times, it was Gilead will provide up to $40 million to support the worst of times . . . ” cancer research at the School of Medicine over four It’s an apt description. On the one hand, we live in years, and a total of up to $100 million—the largest what some call the “post-Gleevec era,” a time when ba- corporate commitment in Yale’s history—for the full sic research conducted over decades is bearing fruit in 10 years outlined in the agreement. Yale maintains the form of remarkably effective, targeted drugs. But ownership of all intellectual property generated by the cost of drug development has risen exponentially medical school research, and Gilead will have the first as clinical trials and regulations have grown more option to develop any compound it deems promising. complex. The average total cost to develop a single ap- “The collaboration brings together one of the proved drug is now pegged at a staggering $1.3 billion, world’s top research universities and a biopharma-

a 60 percent increase since 2005. ceutical company dedicated to addressing unmet courtesy of gilead sciences Early-stage research carried out by academic scien- medical needs, with the goal of finding new treat- Prime movers at Gilead Sciences in the new initiative with the tists in settings like the School of Medicine is unveiling ments for cancer,” Levin said. “This truly is transfor- School of Medicine are (clockwise from left) Howard Jaffe, a 1982 more potential drug targets than ever. But research mative support that leverages Yale Cancer Center’s alumnus of the medical school and president and chairman of the grants are not designed to sustain the many addi- top scientists, our West Campus technology invest- board of the Gilead Foundation; Linda Slanec Higgins, vice president, Biology; and William Lee, senior vice president, Research. tional steps involved in drug discovery, and academic ments, and the resources of the new Smilow Cancer researchers lack resources to explore these targets fur- Hospital. I can’t think of a better partner to have in Medical Institute investigator, and Thomas J. Lynch ther. The expense and complexity of bringing drugs to this collaboration than Gilead.” Jr., m.d., the Richard Sackler and Jonathan Sack- the marketplace have understandably made phar- The project will be governed by a six-member ler Professor of Medicine, director of Yale Cancer maceutical companies risk-averse and selective about Joint Steering Committee chaired by Joseph “Yossi” Center, and physician-in-chief at Smilow Cancer which targets to pursue. The resulting gap between Schlessinger, ph.d., chair and William H. Prusoff Hospital. They will be joined by Gilead scientists academia and industry has become known as the Val- Professor of Pharmacology at the School of Medi- Howard Jaffe, m.d., a 1982 alumnus of the School of ley of Death: only a miniscule number of promising cine. The committee will also include medical school Medicine and president and chairman of the board discoveries manage to traverse this chasm, and even scientists Richard P. Lifton, m.d., ph.d., chair and of the Gilead Foundation; William A. Lee, ph.d., fewer result in drugs approved for clinical use. Sterling Professor of Genetics and Howard Hughes senior vice president, research; and // Gilead (page 8) Donation from leading Asian foundation will advance stem cell science The Li Ka Shing Foundation (lksf), to continue to make of Medicine in 2010. “The team at Yale cells—but, like hescs, they can self- Asia’s largest philanthropic organiza- available to its seems to be very open, and wants to regenerate indefinitely and can develop tion, has made a $1.5 million donation members the most support and leverage each other’s work into any kind of bodily cell or tissue. to the Yale Stem Cell Center (yscc). current technolo- to accelerate science. At the Stem Cell Because ipscs are genetically matched The donation will fund improvements gies used in stem Center, I felt that Haifan has developed to the donor, they may not induce a in two of the yscc’s four core laborato- cell research.” a unique sense of community and rejection response by the immune ries that will benefit the work of more YSCC Director bonding between the different teams.” system, an important characteristic in than 60 faculty members and numer- Haifan Lin, ph.d., In the yscc’s human embryonic developing personalized treatments for ous trainees across the campus. Li Ka-shing professor of cell stem cell (hesc) facility, the dona- individual patients. In announcing the contribution, biology, first met LKSF Director Solina tion will support the introduction of The new ipsc initiative at the Yale University President Richard C. Chau during a trip to Hong Kong last induced pluripotent stem cell (ipsc) yscc will be supervised by In-Hyun Levin said, “We are grateful for the year, but Chau says it was more than technology, which will bring scientists Park, ph.d., assistant professor of Li Ka Shing Foundation’s generos- the proposal on behalf of the yscc Lin closer to tailoring patient-specific cells genetics, one of the world’s first ity, which benefits today’s medical sent later that won lksf’s support. for the treatment of disease. scientists to develop ipsc technology. research in order to develop tomor- “We have all been great admirers of Discovered in 2006, ipscs are Park’s work has focused on the basic row’s cures. This significant donation the work of Yale for 100 years in Chi- typically derived from ordinary adult biology of stem cells and on the use will allow the Yale Stem Cell Center na,” says Chau, who visited the School cells such as skin cells—not embryonic of stem cells to // Li Ka Shing (page 7)

Non-Profit Org. inside this issue 1 Church St., Suite 300, New Haven, CT 06510-3330 U. S. Postage www.medicineatyale.org 2 Lifelines paid Brian Smith discusses how far laboratory New Haven, CT medicine has come—and where it’s headed. Permit No. 526 3 Meeting of the minds School of Medicine’s April symposium, “Biomedicine in the New Century,” draws top-notch speakers and enthusiastic crowds. 8 Given in gratitude Herbert and Marigrace Boyer are honored with the medical school’s highest honor, the Peter Parker Medal, for their generosity. also Advances, pp. 3, 5 Out & About, p. 4 Grants and Contracts, p. 6 lifelines Translational work by diabetes expert is cited in award Brian Smith, who leads the medical school’s Department William V. Tam- of Laboratory Medicine, borlane, m.d., says that the technologies professor of that are making personalized medicine a reality pose pediatrics and a daunting challenges to his world-renowned field. The sheer quantity of figure in the patient information that understanding can now be obtained from and treatment genomic analysis and other techniques raises a William of childhood multitude of practical and Tamborlane diabetes, has ethical questions, and will been awarded require informatics experts the T2-Translation Award by the to devise innovative ways to Society for Clinical and Transla- manage and interpret highly complex data. tional Science (scts). The award recognizes the translation of research from early clinical Brian Smith use to applicability for widespread harold shapiro harold clinical practice. The award honors Tamborlane’s pioneering clinical research, which has led to new delivery methods for physiological Tackling an information explosion replacement of insulin, preventing Chair worries that the U.S. has explored the interface between genome, has brought formidable chal- many of the major long-term com- the immune and coagulation (clotting) lenges to laboratory medicine. plications of childhood diabetes. is not ready for the coming systems in blood diseases, cardiovascu- Labs will soon routinely perform Tamborlane is chief of the Sec- deluge of medical data lar disorders, and metastatic cancer. His complex genomic and proteomic tion of Pediatric Endocrinology and work on these two critical physiologies analyses impossible just a few years ago, deputy director of the Yale Center For a leader in a field at a pivotal may ultimately help to reduce com- vastly improving diagnosis but increas- for Clinical Investigation. His moment of transition, Brian R. Smith, plications associated with heart-lung ing reliance on informatics. “Humans are major achievements have included m.d., is modest, equating his role as bypass machines and the administra- very good at some qualitative pattern pioneering work in the development chair of the Department of Laboratory tion of blood transfusions. recognition, but computers are far of insulin pump therapy, continu- Medicine to mostly “filling out pieces of After attending Princeton as an better at consolidating multiple quan- ous glucose monitoring, sensor- paper.” But Smith’s department, with a undergraduate, Smith received his titative analyses for diagnostics or fol- augmented pumps, and a prototype mission that combines both service and m.d. from Harvard Medical School, and lowing the results of therapy.” But aside design for an artificial pancreas. research, is critical to patients at Yale- completed his internship and residency from technical problems, maintaining Tamborlane has also demonstrated New Haven Hospital (ynhh) and many in internal medicine at the Peter Bent vast stores of patient information raises the role of insulin resistance in pedi- other institutions in New England and Brigham Hospital in Boston. He com- ethical questions. If whole genomes atric metabolic disorders, including beyond, as well as to the work of other pleted fellowships in hematology, oncol- of patients are sequenced many years obesity and type 2 diabetes. medical school departments. ogy, hematopathology, and research before genetic advances reveal new risk The scts presented Tambor Members of the department study pathology at the Brigham, the Dana-Far- factors for diseases, “Do we try to find lane with the award on April 28, at the components of blood and other ber Cancer Institute, and Children’s Hos- every patient previously sequenced and the national joint meeting of the bodily fluids to better understand and pital in Boston before joining Harvard’s call each of them back with the new Association for Clinical Research treat disease, including those mea- faculty in 1981. He came to Yale in 1989. information?” Smith asks. He predicts Training, the American Federation sured in the familiar lab tests ordered Fifty years ago, a patient’s labora- an ever-increasing interaction of special- for Medical Research, and the scts, by doctors. Each day the department tory tests might include analyses of ists in laboratory medicine with other in association with the Association produces about 75,000 lab results for two or three factors, and a technologist physicians to evaluate the clinical signifi- for Patient-Oriented Research. patients at ynhh and for Yale Medical might spend a full day generating the cance of the rapidly proliferating options Tamborlane’s multitude of Group, the medical school’s clinical arm. results. Now, Smith says, it often takes available in laboratory diagnostics. honors and distinctions include the The department’s research mission less than an hour to obtain 20 or more The increasing adoption of electronic Outstanding Physician Clinician in is necessarily broad, says Smith, profes- results for one patient. As technology medical records may help pave the way Diabetes Award from the American sor of laboratory medicine, medicine, alters the medical landscape, the field for improved informatics systems. But Diabetes Association in 2010. and pediatrics, because “our discipline is facing an information explosion that the information overload about to take covers essentially all of physiology and demands new ways of managing and place in medicine is unprecedented, pathophysiology,” with the strongest interpreting the data. Genomics alone, Smith says. “We need a national debate, focus on immunology, hematology, and which now allows rapid sequencing of and I think we’re moving in that direc- Editor Peter Farley cellular therapy. Smith’s own research the billions of base pairs in the human tion,” he says. Assistant Editor Charles Gershman Contributors John Curtis, Kathy Katella, Janelle Weaver Design Jennifer Stockwell A famously funny man backs Yale work on a deadly serious disease Medicine@Yale is published five times each year by the Office of Institutional Planning and For author, blogger, raconteur, and faculty at the Yale Club of New York cells) in the brain’s Communications, Yale School of Medicine, 1 Church St., Suite 300, New Haven, CT 06510-3330 talk-show host Dick Cavett, when City as a special guest for a presen- hippocampus in de- Telephone: (203) 785-5824 Fax: (203) 785-4327 the topic is depression, it’s personal. tation of some of the department’s pression, research E-mail [email protected] Cavett had his first bout with the ill- latest research on depression and that throws light on Website medicineatyale.org ness a year after graduating from Yale bipolar disorder. the very rapid anti- Copyright ©2011 by Yale University. All rights reserved. College in 1958, and debilitating epi- John H. Krystal, m.d., department depressant action of If you have a change of address or do not wish to receive future issues of Medicine@Yale, please write to us at the sodes continued to dog him during chair and Robert L. McNeil Jr., Profes- the drug ketamine above address or via e-mail at [email protected]. his storied reign as host of the various sor of Translational Research, intro- recently demon- Postal permit held by Yale University, 155 Whitney Avenue, New Haven, CT 06520 incarnations of The Dick Cavett Show, duced talks by Hilary Blumberg, m.d., Dick Cavett strated by Krystal which first debuted on abc in 1968. associate professor of psychiatry and and colleagues. For his work in raising aware- diagnostic radiology, and Ronald In 1975, Cavett was successfully Robert J. Alpern, m.d. ness of depression and his efforts to S. Duman, ph.d., Elizabeth House treated with antidepressants, and he Dean and Ensign Professor of Medicine eliminate the stigma associated with and Jameson Mears Professor of overcame his worst episode, in 1980, Jancy L. Houck Associate Vice President for Development and the disorder, the School of Medicine’s Psychiatry. Blumberg presented with electroconvulsive therapy, which Director of Medical Development (203) 436-8560 Department of Psychiatry gave Cavett brain-imaging studies elucidating he deemed “miraculous.” But existing Mary Hu its Mental Health Research Advo- the development of bipolar disorder, therapies do not work for everyone, Director of Institutional Planning and Communications cacy Award in 2009. On March 9 of while Duman discussed the role of and Cavett stressed that new and bet- this year, Cavett joined department neurogenesis (the birth of new nerve ter treatments are sorely needed. Printed on recycled paper ♻

2 www.medicineatyale.org advances Health & Science News Symposium is ‘once-in-a-lifetime event’ Food on the brain: A roster of top biomedical scientists visits Yale for of the school; a documentary film by Emmy Award– winning director Karyl Evans; a performance by the craving vs. self-control two days of talks and intellectual exchange, Yale Medical Symphony Orchestra of an original musical along with a generous helping of good cheer composition commissioned for the occasion; and, most recently, the Association of Yale Alumni in Medicine’s It was the hottest ticket in town—and you didn’t even June Reunion Weekend, which featured several special need a ticket. Bicentennial-related talks, events, and exhibits. This spring, 15 of the top minds in science converged “This bicentennial symposium was a once-in-a-lifetime on New Haven for the School of Medicine’s Bicentennial event for the School of Medicine,” says Robert J. Alpern, m.d., Symposium, “Biomedicine in the New Century.” dean and Ensign Professor of Medicine. “We find ourselves in Held on April 28 and 29 and open to the public, the a great era of advances in biomedical research. When we got

corbis images symposium drew capacity crowds, filling the nearly together to decide how best to celebrate our anniversary there Obese individuals and substance abus- 450 seats of the Mary S. Harkness Auditorium, the medical was uniform agreement that it had to include a scientific sym- ers exhibit similar patterns of brain school’s largest lecture hall, and overflowing to a nearby posium featuring a group of scientists of the highest regard.” activation: overactive reward regions 150-seat auditorium at the Anlyan in response to images of palatable food Center for Medical Research and or drug paraphernalia, respectively, but Education, where a live broadcast of reduced activity in regions involved in the sessions was available. self-control when actually consuming The throng had come to hear the lat- food or drugs. It was unknown whether est thoughts and research updates from these patterns exist in “food addiction,” a star-studded scientific cast, which a compulsive eating disorder that can included seven Nobel Prize winners, affect both obese and lean individuals. on topics ranging from the neurobiol- As reported in the April 4 online ogy of memory to the crisis of inequal- edition of the Archives of General ity in health care to the next generation Psychiatry, a team led by psychology of targeted cancer drugs. doctoral student Ashley N. Gearhardt, The symposium was a signature m.s., m.phil., compared brain activity event in the celebration of the School in food addicts and non-addicts. Im- of Medicine’s Bicentennial, which has ages of a milkshake or a glass of water been marked during the 2010–2011 were presented, and subjects received academic year with the publication of a taste of the drink shortly after. In Medicine at Yale: The First 200 Years, a those diagnosed with food addiction, richly illustrated book-length history michael marsland the milkshake images elicited increased activity in regions linked to motivation and craving, while tasting the shake led to lower activity in self-control regions. “That food-related cues may trigger pathological properties is of special concern in the current food environ- ment, where highly palatable foods are constantly available and heavily marketed,” Gearhardt says.

What helps patients to harold shapiro (2) top Many of the speakers at the Bicentennial Symposium joined Yale President Richard Levin, Dean Robert Alpern, and medical school faculty for a din- survive a heart attack? ner on April 28. (Front row, from left) Levin, Charles Sawyers, Joseph Goldstein, David Baltimore, Eric Kandel, Elizabeth Blackburn, Elaine Fuchs, Robert Lefkowitz, and Alpern. (Back row, from left) Peter Kim, Phillip Sharp, Harold Varmus, Michael Brown, and Michael Marmot. Symposium speakers Robert Rates of mortality after heart attack Califf, Susan Lindquist, and Huda Zogby were unable to attend the dinner. above left Every seat at Mary S. Harkness Auditorium, and in a nearby audi- vary as much as twofold between the torium featuring a live video broadcast, was filled on the symposium’s opening day. above right Robert Califf, director of the Duke Translational Medi- highest- and lowest-performing cal Institute at the Duke University School of Medicine, delivered the final address, “Translational Medicine: Moving from Better Ideas to Better Health.” hospitals, a discrepancy that has not been fully explained. To explore this question, Research Charitable gift annuities: a good choice for today’s economy Scientist Leslie Curry, ph.d., m.p.h.; Elizabeth H. Bradley, ph.d., profes- Frustrated by low returns on your investments? Worried about volatility in the stock market? A charitable gift annuity is a good sor of public health; and Harlan M. investment option in today’s economy. Yale can help you maximize your investment returns while safeguarding your funds and Krumholz, m.d., the Harold H. Hines supporting medical research in the future. A charitable gift annuity can provide fixed income to you now at an attractive rate. Jr. Professor of Medicine, visited 11 U.S. How it works hospitals ranked in either the top or 1. You transfer cash or securities to a Yale gift annuity. the bottom five percent in mortality 2. Yale pays you, or up to two annuitants you name, a lifetime annuity. rates. As reported in the March 15 issue 3. The remainder passes to the School of Medicine, for the purpose you designate, when the contract ends. of the Annals of Internal Medicine, the team interviewed 158 staff members, 1 and identified five factors at work in Rate Information for Immediate and Deferred Gift Annuities Immediate Gift Annuity: the best hospitals: an organizational donor gift annuity 3 culture emphasizing top-notch care; age 70 75 80 85 90 deep involvement of senior managers; 2 rate 4.5% 5.5% 7.5% 9.5% 13% ysm participation in clinical decision-making by all health care professionals, includ- Benefits Deferred Gift Annuity (for payments beginning in 5–15 years): ing nurses and pharmacists; clear com- • You receive an immediate income tax deduction age deferred 5 years deferred 10 years deferred 15 years munication and coordinated efforts for a portion of your gift. 55 4% 5.5% 8.5% among departments; and an approach • Your lifetime annuity is backed by all of Yale’s assets. 60 4.5% 7% 11.5% to solving problems based on sharing • Your annuity payments are treated as part ordinary income, 65 5.5% 9.5% 15% knowledge and learning from mistakes part capital gains income and part tax-free income. rather than pointing fingers. • You have the satisfaction of making a significant gift that 70 7.5% 14% 15% “These essential ingredients are benefits you now and the School of Medicine later. not expensive,” Bradley says. “If we For more information or a personalized charitable gift annuity illustration, could implement our findings in more visit yale.planyourlegacy.org/GIFTcharitg.php or contact Jancy Houck, Associate Vice hospitals, we could improve quality President for Development and Director of Medical Development, at 203-436-8560. without adding to costs.”

Medicine@Yale May/June 2011 3 out & about

February 18 With a gift from Andrew Bronin, m.d., 1 March 17 On Match Day each spring, associate clinical professor of dermatology (left), the fourth-year students at medical Department of Dermatology established the schools across the country receive Dr. Andrew Bronin Clinical Scholarship in Dermatology, word of acceptance in residency one of two new endowments that will support young training programs. At Yale, all of the clinician–scholars in dermatology. Richard L. Edelson, 77 graduating medical students m.d. (right), chair and Aaron B. and Marguerite Lerner who had entered the National Resi- Professor of Dermatology, says that the funds from dent Matching Program learned they the new endowments will enhance “the academic had “matched.” 1. Adelina Hung endeavors of clinician–scholars and their ability to congratulates Rajendra Sawh-Martinez. shape the field.” The first endowment was started 2. Kseniya Golubets and Annie Engberg. with a $1 million gift from School of Medicine alumna 3. Macdale Elwin, Samrawit Goshu, Marie-Louise T. Johnson, m.d., ph.d., in 2010. Charisse Mandimika, and Tamara Carroll. 2 3 terry dagradi john curtis (3)

April 15 Members of the U.S. Army held an event at the School of Medicine to describe the Army Medical Department’s humanitarian operations around the world. General Stanley McChrystal (Ret.), former commander of U.S. forces in Afghanistan and now a senior fellow at Yale’s Jackson Institute for Global Affairs, was a featured speaker at the event, titled Common Ground: Army Medicine in Support of Humanity. 1. Carolyn W. Slayman, ph.d., Sterling Professor of Genetics, professor of cellular and molecular physiology, and deputy dean for academic and scientific affairs (left), with McChrystal (center) and Army personnel. 2. A medical Deployable Rapid Assembly Shelter (drash) unit was on display in Harkness Ballroom. The unit, which includes a surgical bed and a variety of essential medical equipment, can be set up and functioning in less than an hour and represents the next level of care after battlefield treatment.

1 2 michael marsland (2)

April 26 At the Yale Club of April 27 The 32nd annual Seton New York City, Carolyn M. Ma- Elm and Ivy Awards, presented at zure, ph.d., professor of psychi- Yale’s Woolsey Hall, honored peo- atry and psychology, associate ple and organizations that further dean for faculty affairs, and partnership between New Haven director of Women’s Health and Yale. 1. New Haven Mayor Research at Yale (whry), spoke 1 John DeStefano Jr. (left) and Yale about the latest biomedical University President Richard Levin research that whry is sup- 2 (right) with medical students Oluwarotimi Okunade, Charisse Mandimika, porting and conducting. (From Amy Moreno, and Jorge Ramallo-Pardo of the Yale chapters of the Student left) whry Advisory Council National Medical Association and Latino Medical Student Association, members Diane Young Turner; which were honored with an Ivy Award for their work encouraging New

Kitty Northrop Friedman, j.d.; michael marsland (2) Haven high school students to pursue careers in the sciences and health Mazure; Roslyn Milstein Meyer, professions. 2. Georgina Lucas, deputy director of the Robert Wood Johnson Founda- ph.d.; and Fran DeToro. chi chi ubiña tion Clinical Scholars Program at Yale, also received an Ivy Award.

4 www.medicineatyale.org advances Health & Science News A new alternative for asthma patients Turner syndrome seen “Breakthrough treatment” offers an option for “This is exactly the clinical response you would predict based on the trials evaluated by the fda. The patient is sooner with new test those asthma patients whose attacks cannot be pleased he went through the procedure,” says Chupp. controlled with conventional drug therapies Patients who undergo BT receive follow-up care from a team that includes Nicole Grant, r.a., and Carol Holme, Asthma can be difficult to treat, so physicians at the Yale who provide assessment immediately after the procedure, Center for Asthma and Airway Disease (ycaad) are always and Radhika Nandlal, r.n., who provides care and advice to searching for novel therapeutic approaches to treat severe BT patients who return to ycaad over the long term. cases for which drug treatment has proved ineffective. As the only major asthma center in the Northeast, ycaad

photo researchers, inc. A case in point is bronchial thermoplasty (BT), a new mini- physicians and scientists enjoy unique opportunities to con- Turner syndrome (TS) is a rela- mally invasive procedure made possible by a device recently duct research aimed at understanding the biological pathways tively common genetic condition in approved by the fda at the root of asthma as well as to improve treatments like BT. females in which some or all of the that uses radiofrequency The center maintains a large repository that includes X chromosome is deleted, causing energy to treat moderate clinical and physiological data, dna samples, plasma, and stunted growth and heart and kidney to severe asthma. lung specimens from asthma patients who are stable or are problems. TS can be diagnosed with a Each year thousands experiencing flare-ups. All of this data is regularly uploaded karyotype (above), but these are labor of patients visit ycaad, into a Web-supported database so that information is readily intensive and impractical as a routine which recently became available, making it easier to recruit patients for clinical trials test, so the disorder often goes unde- the first center between and identify those who could benefit from specific treat- tected until girls reach 10 years of age. Boston and New Jersey Lauren Cohn Geoffrey Chupp ments like BT. In the March issue of the Journal of to offer BT. Because Clinical Endocrinology & Metabolism, ycaad’s multidisci- Scott A. Rivkees, m.d., professor of plinary approach cre- pediatrics, and colleagues describe a ates an ideal setting for genetic test for TS that is quicker, less performing and refining expensive, and more amenable to the procedure, the center large-scale use than karyotyping. The is one of 30 in the country new screen, which analyzes variations participating in a phase in dna at 18 sites on the X chromo- IV post-market trial of some, diagnosed TS with almost per- the new device. fect accuracy in 132 females without Asthma symptoms TS and 74 females known to have TS result from an excess of based on prior karyotype analyses. smooth muscle cells in The team notes that very short girls the airways of the lungs. could be tested early for TS, enabling When various triggers intervention with growth hormone cause airway inflamma- and treatments for organ defects. “If tion, bronchial muscle broadly used in the clinical setting at cells contract and con- young ages, this test can prevent the strict the airways, making delayed recognition of TS,” Rivkees says. breathing difficult. In BT, a flexible camera harold shapiro harold Small brains reveal known as a bronchoscope is adapted with the BT device to gently heat and eliminate Jonathan Puchalski performs bronchial thermoplasty (BT) at the Yale a gene’s outsize role smooth muscle. This prevents the airways from constricting. Center for Asthma and Airway Disease, one of the few sites in the North- Microcephaly is a developmental dis- The studies that led to fda approval of the BT procedure east equipped for this recently approved, minimally invasive procedure. showed that it significantly mitigated asthma symptoms BT targets the muscle tissue that causes airway constriction, offering order characterized by significantly re- a new medical option for asthma patients whose symptoms cannot be duced brain size and a smaller number and flare-ups of the disease, improving asthma patients’ successfully controlled with medications. of neurons, as well as profound mental quality of life. retardation. Although several genes “With this breakthrough treatment, we are confident we have been implicated in this disorder, will be able to alleviate much of the suffering of our patients “We’re trying to get better at figuring out what therapy is little is known about its cellular and with severe asthma,” says Geoffrey L. Chupp, m.d., associate best for what person,” says Lauren E. Cohn, m.d., assistant molecular underpinnings. professor of medicine and ycaad director. “In the past, these professor of internal medicine and ycaad co-director. “Be- In a study published May 13 in The patients received high doses of medication and continued to cause we see so many patients with this disease, we really are American Journal of Human Genetics, suffer from frequent asthma attacks and limitations on rou- starting to understand how to group our patients and how to Murat Günel, m.d., Nixdorff-German tine daily activities, as well as frequent emergency room visits. get the sense of who might need BT.” Professor of Neurosurgery and profes- Bronchial thermoplasty gives new hope to these asthmatic In 2007, Chupp and Jack Elias, m.d., chair and Walde- sor of genetics and neurobiology, and patients and a non-drug option to control their disease. ” mar Von Zedtwitz Professor of Medicine, reported in The collaborators analyzed dna from three Jonathan T. Puchalski, m.d., assistant professor of medi- New England Journal of Medicine that asthmatic patients have families affected by an extreme con- cine and director of the Thoracic Interventional Program high levels of a protein called ykl‑40 that helps regulate the genital form of this condition resulting in the medical school’s Section of Pulmonary and Critical immune response and can cause lung inflammation. They in a 90 percent reduction in brain size Care Medicine, performs the BT procedure with the help of went on to show that those with a particular mutation in the and abnormal layering of cells in the a team that includes Kimberly Ebel, r.n., Suzanne Koshis, ykl-40 gene are at greater risk of developing asthma and cerebral cortex. r.n., and Kelsey Johnson, p.a. Patients are sleepy during have lower lung function. The team homed in on muta- the procedure but breathing on their own, and they are usu- Cohn has joined Chupp and Elias in a search for bio- tions shared by family members in a ally able to go home afterwards. markers that can predict patients’ response to BT. The team gene known as nde1. In the develop- Because the BT procedure itself can sometimes trigger believes that the ykl-40 mutation or levels of the protein in ing nervous system, nde1 proteins an asthma attack, it is generally performed in three out- the blood may be a good candidate, since ykl-40 levels ap- accumulate at centrosomes—struc- patient sessions in which different regions of the lungs are pear to decrease significantly after BT. tures critical for cell division—in cells treated, spaced about three weeks apart. “We customize the treatment approach for every patient that generate neurons, but the nde1 One patient who was recently treated with the procedure and determine if they’re a candidate for BT or some other mutations found in these families at ycaad had suffered from severe asthma his entire life. advanced or investigational treatment,” says Chupp. “ykl-40 undermine this clustering. These data With poor lung function, he was chronically short of breath might be a clinically useful marker of responsiveness.” are evidence for crucial roles of nde1 and had trouble exercising. Puchalski believes that BT is a promising treatment for and centrosomes in normal production Like many patients who undergo BT, this patient’s some patients who obtain unsatisfactory results from asthma and organization of neurons during symptoms worsened for a brief period immediately after the inhalers or oral medications such as beta-agonists. “This development. Also, Günel says, evolu- procedure. After four months, however, he had decreased new procedure offers a potential upgrade for treatment over tionary changes in nde1 over 5 million his medications and no longer used a rescue inhaler when inhaled drugs or other medications because we are attack- years may underlie the greater size and playing sports. He has increased his heart rate by 20 points ing the problem at its very root,” he says. Chupp agrees: complexity of human brains relative to when exercising on a treadmill, and his lung function has “For those with severe asthma, this is a terrific option where those of non-human great apes. also slightly improved. medication can fall short.”

Medicine@Yale May/June 2011 5 Metastasis in Melanoma, 4 years, $1,505,671 Classification System, 1 year, $33,000 • Elizabeth Grants and contracts awarded Jesse J. Rinehart, nih, Investigation of Electrolyte H. Bradley, Commonwealth Fund, All-Cause Hos- Homeostasis via Quantitative Proteomics, 5 years, pital Readmission Rate for Patients with Heart $771,560 • Scott A. Rivkees, Food and Drug Failure and Acute Myocardial Infarction: What to Yale School of Medicine Administration, Radioactive Iodide Therapy of Hospital Practices Make a Difference and How Are Pediatric Graves’ Disease, 4 years, $1,600,000 They Adopted? 2 years, $390,850; South Essex July/August, 2010 Joseph S. Ross, nih, Impact of Publicly Reporting Partnership nhs Foundation Trust, sept Leader- Hospital Outcomes Measures for Older Adults, ship Workshop, 1 year, $140,000 • Joseph Federal 3 years, $442,710 • Douglas L. Rothman, nih, 13C Brennan, Abbott Laboratories Inc., Cardiovascular David J. Adle, nih, Functional Characterization of Mass in Older Women, 1 year, $424,412; nih, Role mrs Studies of Human Brain Mitochondrial Training Fellowship Grant, 1 year, $34,434 an ER-Resident Ligase in Yeast, 3 years, $150,234 of csf-1 in Osteoclast Function, 1 year, $413,750 Metabolism in Healthy Aging, 4 years, $2,052,625 Ketan R. Bulsara, Stryker Instruments, Skull Base Serap Aksoy, nih, Evidence-Based Control Strate- Shuta Ishibe, nih, Role of Focal Adhesion Kinase James E. Rothman, nih, Mechanisms of Intracel- Cerebrovascular Dissection Fund, 1 year, $7,700 gies of Sleeping Sickness Vectors, 3 years, $176,780 (Fak) in Nephrosis and Nephritis, 5 years, lular Membrane Fusion, 5 years, $3,646,441 Jessica A. Cardin, Esther A. & Joseph Klingenstein Allen E. Bale, nih, Genetic Epidemiology of Early- $2,068,750 • James D. Jamieson, nih, Medical Jonathan Saxe, nih, Investigating the Role of a Fund, Distinct Sources of Inhibition Differentially Onset Basal Cell Carcinoma, 2 years, $165,500 Student Training Program, 5 years, $10,965,240 Novel piwi-Interacting Protein in Spermatogene- Regulate Cortical Activity, 1 year, $50,000; White- Michael H. Bloch, nih, Longitudinal Structural mri Susan Kaech, nih, Defining Signatures for sis, 2 years, $105,508 • Richard S. Schottenfeld, hall Foundation, Inc., Role of Inhibition in Visual Study of Adulthood Outcome in Tourette Syn- Immune Responsiveness by Functional Systems nih, invest Drug Abuse Research Fellowship, Gain Modulation and Perception, 3 years, drome, 5 years, $902,154 • Titus Boggon, nih, Reg- Immunology, 1 year, $210,200 • Insoo Kang, 1 year, $39,000 • William C. Sessa, nih, Regula- $225,000 • Tobias Carling, Doris Duke Charitable ulation of Polycystin-2 Channel Activity, 4 years, Department of the Army, Studying the Role for tion of Vascular Remodeling and Angiogenesis by Foundation, Systematic Analysis of Human Endo- $1,730,781 • Angelique Bordey, U.S. Army Medical CD4+ T Cell Subsets in Human Lupus, 3 years, Nogo, 5 years, $2,566,184 • Albert C. Shaw, nih, crine Tumor Genomes, 3 years, $255,000; Damon Research Acquisition Activity (Department of $1,241,250; Department of Defense, Studying the Defining Signatures for Immune Responsiveness Runyon Cancer Research Foundation, Molecular Defense), Understanding the Etiology of Tuberous Role for CD4+ T Cell Subsets in Human Lupus, by Functional Systems Immunology, 1 year, Genetics of Endocrine Tumor Disease, 3 years, Sclerosis Complex, 3 years, $730,792 • Richard 3 years, $3,723,750 • Barbara I. Kazmierczak, nih, $713,174 • Haina Shin, nih, Antigen-Specific CD8 $225,000 • Anees Chagpar, University of Louis- Bucala, nih, Defining Signatures for Immune Innate Immune Responses to Type III Secretion T Cell Migration and Protective Immunity in ville, Louisville Breast Cancer Update, 1 year, $7,108 Responsiveness by Functional Systems Immunol- System Components and Effectors, 4 years, Permissive and Restrictive Tissues, 3 years, $143,670 Jaehyuk Choi, Dermatology Foundation, Genetic ogy, 1 year, $53,738 • William B. Cafferty, nih, $1,799,161 • Tae Hoon Kim, nih, Analysis of Higher Satinder K. Singh, nih, Transport and Inhibition Screen for Tumor Suppressors in Mouse Skin Using Plasticity of Intact Circuits Restores Function after Order Chromatin Structures in Normal and Cancer in a Biogenic Amine Transporter, 3 years, $741,325 PiggyBac Transposon Mutagenesis, 1 year, $30,000 Spinal Cord Injury, 3 years, $747,000 • Michael J. Epigenomes, 5 years, $1,717,065 • Steven H. Klein- David L. Snow, nih, Research Training Program in Jennifer N. Choi, Dermatology Foundation, Caplan, Department of Defense, A New Thera- stein, nih, Defining Signatures for Immune Substance Abuse Prevention, 5 years, $1,542,175 Isotretinoin Versus Doxycycline as Preemptive peutic Strategy for Autosomal Dominant Polycys- Responsiveness by Functional Systems Immunol- Daniel J. Spergel, nih, Calcium Signaling in the Therapy for egfr Inhibitor–Induced Papulopustular tic Kidney Disease: Activation of amp Kinase by ogy, 1 year, $241,804 • Albert I. Ko, nih, Disease Pubertal Activation of the GnRH Pulse Generator, Rash, 1 year, $20,000 • Chuhan Chung, National Metformin, 3 years, $1,241,250 • Sreeganga S. Determinants of Urban Leptospirosis, 5 years, 15 months, $17,928 • Thomas A. Steitz, nih, Struc- Pancreas Foundation, Regulation of Pancreatic Chandra, nih, The Physiological Functions of Synu- $3,472,193; nih, Natural History of Urban Leptospi- tures of dna and rna Polymerases and Functional Fibrotic Responses by Pigment Epithelium-Derived cleins, 1 year, $1,851,531 • Marek C. Chawarski, nih, rosis, 4 years, $1,221,739 • Diane S. Krause, nih, Complexes, 4 years, $1,871,229 • Hanna E. Factor (pedf), 1 year, $44,516 • Gary W. Cline, Behavioral Drug and hiv Risk Reduction Counsel- mkl in Megakaryocytopoiesis, 4 years, $1,443,989 Stevens, nih, Prenatal Stress and the Develop- Medical College of Georgia, Database Mining of ing with mmt in China, 5 years, $3,123,146 • Yung- James F. Leckman, nih, Training Program in ment of Inhibitory Neurons in the Forebrain, Phenotype Induced by High-Fat Diets, 1 year, Chi Cheng, nih, Biochemical Pharmacology of Childhood Neuropsychiatric Disorders, 5 years, 5 years, $870,435 • Stephen M. Strittmatter, nih, $3,000 • Susan R. Compton, aclam Foundation, Anti-hiv Compounds, 5 years, $2,068,750 • Tian H. $2,274,453 • Csaba Leranth, nih, Bisphenol A Prion Protein in Alzheimer’s Disease Pathophysiol- Assessment of Risk of Transmission of Mouse Par- Chi, nih, Epigenetic CD4 Regulation Stability and Effect on Primate Brain, 2 years, $1,413,822 • Ethan ogy, 5 years, $1,696,375 • Nancy E. Suchman, nih, vovirus from Immunodeficient C57BL/6 Mice, Epimutations, 11 months, $413,275 • Elizabeth P. Marin, nih, The Role of Protein Palmitoylation in Fostering Mothers’ Emotionally Responsive Par- 1 year, $30,000 • William E. Damsky, Joanna M. B. Claus, nih, The Meningioma Consortium: Endothelial Cell Function, 5 years, $673,650 enting, 5 years, $2,108,700 • Patrick Sung, nih, Nicolay Melanoma Foundation, Inc., Joanna M. Genome-Wide Association Study, 3 years, $3,828,168 Graeme F. Mason, nih, Ethanol as Fuel for the dna Repair Genes and Proteins of the rad52 Nicolay Melanoma Foundation Award, 1 year, Joseph E. Craft, nih, Immune Response in Lupus, Brain in Rats, 2 years, $439,405 • Carolyn Mazure, Group, 5 years, $2,124,273 • Joann B. Sweasy, nih, $10,000 • Kamil Detyniecki, National EpiFellows 5 years, $2,146,502 • Michael C. Crair, nih, Neuro- nih, Yale bircwh Scholar Program on Women’s dna Polymerase Beta Variants in Cancer, 5 years, Foundation, Patient Recognition of Seizures biology of Cortical Systems, 5 years, $1,002,485 Health and Addictive Behaviors, 5 years, $2,021,612 • Hemant D. Tagare, nih, Fast 3D During In-patient Video-eeg Monitoring, 1 year, Charles S. Dela Cruz, nih, Molecular and Cellular $2,476,819 • Sherry McKee, nih, Does Tobacco Reconstruction Algorithms for Cryo-EM, 4 years, $19,000 • Kavita Dhodapkar, Charles A. Dana Interaction Between Cigarette Smoke Exposure Legislation Reduce Alcohol Consumption? 2 years, $1,666,512 • Elisabetta Ullu, nih, rna Metabolism Foundation, Inc., Targeting Human Glioma and rsv in the Lung, 5 years, $669,600 • Richard $512,190 • Ruth R. Montgomery, nih, Defining in Trypanosomes, 5 years, $3,953,019 • Emily Stem Cells via Dendritic Cells, 3 years, $200,000 L. Edelson, nih, Dermatology Training Grant, Signatures for Immune Responsiveness by Func- Wang, nih, Improving Cardiovascular Outcomes Xuemei Dong, Arthritis Foundation, The Tran- 5 years, $1,629,774 • Tore Eid, nih, Glutamine Syn- tional Systems Immunology, 1 year, $596,225 in Individuals with a History of Incarceration, scription Factor Mash2 in Follicular Helper T Cell thetase and the Mechanism of Seizures in Mesial Christopher Moore, Agency for Healthcare 5 years, $689,855 • Sherman M. Weissman, nih, Differentiation, 2 years, $100,000 • Jamie L. Duke, Temporal Lobe Epilepsy, 5 years, $1,810,155 • Steph- Research and Quality/dhhs, Identifying Unneces- Transcriptome and Methylome Analysis of Single Phrma Foundation, Computational Modeling of anie C. Eisenbarth, nih, Role of the nlrp3 Inflam- sary Irradiation of Patients with Suspected Renal Cells, 2 years, $455,177 • Lynn D. Wilson, nih, Genome-Wide Targeting of Somatic Hypermuta- masome in Adaptive Immunity, 5 years, $667,575 Colic, 4 years, $1,973,901 • Michael H. Nathanson, Racial Disparities in Clinical Outcomes and the tion, 2 years, $33,333 • Ronald S. Duman, Repligen Jack A. Elias, nih, Training in Respiratory Biology nih, Ca2+ Waves in Hepatocytes: Mechanisms and Therapeutic Use of Radiotherapy for Patients with Corporation, Influence of Uridine on Behavior in and Pathobiology, 5 years, $2,908,390 • Veraraga- Effects, 5 years, $2,396,796 • Ingrid M. Nembhard, Cutaneous Lymphoma, 1 year, $82,750 • John J. the Forced Swim Test, 1 year, $19,569 • Daniel R. van P. Eswarakumar, nih, Mechanisms of fgrfr2 Agency for Healthcare Research and Quality/ Wysolmerski, nih, Function of the Calcium Duncan, Howard Hughes Medical Institute, Eluci- Signaling in Salivary Gland Branching Morphogen- dhhs, Understanding the Implementation of New Sensing Receptor in the Breast, 5 years, $1,623,595 dating the Role of pdgf in Neovessel Formation, esis, 5 years, $2,056,899 • Erol Fikrig, nih, Defining Practice in Health Care Organizations, 10 months, Andrew Xiao, nih, A Novel Enzymatic Activity of 1 year, $27,000 • E. Jennifer Edelman, Society of Signatures for Immune Responsiveness by Func- $488,402 • James Noonan, nih, Identifying wstf and its Role in Tumorigenesis, 3 years, General Internal Medicine, Prescription Opioids tional Systems Immunology, 1 year, $210,864 Enhancers with Human-Specific Developmental $747,000 • Kimberly A. Yonkers, nih, Project and their Impact on Quality of Life, hiv Progres- Harald G. Foellmer, nih, Development of a Flavivi- Functions, 5 years, $3,352,861 • Marcella Nunez- start: Screening to Augment Referral to Treat- sion, and cart Adherence, 1 year, $5,000 • Paul S. rus E Protein Fusion Loop Vaccine, 2 years, $165,500 Smith, nih, Measuring Racial/Ethnic Discrimina- ment, 5 years, $3,541,448 • Herbert Yu, nih, Epi- El-Fishawy, American Academy of Child and Ado- Brian W. Forsyth, nih, Development of an Interna- tion/Bias on Health Care Delivery, 2 years, demiologic Study of Hepatocellular Carcinoma in lescent Psychiatry, A Pilot Study of Whole-Exome tional Guide to Monitor and Support Child Develop- $395,959 • Kevin Pelphrey, nih, A fnirs System to the U.S., 5 years, $6,987,938 • Yongli Zhang, Sequencing and Homozygosity Mapping in the ment, 5 years, $2,583,807 • Jorge E. Galán, nih, Further Research on Neurodevelopmental Disor- nih,Single-Molecule Manipulation of snares, Identification of Genes that Contribute to Autism, Molecular Genetic Analysis of Salmonella Cell ders, 1 year, $444,700 • Francheska Pereplet- 5 years, $1,551,550 • Heping Zhang, nih, Research 15 months, $15,000 • Gerald Friedland, Albert Invasion, 5 years, $2,602,374 • Mark B. Gerstein, chikova, Nat’l Inst. of Mental Health and Neuro Training in Mental Health Epidemiology, 5 years, Einstein College of Medicine, Impact of hiv Co- Department of Energy, Tools and Models for Sciences (India), Adapting Dialectical Behavior $2,243,687 • Yong Zhu, nih, Can Shift-Work Shift Infection and TB Genotype on Treatment Out- Integrating Multiple Cellular Networks, 2 years, Therapy for Children with Suicidality and/or Self- Epigenetic Patterns? 2 years, $445,035 • Lingjun comes in mdr, 1 year, $108,069 • Anna-Rachel $1,170,951 • Michael Girardi, nih, Local Immuno- Harm Behaviors: Pilot Randomized Clinical Trial Zuo, nih, Deep Sequencing of cnr1 Gene Network Gallagher, American Heart Association (Founders regulation of Carcinogenesis, 5 years, $1,809,151 with Maltreated Children in Foster Care, 1 year, in Substance Dependence, 5 years, $909,090 Affiliate), The Role of Fibrocystin in Wnt signaling Abha R. Gupta, nih, Identification of Candidate $180,074 • Ismene L. Petrakis, nih, Translational and Mechanism of Repair, 3 years, $231,000 Genes at the Synapse in Autism Spectrum Disor- Neuroscience Research in Alcoholism, 5 years, Non-Federal Mark B. Gerstein, Brigham and Women’s Hospi- ders, 4 years, $681,027 • David Hafler, nih, Defin- $1,072,316 • Christopher Pittenger, nih, Patho- Vikki M. Abrahams, American Heart Association, tal, Analysis of Patterns of Structural Variation in ing Signatures for Immune Responsiveness by physiologically Realistic Mouse Models of Neuro- Effect of Antiphospholipid Antibodies on Tropho- the 1,000 Genomes Data Set, 21 months, $442,594 Functional Systems Immunology, 1 year, psychiatric Disease: Tourette Syndrome, 5 years, blast Function and Vascular Remodeling in Preg- Daniel R. Goldstein, American Society of Trans- $2,430,086; nih, Costimulatory Mechanisms of $2,214,743 • Katerina Politi, nih, Mechanisms of nant aps Patients, 3 years, $196,405 • Amy M. plantation, Nanoparticles: A Novel Approach to Autoimmunity, 5 years, $8,540,473; nih, Costimu- Mutant Epidermal Growth Factor Receptor– Ahasic, Cystic Fibrosis Foundation, Cystic Fibrosis Deliver Tolerogenic Agents in Experimental Trans- latory Mechanisms of Autoimmunity, 1 year, Induced Lung Tumorigenesis, 3 years, $810,141 Center, 1 year, $26,980 • Jeremy Baskin, Jane plantation, 1 year, $40,000 • Jose L. Gomez-Vil- $2,859,450 • Isaac E. Hall, nih, Urinary Biomarkers Lori A. Post, Agency for Healthcare Research and Coffin Childs Memorial Fund, Investigation of a lalobos, Aerocrine Inc. usa, Characterize the Rela- for Recovery After Acute Kidney Injury and Progno- Quality/dhhs, ED Disability Diagnostic Tool: A hit Protein Complex Implicated in P14P Synthesis in tions Between feno and Asthma Severity in the sis in Hospitalized Patients, 1 year, $65,841 • Mark Feasibility Study, 5 years, $2,485,754 • Marc N. the Brain, 3 years, $143,500 • Ariel Bazzini, Pew ycaad Cohort, 1 year, $25,000 • Christopher H. W. Hochstrasser, nih, Predoctoral Program in Potenza, nih, Translational Research of Cocaine, Latin American Fellows Program, Regulation of Gottschalk, Teva Pharmaceuticals usa, Multiple Cellular and Molecular Biology, 5 years, $11,541,618 Striatum, and Impulsivities, 4 years, $3,834,967 the Maternal to Zygotic Transition in Zebrafish, Sclerosis Fellowship-teva, 1 year, $50,000 • Jeffrey Dewan Syed Fahmeed Hyder, nih, Multivalent Vincent J. Quagliarello, nih, Program of Research 4 years, $65,000 • Michael H. Bloch, American Grotzke, Cancer Research Institute, Inc., Mem- paracest Agents for Quantitative Molecular in Infectious Diseases of Elders, 5 years, $671,625 Academy of Child and Adolescent Psychiatry, brane Receptors and Associated Signaling Path- Imaging, 4 years, $1,347,079; nih, Translation of Yibing Qyang, nih, Derivation and Functional Double-Blind, Placebo-Controlled Trial of ways in Cross-Presentation, 3 years, $144,000 Smart Contrast Agents for Brain Tumor Character- Characterization of Heart Cells from Human N-acetylcysteine for Childhood Tourette Syn- David Hafler, Brigham and Women’s Hospital, ization by MR, 5 years, $1,613,701 • Karl L. Insogna, Embryonic and Induced Pluripotent Stem Cells, drome, 2 years, $60,000 • Daniel J. Boffa, calgb tim Family of Genes: Role in T Cell Immunity nih, Impact of a Protein Supplement on Bone 5 years, $504,930 • David L. Rimm, nih, Predicting Foundation, Evaluation of Novel Molecular nsclc and Tolerance: Project 2, 3 years, $862,257

6 www.medicineatyale.org Marc Hammarlund, Ellison Medical Foundation, Pharmacology and Therapeutics, Development of in Alzheimer’s Disease Mouse Model, 1 year, $50,054 Medicine, Tailoring Clinical Guidelines to Comor- Mechanisms of Age-Related Decline in Axon Risk Prediction Models in Older Adults on Antihy- Lynda U. Odofin, University of Vermont, Preva- bidity, 8 months, $57,994 • Ambika R. Shenoy, Regeneration, 4 years, $400,000 • Jonas O. pertensive Medications for Cardiovascular and lence of Clostidium difficle (C. diff.) in Connecticut Cystic Fibrosis Foundation, cftr Function in Hannestad, Nancy Taylor Foundation for Chronic Falls Outcomes, 1 year, $35,000 • Mathieu Swine Farms, 17 months, $12,520 • A. David Paltiel, Macrophages and Neutrophils, 1 year, $68,250 Diseases, Inc., Glutamate Receptor Type 5 During Lemaire, Kidney Foundation of Canada, Novel Massachusetts General Hospital, The Cost- Robert S. 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Ruger, Greenwall Xiong, Alex’s Lemonade Stand, Elucidating the Foundation, The rwjf Clinical Scholars Program Foundation, The Role of Lactate Metabolism in Foundation, Ethical Issues in Health Policy, 3 years, Initiation Mechanism of the Fanconi Anemia core Grant, 2010–2012, 2 years, $1,035,425; Robert P. aeruginosa Biofilm Formation, 2 years, $150,000 $232,073 • Christian Schlieker, Ellison Medical Pathway of dna Damage Repair, 2 years, Wood Johnson Foundation, The rwjf Clinical Marcella Nunez-Smith, Josiah Macy Jr. Founda- Foundation, Deciphering the Nuclear Quality $200,000 • Yang Yang, American Federation Scholars Program Cohort Grant, 2010–2012, tion, Promotion and Retention of Diversity in Control Network and its Relation to Aging, 4 years, for Aging Research, Nicotinic Restoration of 2 years, $1,020,995; Robert Wood Johnson Foun- Medical Education (PaRoDime), 2 years, $250,000 $400,000; Charles H. Hood Foundation, Investi- Prefrontal Cortex Physiology in Aged Monkeys, dation, The rwjf Clinical Scholars Program: Haakon B. Nygaard, American Foundation for gating Nuclear Envelopathies from the Perspective 1 year, $45,710 • James J. Yue, Orthopaedic 3rd year Cohort (2010–2011), 1 year, $98,875 Aging Research, The Role of Cellular Prion Protein of Protein Quality Control, 2 years, $150,000 Research and Education Foundation, Yale David S. Lee, American Society for Clinical in Beta-Amyloid-Induced Epilepsy and Early Death Amy R. Schwartz, New York University School of Comprehensive Spine Fellowship, 1 year, $69,500

// Li Ka Shing (from page 1) treat neuro- sequencing abilities. An additional benefit of the dona- social progress and create a cycle of muscular and liver diseases. One such project tion, Lin says, derives from the lksf’s charity in the world by expanding The contribution will also signifi- is research by Jun status as a private foundation. The use of access to quality education and health cantly enhance the dna sequencing Lu, ph.d., assistant federal funding, such as grants awarded care, encouraging cultural diversity capabilities of the yscc’s genomics professor of genet- by the National Institutes of Health and exploration, and stimulating com- core. Genomics has become central to ics, on the role of (nih), is restricted to certain lines of munity involvement and sustainable biology in recent years, and the field of non-coding rnas stem cells approved by the U.S. govern- development. To date, the foundation stem cell research is no exception. in development ment; these grants cannot be used to has given approximately $1.6 billion in “Stem cell study is becoming Haifan Lin and disease, which fund work on other cell lines. However, charitable donations. increasingly a study at the genetic level relies on the deep genome sequencing “very often these non-nih-approved cell Through ventures in a variety of in- and epigenetic level,” Lin says. “Now that the new Illumina sequencer will lines are much more important and bet- dustries, including container terminals, you need to use deep sequencing to enable. The availability of deep se- ter than the few government-approved telecommunications, retail, real estate, look at the entire genome, instead of quencing will also allow Andrew Xiao, lines,” Lin says. “This donation really hotels, infrastructure, and energy, Li just one of your favorite genes.” ph.d., assistant professor of genetics, gives us a huge advantage.” Ka-shing has built a $26 billion fortune The lksf donation has funded and colleagues to examine the entire Dean and Ensign Professor of Medi- that makes him the 11th wealthiest the replacement of the core’s Illumina genome in his research on chromatin, a cine Robert J. Alpern, m.d., says, “We’re person in the world, according to Forbes sequencer with a newer model, as dna–protein complex that controls the delighted that the Li Ka Shing Founda- magazine. In 2006, Li pledged to do- well as the hiring of a new research genome’s integrity. A third example is tion has chosen to support Yale’s Stem nate one third of his fortune, or about associate and the enhancement of Lin’s own work in understanding the Cell Center. One of the key features $10 billion, to philanthropic projects. analytical software—improvements role that bits of genetic material called of the center is its ability to offer core Li, who has two sons, is known to refer that Lin says will increase the core’s small rnas play in stem cell biology. services that enhance stem cell research to the lksf as his “third son.” sequencing output threefold. Lin studies how pirnas, a class of across the university. This donation will “This is a wonderful contribution These changes will benefit not small rnas discovered in his lab, guide allow these cores to provide the most from lksf, and reflects the visionary only Yale faculty conducting stem cell epigenetic factors to specific points up-to-date equipment and services.” insight of its founder about what’s research, but also graduate students within the genome. “We’ve now found The Hong Kong–based lksf was needed to effectively promote stem and postdoctoral fellows, and visiting over 60,000 of these rnas,” Lin says. founded in 1980 by global entrepreneur cell research,” says Lin, “and it is a scientists from elsewhere in Connecti- “To study these rnas, the only effec- and philanthropist Li Ka-shing. The demonstration of the important role cut who make use of the core’s dna tive way is to use this deep sequencing.” lksf supports projects that propel of philanthropists in science.”

Medicine@Yale May/June 2011 7 Benefactors of Boyer Center receive medical school’s highest honor In April, Herbert Boyer, ph.d., a tow- Adelberg, ph.d., then chair of the human genes into E. ering figure in molecular medicine for Department of Microbiology at the coli bacteria—launched almost 50 years, and his wife, Mari- School of Medicine, to ask for bacterial the biotech industry, grace, received the Peter Parker Medal, strains he needed for an experiment. and opened the door the medical school’s highest honor, for Within a week, the strains were in the to later developments their outstanding contributions to the mail and a scientific collaboration had in genetic engineer- School of Medicine. begun. In 1963 Boyer came to Yale as a ing and gene therapy. The award presentation was an postdoc in Adelberg’s lab. With venture capitalist anniversary of sorts, as it has been 20 “The fruit of my career,” said Robert Swanson, they years since the dedication of the Boyer Boyer at an award ceremony held in formed Genentech, now Center for Molecular Medicine, one of the Medical Historical Library, “dates a leader in the pharma-

the medical school’s most important back to Ed Adelberg and my associa- ceutical industry. terry dagradi research buildings. Boyer, who was a tion with him.” “Herb had the Herbert and Marigrace Boyer are presented with the Peter Parker postdoctoral fellow at the School of Boyer’s greatest contribution to incredible good sense Medal by Dean Robert Alpern. Medicine from 1963 to 1966, made the medicine came after he met Stanley to apply recombinant construction of that building pos- Cohen, ph.d., a Stanford professor, technology to develop treatments years ago it wasn’t obvious that it was sible with a $10 million gift, given in at a conference in Hawaii. Boyer had that would make people better, and the way to go—the Boyer Center was a gratitude to Yale for helping him start found a way to use enzymes to cut he was able to create recombinant collection of faculty from many differ- his research career. snippets of dna that maintained their insulin and recombinant growth ent departments, all working together “The Boyer Center has been critical genetic code and could be spliced onto hormones,” Alpern said. Boyer broke on many different problems.” to the medical school during the past other bits of dna. Once inserted into boundaries not only in science, In his brief remarks, Boyer paid two decades, and its twentieth year circular strands of dna known as Alpern noted, founding his company tribute to his mentor, Adelberg, who marked the time to honor Herb and plasmids, which Cohen was studying, when academic scientists considered died in 2009. “Not only was he a fine Grace Boyer with the Peter Parker Med- Boyer’s snippets could be inserted into alliances with business the equivalent scientist, but he was a gentleman of al,” says Dean Robert J. Alpern, m.d., bacteria, which could then produce a of “embracing the dark side.” Now, the first order,” Boyer said. Under Ensign Professor of Medicine. desired protein in large quantities. Alpern said, it is common practice. Adelberg’s tutelage, Boyer continued, As a doctoral student at the This technology—which Boyer Boyer was also prescient in another he discovered how he wanted to University of Pittsburgh in the early and Cohen used to develop re- way. “Now we all talk about interdisci- spend his career. “I appreciate all the 1960s, Boyer wrote to Edward A. combinant insulin by inserting plinary science,” Alpern said. “Twenty things that happened here at Yale.”

Expert on food-borne infectious bacteria Leader in blood vessel biology and disease is recognized with a top microbiology prize is appointed as Alfred Gilman Professor

Jorge Galán, ph.d., d.v.m., the Lucille faculty with expertise in genetics, William C. Sessa, ph.d., a leading Institute at St. Bartholomew’s Hospi- P. Markey Professor of Microbial immunology, and cell biology study researcher on blood vessel function tal Medical College in London. Pathogenesis, has won the 2011 Robert pathogenic microbes. and vascular disease, has been des- Sessa joined the Yale faculty in Koch Award, one of He and members of his lab study ignated as Alfred 1993 as an assistant professor of the highest honors the molecular “cross-talk” that occurs Gilman Professor of pharmacology, and has been a full in microbiology, between pathogens and their hosts Pharmacology. professor at the School of Medicine for his work on the during infection. Galán is particu- Sessa’s research since 1999. He serves as director mechanisms of larly well-known for his studies of a focuses on the vas- of the interdepartmental Vascular infection by food- bacterial nanomachine known as the cular endothelium, Biology and Therapeutics Program, borne pathogens type III secretion system, which many cells that line all and as vice chair of the Department such as Salmonella pathogenic bacteria use to deliver blood vessels and of Pharmacology. and Campylobacter. virulent proteins into host cells. form the largest Sessa has authored or co-authored Jorge Galán These bacteria cause Understanding this nanomachine William Sessa endocrine organ in more than 200 research articles or millions of cases of infectious gastro- could lead to a new classes of vaccines the human body. papers. enteritis worldwide each year, a major and antimicrobials to prevent many His laboratory is investigating His numerous honors include the public health burden in both industri- important bacterial infections. the factors, including genes, that can American Heart Association’s Estab- alized and developing countries. The Robert Koch Award, which cause dysregulation of the endothe- lished Investigator Award; the Young “With his fundamental research on includes a prize of 100,000 euros, is lium and contribute to cardiovascular Alumnus Award from the Philadelphia mechanisms of bacterial pathogenesis named in honor of the German physi- diseases, such as atherosclerosis, and College of Pharmacy and Sciences; [Galán] contributed substantially to the cian who formulated Koch’s postulates, other diseases. He is also using pro- the American Society of Pharmacol- foundation of cellular microbiology as the first systematic criteria guiding teomics techniques to discover novel ogy and Experimental Therapeutics’ a scientific field,” stated the award cita- research on microbial diseases. proteins that may regulate blood John J. Abel Award in Pharmacology; tion from the Robert Koch Foundation, Koch, one of the founders of the vessel function. a merit Award from the National based in Berlin, Germany. field of microbiology, was awarded the Sessa earned his ph.d. at New Institutes of Health; the Robert M. Galán chairs the School of Medi- 1905 Nobel Prize in Physiology or Medi- York Medical College and was a post- Berne Distinguished Lectureship from cine’s multidisciplinary Section of cine for his seminal work on tuberculo- doctoral fellow and senior scientist the American Physiological Society; Microbial Pathogenesis, in which sis and other infectious diseases. at the William Harvey Research and the William Harvey Medal.

// Gilead (from page 1) Linda Slanec Hig- this collaboration will lead to impor- plx-4032, a compound that has had this phenomenon as well. Next, the gins, ph.d., vice president, biology. tant advances in the understanding unprecedented success in the treat- painstaking process of crystallizing the “Yale’s faculty in this partnership of the genetic basis of cancer as we ment of malignant melanoma, one of mutated protein to discern its structure bring critical, complementary skills to collectively seek to develop novel tar- the deadliest and most intractable can- begins, with the aim of revealing sites form an optimal team,” says Alpern. geted therapies for patients in areas of cers. (plx-4032 is expected to receive where drug molecules or antibodies “Tom Lynch brings experience in clini- unmet medical need.” fda approval in the coming months.) can block cells’ aberrant behavior. After cal trials, Rick Lifton has been a lead- Jaffe says that the collaboration “Dr. Schlessinger has a pedigree that a compound is refined for maximum ing innovator in genetics and genomics, was inspired because “Yale had suc- is unique,” says Jaffe. “He’s been inti- effectiveness, it can be tested in ani- and Yossi Schlessinger has unparalleled ceeded in bringing together a critical mately involved in the creation of two mals, and finally in humans. Genomics success in cancer drug development.” mass of fantastic talent” in genomics, transformative medications.” may then enter the picture again to Gilead’s Chief Scientific Officer, drug development, clinical trials, and In the collaboration, tumor samples determine the profile of each patient’s Norbert W. Bischofberger, ph.d., personalized medicine. He agrees with will be analyzed to identify gene muta- tumors to create personalized therapies. executive vice president, research and Alpern that Schlessinger is an ideal tions that disrupt normal cellular func- “When we find cancer targets that development, says that pairing with leader for the initiative, because of his tions and promote the uncontrolled cell are new, we will work with Gilead on Yale dovetails well with the company’s role in the development of two of the growth and metastasis seen in cancer. designing drugs, which they can then current focus on oncology. “Based most significant targeted cancer thera- Mutations are believed to underlie test in the clinic,” Schlessinger says. on the strong track record of the Yale pies of recent years: Sutent, a treatment the development of drug resistance “This is a tremendous opportunity for cancer research team, I am confident for stomach and kidney cancers, and in cancer, and the team will explore Yale and Gilead.”

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