november/december 2011 volume 7, issue 5 Advancing Biomedical Science, Education, and Health Care

New chair in interventional radiology honors ‘24/7’ physician Robert I. White Jr., m.d., professor of surgery, and co-chief of the medical professor and chair of the Department diagnostic radiology and director of the school’s Section of Vascular and Inter- of Diagnostic Radiology. “The Robert Yale Vascular Malformation Center, is ventional Radiology. “Jeff is the model White professorship will allow him to a tireless, passionate evangelist for his of a clinical scientist,” says White, who broaden the scope of his activities in chosen field of interventional radiol- has combined research and patient care this important discipline.” ogy, a medical subspecialty that offers throughout his career. As director of Yale’s interventional image-guided, catheter-based therapy A graduate of Columbia University, radiology fellowship program, Pollak for disorders of virtually every major Pollak earned his medical degree at Co- is an important mentor to the sub- organ in the body. So it’s fitting that lumbia University College of Physicians specialty’s future practitioners. Ashraf a new endowed chair at the School and Surgeons. He did his diagnostic Thabet, m.d., a 2004 graduate of the of Medicine in interventional radiol- radiology residency at the Columbia- School of Medicine who now works an ogy—only the third such chair in the Presbyterian Medical Center. His fel- interventional radiologist at Massachu- nation—carries his name. lowship in vascular and interventional setts General Hospital in Boston, Mass., And White says he “can think of radiology was at the Hospital of the calls Pollak “an insightful, brilliant, no better person” to hold the Robert University of Pennsylvania. but low-key” physician, “a truly gifted I. White Jr., m.d., Professorship of “Dr. Pollak is an exceptional in- interventionist,” and an ideal choice for henry douglas Interventional Radiology than its inau- terventional radiologist who practices the new White Chair. Jeffrey Pollak (right) is the inaugural appointee gural appointee, Jeffrey S. Pollak, m.d., continuously on the forefront of his White is world-renowned for to a new endowed chair in interventional radi- professor of diagnostic radiology and field,” says James A. Brink, m.d., his expertise in the // Chair (page 7) ology named in honor of Robert White (left).

A time and a place: Unlocking access to hiv care worldwide a new window on Indonesian foundation’s $5 million gift will the life of the brain enable innovative Yale researcher to expand A new study of work on links between hiv, substance abuse remarkable size and scope offers A pioneering hiv/aids researcher, epidemiologist, and clini- clues to how the cian, Frederick L. Altice, m.d., m.a., has traveled the world human brain pursuing his work on the interface between infectious dis- develops, from eases and substance abuse. He has helped to improve access its early stages to care and treatment programs for hiv-infected drug users into old age. Nenad Sestan in Malaysia, the Ukraine, Iran, Russia, Kazakhstan, and The landmark Peru. Director of Clinical and Community Research and the research, led by Nenad Sestan, founder of the School of Medicine’s hiv in Prisons program, m.d., ph.d., associate professor he also provides care to current and former prisoners very of neurobiology and a member of close to home, at the New Haven Community Correctional Yale’s Kavli Institute for Neurosci- Center, less than two miles from the medical campus. ence, found that gene expression Altice’s global commitment has now been recognized with in the human brain is exquisitely a gift from the Indonesia-based Nusantara Trust Fund Foun- choreographed across develop- dation, a private philanthropic organization that provides aid mental periods and brain regions. and assistance for humanitarian programs in Southeast Asia, This tailoring of gene expression particularly through projects that address rural development, occurs particularly during the pre- education, and health disparities. The gift, which includes natal period, during which there a resource fund of $2 million, will enable Altice, professor are rapid changes in brain struc- of medicine and public health, to expand on the research ture and function. In addition to infrastructure he’s helped to build in Southeast Asia over the its contribution to our knowledge last decade. of normal neural development, the

“We have been impressed with the research programs that shapiro harold study may help clarify why some Dr. Altice has developed in Malaysia and hope to encourage Frederick Altice has researched hiv in prisons, including the New Haven people are more susceptible to an expansion of these programs to Indonesia // Gift (page 6) Community Correctional Center, for two decades. particular psychiatric // Brain (page 8)

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 As director of the School of Medicine’s New Haven, CT Clinical Skills Program, Margaret Bia helps Permit No. 526 students to master patient-centered care. 3 Keeping up the fight Three decades after aids first emerged, medical school faculty work at home and abroad to slow the spread of the hiv virus. 6 iPads for all Sweeping aside mountains of printed course materials, tablet computers bring powerful educational advantages in the bargain. also Advances, pp. 3, 5 Out & About, p. 4 lifelines VA Connecticut Healthcare System appoints director Margaret “Peggy” Bia directs the medical school’s In July, Janice Clinical Skills Program, a M. Boss, m.s., key component of the cur- was named riculum that includes both classroom instruction and director of the experience in patient care. VA Connecti- The program emphasizes cut Healthcare patient-centered medicine, System. which Bia believes is increas- Boss brings ingly important to sustain in the rapidly changing arena Janice Boss a wealth of of modern medical practice. experience to her new position. Since 1983 she has held a variety of leadership posts at VA medical centers around the country, most recently as director for the VA Medical Center (vamc) Margaret Bia in Wilkes-Barre, Penn. terry dagradi Boss began her career in the Department of Veterans Affairs (VA) at the vamc in Boston, Mass., where she started as an Carrying the torch administrative resident and went Physicians must hold fast cine, attended Weill Cornell Medical rate of success for kidney transplants on to serve in four other adminis- College as a couple, and were accepted is over 90 percent for the first year trative positions. She then moved to a focus on the patient, jointly to residency programs at the Uni- after surgery, and over 80 percent for to Baltimore, Md., to join the VA’s says clinician-educator versity of Pennsylvania Health System. the first five years. A vastly expanded Eastern Division office. “I was going to be an internist, but body of knowledge and refinements in During the Clinton adminis- That Margaret J. Bia, m.d., is a perennially all the smartest people there, the best technology and medications account tration, when the VA was reor- favorite target in the annual Second Year teachers, were nephrologists,” Bia says. in large part for this difference in ganized and decentralized into Show—a traditional night of song and So she changed course and—again, outcomes. But equally important, Bia 22 Veterans Integrated Service dance in which Yale medical students with her husband—came to Yale for a insists, is a patient-­centered approach Networks (visns), she returned poke fun at their faculty mentors—is fellowship in nephrology. “I was fasci- to treatment, in which transplant clini- to Boston to establish the first a measure of the deep impression she nated with the hard body of knowledge cians work as a team and apply a partic- network office, for visn 1. makes on each class. But it’s not who she of nephrology. That I could understand ular set of skills in order to learn what In 1996, Boss moved to is, Bia says, but what she stands for, that it, and then teach it to others, really influences a given patient’s behavior. California to become director of accounts for her impact. turned me on.” “You could know everything in the network operations for visn 22, Raised in Brooklyn in a largely Now director of the medical medical textbooks,” she says, “but if based in Long Beach. She held Irish neighborhood, Bia, professor of school’s Clinical Skills Program—a you don’t know other things, like your subsequent positions as associ- medicine, lost her father when she program she built with several col- patient’s culture and the context in ate director at vamc San Diego, was 11. With seven children to care for, leagues over many years—Bia is which they live, a lot of your efforts as director of the vamc in Iron Bia’s mother began taking in foster responsible for seeing that medical are squandered.” Mountain, Mich., for two-and-a- children for income. “There were tons students gain hands-on experience Recognizing the value of patient- half years, and as interim director of babies,” Bia says. “And I had tons of through practice sessions and by inter- centered medicine is especially critical at the Philadelphia vamc. cousins. Practically every woman was viewing and examining patients with in today’s atmosphere of medical prac- Boss received her bachelor’s de- either the mother of seven or eight the guidance of clinical tutors. It’s a tice, Bia says, because “the patient is gree from Trenton State College and kids, or a nun. I didn’t want to be a valuable opportunity, she says, for no longer at the center of patient care. a master’s degree in healthcare ad- mother of ten children, and I didn’t students to build the skills required for It’s profit. The more procedures you do, ministration from the University of want to be a nun. I wanted to do some- truly understanding their patients. the more money you make.” But thanks Houston. She is a Certified Health- thing women didn’t do.” Bia joined the faculty of Yale’s to advocates like Bia, patient-centered care Executive in the American Col- So Bia entered medical school in the Department of Internal Medicine medicine is now a core part of Yale’s lege of Healthcare Executives. late 1960s—when fewer than 8 percent as a transplant specialist in 1978. At medical curriculum, and educators can of American physicians were women. that time, a kidney transplant’s odds point to a body of data showing that “They hardly ever made women of success were about 50 percent, this approach yields better outcomes. doctors,” she says, “but I thought it only young patients were allowed to “Talking to patients doesn’t always looked like a good way to serve.” have the procedure, and the powerful pay well, but good patient care means

Bia and her husband, Frank J. Bia, immunosupressant medications given you have to connect,” Bia says. “I see Editor Peter Farley m.d., m.p.h., professor emeritus of medi- to patients were harmful. Today, the myself as a torchbearer.” Assistant Editor Charles Gershman Contributors John Curtis, Jennifer Kaylin, Jill Max, Victoria Wilcox, Sarah C.P. Williams Design Jennifer Stockwell Medical student is first to receive newly endowed Baim Scholarship Medicine@Yale is published five times each year by the Office of Institutional Planning and Communications, Yale School of Medicine, Jeffrey Low, of the Class of 2015, is in high school, Low to a press release, Low received the 1 Church St., Suite 300, New Haven, CT 06510-3330 the first recipient of the Donald S. had co-authored scholarship based on his “demonstrated Telephone: (203) 785-5824 Fax: (203) 785-4327 Baim, m.d. ’75 Scholarship, established papers published in pursuits in innovation, invention and E-mail [email protected] by Boston Scientific Corporation in prominent medical blending business and technology with Website medicineatyale.org February 2011 with a $1.7 million journals. As a Har- a grounded interest in clinical medicine Copyright ©2011 by Yale University. All rights reserved. If you have a change of address or do not wish to receive endowment. The scholarship honors vard undergraduate, and biomedical science.” future issues of Medicine@Yale, please write to us at the Baim, an interventional cardiology pio- Low did consulting “Dr. Baim had a profound and above address or via e-mail at [email protected]. Postal permit held by Yale University, neer who served as Boston Scientific’s for health care firms enduring impact on an entire genera- 155 Whitney Avenue, New Haven, CT 06520 chief medical and scientific officer from Jeffrey Low and the government tion of cardiologists and the clinical 2006 until his death in 2009. of Tanzania, where practice at Boston Scientific, where he As a middle school and high school he worked on a project to develop a low- served as the ‘voice of the patient,’ ” said Robert J. Alpern, m.d. student in San Francisco, Jeffrey Low cost device for monitoring hiv. Tim Pratt, executive vice president, Dean and Ensign Professor of Medicine Jancy L. Houck found an early love for medicine. While The Baim scholarship will be chief administrative officer, general Associate Vice President for Development and volunteering in the spine center of a awarded each year to an incoming Yale counsel, and secretary of Boston Scien- Director of Medical Development (203) 436-8560 community hospital, Low had the op- medical student according to both tific. “This fund ensures that his spirit Mary Hu Director of Institutional Planning and Communications portunity to perform clinical research financial need and intellectual and and legacy will live on in outstanding for surgeons who had invented a suc- clinical drive, and covers half of his or students like Jeffrey and future scholar- cessful orthopaedic device. While still her tuition for four years. According ship recipients.” Printed on recycled paper ♻

2 www.medicineatyale.org advances Health & Science News hiv/aids: Yale covers the waterfront Are ‘better’ devices a School of Medicine researchers and physicians Connecticut in 1991. Altice and colleagues in the Yale aids Program, including Sandra A. Springer, m.d., assistant good choice for all? are working at home and abroad to tackle professor of medicine, and R. Douglas Bruce, m.d., m.a., the worldwide hiv/aids pandemic m.sc., assistant professor of medicine and epidemiol- ogy, have worked to treat hiv-infected inmates in prisons Since it was first clinically observed in 1981, hiv/aids has around the U.S. and abroad—not only for hiv, but also for become perhaps the greatest epidemiological challenge of the other ailments that often affect them, such as tubercu- the last half-century. The last two decades have seen signifi- losis, mental illness, and substance abuse. cant advances in scientists’ understanding of and ability to Although the success of New Haven’s nsep has treat the disease, but in epidemiological terms, with more dramatically reduced the rate of hiv infection via shared than 34 million cases worldwide and 2.7 million new hiv in- needles, there is still a wide overlap between those with

istockphoto.com fections per year, hiv/aids remains a dangerous pandemic. hiv and those with substance abuse disorders, particularly Innovations in medical devices—such The diverse group of Yale scientists working in the field among prisoners. “hiv is a proxy for risk-taking behavior,” as artificial joints, pacemakers, and de- mirrors the complexity of the disease itself: at Yale, not only fibrillators—aren’t always beneficial in are biologists, epidemiologists, and clinicians working in the long run. Small refinements in func- tandem to understand, treat, and prevent the spread of hiv/ tion or durability can come at huge cost aids, but so are economists and mathematical modelers. to patients, with only minor improve- With colleagues in social work and nursing, Warren ments in long-term failure rates. To as- A. Andiman, m.d., professor of pediatrics and epidemiol- sess such trade-offs, a group led by Lisa ogy, established the Yale aids Care Program in 1986. The G. Suter, m.d., assistant professor of program expanded as the patient population grew, and in medicine, developed a computer model 1991 Gerald Friedland, m.d., a renowned clinician and re- that simulates patient outcomes with searcher, joined the faculty. Andiman then became director new devices, focusing on total knee of the Pediatric aids Care Program, and Friedland, profes- replacement (above) as a test case. sor of medicine and epidemiology, became director of its Someone who has a knee replace- adult counterpart, the Yale aids Program. Since then, Yale ment in their fifties has an 18 percent scientists and clinicians have been at the front lines of care chance the device will wear out within for those with hiv.

20 years and have to be replaced again. The Yale aids Program’s Nathan Smith Clinic (nsc), mariette peeters / pangea global aids foundation But because of the higher risk of death established in 1990, was the first in Connecticut dedicated Since 2009, R. Douglas Bruce (right) has worked with the Pangaea among older patients, only 9 percent exclusively to the care of adults with hiv. Today the nsc Global AIDS Foundation on the implementation of Tanzania’s metha- of those in their 70s who receive a is the largest hiv clinic in Connecticut, serving more than done treatment programs, the first use of methadone as a public health knee replacement will need a second 850 patients, including those on Medicaid and Medicare intervention in sub-Saharan Africa. replacement. The Suter team reports and the uninsured. All patients are assigned a primary explains Bruce. And because drug addiction can interfere in the November 4 issue of the New care provider and also have access to specialty services, so drastically with successful treatment of hiv, “often we England Journal of Medicine that, as a including psychiatry and women’s health, and linkages have to address that before we can address hiv care.” group, older patients may not live long with substance abuse programs—particularly important Bruce came to Yale in 2000 and worked alongside Altice enough for longer-lasting devices to be given the prevalence of mental illness and substance abuse and Springer for several years, treating hiv-infected inmates worth their additional cost. among the hiv-infected population. in New Haven’s prison system. “As things evolved, I realized The researchers say their model can Embracing not only patient care but also clinical that some of the treatments we were offering in mobile set- be easily applied to other device innova- research and the training of medical students, residents, tings and in the jail weren’t sufficient,” he says. Specifically, tions to evaluate their true benefits. and fellows, the Yale aids Program—a part of the Sec- he was dissatisfied with the amount of time it took to get tion of Infectious Diseases in the Department of Internal drug users on methadone—a synthetic opioid used to treat Medicine—reflects the School of Medicine’s three missions addiction to opioids like painkillers and heroin. Due to its Getting a close look at of research, education, and patient care. But it also has a low cost, methadone is a practical means of addiction treat- fourth mission of community, says Merceditas S. Villanue- ment, but, due to regulations in clinics, it used to take up a virus-detecting rig va, m.d., associate professor of medicine and the program’s to eight weeks to get a person into methadone treatment in Viruses ranging from common influ­ director since 2009. “Community” can refer to both the New Haven. Within that lengthy period, substance-depen- enza to hepatitis C rely on strands local and international communities, but in some regards, dent people who were struggling in the community or who of rna to infect human cells and Villanueva says, the two are closely linked. had been released from prison and were unable to stop using spread their genetic information. Yale A number of successful programs that have been piloted drugs on their own usually ended up in the hospital, jail, “or researchers have now made a step in New Haven have seen subsequent implementation around worse, dead,” Bruce says. The cycle simply wasn’t ending. toward understanding how the human the world. In the early 1990s, Edward H. Kaplan, ph.d., and “Eight weeks was too long.” immune system recognizes viral rna Robert Heimer, ph.d., and Kaveh Khoshnood, ph.d., m.p.h., In a clinic at New Haven’s Hill Health Center, as well strands to mount an immune response, demonstrated the success of New Haven’s needle/syringe as one in the Fair Haven section of New Haven, Bruce set work that could reveal new ways to exchange program (nsep), one of the first in the nation. out to make quick treatment more accessible // HIV (page 7) target such viruses with drugs. Established with special permission from the Connecticut Scientists knew that a protein called state legislature, the program’s goal was to slow the spread of rig-I binds to viral rna that’s entered hiv infection among injection drug users (idus) by provid- Support medical advances a human cell and alerts the cell of its ing them with free, sterile syringes. By 1992, Kaplan, now the presence. To find out more about how William N. and Marie A. Beach Professor of Management by giving from your ira rig-I recognizes viral infection, Anna Sciences at the School of Management, professor of public Why now? Marie Pyle, ph.d., the William Edward health at the School of Medicine, and professor of engineering There is still time for individuals aged 70 and older to make charita- Gilbert Professor of Molecular, Cellular, and the School of Engineering and Applied Sciences; Heimer, ble gifts directly from individual retirement accounts (iras). Contri- and Developmental Biology, along with professor of epidemiology and public health and associate butions up to $100,000 can satisfy minimum distribution require- professor of pharmacology; and Khoshnood, associate profes- postdoc Dahai Luo, ph.d., and Brett ments and will not be treated as taxable income. But hurry—this Lindenbach, ph.d, assistant professor sor of epidemiology; had accumulated enough data to show, opportunity is set to expire on December 31, 2011. of microbial pathogenesis, determined via mathematical models, that the program was reducing new the 3-D structure of rig-I bound to hiv infections by a third. Why Yale School of Medicine? double-stranded rna (dsrna), which is Kaplan, Heimer, and Khoshnood’s work was the first By using the charitable ira rollover to make your gift to the School produced when viruses replicate. to offer hard evidence of the efficacy of nseps as an hiv of Medicine, you benefit from significant tax savings while helping As reported in the October 14, 2011 prevention strategy. Since then, Yale faculty have worked to secure the excellence and strength of the School. Your gifts can issue of Cell, the group discovered that to implement nseps in broader domestic and international support groundbreaking medical research that will impact genera- tions of patients. Or, you can fund scholarships that assist talented when bound to dsrna, rig-I undergoes settings. For instance, Heimer has evaluated nseps in students on their path to becoming the physicians of tomorrow. a dramatic change in shape, in which Russia and Estonia, and Frederick L. Altice, m.d., m.a., one section of the protein folds out to professor of medicine and public health, has implemented Learn more: make room for the rna. The authors a needle exchange in Malaysia, where he’s worked since Contact Jancy Houck, associate vice president for development and write that their work on rig-I’s struc- 2005 (see related story, page 1). director of medical development at 203-436-8560; visit www.yale. ture “reveals multiple strategies for Another local initiative that has seen global imple- planyourlegacy.org; or consult your tax advisor. therapeutic design.” mentation is the hiv in Prisons program, launched in

Medicine@Yale November/December 2011 3 out & about

September 18 Students and faculty brought their competitive spirit to Yale’s Cullman-Heyman Tennis Center for the Student/Faculty Tennis Classic. 1. (From left) Ben Albright ’15; Dean and Ensign Professor of Medicine Robert J. Alpern, m.d.; Jovana Pavisic ’13; and Robert Udelsman, m.d., m.b.a., chair and William H. Carmalt Professor of Surgery. 2. A volley by Agnès Vignery, d.d.s., ph.d., associate professor of orthopaedics and rehabilitation. 3. Eileen Harder ’14, the event’s organizer, with Pasquale Patrizio, m.d., professor of obstetrics, gynecology, and reproductive sciences. 1 2 3 terry dagradi (3)

September 20 As part October 3 Representatives of University College London (ucl) gathered with their Yale counterparts of its Hope on Wheels for a meeting of the Yale-ucl Collaborative. 1. (From left) Natasha Lewis, ll.b., director of legal services program, which supports at ucl; Lori Manders, director of development and alumni relations at ucl; William C. Sessa, ph.d., pediatric cancer research Alfred Gilman Professor of Pharmacology; and John Martin, m.d., professor of cardiovascular medicine and treatment programs at ucl and co-director of the Yale-ucl Collaborative. 2. (From left) Woodbridge Fellow Sarika Arya; around the U.S., repre- Sessa; Martin; David Price, ph.d., vice-provost (research) at ucl; Manders; Sir Cyril Chantler, chair of ucl sentatives of Hyundai Partners; Michael Simons, m.d., the Robert W. Berliner Professor of Medicine and Cell Biology, chief of Car Sales named Gary the Section of Cardiovascular Medicine, and co-director of the Yale-ucl Collaborative; Robert J. Alpern, Kupfer, m.d., professor of m.d., dean and Ensign Professor of Medicine; Mary J. Hu, m.b.a., director of Institutional Planning and pediatrics and pathology, Communications at the School of Medicine; Cynthia Carr, j.d., ll.m., visiting lecturer at Yale Law School; chief of the Section of Steven M. Girvin, ph.d., deputy provost for Sci- 1 Pediatric Hematology and ence and Technology and the Eugene Higgins Oncology, and director Professor of Physics and Applied Physics; Rich- of the Pediatric Oncology ard Lifton, m.d., ph.d., chair and Sterling Profes- Program at Smilow Cancer sor of Genetics; Stephanie S. Spangler, m.d., Hospital at Yale-New deputy provost for health affairs and associate Haven, a Hope on Wheels vice president for West Campus planning; Scholar, and donated Donald L. Filer, associate secretary and director $100,000 for his work. 1 of international affairs; Lewis; and Michael 1. Peter DiPersia, general Whorton, ph.d., vice-provost (international) manager of the eastern region at Hyundai Motor America. and Fielden Professor of French Language and 2. (From left) Cynthia N. Sparer, m.p.a., executive director of Yale- Literature at ucl. New Haven Children’s Hospital (ynhch); Clifford W. Bogue, m.d., associate professor of pediatrics, interim chair of the Department 2 of Pediatrics, and physician-in-chief at ynhch; Kupfer; and DiPersia.

2 harold shapiro (2) terry dagradi (2)

October 27–28 Yale’s Child 1 2 Study Center (csc) held its annual meeting of the Child Study Center Associates, the final event in a series of four marking the csc’s hundredth year, in honor of the late Albert J. Solnit, m.d., who served as csc director from 1966 to 1983. 1. (From left) Barbara F. Nordhaus, m.sc., m.s.w., assistant clinical pro- fessor in the csc, and Ruth Lord. 2. (From left) Joan Harris, Carol Schaefer, and

Chuck Schaefer. terry dagradi (2)

4 www.medicineatyale.org advances Common threads seen in autoimmune diseases Health & Science News As genes conferring risk for autoimmunity The vast majority of genes in the implicated regions play Telltale dna aids early a role in the immune system. Many affect white blood cells, are revealed, the shared pathways underlying particularly helper T cells, which prime their B cell cousins to diabetes diagnosis seemingly different illnesses are coming to light fight perceived threats. In addition, the researchers noted that over a third of the genes associated with ms had been previ- Researchers studying what goes wrong in autoimmune ously flagged as possible culprits in at least one other autoim- diseases now have a road map to guide future work, mune disorder, findings that should “put to rest” any doubts thanks to two ambitious international studies published that ms is primarily an autoimmune disease, says Hafler. in August in which School of Medicine researchers played The PLoS Genetics study, on which Hafler, Cotsapas, and key roles. One, reported in Nature, doubles the number others joined a group organized by the Federation of Clinical of known genetic culprits in multiple sclerosis (ms). The Immunology Societies (focis), investi- other, in PLoS Genetics, finds that the genetic basis of auto- gated whether seven common autoim- courtesy of kevan herold immunity is largely shared among autoimmune disorders. mune disorders share genetic influences, In type 1 diabetes, the immune system Autoimmune diseases, which occur when the immune as would be expected from the way these kills insulin-producing beta cells (above) system attacks the body’s healthy tissue, are three times more disorders co-occur within individuals and in the pancreas. By the time the illness common among women than men, and rank among the top families. “People often get more than one,” is diagnosed, most beta cells have been 10 causes of death for women under age 65 in the United says Hafler. destroyed, creating a challenge for States, according to Chris Cotsapas, ph.d., assistant professor Cotsapas, Hafler, and colleagues on the potential treatments to be effective. of neurology and genetics and lead author of the PLoS paper. focis team analyzed data from previous Chris Cotsapas When cells die they rupture, and “All autoimmune diseases have a substantial heritabil- gwas of celiac disease, lupus, type 1 diabe- the dna in their nuclei escapes into ity,” Cotsapas says, much of which is due to variants in the tes, Crohn’s disease, ms, rheumatoid arthri- the bloodstream. Though the dna major histocompatibility complex, a section of chromo- tis, and psoriasis, focusing on 107 genetic sequence in every cell is identical, the some 6 that is well populated with immune-related genes. variants that had been tied to autoimmune body’s organs have diverse functions, Other genes also play a role. For example, recent disease. They found that nearly half the so dna is “marked” with tissue-specific genome-wide association studies (gwas) have implicated genes were associated with increased risk modifications that enable or suppress over 20 additional genomic regions in ms, a condition in of multiple autoimmune disorders. “I was the expression of appropriate genes. which the immune system targets myelin, a fatty sheath really surprised that the degree of sharing In an early edition of Proceedings around nerve cell extensions that is crucial for efficient was that high,” says Cotsapas. David Hafler of the National Academy of Sciences, neural transmission. But these studies left much of the Next, the researchers grouped the a group led by Kevan C. Herold, m.d., heritability of the disease unexplained, leaving researchers variants by their associated diseases and found that many professor of immunobiology and wanting a bigger and better study. affected genes code for proteins that closely interact in net- medicine, describe a marker found only “Everyone realized that no one could do it individu- works. “They talk to each other, and that suggests that there in beta-cell dna. In a mouse model of ally,” says ms expert David Hafler, m.d., the Gilbert H. are entire pathways that underlie risk to multiple diseases,” type 1 diabetes, the team saw a rise in Glaser Professor and chair of neurology, part of the team Cotsapas says. Crohn’s disease, ms, and psoriasis have symp- blood-borne beta-cell dna just as the that published the study in Nature. That paper, authored toms that are “about as different as you can get,” but these cells began to die, long before diabetes by the International Ms Genetics Consortium and the conditions share a pathway involving helper T cells. Other symptoms appeared. Higher levels of Wellcome Trust Case Control Consortium 2, involved 11 autoimmune conditions might converge on a different pro- beta-cell dna were also seen in newly years of work by nearly 250 researchers in 15 countries. tein network, says Hafler. “If you look at a certain pathway, diagnosed type 1 diabetes patients. In genome-wide comparisons of dna from about 10,000 certain diseases share that pathway, and others do not.” “Early detection of cell death may people with ms and from 20,000 unaffected people, Hafler The new findings, Hafler says, are examples of the allow for better monitoring and earlier and colleagues confirmed 23 out of 26 previously reported ge- “brave new world” of autoimmune disease research in the interventions in people at risk for devel- netic associations with ms, and they identified an additional post-genomic era, a world in which we will find treatments oping type 1 diabetes,” says Herold. 29 gene regions that had never before been tied to the illness. for these diseases by seeing them in completely new ways.

New one-two punch brings down bacteria Gift links tribal colleges with Child Study Center Recent experiments in which stretches When Charles W. child development and mental health csc faculty, informational sessions of proteins and genetic material are Carl Jr., m.d., talks each July. It will also support the de- about research and clinical programs at inserted into bacteria to silence genes about his 2005 trip to ployment of csc faculty to reservations the csc and elsewhere on the medical have shown great promise as a means the Navajo Nation—a and tribal colleges, to increase under- campus, and tours of New Haven and of treating bacterial infection. By inacti- 27,000 square-mile standing of Native American culture Yale. The fellowship includes travel vating genes such as those a bacterium Native American and child care priorities. expenses, lodging, and a small stipend. needs to copy its genome, or those that reservation in the The program’s goal, says Carl, a The program is already growing, help it to resist antibiotics, the method Southwestern U.S.— psychiatrist in private practice in Mas- says csc Director Fred R. Volkmar, can kill the cells directly or make them his voice fills with Charles Carl sachusetts, is “to create a knowledge m.d., the Irving B. Harris Professor more vulnerable to antibiotic drugs. emotion. Carl and his base and a skill base in the Native of Child Psychiatry, Pediatrics, and Yale scientists have now developed wife, Dianne, visited the reservation American community. There’s a huge Psychology; in 2011, 13 fellows were a technique that gets these molecules after making a donation to the Ameri- need on the reservations for informa- accepted from a pool of more than 60 into bacterial cells more efficiently, can Indian College Fund, which works tion and training. I hope that by having applications. Volkmar says the program making the procedure more effective to improve opportunities in higher an exchange, we’ll be able to help Native is designed to “help people become than ever. The new method, which was education for Native Americans. The Americans to help their own people.” more aware of the range of excellent developed in the laboratory of Nobel experience was “profoundly moving,” In 2010, the csc welcomed its first clinical and research models, interven- laureate Sidney Altman, ph.d., Sterling says Carl, a 1952 graduate of Yale Col- group of five fellows, who attended a tions, and other resources that exist. Professor of Molecular, Cellular, and lege and 1963 graduate of the School of structured series of workshops with The hope is that it can be inspiring.” Developmental Biology and professor Medicine. “It turned me on to the need of chemistry, combines a fragment of in the Native American community for protein based on a molecule in human services, [especially] for child mental immune cells with a stretch of genetic health services.” material that can bind to and inactivate The trip inspired Carl to donate a bacterial gene. $450,000 in 2008 to the School of In the October 4, 2011, issue of Medicine’s Child Study Center (csc) Proceedings of the National Academy to establish an exchange program of Sciences, Altman’s team reports known as the Charles W. Carl Jr., m.d. that when they used the method to Training Fellowship Program in Child inactivate genes that underlie bacterial Development and Mental Health. Now in its third year, the fellowship enables resistance to the antibiotics penicillin terry dagradi Native American students and teachers and chloramphenicol, it was as much Twelve students and one faculty member from Native American tribal colleges came to Yale last as a hundred times more effective than from tribal colleges to visit the csc for summer for training in child development and mental health at the Child Study Center. Fred Volk- similar compounds tested thus far. a two-week educational immersion in mar (standing, second from left) and Barbara Nordhaus (not pictured) coordinate the program.

Medicine@Yale November/December 2011 5 Tablets an excellent prescription for School of Medicine’s students This fall, all 518 medical students joining the pilot program. at Yale received Apple iPad tablets “I absolutely have to have to download course curricula, take everything printed out, notes in class, and assist them in their so I didn’t know how an clinical training. “It’s hard to think iPad could replace that.” of anything else that has had such But after a semester of a profound and rapid impact,” says using the tablet, she says, Michael Schwartz, ph.d., assistant “I really, really loved it.” dean for curriculum. Bing says she appreci- The initiative grew out of a ates having access to all remarkably successful pilot program the course material while in which a handful of students at the listening to a lecture, and School of Medicine were given iPads also welcomes the iPad’s during the spring 2011 semester. portability. “I travel a lot, Though originally a move to make and I used to bring paper the School of Medicine a greener copies of everything with campus, the response from both pro- me to study on the road,” fessors and students suggested that she says. “With the iPad in addition to being an efficient and it’s so much easier. It’s all environmentally smart way to deliver right there with the touch learning materials, tablet computers of a finger.” have the potential to transform medi- The School of Medi- cal education at Yale. cine’s iPad initiative is part terry dagradi Robert Camp, m.d., ph.d., of a growing trend at medical schools Seeing is believing: the printed curriculum materials formerly used by a single School of Medicine who teaches pathology to first- and across the country, including those at student in one year, held by Richard Belitsky, deputy dean for education, tower over Assistant second-year students, says the iPad Brown; the University of California, Dean for Curriculum Michael Schwartz’s iPad tablet. is ideal for small-group teaching. Irvine; Stanford; and the University iPad, although they are advised to test results, X-rays, or whatever else “Computer screens, which we used to of Minnesota. But Yale’s program is download the fall, winter, and spring together. It enables a greater level of use, create a barrier between you and different in that all students, not just courses separately because faculty personal connection.” the person you are talking to. It’s not those in their first and second years, continue to update documents until Schwartz, says it had cost roughly interactive. But the iPad is more like have received the tablets. Yale has the start of the course. $1,000 per student to provide paper a piece of paper. You hold it more like securely encrypted its iPads, a feature Nicholas Bergfeld, a member of copies of all course materials, about a book and you can pass it around. It that will allow third- and fourth- the pilot group who is now in his the same price as an iPad and sup- tends to engender more group think- year students to protect patients’ second year at the medical school, porting applications. “We pretty ing and group discussion.” privacy when they use the tablets in says he can foresee the iPad enhanc- much break even,” he says, “but A self-described “paper person,” their clinical work. It takes students ing his interaction with patients the iPad is better for the environ- Vicki Bing of the Class of 2014 says about 30 minutes to download the during his clinical studies. “You ment–and as an information delivery she had “huge reservations” before entire curriculum for one year on the and the patient can look at their lab system, it’s much more versatile.”

// Gift (from page 1) and other countries introducing methadone, a synthetic Health, and the Prison Department, in the region . . . in line with the vision opioid used to treat addiction to opioid Altice has been deeply involved in and mission of the foundation,” says drugs such as heroin. expanding methadone, hiv, and tu- Tatag Wiranto, ph.d., chairman of the Earlier that year, Altice had formed berculosis (tb) treatment in Malaysian Nusantara Trust Fund Foundation and a close collegial relationship with prisons and community settings. His Deputy Minister for the Development Adeeba Kamarulzaman, m.b.b.s., current work in Malaysia includes the of Disadvantaged Regions in Indone- f.r.a.c.p., professor of medicine and introduction of preventive hiv and tb sia. “We believe that through strategic now dean of the Faculty of Medicine therapies into prisons and a program partnership with researchers and at the University of Malaya in Kuala for reforming compulsory drug deten- educators from the best institutions in Lumpur and president of the Malaysian tion centers that detain suspected the world, such as Yale, we will be able aids Council from 2006 to 2010. Aware drug users without fair trials. to build our capacity to ensure success of Altice’s expertise as an intervention- The new resource fund donated by and the sustainability of our efforts to ist, Kamarulzaman enlisted his help the Nusantara Trust Fund Foundation improve the lives of our people.” in implementing Badawi’s changes will enable Altice to expand on and rep- Altice’s interest in hiv/aids took throughout Malaysia. licate these efforts in other Southeast

root three decades ago. As a medi- “I said, ‘Sure, but I need to under- Asian countries, especially Indonesia, courtesy of frederick altice cal student in the early 1980s, while stand the epidemic,’ ” Altice recalls. where Altice plans to expand and adapt Frederick Altice (right) met Tatag Wiranto, conducting research at the Centers Altice’s role in fighting the Malaysian innovative care delivery models for chairman of the Nusantara Trust Fund Foun- for Disease Control and Prevention, hiv/aids epidemic has been broad, prisons and rural settings. dation in Jakarta, Indonesia, in November for Altice began to describe the early but he began with both feet on the “We are developing new research a check presentation. epidemiology of the disease. Later that ground—literally. His outreach took methods and adapting innovative fellowship in the department’s Section decade, he was part of a group of Yale him to many locations on the streets models of care that are transcending of Infectious Diseases at Yale. From researchers who had established one of Malaysia, including “under bridges the usual academic boundaries to cre- 1991 to 1992, he received additional of the first needle exchange programs where people shot up drugs,” he says. ate new knowledge,” Altice says. Eager training in the Robert Wood Johnson in the U.S., providing drug users in In persuading Malaysian leaders to to collaborate with colleagues at other Clinical Scholars program. In 1993, New Haven with clean syringes in adopt some of his recommendations, universities and research institutions after observing the untreated health an effort to prevent the spread of hiv Altice was able to point to his past throughout Asia, he says his work is problems of many people participating (see related story, page 3). Since 1991, work in Iran—like Malaysia, a Muslim “less about ownership and more about in the New Haven nsep, Altice helped Altice’s prison program has promoted country—where he provided guid- mission.” Before seeking funding on an to launch the Community Health Care hiv prevention and care for prisoners ance in the introduction of methadone even larger scale, “we’re going to exam- Van, a mobile clinic offering a range of and former prisoners in Connecticut treatment in prisons. ine multiple pilot projects initially,” he health care services to members of the and elsewhere. In 1993, Altice estab- “Rick understands cultural and says, “and expand our training . . . to New Haven community. lished the Community Health Care religious sensitivity. These things get more people interested. I would re- “Rick has always been committed Van, a free mobile clinic connected with can make or break partnerships with ally like to shift the mentality towards to helping less fortunate people, in New New Haven’s needle/syringe exchange countries like Malaysia,” says Kama- research and treatment.” Haven and throughout the world,” program (nsep), which integrates drug rulzaman. “We love him because of Altice, who holds an appointment says Robert J. Alpern, m.d., dean and treatment and care. his accessibility, generosity of spirit, as a visiting professor at the University Ensign Professor of Medicine. “This In 2005, Malaysia’s former Prime and knowledge.” of Malaya, received his m.d. from the gift acknowledges this and provides Minister, Abdullah Ahmad Badawi, Working with the Malaysian Emory University School of Medicine ongoing support for his research efforts announced health policy changes that anti-drug agency Agensi Anti Dadah and completed his residency in the at the interface between substance included implementing nseps and Malaysia (aadk), the Ministry of Department of Internal Medicine and a abuse and the spread of hiv.”

6 www.medicineatyale.org // HIV (from page 3) for people with sub- and treat hiv/aids. Michael J. Kozal, stance abuse disorders. “We’ve made m.d., professor of medicine, uses new it so you can get into treatment in sequencing technologies such as dna Yale aids Program at a glance 24 hours, and have captured a larger micro-arrays and ultra-deep genomic At Yale, hiv/aids is the clinical and research focus of a vast number of individuals, piece of a very ill pie,” he says. sequencing methods, to understand centers, and programs. Among them are the Yale aids Program; the Pediatric aids Springer’s work focuses on the the genetic factors that make patients Care Program; and the Center for Interdisciplinary Research on aids (cira), a consor- adherance of hiv-positive prisoners resistant to arv medications. As tium of more than 100 scientists involved in research on and treatment and preven- to antiretroviral (arv) medications, director of hiv Clinical Trials at Yale tion of hiv/aids in the United States and abroad. cira’s director is Paul D. Cleary, particularly during and following re- and chief of the Section of Infec- ph.d., dean of the Yale School of Public Health, chair of the Department of Epidemi- lease from prison, when patients are tious Diseases at the VA Connecticut ology and Public Health, and the Anna M.R. Lauder Professor of Public Health. most likely to relapse into patterns of Healthcare System in West Haven, As director of the Yale aids Program from 1991 until 2009, Gerald Friedland, alcohol and opoid use. Her novel re- Conn., Kozal spearheads trials of new m.d., professor of medicine and epidemiology, oversaw its growth from search involves evaluating the use of hiv medications, and has been able friedland a regional center for patient care into a leading international center for extended-release naltrexone—which to offer patients alternatives when hiv/aids research, treatment, and prevention. One of the program’s nine can be given just before release from older treatment modalities fail. faculty members, Friedland is an expert in hiv therapies and the inter- prison but has longer-lasting ben- In the clinical realm, one of the face between hiv and tuberculosis. His work with vulnerable populations altice efits than comparable treatments—to most encouraging recent successes includes extensive research and patient care in rural South Africa. Frederick manage addiction and to improve has been the eradication of transmis- L. Altice, m.d., m.a., professor of medicine and public health, is a specialist hiv treatment outcomes. sion of hiv from mother to child in infectious diseases and addiction medicine and has worked to reform In recent years, Bruce has worked during pregnancy and childbirth. At barakat treatment strategies for prisoners and those with substance use disorders to implement methadone treatment Yale-New Haven Hospital, the virus in the U.S. and around the world. Lydia A. Barakat, m.d., assistant professor programs internationally. In 2009, he has not been transmitted from an in- of medicine, is medical director of the program’s Nathan Smith Clinic (nsc). was invited to Tanzania to help launch fected mother to a child in more than Her areas of interest are quality management and enhancing hiv training bruce what was the first use of methadone 15 years. Yale’s Pediatric aids Clinic, within the medical residency program. R. Douglas Bruce, m.d., m.a., m.sc., as a public health intervention in sub- in fact, has only several dozen pa- assistant professor of medicine and epidemiology, is an expert in the Saharan Africa. Despite the success of tients still on treatment, the youngest intersection of substance abuse and infectious diseases, particularly hiv such programs, there is much work yet of whom is sixteen. When these last francis and hepatitis C. John S. Francis, m.d., ph.d., assistant professor of medicine, to be done. To decrease the number patients reach adulthood, they will has treated patients with hiv/aids at Yale-New Haven Hospital and the of new hiv infections each year, “we transition to adult clinics, and then nsc for more than five years, and now cares for patients primarily at the have to take a significant number the clinic will likely close its doors, VA Connecticut Healthcare System. Francis supervises internal medicine kozal of people with hiv out of the injec- says Andiman, the clinic’s director. residents and infectious disease fellows, and also works closely with Yale tion pool,” Bruce says. “To do that, Andiman credits this achieve- medical students as an academic advisor. Michael J. Kozal, m.d., profes- we have to get tens of thousands of ment—part of a trend taking place sor of medicine, is a specialist in the genetic determinants of hiv drug people into treatment.” across the U.S.—to the implementa- shenoi resistance and the use of new technologies to detect drug-resistant viral The advent of arv therapies in tion of hiv screening of pregnant variants. Sheela Shenoi, m.d., m.p.h., assistant professor of medicine, does the mid-1990s was a major break- women. If a woman is known to be clinical research on hiv/aids and tuberculosis, particularly in resource- through, effectively changing hiv/ hiv-positive, certain precautions, such limited settings. Sandra A. Springer, m.d., assistant professor of medicine, springer aids from a fatal disease to what is as tailored arv regimens for mothers specializes in clinical research and the care of patients with hiv/aids, now considered a chronic, manage- and the use of breast-milk substitutes particularly prisoners and those afflicted by substance abuse. Merceditas S. able disease. “People are not dying in for infants, can be taken to drastically Villanueva, m.d., associate professor of medicine, is the current director of the numbers they used to,” Villan- reduce the chances of transmission. villanueva the Yale aids Program, having succeeded Friedland in 2009. ueva says. One of the earliest arv Such advances have resulted in re- medications, stavudine, was devel- markable improvements in the U.S., oped at Yale by the late Professor but in many places where the disease Resource allocation is of criti- have bred success in the U.S. of Pharmacology William Prusoff, is most prevalent, a lack of resources cal importance, says A. David Paltiel, According to Villanueva, Ameri- ph.d., and the late Tai-Shun Lin, has impeded progress. In Pretoria, ph.d., professor of public health. Paltiel can physicians, privileged with ph.d., senior research scientist. In South Africa, for instance, where one uses mathematical models to predict resources, funding, and supportive 1994, stavudine—which works by quarter of all pregnant women have the ways certain treatments or preven- government policies, have a duty thwarting replication of the retrovi- hiv, without treatment about 40 tative measures—making hiv screen- to help the less well-off, and it’s a rus—was approved by the Food and percent of children born to infected ing routine, for instance—would affect responsibility that Yale scientists and Drug Administration as a treatment mothers become infected. Brian W. both the epidemic’s trajectory and the physicians have not taken lightly. for hiv. Known more commonly Forsyth, M.B.Ch.B., professor of economics of treatment and prevention. “Yale brings to the table so many under the trade name Zerit, it has pediatrics and in the Child Study “Our work helps decision-makers know talents, and has been a conduit to been used in combination with other Center, has conducted a number of what every dollar spent will buy,” says improving the care for hiv/aids drugs to extend the lives of many studies aimed at improving the pre- Paltiel, who is also a professor at the within the local and international thousands with hiv. vention of mother-to-child transmis- Yale School of Management. communities,” Villanueva says. “The Today, clinical trials of new sion in sub-Saharan Africa and other “What’s good in the first world people that I work with are very out- anti­retroviral therapies are an active resource-poor areas, where, Andiman is good in the third world,” says For- of-the-box thinkers, and the research component of the School of Medi- says, “the problem is one of access [to syth, who is working to put in place spawned in our program is motivated cine’s efforts to better understand care], money, and political will.” in South Africa those measures that by their huge hearts.”

// Chair (from page 1) diagnosis and hht Centers of Excellence around and senior credit officer at The whose family also made a contribution treatment of Hereditary Hemorrhagic the world has gained him a fan club Northern Trust Company in Chicago, to the new chair, half-seriously says she Telangiectasia (hht; also known as among his patients that would be the Ill., echoes these comments. Blevens, thinks of White as “almost walking Osler-Weber-Rendu syndrome), a heri- envy of any rock star. In gratitude, who has served on the board of hht on water”, adding, “He literally has table genetic condition in which blood more than a dozen of those patients Foundation International, credits saved multiple lives in our family.” vessels in certain parts of the body tend and their families pooled the consid- White with saving his life, and marvels HHT is prevasive in the Lange family, to form without capillaries. These tiny erable resources needed to create the that he is seemingly “available 24/7” for so White has been deeply involved vessels are crucial to depressurizing new endowed chair. White and his his patients, “answering every e-mail with the medical care of many of her blood as it flows from arteries to veins, wife, Patricia Kelly-White, who has within an hour or two.” loved ones. “He’s such a warm, caring and in hht high-pressure arterial joined her husband in raising aware- Diana R. Meiches of Prides person, and has such charisma,” Lange, blood flows directly into veins with ness of hht, also pitched in. Crossing, Mass., another former hht says. “ I could not adequately express full force, creating fragile sites that are One donor, Lisa Ruscitti of Ridge- Foundation board member, calls our feelings, our appreciation, and our prone to ruptures and bleeding. field, Conn., whose son Jackson was White “one of the most brilliant men admiration for Dr. White.” Some symptoms associated with diagnosed with hht at Yale after he suf- I’ve ever met,” and says he “absolutely White says that the new professor- hht, such as frequent nosebleeds, are fered a brain hemorrhage at four weeks epitomizes compassionate care.” ship will provide Pollak with the free- fairly benign. But some patients have old, uses the superlatives one hears again White treated Meiches’ husband, dom to do the clinical research needed to vascular malformations in the liver, and again from White’s patients and Marc A. Meiches, chairman, presi- evaluate medical outcomes and advance lungs, or brain that can suddenly burst, their relatives. She calls him a “wonder- dent, and chief executive officer of the field. “I want to see this specialty with life-threatening consequences. ful person” who “goes above and beyond Electric Insurance Co., for hht, and become important in people’s minds, White’s treatment of hundreds what a physician needs to do.” “there is no doubt in my mind that he and having this chair in interventional of families with hht and his in- Another grateful hht patient, saved Marc’s life,” she says. radiology will really reflect that,” says volvement in the establishment of Bradley E. Blevins, senior vice president Anna B. Lange, of Richmond, Va., White. “Jeff is the future.”

Medicine@Yale November/December 2011 7 Leader in ‘telemental health medicine’ is honored by the Department of Veterans Affairs Linda S. Godleski, m.d., has received telemental health curricula for the techniques nation- Vanderbilt University, UVA, the Uni- the David M. Worthen Award for VA, which has one of the largest such wide, expanding versity of Hawaii, and the University Career Achievement in Educational programs in the world. the use of clinical of Louisville. She has served as a con- Excellence from the Department Telemental health medicine has videoconferencing, sultant to a number of academic and of Veterans Affairs (VA), the VA’s proved to be an efficient and econom- in-home messag- federal agencies, as well as the Ameri- highest recognition for academic ic method of providing behavioral ing, videophones, can Telemedicine Association. Her accomplishments. health services for patients who live and pilot Internet work has been presented extensively at Godleski, associate chief of staff in rural areas and might not other- applications. VA and academic conferences, includ- for education for the VA Connecticut wise have access to mental health Linda Godleski Godleski has ing expert testimony before Congress, Healthcare System in West Haven, care professionals. Godleski and her also led the VA in strategic planning and she has published widely in peer Conn., and associate professor of psy- colleagues have used the method for new educational initiatives, includ- reviewed journals. chiatry at the School of Medicine, has for clinical assessments, individual ing an extensive expansion of medical The Worthen Award recognizes pioneered the application of telemedi- and group psychotherapy, psycho- and associated health programs with a VA employee from any health dis- cine (the use of technology to provide educational interventions, cognitive Yale and other VA affiliates. cipline who has made contributions medical care when distance separates testing, and general psychiatry. Godleski received her medical of national significance to educa- providers from patients) to psychia- Godleski has chaired the Tele- degree from the University of tion in the health professions. First try, in an emerging field known as mental Health Field Advisory Work Virginia (uva) School of Medicine, issued in 1988, it commemorates the “telemental health medicine.” Group for the Veterans Health where she also completed her psy- late David M. Worthen, m.d., former As director of the VA National Administration (vha), which has chiatry residency. head of vha Academic Affairs and Telemental Health Center, Godleski been instrumental in developing a Prior to joining Yale she served an inspirational leader of VA’s educa- has been a leader in developing “toolkit” to deploy telemental health on the faculty of medical schools at tional mission.

// Brain (from page 1) or neurological dreams. Yet in thinking disorders, especially autism and about the study, which schizophrenia, which many scientists would ultimately analyze believe are caused by perturbations in more than 17,000 dis- early brain development. tinct mrna transcripts, Sestan has long been interested in he decided that “this understanding the transcriptome, the cannot be done by one term for the totality of expressed rna person, one lab, or even molecules, of the human brain. We one institution.” share most of our genes with other Indeed, the study, animals, and in Sestan’s view, it is the published in the Octo- spatiotemporal dynamics of the brain ber 27 issue of Nature, transcriptome—when and where involved an international genes are expressed—that underlies team of collaborators, as humans’ unique attributes. well as several scientists In the new research, Sestan and from Sestan’s own labo- colleagues measured the relative ratory: Hyo Jung Kang, abundance of messenger rna (mrna) ph.d.; Yuka Imamura terry dagradi molecules in 16 important brain re- Kawasawa, ph.d.; Feng It took an unusually large team of postdocs and graduate students (including some not pictured gions at 15 developmental stages across Cheng, ph.d.; Ying here) in the laboratory of Nenad Sestan (standing, third from right) to complete a large-scale the life­span. Because mrna is the Zhu; Xuming Xu, ph.d.; Mingfeng analysis of gene expression in the developing human brain across the lifespan. molecular middleman between genes Li, ph.d.; Andre Sousa; Mihovil neural machinery resides for many prevalence, and severity of brain and the protein-making machinery of Pletikos, m.d.; Kyle Meyer; Goran capabilities, such as language and disorders between sexes.” the cell, with some adjustments mrna Sedmak, m.d.; Yurae Shin; Matthew reasoning, that we think of as dis- Though this study excluded tis- levels are a reliable indicator of which Johnson, ph.d.; Zeljka Krsnik, ph.d.; tinctively human. sue from people with overt medical genes are slated for translation into Simone Mayer; and Sofia Fertuz- This massive effort uncovered or large-scale genetic abnormalities, proteins at any given time. inhos, ph.d. some surprising results. For starters, some of the same sex-biased genes Previous efforts to decipher the Thanks to the generosity of brain the study found that nearly nine of observed in the work by Sestan and transcriptome of the human brain donors, Sestan’s team had access to 57 every ten genes in the human genome colleagues have been fingered by other have looked at only a few brain areas post-mortem human brains repre- are expressed in the brain, “basically researchers as increasing the risk of and/or a few time points, so when senting developmental stages from saying you use most of your genes to psychiatric and neurological disorders. recently developed technology made 40 days after conception to 82 years build your brain,” Sestan says. dna They include genes suspected of con- it possible to interrogate most of the of age. They gathered 1,340 tissue “switches” can turn gene expression on tributing to schizophrenia and autism, human genome in one swoop, Sestan samples for analysis, including from or off, and expression of most of these two disorders that may start brewing saw a chance to do the study of his 11 areas of the neocortex, where the genes varied by developmental period, early in development and affect males brain region, or both. “What was also and females differently. surprising and completely unknown Sestan and colleagues also found before,” Sestan says, “is that most of 29 groups of genes that were expressed these changes occur during prenatal together in certain brain regions dur- and early postnatal development.” ing specific developmental periods. In addition, from one brain region They were able to tie some of these or time point to another, “genes gene expression networks to particular switch their versions like suits,” ac- biological processes, yielding clues cording to Sestan. They can do so to what the genes do. Furthermore, because an mrna sequence can be some of the genes at the hub of these spliced in different configurations, networks have been implicated in meaning a single gene can create dif- schizophrenia, mood disorders, Rett ferent versions of a protein. syndrome, and intellectual disability. While mrna expression signifi- Now, researchers who study such dis-

courtesy of the lasker foundation cantly differed between brain regions orders can look to these co-expressed and across developmental periods, it genes for causal leads. Sterling Professor of Genetics and Pediatrics Arthur Horwich, m.d. (third from left), is a co- recipient of the 2011 Albert Lasker Basic Medical Research Award for his seminal work on the varied less by ethnicity or sex. Even Sestan and his collaborators hope mechanisms of cellular protein folding (see Medicine@Yale, September/October 2011). The so, expression of 159 genes differed that their study will help scientists recipients were honored at a ceremony in New York City on September 23. (From left) Franz- between males and females. Most of who study these conditions and oth- Ulrich Hartl, m.d., dr.med., of the Max Planck Institute of Biochemistry in Germany, Horwich’s these sex-based expression differ- ers. To that end, they have made their longtime collaborator and co-recipient; Tu Youyou, of the China Academy of Chinese Medical ences appeared before birth and van- data set publicly available. After all, Sciences, recipient of the Lasker-DeBakey Clinical Medical Research Award; Horwich; and John I. Gallin, m.d., representing the Clinical Center of the National Institutes of Health, recipient of ished by adulthood, but Sestan says as Sestan well knows, it will take a the Lasker-Bloomberg Public Service Award. they “may offer some insight into village of scientific sleuths to solve the why there is a difference in incidence, mysteries of our most complex organ.

8 www.medicineatyale.org