march/april 2011 volume 7, issue 1 Advancing Biomedical Science, Education, and Health Care

Kavli institute to cast an even wider scientific net Building upon a grant made in 2003 Under the direction of Pasko Duberg Professor of and build ties with researchers at Kav- that established the Kavli Institute Rakic, m.d., ph.d., Kavli Institute Neurobiology at the li Institutes elsewhere. The disciplines for Neuroscience at Yale, The Kavli scientists have conducted influential School of Medicine. expected to contribute to the Yale Foundation has announced that it research on the molecular, cellular, “To achieve this Kavli Institute’s research range from will contribute additional endow- and functional organization of the laudable goal we genetics to psychology, and the insti- ment funds to diversify and strength- cerebral cortex, the part of the brain must embrace a tute will also foster the development en the institute’s interdisciplinary responsible for higher brain functions multidisciplinary of novel concepts and technologies to brain research. such as language and reasoning. approach, using investigate the functional properties Since the beginnings of neurosci- The new commitment will enable the most advanced of the living brain. ence research, Yale researchers have the Kavli Institute to expand its technologies in a variety of experi- In addition to providing research excelled in the quest to understand mission to embrace Yale research on mental model systems. It also requires support, the new funds will provide the fundamental mechanisms of the nervous system more broadly, collaboration and frequent exchange support to top Yale graduate students how the human brain develops and drawing on the expertise of the nearly of ideas between scientists of differ- in neuroscience, who will be desig- functions. Such findings from basic 100 neuroscientists working in 20 de- ent backgrounds. All of these will be nated as Kavli Scholars. neuroscience may have profound partments across the Yale campus. cultivated at the Kavli Institute.” “We are very excited by the expand- implications for understanding brain “Understanding the human brain To realize this wider vision, the ed approach to neuroscience research disorders such as autism, schizophre- is considered the ultimate challenge institute’s Steering Committee will the Kavli Institute for Neuroscience at nia, mental retardation, dyslexia, and of science in the 21st century,” says set the institute’s research agenda, Yale is undertaking,” says Fred Kavli, neurodegenerative diseases. Rakic, chair and Dorys McConnell foster scientific collaborations at Yale, founder and chairman // Kavli (page 7)

In life and work, New line of attack on a dreaded disease alumnus touched In honor of a friend fighting a brain tumor, countless hearts Turkish financier’s multimillion-dollar gift There could funds genomic analysis of deadly glioblastomas be no greater gratification for Few diseases are as feared, or as deadly, as glioblastoma a physician– multiforme­ (gbm), the most aggressive and most common scientist than form of brain cancer, which accounts for about 60 percent seeing the fruits of all brain tumors diagnosed in the each of his or her own year. Over the past five years, improvements in radiother- research become Donald Baim apy and surgical techniques, and the advent of drugs that an integral part block blood vessel formation in tumors have significantly of medical practice, providing pa- increased survival time in patients with gbm. But despite michael marsland tients with a better treatment than these advances, on average these patients live less than one President Richard Levin (center) joined neurosurgeon any that had existed before. year after diagnosis. and geneticist Murat Günel (left) and financier Mehmet Kutman (right) The late Donald S. Baim, m.d., One promising avenue for transforming the prognosis at Woodbridge Hall to mark Kutman’s donation establishing the Yale a member of the medical school’s faced by gbm patients is genomic research, which can iden- Program in Brain Tumor Research. The new program will apply genomic Class of 1975 and an internationally techniques to the study of brain tumors, especially glioblastoma multi- tify aberrant genes present in gbm tumors and determine forme, the most common and most aggressive form of brain cancer. renowned innovator in the field of how such genes vary from patient to patient. Recent genetic interventional cardiology, had that sequencing research on gbm has already paid dividends: Research, researchers at Yale School of Medicine will be rare privilege. four new classifications of gbm based on genomic data are bringing the power of the latest genomic techniques to Baim, who died unexpectedly guiding the development of more precisely targeted thera- better understand brain tumors, with a particular focus on in 2009 at age 60, served as chief pies, as well as personalized approaches to treatment based gbm and related illnesses. medical and scientific officer at Bos- on the genetic makeup of a given patient’s tumor. “Mehmet Kutman’s generous support for Yale’s genom- ton Scientific Corp. bsc( ), a global Last year’s launch of the Yale Center for Genomic Anal- ic research will spur the effort to find new treatments for developer, manufacturer, and mar- ysis (ycga) placed the School of Medicine at the forefront patients whose lives are threatened by these brain cancers,” keter of medical devices, since 2006. of genomic sequencing research. Now, with a $12 million, says Yale President Richard C. Levin. Despite his relatively short four-year multi-year gift from Turkish financier Mehmet Kutman, The new program will be directed by Murat Günel, m.d., tenure, Baim was greatly beloved m.b.a., to launch a new Yale Program in Brain Tumor Nixdorff-German Professor of // GBM (page 7) and admired by // Baim (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 Deputy Dean Carolyn Slayman takes the New Haven, CT long view—and keeps a cool head. Permit No. 526 3 A century of progress The Yale Child Study Center celebrates 100 years of research and compassionate care 4 Synthesizing success Decade-long race to make an anti-cancer compound in the lab is won by Yale chemists also Advances, pp. 3, 5 Out & About, p. 4 Grants and Contracts, p. 6 lifelines Advocate for the mentally ill backs young scientists Three of Carolyn Slayman’s grandparents, and both In January, the National Alliance parents, were teachers, an for Research on Schizophrenia and influence that steered her Depression (narsad), the lead- toward academics. After earning her ph.d. in the Rock- ing charity providing funds for efeller University laboratory research on psychiatric illness, an- of Nobel Prize winner Edward nounced that 10 School of Medi- Tatum, a postdoctoral stint cine scientists had won narsad at Cambridge University, Young Investigator awards. The and a brief tenure at Case Western University, Slayman awards—which provide up to joined the School of Medi- $60,000 over two years to “the cine faculty in 1967, rising most promising young scientists through the ranks to be the conducting neurobiological re- medical school’s first female search” relevant to understanding department chair, and the first woman to be named a mental illnesses including schizo- deputy dean. phrenia, mood disorders, bipolar disorder, autism, and anxiety dis- Carolyn Slayman orders such as obsessive-compul- terry dagradi sive disorder and post-traumatic stress disorder—went to: Jessica A. Cardin, ph.d. Taking it in stride Assistant professor of neurobiology Silvia Corbera, ph.d. Deputy dean is stalwart In 1995, Slayman became the first lent of 300 complete human genomes Postdoctoral associate in psychiatry woman appointed as a deputy dean per month, “opening up thinking in Douglas J. Guarnieri, ph.d. in a whirlwind of change at the medical school, and she came ways people couldn’t have begun to Associate research scientist in psychiatry in biomedical research well-prepared, having also been the first imagine even a few years ago.” Imaging Jason K. Johannesen, ph.d. woman to head a department when she techniques, from microscopes that bring Assistant professor of psychiatry Many awards and mementos, collected was named chair of the Department of a cell’s individual proteins into view to Roger J. Jou, m.d., m.p.h. over decades in science and academia, Human Genetics (now Genetics) in 1984. scanners that map out functions in the Clinical fellow in the Child Study Center line the office shelves of Carolyn W. Slayman has witnessed a sea living human brain, have transformed Janghoo Lim, ph.d. Slayman, ph.d., but one stands out: change in the status of women in the scientific landscape. And through it Assistant professor of genetics a certificate from the Bob Bondurant science and medicine since the late all, once-impenetrable walls between Ruth Sharf, ph.d. School of High Performance Driving for 1950s, when she enrolled at The Rocke- fields and departments have tumbled Postdoctoral associate in psychiatry excellence in skid control. feller University for doctoral studies. In down, as research became an increas- Megan V. Smith, dr.ph., m.p.h. Slayman visited the Arizona school those days, each entering class at Rock- ingly multidisciplinary endeavor, “driven,” Assistant professor of psychiatry on a corporate field trip, donning a full- efeller, hand-picked by Detlev Bronk, Slayman emphasizes, “by the science Bao-Zhu Yang, ph.d. body racing suit and taking the wheel of ph.d., the University’s president, had 14 itself, not declared from above.” Assistant professor of psychiatry some seriously powerful automobiles. men and one woman. When asked at a But for all the momentum toward Lingjun Zuo, m.d., ph.d. In most of the day’s activities — thread- question-and-answer session for new “big science,” Slayman believes that Associate research scientist in psychiatry ing a car through traffic cones at speed, students why this 14:1 ratio persisted, scientists will always form working units In 2011, narsad will distribute for example — Slayman was an average Bronk coolly replied, “Because that’s the on a human scale, never relinquish- $12.6 million in Young Investiga- performer. But when it came to pulling right number.” At Yale today, women ing “the ability to talk around a table.” tor awards to 214 scientists around out of a skid, she nailed it. make up a third of the total medical She sees her role as one of “balancing the world. Since 1987, the group has An impressed instructor surmised faculty, and since 1998, there have been resources and possibilities,” providing awarded more than $274 million in that Slayman honed this skill on snowy more women than men in each enter- individual teams with the wherewithal such grants, which can enable young roads in her home state of Maine. But ing medical school class. to succeed while also playing match- scientists to pursue studies that will it couldn’t have hurt that Slayman’s The changes in biomedical science maker, urging researchers to “reach out, attract major grants from federal demeanor is almost preternaturally have been no less dramatic. Having grad- interact, communicate, collaborate,” to agencies or the private sector. On calm, an unflappability that serves her uated from Swarthmore College just five make an academic whole bigger than average, Young Investigators have well in the demanding, unpredictable years after Watson and Crick’s landmark the sum of its parts. gained sufficient leverage from their role of Deputy Dean for Academic and paper on the structure of dna, Slayman, “There are 1,212 really smart people grants to raise 19 times the amount Scientific Affairs at the School of Medi- also Sterling Professor of Genetics and on our faculty doing important things, of their original narsad grant. cine. “No two days are alike,” she says. professor of cellular and molecular physi- so there are bound to be problems,” “And you never know what’s coming ology, has enjoyed helping to create a Slayman says. “But there’s also a con- when an e-mail pops up or the tele- gene-sequencing facility at Yale’s West stant, positive ferment — good things phone rings.” Campus that can generate the equiva- coming from all directions.”

Managing Editor Peter Farley Assistant Editor Charles Gershman Contributors Helen Dodson, Jill Max, ‘Old Blues’ support ALS research to honor a friend and classmate Suzanne Taylor Muzzin, Janelle Weaver Design Jennifer Stockwell When John Tagliaferro, Cary Koplin, The Charles Skubas YC ’66 Fund for Medicine@Yale is published five times each year by the Office of Institutional Planning and and Greg Weiss of the Yale College als Clinical Support and Research. Communications, Yale School of Medicine, Class of 1966 learned that classmate By reaching out to classmates, 1 Church St., Suite 300, New Haven, CT 06510-3330 Telephone: (203) 785-5824 Fax: (203) 785-4327 Charles A. Skubas was ill with amyo- former teammates, and fraternity E-mail [email protected] trophic lateral sclerosis (als, or Lou brothers, Tagliaferro, Koplin, and Website medicineatyale.org Gehrig’s disease), they knew they Weiss, in collaboration with mem- Copyright ©2011 by Yale University. All rights reserved. would find a way to honor him. bers of Yale’s Office of Development, If you have a change of address or do not wish to receive future issues of Medicine@Yale, please write to us at the Skubas, a member of the Delta Kappa have raised more than $283,400 so above address or via e-mail at [email protected]. Epsilon fraternity and a lifelong athlete, far. The fund will support enhanced Postal permit held by Yale University, 155 Whitney Avenue, New Haven, CT 06520 was diagnosed with the progressive and patient care and research in als and neurodegenerative disease in 2007. He related diseases, and will be used at Robert J. Alpern, m.d. passed away on January 3, 2011. After the discretion of David A. Hafler, Dean and Ensign Professor of Medicine visiting an increasingly frail Skubas m.d., Gilbert H. Glaser Professor Jancy L. Houck Associate Vice President for Development and Director of in New Haven, Tagliaferro, Koplin, and chair of neurology at the School Medical Development (203) 436-8560 and Weiss pledged to start a fund that of Medicine, and chief neurologist at Mary Hu would not only pay tribute to Skubas but Yale-New Haven Hospital. Director of Institutional Planning and Communications This issue follows Volume 6, Issue 5 (December 2010). would also support the fight against als A lifelong athlete, Charles Skubas was a member The January/February 2011 issue was not published. and related diseases. What emerged was of Yale’s varsity football team in the mid-1960s. courtesy of amanda tagliaferro Printed on recycled paper ♻

2 www.medicineatyale.org advances Health & Science News A big birthday for Child Study Center A cellular doorkeeper’s A century of child development research and role in hypertension compassionate care for childhood disorders is marked by world-renowned Yale department

As the School of Medicine’s bicentennial year draws to a close, Yale’s venerable Child Study Center (csc) has begun celebrat- ing a milestone of its own—its 100th anniversary. One of the School of Medicine’s 28 departments, the csc was born in 1911 when Wisconsin native Arnold Gesell,

istockphoto.com ph.d., m.d., a young assistant professor in Yale University’s From their perch atop the kidneys, the new graduate Department of Education, persuaded medi- adrenal glands help to control blood cal school Dean George Blumer, m.d., to give him a single pressure by secreting the hormone room in the New Haven Dispensary (a community clinic at aldosterone. In aldosteronism, often the medical school founded in the late 19th century) for use cushing/whitney medical library caused by adrenal tumors called adeno- in a study of mentally retarded children. From these humble Arnold Gesell, founder of the clinic that would become the Yale Child mas, excessive levels of this hormone beginnings, the csc has become a world-renowned center for Study Center and a pioneer in research on children, employed the relatively cause severe hypertension, but the the study and treatment of developmental disorders and other new medium of motion pictures to record and observe behavioral patterns in infants. mechanisms of tumor-induced aldoste- psychological conditions affecting children. ronism have been poorly understood. In 1921, Gesell was named to lead an expanded Clinic of the Maurice Falk Professor of Child Psychiatry in the csc In the February 11 issue of Science, Child Development, where his work profoundly influenced a and associate dean for student progress at the School of a team led by Richard P. Lifton, m.d., burgeoning field. As one of the first researchers to attempt a Medicine, began developing a plan to improve low-achieving ph.d., chair and Sterling Professor of quantitative study of development by measuring the respons- elementary schools in New Haven in 1968. Modeled on the Genetics, reports that many adenomas es of infants and children to different stimuli, Gesell used the understanding that development and learning are inextrica- carry mutations in the gene kcnj5, relatively new medium of film to record and study behavioral bly linked, that program, now known as the School Develop- which encodes channels that selec- patterns, eventually filming about 12,000 children. He con- ment Program, or sdp, informs state and national education tively allow potassium ions through cell cluded that mental development occurs in identifiable stages, policy and practice and has been implemented in hundreds of membranes. The mutated channels are similar to those seen in physical development. Although some schools around the world. less selective, allowing sodium to enter of his views have since fallen out of favor, Gesell’s overall Today the csc remains at the forefront of the field of and unleashing a signaling cascade influence on American psychology, as well as on child-rearing child development. Researchers at the Center are making sig- that causes adenoma cells to secrete practices, has been a lasting one. nificant strides in many areas, using brain-wave technology, aldosterone and to overproliferate. A Following Gesell’s retirement, Milton J.E. Senn, m.d., genomics, and neuroimaging, and conducting clinical trials to kcnj5 mutation was also found in a was recruited in 1948 to serve as both chairman of the De- study such diverse phenomena as the lasting effects of stress family with aldosteronism not caused partment of Pediatrics and director of the renamed and and trauma during early brain development; accurate diag- by adenomas, suggesting that these reorganized csc. The designation as a center reflected the nosis of autism in infancy; psychosocial care for children di- mutations can also cause noncancer- University’s desire for a multidisciplinary approach to the agnosed with cancer; the genetic and neural bases of autism, ous adrenal cells to overproliferate and study of children and child development. An innovator in Tourette’s syndrome, and other developmental disorders; and secrete too much aldosterone. pediatrics, Senn was a pioneer in bringing mental health the efficacy of drugs in treating childhood disorders. The “This gene was not on anybody’s principles into pediatric practice, and as the csc’s new leader Albert J. Solnit Training Program, established in 2004 as a list to sequence in an investigation of he welcomed the insights of social workers, early childhood lasting tribute to the former csc director, perpetuates Solnit’s this disease,” Lifton says. “We really hit educators, and other nonmedical child specialists. dedication to clinical excellence and superior education. This the jackpot.” Senn was succeeded in 1966 by Albert J. Solnit, m.d., who six-year, combined clinical and research program admits only had been the first resident in child psychiatry at Yale. Solnit two students per year, qualifying graduates for both the adult was a child psychiatrist, pediatrician, and psychoanalyst and child psychiatry board exams and preparing them to help Uncovering genes who pioneered work on social policy and child custody. He children and families who face the potential disruptions and built even more interdisciplinary connections, fostering col- devastations of a diagnosis of a mental health disorder. that orient organs laborations with Yale Law School and overseeing the formal Volkmar credits the center’s broad, multifaceted approach Our bodies exhibit symmetry — two establishment of the csc as a department of both the medical for its continued success. “Because there’s so much going on eyes, ears, arms, legs, and so on. But school and Yale-New Haven Hospital. here, it means there’s more potential for cross-disciplinary internal organs such as the heart, liver, The csc also was deeply influenced by its fourth director, work,” he says, a model that will guide the csc through its and stomach must develop asym- the late Donald J. Cohen, m.d., one of the most influential second century of achievement. metrically to function normally. In American child psychiatrists of his generation. Cohen upend- heterotaxy (Htx), a rare and potentially ed tradition, rejecting conventional notions that development deadly birth defect, left – right asym- can be explained in either environmental or genetic terms and The next century of progress metry is disrupted, causing organs to be seeking to bridge these two viewpoints. In Cohen’s studies of malformed or in the wrong position. autism, for example, he blended the latest research findings, According to recent data from the National Health and Nutrition In a new genomic study published and he came to view the disorder as both genetically and neu- Examination Survey, approximately one in five children in the online January 31 in Proceedings of the rologically based—a break from the then-common belief that U.S. will meet the diagnostic critera for a mental health disorder National Academy of Sciences, Htx pa- autism resulted from flawed parenting. such as Tourette’s syndrome, autism, anxiety, bipolar disorder, or tients were found to be twice as likely In the difficult period following Cohen’s death in 2001, depression. For 100 years, researchers and physicians at the Yale as control subjects to harbor copy John E. Schowalter, m.d., now professor emeritus in the csc, Child Study Center (csc) have provided compassionate care for number variations (cnvs), stretches filled in as interim director until 2002, when Alan E. Kazdin, children and adolescents, rapidly translating scientific discoveries of duplicated or missing genetic ph.d., now John M. Musser Professor of Psychology at Yale into practical treatments in the clinic, the home, and the com- material. Many genes disrupted by and a leader in the development of evidence-based treatments munity. Your gifts to these csc programs will sustain this legacy these cnvs have counterparts in the for mental disorders in children, was named the csc’s fifth into the next century: frog Xenopus tropicalis, and when the director. The current director, Fred R. Volkmar, m.d., the The Albert J. Solnit Integrated Training Program (up to $15 million) authors knocked out Xenopus genes Irving B. Harris Professor of Child Psychiatry, Pediatrics, and A highly selective six-year program (see story above) that gives they thought might be involved in Psychiatry, was inspired by Cohen’s work, and initially came future clinicians intensive training to provide crucial treatment and left–right patterning, they identi- to the csc in 1980 to work with him. Volkmar has gone on to support to children with mental disorders, and their families. become a leading scholar in autism and related disorders. fied five that are essential for proper Clinical Excellence Fund ($250,000–$1 million) Enables the trans- Over the last 100 years the csc has been home to genera- development, none of which had lation of scientific research to innovative therapies in the Child tions of faculty and trainees who have shaped both the science previously been tied to asymmetry. Study Center’s general and specialty clinics (autism, Tourette’s and social policy surrounding childhood development and “Combining human genetics with syndrome/ocd, trauma, and anxiety disorders). model systems such as the frog will mental health issues. The Center now includes the Edward allow us to rapidly identify genes that Zigler Center in Child Development and Social Policy, named Community Program Fund ($100,000) Provides support for affect embryonic development and for Edward F. Zigler, ph.d., Sterling Professor Emeritus of international programs that work with governments and organi- better understand the causes of these Psychology and chief architect of the Head Start and Early zations around the world to improve children’s mental health. childhood diseases,” says co-author Head Start programs. The Zigler Center has dramatically For more details, contact Zsuzsanna Somogyi at (203) 436-8559. Mustafa K. Khokha, m.d., associate changed the landscape of services for children and families professor of pediatrics and genetics. locally, regionally, and globally. James P. Comer, m.d., m.p.h.,

Medicine@Yale March/April 2011 3 out & about

January 11 Yale’s Child Study Center (csc) kicked off its 100th year with a Centennial January 20 89 people from the medical campus were in attendance at a School of Series Symposium on infant mental health in honor of Arnold Gesell, m.d., the csc’s Medicine Night at Mory’s, held in the venerable York Street bar and eatery that re- founder (see related story, p. 3). From left: Linda Mayes, m.d., Arnold Gesell Professor opened last November after a two-year hiatus. 1. From left: Ralph Brooks; Sheela She- of Child Psychiatry; Helen Egger, m.d., visiting noi, m.d., instructor in internal medicine; and Auguste H. Fortin VI, m.d., m.p.h., asso- assistant professor in the csc; (back row) Fred ciate professor of medicine. 2. Karen Peart, j.d., associate director of media relations R. Volkmar, m.d., director of the csc and the in Yale’s Office of Public Affairs and Communications, and her son, Jordan. 3. Mory’s Irving B. Harris Professor of Child Psychiatry, general manager Robin Soltez (left) and hostess Jennifer Dunne. 4. Yale College’s all- female a capella group Proof of Pediatrics, and Psychiatry; Katarzyna Chawarska, 1 ph.d., associate professor in the csc; and the Pudding performed for the Walter S. Gilliam, ph.d., associate professor in crowd. 5. From left: Christo- the csc and director of The Edward Zigler Cen- pher G. Burd, ph.d., associate ter in Child Development and Social Policy. professor of cell and develop- mental biology at the Univer- sity of Pennsylvania School of Medicine; Dean and Ensign Professor of Medicine Robert J. Alpern, m.d.; and James E. Rothman , ph.d., the Fergus F. Wallace Professor of Biomedi- cal Sciences and chair of the Department of Cell Biology. 2 3 terry dagradi (2)

1 2 4

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4 5 harold shapiro (5)

February 18 A Reception Honoring Flora M. Vac- carino, m.d., who was named Harris Professor of Child Psychiatry in October, was held in the School of Medicine’s Beaumont Room. Carolyn M. Mazure,

john curtis (5) ph.d., associate dean for faculty affairs, professor of February 18 The Class of 2013 carried on a 62-year tradition, poking fun at the medical psychiatry and psychology, and director of Women’s school’s faculty and administration in “Staph Inception,” this year’s Second Year Show. Health Research at Yale (left), celebrates with the 1. “Boy band” member Wayne Gui in one of the dance numbers. 2. From left: honoree, who recently founded the Program in Neu- Maria Koenigs, Kara Furman, Stephanie Meller, Irina Shklyar, and Meg Whicker as mem- rodevelopment and Regeneration, an interdepart- bers of a glee club that faces off with the boy band. 3. Amanda Hernandez plays the mental initiative that will use induced pluripotent lead in “Fashion Design Girl.” 4. Misia Yuhasz, the lead dancer in “Dean Belitsky.” stem cells as a research tool to understand neuronal 5. From left: Matt Garner, Michael Alpert, Chris Sauer, Kyle Ragins, Ray Chen, and development in individuals with specific neuropsy-

Dhruv Kullar in “Residency.” hauemily chiatric disorders.

4 www.medicineatyale.org advances Health & Science News In 11 steps, chemists make a giant leap Now? Later? Brain cells The ‘blood, sweat, and tears’ of Yale researchers retrieved from the seabed, the group isolated a chemical that killed cancer cells and microbial pathogens such as help us make the call push them over the top to crack the daunting, staph bacteria with remarkable potency. The structure decade-old puzzle of a potent anticancer agent of the compound suggested that it might have a bacterial origin itself, and after five years of subsequent analysis the In the latest chapter of a 15-year scientific story spanning team discovered a previously unknown species of symbiotic the globe from the South Pacific to New Haven, a team of bacterium living on the sea squirt that produced yet an- scientists in Yale’s Department of Chemistry has achieved other chemical with impressive anticancer and antibacterial

istockphoto.com the first synthesis of an elusive chemical compound, open- properties, which they called lomaiviticin. We all prefer receiving large rewards ing the door to the development of a new class of molecules But the bacterium that produces lomaiviticin is ex- right away, but we typically must to target and destroy cancer stem cells. Many researchers tremely rare, and it cannot be easily coaxed into creat- choose between small, quick payoffs believe that these cells are a root cause of some of cancer’s ing the molecule in the laboratory. For the past decade, and bigger ones that occur later. deadliest characteristics, including resistance to chemo- chemists worldwide have been striving without success to Neuroscientists have determined that therapy, tumor relapse, and metastasis. synthesize lomaiviticin to obtain sufficient quantities for a brain region called the basal ganglia The story begins in 1996, when a team of scientists exploring its anticancer properties more deeply. Now, as is crucial in helping us evaluate the size from Wyeth-Ayerst Research (now part of Pfizer) and the reported online January 31 in the Journal of the American and timing of such incentives. University of Utah were analyzing marine organisms they Chemical Society, a team at Yale, led by Seth Herzon, ph.d., As reported in the January 13 issue had collected in Fiji in the hopes of finding useful chemi- has managed to synthesize a form of the compound known of Neuron, a team led by Daeyeol Lee, cals for drug development. From a bright orange sea squirt as lomaiviticin aglycon for the first time. ph.d., associate professor of neurobiol- “About three quarters of anticancer ogy and psychology, determined which agents are derived from natural prod- basal ganglia structures govern these ucts, so there’s been lots of work in this choices. Lee and colleagues recorded area,” says Herzon, assistant professor of the activity of neurons in the caudate chemistry. “But this compound is struc- nucleus and ventral striatum of the turally very different from other natural basal ganglia in monkeys that shifted products, which made it extremely dif- their gaze toward different patterns ficult to synthesize in the lab.” on a computer screen to receive either Herzon’s team, which managed to a tiny amount of apple juice delivered synthesize the molecule in just 11 steps instantly or a larger quantity provided starting from basic chemical building seconds later. The team found that the blocks, has been working on the prob- caudate nucleus contributed more to lem since 2008 and spent more than these judgments than did the ventral a year on just one step of the process striatum. Neurons in the caudate involving the creation of a carbon–car- seemed to compare the values of the bon bond. It was an achievement that treats based on their delay and magni- many researchers deemed impossible, tude, revealing a new role of this brain trying to work around it using other region in decision-making. techniques, but the Herzon team’s per- The work may help to explain psy- sistence paid off. chiatric conditions characterized by a courtesy of seth herzon “A lot of blood, sweat, and tears went into creating that bond,” Herzon bias toward immediate gratification. (From left) Graduate student Cristina Woo, Seth Herzon, and postdoctoral fellow Liang Lu solved the “We don’t know the anatomical basis “extremely difficult” problem of synthesizing a chemical that has drawn worldwide attention for its says. “After that, the rest of the process of . . . problem gambling or impulsive potential in fighting a variety of cancers. was relatively easy.” // Herzon (page 8) behavior,” Lee says. “Now we are starting to pinpoint those areas, even down to individual neurons.” Sorting out the steps Surgeons-turned-detectives explore the dawn of chemotherapy in Salmonella infection Thanks to the unearthing of long- senior research scientist in Salmonella bacteria invade the gut by lost medical records by two dogged the Department of Pathol- piercing a needle-like structure through surgeons, the full story of the first ogy, whom they’d enlisted to the intestinal lining to inject their own use of intravenous chemotherapy for help, finally found a report proteins into cells. First the needle cancer, which occurred at Yale in the that looked promising, but complex moves into place, and then, in early 1940s, can now be told. the medical record number sequence, proteins called translocases The general outlines of this event— contained errors. Thanks and effectors infiltrate the host cell. that a lymphoma patient, known only to the help of a persistent In a report published online Febru- as “J.D.” in the medical literature, archivist, they eventually ary 3 in Science, a team led by Jorge E. received the first known chemotherapy narrowed the possibilities Galán, d.v.m., ph.d., the Lucille P. Mar- at New Haven Hospital (now Yale- down to one patient. In a key Professor of Microbial Pathogenesis, New Haven Hospital) in 1942—have moment of triumph, Fenn analyzed the molecular choreography been recounted by historians based on sent Udelsman a one-word underlying this step-by-step process. the recollections of those involved in e-mail: found! They found that a protein known the case, but the specifics have until The records revealed that as SpaO prepares the bacterium for now remained a mystery. an immigrant from Poland attack by forming a large complex that Two years ago, Clinical Professor first came to New Haven includes components of the needle and of Surgery John E. Fenn, m.d. and Hospital in 1941 for treat- translocases, but few effectors. How- Robert Udelsman, m.d., m.b.a., chair ment of massive tumors in ever, mutant bacteria that lacked trans- and William H. Carmalt Professor of and around his neck that had locases showed high levels of effectors Surgery, became fascinated by J.D.’s diminished his ability to eat, in the SpaO complex, indicating that case and determined to try to locate his sleep, breathe, and turn his the complex acts as a sorting platform, medical records. The problem was that head. Radiation treatments queuing up translocases and effectors they had no name, date of birth, medi- were quite effective at first, to deliver them sequentially. cal record number, or precise dates of but by August of the fol- charles gershman Galán says that understanding treatment—only the patient’s initials. lowing year the tumors had Robert Udelsman (left) and John Fenn took such mechanisms could lead to new For months the two pursued recurred and had developed resistance on the task of locating the misplaced medical therapies that do not kill microbes but records from that era, including to treatment with X-rays. As no other records of the first patient treated for cancer pathology reports, of every “J.D.” therapeutic options for cancer had yet with intravenous chemotherapy, an event prevent them from doing harm, an ap- that grew out of wartime research seeking proach that could thwart the develop- they could find. Michael Kashgar- been developed, doctors had nowhere antidotes for chemical weapons conducted at ment of drug resistance in pathogens. ian, m.d., professor emeritus and else to turn. // Surgeons (page 8) the School of Medicine in the 194os.

Medicine@Yale March/April 2011 5 Illumination Microscope (sim), 1 year, $496,785 Fund Travel Grant, 5 months, $1,000; Burroughs Grants and contracts awarded Mikhail Torban, Nat’l Inst. on Drug Abuse, invest Wellcome Fund, Burroughs Wellcome Fund Drug Abuse Research Fellowship, 1 year, $44,000 Seminar Grant, 10 months, $1,000 • Deepak Benjamin E. Turk, nih, Identification of Exosite- Narayan, Plastic Surgery Educational Founda- to Yale School of Medicine Targeting Inhibitors of Anthrax Lethal Factor, tion, Hemangioma: Stem Cell Tumor of Pericyte 1 year, $165,500 • Li Wen, nih, Environment, Innate Origin, 1 year, $10,000 • Ali Kemal Ozturk, May/June, 2010 Immunity and Type 1 Diabetes, 4 years, $1,655,000 American Association of Neurological Surgeons, Whole Exome Sequencing in Five Large Intracra- Federal Non-Federal nial Aneurysm Families, 1 year, $15,000 • A. David Choukri Ben Mamoun, nih, Transcriptional nih, mcp-1 and Attenuation of the Foreign Body Mert O. Bahtiyar, American Inst. of Ultrasound Paltiel, Harvard Medical School, Modeling the Regulators of the Malarial var Multigene Family, Response, 4 years, $1,357,100 • Daeyeol Lee, in Medicine, Fetal Cardiac Response to Intra- Impact of hiv Prevention Interventions, 4 years, 2 years, $447,316 • Angelique Bordey, nih, Cer- nih, Decision Making and Orbitofrontal Cortex, amniotic Infection, 2 years, $10,000 • Richard E. $263,253 • Chirag R. Parikh, Northern ebellar Neurogenesis, 5 years, $2,017,031 • Michael 5 years, $1,861,875 • Ifat Levy, nih, Cognitive Bases Carson, Mount Sinai School of Medicine, 5htt Institute for Research & Education, The Aging J. Caplan, nih, Cell Biology of Renal Sodium Pump: of Risk-Taking Over the Lifespan: Psychophysics and 5-HT2A Receptors in Impulsive Aggression Kidney in hiv Infection: Biomarkers of Early Sorting and Function, 5 years, $2,952,924 • Sonia and Brain Imaging, 5 years, $1,661,141 • Paul J. and Effects of Fluoxetine, 1 year, $217,675 • Susan Detection for Kidney Injury, 1 year, $2,312,475 Caprio, nih, Study to Investigate the Patho- Lombroso, nih, Molecular and Cellular Analysis of R. Compton, American Association for Labora- Marc N. Potenza, Mount Sinai Medical Center, physiology of Type 2 Diabetes in Youth, 5 years, Brain Enriched ptps, 5 years, $2,098,409 • James tory Animal Science, Evaluation of Risk Factors Norepinephrine Transporter Imaging in Alcohol $2,077,807 • Richard E. Carson, nih, State-of-the- C. McPartland, nih, Connectivity in Social Brain for Mouse Parovirus Transmission, 1 year, $43,545 Dependence and Obesity, 3 years, $201,255; Art pet/CT Instrumentation, 1 year, $2,300,000 Systems in Autism, 2 years, $454,660 • Ruslan Weiguo Cui, Burroughs Wellcome Fund, Mount Sinai School of Medicine, Norepineph- Christopher M. Colangelo, nih, 5500 qtrap Mass M. Medzhitov, nih, Role of Basophils in Initiat- Burroughs Wellcome Fund 2010 Travel Grant rine Transporter Imaging in Alcohol Dependence Spectrometer for Yale Keck Lab, 1 year, $491,747 ing Th2 Immune Responses, 5 years, $2,066,130 Program, 1 month, $3,500 • Patrick G. Gallagher, and Obesity (arra supplement), 1 year, $433,730; Todd Constable, nih, Method for Measuring Walther H. Mothes, nih, Two-Photon Micro- Doris Duke Charitable Foundation, Erythrocyte Mount Sinai School of Medicine, Serotonin 1B Functional Subunits in Human Cortex, 4 years, scope for Intravital Imaging, 1 year, $487,929 Hydration Pathways as Modifiers in Sickle Cell Receptor Imaging in ptsd with and without $1,613,625 • Pietro De Camilli, nih, Molecular Michael H. Nathanson, nih, A Laser Scanning Disease, 3 years, $486,000 • Joel E. Gelernter, Co-morbid Depression, 1 year, $30,878; Mount Mechanisms in Synaptic Vesicle Recycling, 4 years, Confocal Microscope for Research and Education, Butler Hospital, Dex/crh Test Response Endo- Sinai School of Medicine, Serotonin 1B Receptor $1,469,133 • Gary V. Desir, nih, Renalase in Acute 5 months, $931,206 • Karin Reinisch, nih, Struc- phenotypes, 1 year, $16,545 • Susan Michelle Imaging in Major Depressive Disorder, 1 year, Kidney Injury: Utility as Biomarker and Therapeu- tural Studies of the mhc Class 1 Peptide Loading Goebel Goody, fraxa Research Foundation, $7,614 • Valerie Reinke, March of Dimes, Control tic Agent, 1 year, $500,000 • Daniel C. DiMaio, Complex, 2 years, $413,750 • Scott A. Rivkees, step: A Novel Therapeutic Drug Target in Fragile of Cell Proliferation by vrk1 in Mouse Germ Cells nih, Cell Transformation by Bovine Papilloma­ nih, Periventricular White Matter Injury Preven- X Syndrome, 2 year, $90,000 • Albert Ko, and Embryos, 3 years, $324,099 • Harvey A. virus, 5 years, $2,678,587 • Ronald S. Duman, nih, tion, 4 years, $1,603,281 • Marc I. Rosen, nih, Chembio Diagnostic Systems, Inc., Rapid Test for Risch, Cancer Research Center of Hawaii, Col- Antidepressants: Signal transduction and gene Improving Clinician Ratings of Money Misman- Leptospirosis, 2 years, $421,715 • Mark J. Mamula, laborative Genetic Study of Ovarian Cancer Risk, expression, 5 years, $1,768,750 • Leah Ferrucci, agement: Addictions Impact, 4 years, $1,295,519 Academy for Applied Science, Research and 1 year, $28,828 • Scott A. Rivkees, JS Genetics, nih, Epidemiology, Genetics and Behaviors in a Michael Rowe, nih, Citizenship and Mental Engineering Apprenticeship Program 2010, Identification of Oligodendrocyte Stimulators, Study of Basal Cell Carcinoma, 3 years, $113,436 Illness, 2 years, $455,125 • Alan C. Sartorelli, nih, 2 months, $2,600 • Luis N. Marenco, Univer- 10 months, $227,346 • Lara Elise Rosenbaum, Helen Fox, nih, Cognitive Processes for Pharma- Hypoxia-Activated O6-Benzylguanine Prodrugs, sity of Alabama at Birmingham, OR-ModelDB: Howard Hughes Medical Institute, Evaluating cotherapy and Treatment Outcome in Cocaine 3 years, $955,802 • John Schell, nih, Using vsv A Resource for the Computational Biology the Role of E-Cadherin in Melanoma Invasion and Dependent Individuals, 5 years, $773,253 • Cary Vectors to Elicit Broadly Neutralizing Antibodies of Chemo­sensory Receptors, 1 year, $24,930 Metastasis, 2 years, $38,000 • Mark Shlomchik, P. Gross, nih, Use and Outcomes of Radiation Against siv Envelope, 3 years, $156,438 • Sunny Richard A. Marottoli, American Medical Asso- University of Buffalo, Identification of Specific Therapy for Medicare Patients with Common Shin, nih, Molecular and Cellular Characterization ciation Foundation, Medical Fitness to Drive, Roles for Ets-1 in B Cell Tolerance, 5 years, $168,572 Cancers, 3 years, $1,565,949 • David Hafler, nih, of Host Response Pathways Triggered by Vacuolar 8 months, $8,000 • Linda C. Mayes, University Gerald I. Shulman, Covidien AG, Rat Model of Autoimmune Centers of Excellence: Investigation Bacterial Pathogens, 7 months, $94,770 • Jody of Maryland at College Park, Novel Behavioral Surgical Alleviation of Type 2 Diabetes by rygb of Innate Immunity in Multiple Sclerosis, 5 years, Sindelar, nih, Aging Research at the 2010 through Activation Intervention, Reward Processing, or Catheterization of the Small Intestine, 2 years, $1,653,739; nih, T Cell Recognition of Myelin in 2014 ashecon Biennial Conferences, 5 years, and Youth Smoking Cessation, 3 years, $80,623 $352,515 • Janis Lee Tondora, Columbus House, Multiple Sclerosis, 1 year, $390,668 • Nathan $125,000 • Carter Takacs, nih, Roles of mirnas Diane McMahon-Pratt, Intelligent Optical pcp Training for Columbus House, 8 months, Hansen, Nat’l Inst. of Mental Health, Interven- During Vertebrate Brain Morphogenesis, 3 years, Systems, Inc., Rapid Field Test Kit for Differentia- $10,706 • Xiao-Jing Wang, The Swartz Founda- tion to Reduce Acute Stress and hiv Risk in Newly $155,538 • Seyedtaghi Takyar, nih, mir-1 is a tion of Human and Animal Leishmania in the tion, Sloan/Swartz Summer Meeting, 2 months, hiv Diagnosed Men, 3 years, $732,594 • Fumiaki Critical Regulator of vegf-Induced Angiogenesis, Sand Fly Vector, 6 months, $10,000 • Pramod $24,934 • Stephen Waxman, Nancy Taylor Imamura, nih, Molecular Mechanisms Regulating 2 years, $237,600 • Taiwo Adedapo Togun, nih, Kumar Mistry, Genzyme Corporation, Bio- Foundation for Chronic Diseases, Inc., Proof-of- Mitral Cell Development, 3 years, $496,500 Identification of Genomic Biomarkers of Trastu- marker Discovery and Validation in Gaucher Principle of Novel Pharmacotherapies for Neuro- Akiko Iwasaki, nih, Autophagy in Antiviral Immu- zumab Response, 3 years, $82,760 • Derek K. Disease, 1 year, $148,345 • Yorgo Eugene Modis, pathic Pain: Production of Gene-slicing Molecules nity, 5 years, $2,046,572 • Themis Kyriakides, Toomre, nih, Super-Resolution Structured Burroughs Wellcome Fund, Burroughs Wellcome for Studies on Pain, 2 years, $223,038

New grant from VA supports a fresh look at primary care training The United States faces a severe but the majority of The center health psychology. They will learn shortage of physicians in the coming patients are now will also establish how to work effectively as members of decades. As the health care needs of treated in outpatient a one-year post- a team, how to appreciate the input of the aging Baby Boomers grow rapidly, settings. “Training graduate fellowship others and their contribution to caring the number of medical school students hasn’t really kept up in primary care for patients, and conflict manage- electing to enter the field of primary with the reality of for nurse practi- ment. “All those things with regard care is in sharp decline. According how internists prac- tioners, becoming to teamwork that are assumed that to the National Resident Matching tice,” says the School the first program health professionals know but that Program, students choosing residency of Medicine’s Patrick Rebecca Brienza Patrick O’Connor in the country to there’s actually no real training for,” training in general internal medicine G. O’Connor, m.d., offer such training. says Brienza. fell from 575 in 1999 to 264 in 2008. m.p.h., professor of medicine and sec- Residents and nurse practitioners will The new training model fits in well One of the factors that has been tion chief of general medicine. train in teams, taking care of patients with changes brought about by the re- found to influence students’ views of Under the existing system, resi- together for a 12-month period, with cent health care reform legislation, with general internal medicine as a career dents spent just one half-day a week at the nurse practitioners providing con- its concept of a “medical home,” an choice is the quality of the education- the vahcs, but they will now go there tinuity of care during the time resi- outpatient-based primary care practice al experience in internal medicine. for training every day for two months dents are training at other locations through which care is coordinated. The VA Connecticut Healthcare at a time, a total of 10 months of between their two-month stints. The program is itself a collabora- System (vahcs) is now poised to intensive training over the three years “The current way we train post- tion between the VA, Yale School of address that issue with a new $5 mil- of residency. Interns and first-year graduate m.d.s and nurse practitioners Medicine, Yale School of Nursing, lion grant from the Department of residents will continue to spend a half is really a ‘silo’ model, where there’s no University of Connecticut School of Veterans Affairs to establish a Center day per week at the VA in between the cross-pollination for collaboration,” Medicine, and Fairfield University of Excellence in Primary Care Educa- two-month intensive blocks. “Restruc- says Brienza. “We’ve learned that car- School of Nursing. The five institu- tion. The Yale-affiliated vahcs is one turing their schedule will allow them to ing for patients in multidisciplinary tions will contribute a total of over of only five facilities in the country to really learn what a primary care doctor care teams is a better approach, with 200 trainees over a five-year period. receive the five-year grants, which will actually does, which is to be there every better outcomes for patients.” The cen- “Training programs need to support a new approach to training day for their patients and have longi- ter will provide training in interpro- prepare physicians not only for the internists and other health care profes- tudinal relationships,” says Assistant fessional collaboration to residents and present, but also for the future, when sionals. Traditionally, internal medi- Professor of Medicine Rebecca Brienza, nurse practitioners, as well as students they’ll have more responsibility for cine residents have spent most of their m.d., m.p.h., who will serve as director in medical school, undergraduate team care and organization of ser- time training in inpatient settings, of the new center. nursing programs, pharmacy, and vices for patients,” says O’Connor.

6 www.medicineatyale.org // GBM (from page 1) Neurosurgery at treatment for this fatal disease.” the prognosis for survival of patients inexpensive genomic technique known Yale and an accomplished researcher on The gift, which was announced with gbm is unacceptably short,” says as exome sequencing, in which only genetic causes of brain disorders, who at a February 17 signing ceremony at Robert J. Alpern, m.d., Dean and those parts of the genome containing was the recipient of Kutman’s dona- Yale’s Woodbridge Hall, was made Ensign Professor of Medicine. “Basic protein-coding genes are sequenced. tion. “This gift brings unprecedented by Kutman in honor of a close friend research leading to an understanding of This approach will be valuable for opportunities for us to extend our and fellow board member at Istanbul- the biology of these tumors is essential. studying a variety of brain tumors, says expertise in genomic sequencing to one based Global Investment Holdings, a The generous gift of Mr. Kutman will Günel, because the genomic research of the deadliest diseases, and hopefully, merchant bank with diverse interests permit Murat Günel to use state-of- on other brain tumors completed by to make a difference for patients,” says in Turkish seaports, real estate, energy the-art genomics to study the mo- scientists so far suggests that some Günel, also professor of neurobiology generation and distribution, and finan- lecular mechanisms responsible, thus genes may have a major effect, and and genetics and co-director of the Yale cial institutions. Kutman’s colleague is paving the way for new treatments.” that even a single gene mutation could Neurogenetics Program. currently being treated for gbm. Günel says that sequencing of play a role in a large percentage of “Mr. Kutman’s selection of Dr. “I have a great deal of confidence gbm tumors so far, while quite pro- tumors. However, Günel says, it will be Günel to perform these studies is a in both Dr. Günel and Yale School of ductive, is incomplete. “As we work important to compare data from exome testimony to Murat’s international Medicine,” says Kutman. “We hope very to contribute to a complete catalog scans with those of the entire genome, reputation in neuroscience. He is a much to break ground in genomics-​re- of the mutations present in brain because non-coding genomic regions gifted clinician and investigator who lated gbm research in the near future.” tumors, we will be able to understand are believed to play an important role in can use these resources to focus on Based on this agreement, some individual tumors and come up with tumor formation in the brain. the genetic basis for glioblastoma,” 400 samples of brain tumors from better therapies,” he says. Though the Yale Program in says Joseph M. Piepmeier, m.d., Nix- Turkish hospitals will be delivered to School of Medicine researchers Brain Tumor Research has just been dorff-German Professor of Neurosur- Yale, a valuable research resource that at the ycga led by Günel’s longtime established, research on the genetic gery and director of surgical neuro- will supplement the many pathologi- mentor and colleague Richard P. roots of gbm is already up and run- oncology at the School of Medicine. cal specimens already on hand at the Lifton, m.d., ph.d., chair and Sterling ning at the School of Medicine, says “Under Dr. Günel’s leadership, the medical school. Professor of Genetics and Howard Günel. “We’re sequencing brain Yale Program on Neurogenetics is “In spite of much research and the Hughes Medical Institute investiga- tumors right now,” he says. “There’s now positioned to discover effective application of the latest in technology, tor, have pioneered a speedy and no time. A cure cannot wait.”

// Kavli (from page 1) of The Kavli Founda- and other programs and activities. tion. “Science flourishes with collabora- The Foundation is also a found- tion and this will be a great stimulus to ing partner of the Kavli Prizes. First more innovative research.” awarded in 2008, the prizes recognize Robert W. Conn, ph.d., presi- scientists for seminal advances in as- dent of the Foundation, adds, “The trophysics, nanoscience, and neurosci- Foundation is very pleased that Yale ence. A prize in each of these areas is will be significantly expanding the awarded every two years, with interna- scope of activities at the Kavli Insti- tional prize committees independent of tute for Neuroscience. It’s also won- the Foundation choosing the recipients. derful that, with the establishment For his decades of influential research of the Kavli Scholar program, Yale’s on the cerebral cortex, Rakic was one top graduate students in neuroscience of the recipients of the inaugural Kavli will have even more reason to be part Prize in Neuroscience. James E. Roth- of this exciting research enterprise.” man, ph.d., the Fergus F. Wallace Pro- Founded in 2000 by Fred Kavli, fessor of Biomedical Sciences and chair a Norwegian-born businessman and of the Department of Cell Biology, was philanthropist, The Kavli Foundation a recipient of the in 2010 is dedicated to advancing science for for his discoveries on the molecular the benefit of humanity, promoting mechanisms of synaptic transmission. public understanding of scientific re- “We are very grateful to Fred search, and supporting scientists and Kavli for his continued support of the their work. The Foundation’s mission Yale Kavli Institute and our neurosci- is implemented through an interna- ence programs,” says Robert J. Alp- tional program of research institutes ern, m.d., dean and Ensign Professor in the fields of astrophysics, nanosci- of Medicine. “This recent gift will ence, neuroscience and theoretical allow us to expand the size and scope michael marsland physics, and through the support of the Kavli Institute to provide the From left: Miyoung Chung, vice president for scientific programs at the Kavli Foundation, and Robert W. Conn, Kavli Foundation president, joined Yale President Richard C. Levin and Pasko Rakic, of conferences, symposia, endowed means to explore new directions for director of the Kavli Center for Neuroscience at Yale, to mark the foundation’s renewed support for professorships, journalism workshops Yale’s .” the center, which will expand its reach to embrace a broader range of neuroscience research at Yale.

// Baim (from page 1) his bsc colleagues, interventional cardiology, the branch of the clinic, the lab, and the classroom. catheter-based methods. He went on who have contributed $1.7 million to cardiology focused on catheter-based Born in , Baim spent to make seminal refinements to those establish The Donald S. Baim, m.d., delivery of therapies such as angio­plasty, his childhood in Miami Beach, Fla., and methods over the course of a three- ’75 Scholarship Fund at the School of stents, valve repair, and ablation, the received his undergraduate degree in decade career, including 25 years on Medicine. The fund will provide an an- destruction of abnormal tissue to treat physics from the . the faculty of Harvard Medical School, nual scholarship to a promising student cardiac arrhythmias. In a 2010 remem- Two fellow members of Baim’s medical during which he published more with financial need in each year’s enter- brance published in the trade journal In school class at Yale—Martin B. Leon, than 300 articles, treated thousands ing class, covering half the tuition for Vivo, colleague and friend Gregg Stone, m.d., professor of medicine and associ- of patients, and saw interventional all four years of medical school. m.d., professor of medicine and director ate director of civt at Columbia, as well cardiology rise from relative obscurity “We are extremely grateful for the of cardiovascular research and education as vice chairman of the Cardiovascular to become the standard of care for any generosity of Boston Scientific and the at the Center of Interventional Vascular Research Foundation in New York; and number of heart disorders. contribution it is making to genera- Therapy (civt) at Columbia Univer- Steven N. Oesterle, m.d., now senior “Don Baim was the guy who intro- tions of young physicians,” says Robert sity Medical Center, describes Baim’s vice president for science and technol- duced science to what [in the 1980s] J. Alpern, m.d., dean and Ensign “almost Zen-like relationship with ogy at Medtronic—were Baim’s lifelong was a very anecdotal, almost guild-like Professor of Medicine. “Dr. Baim was devices—he intuitively understood how friends, and also became leaders in profession,” Oesterle recalled in In Vivo. a remarkable alumnus who made great a device would interact with the pathol- interventional cardiology. In announcing the scholarship advancements in the field of cardio- ogy and pathophysiology of a disease It was during a postgraduate fel- fund, Ray Elliott, president and chief vascular medicine, and we are pleased and how that interaction might help an lowship in cardiology with John B. executive officer of bsc, said, “Boston to continue his legacy through this individual patient.” Simpson, m.d., ph.d., at Stanford Scientific is proud to honor our es- scholarship fund.” He was also one of those rare in- University School of Medicine that teemed former colleague by supporting Baim was a founding figure and dividuals known in academic medical Baim first displayed his uncanny the next generation of medical leaders one of the most prolific innovators in circles as a “triple threat,” excelling in skill in treating heart disease using at his alma mater.”

Medicine@Yale March/April 2011 7 Wallace Professor of Biomedical Research Expert on prevention of falls in the elderly studies role of brain circuits in metabolism is honored for a pioneering body of research Tamas L. Horvath, d.v.m., ph.d., pro- and genetic techniques to better un- The American Geriatrics Society (ags) were associated with a range of serious fessor and chair of the Section of Com- derstand biological events at the level has awarded Mary E. Tinetti, m.d., adverse outcomes, and that multifac- parative Medicine, has been named the of the organism. the Edward Henderson Award, which eted risk-reduction strategies were both inaugural Jean and Horvath, also a professor of neuro­ recognizes a distin- successful and cost-effective. David W. Wallace biology and of obstetrics, gynecolo­ guished clinician, Her work has transformed the Professor of Biomed- gy, and reproductive sciences, is the educator, or research- prevailing view of falls as an in- ical Research. founding director of the Yale Program er who has made evitable consequence of aging to a Horvath’s re­ in Integrative Cell Signaling and Neu- significant contribu- preventable event with a multidimen- search is focused on robiology of Metabolism, which was tions to the field. sional set of risk factors that can be neuronal circuits launched in 2009. The ags is identified and controlled. that support energy A winner of the National Institutes honoring Tinetti Tinetti has also investigated and Tamas Horvath metabolism, as of Health Director’s Pioneer Award in Mary Tinetti for her pioneering published extensively on functional well as pathological 2010, Horvath has also been honored work on falling in disability and mobility impairment. conditions, such as obesity and diabe- with an Alexander von Humboldt the elderly and its prevention. Tinetti She is now involved in efforts to trans- tes, that affect these circuits. He also Professorship by the Republic of Ger- will receive the award and will pres- late these research findings into clinical studies the role of metabolic signals many’s Ministry of Science. ent the Henderson State-of-the-Art and public health practice. in neurodegenerative diseases. The Wallace Professorship in Bio- Lecture at the ags’s 2011 Annual Most recently, Tinetti has focused Horvath investigates the role of medical Research was established in Scientific Meeting in Washington, her research on clinical decision- synaptic plasticity in the mediation August 2010 by philanthropists Jean D.C., in May. making in the face of multiple health of peripheral hormones’ effects on and David W. Wallace of Greenwich, Tinetti is the Gladys Phillips conditions. the central nervous system as well as Conn. The endowed chair supports Crofoot Professor of Medicine and Tinetti has been awarded many the role of mitochondrial membrane the academic, research, and teach- Epidemiology and Public Health, and of the highest accolades in geriatrics. potential in normal and pathological ing activities of a School of Medicine director of the Yale Program on Aging In 2009, she received a MacArthur brain functions. His research com- faculty member whose work advances at the School of Medicine. Foundation Fellowship (popularly bines classical neurobiological ap- the school’s strategic vision and who is She was the first investigator to known as a “genius” award) recogniz- proaches, including electrophysiology recognized as among its most promis- show that older adults at risk for falling ing her contributions to the area of and neuroanatomy, with endocrine ing and productive researchers. and injury could be identified, that falls fall prevention in older adults.

// Herzon (from page 5) In 2010, you’re left with resistant tumor cells Herzon was named a Searle Scholar, that tend to keep coming back,” Mor an award granted each year to 15 explains. “If you can kill the stem cells New AAAS Fellows “exceptional young faculty in the before they have the chance to form a Three School of Medicine faculty Jorge E. Galán, ph.d., d.v.m., biomedical sciences and chemistry,” tumor, the patient will have a much members have been elected Fellows the Lucille P. Markey Profes- sor and chair of the Section according to the program’s website. better chance of survival—and there of the American Association for the of Microbial Pathogenesis, In addition to lomaiviticin aglycon, aren’t many potential therapies out there Advancement of Science (aaas), an is renowned for his work on Herzon’s team has also created smaller, that target cancer stem cells right now.” international nonprofit organiza- the mechanisms of patho- similar molecules that have proven Cancer stem cells are thought to be pre- tion dedicated to advancing science genesis of the intestinal extremely effective in killing ovarian cursors to tumors in a number of other around the world. pathogens Salmonella enterica and Campy- lobacter jejuni. stem cells, says Gil Mor, m.d., ph.d., cancers as well, including in the brain, Founded in 1848, the aaas a researcher at the School of Medicine lung, and prostate, and in leukemia. serves some 262 affiliated societies Haifan Lin, ph.d., director and Yale Cancer Center who is collabo- Herzon, Mor, and colleagues will and academies of science. of the Yale Stem Cell Center and professor of cell biology, rating with Herzon to test the new class continue to analyze lomaiviticin agly- The association’s mission is to is a world leader in under- of molecules as cancer therapies. con to better understand its actions “advance science, engineering, standing the role that bits of But Mor and Herzon are par- on cancer stem cells at the molecular and innovation throughout the genetic material called small ticularly excited about lomaiviticin level, and they hope to begin testing world for the benefit of all people.” rnas play in stem cell differ- aglycon’s potential to kill ovarian the compounds in animals shortly. The aaas also publishes the jour- entiation and self-renewal. cancer stem cells because the disease “This is a great example of the nal Science. Hongyu Zhao, ph.d., profes- is notoriously resistant to Taxol and synergy between basic chemistry and At the aaas Annual Meeting sor of public health (biostatis- carboplatin, two of the most common the applied sciences,” Herzon says. in Washington, D.C., in February, tics), genetics, and statistics, chemotherapy drugs. “Our original goal of synthesizing this 503 new Fellows were lauded for develops statistical, compu- tational, and visualization “Ovarian cancer has a high rate of natural product has led us into entirely their exceptional contributions to tools for molecular biology recurrence, and after using chemother- new directions that could have broad science and technology. and genetics. apy to fight the tumor the first time, impacts in human medicine.”

// Surgeons (from page 5) At about the Indeed it did: when nitrogen mustard On August 25, 1942, J.D., recog- shaped the development of better same time, under the auspices of the was administered intravenously to nizing that he had no other alterna- oncology drugs thereafter. Nearly War Department’s Office of Scientific mice with lymphoma, their tumors tives, consented to the treatment and 70 years later, the pair has published a Research and Development, formed shrank rapidly and soon disappeared, became the first patient to receive paper in the March issue of the Journal by President Franklin D. Roosevelt, an unexpected and unprecedented intravenous chemotherapy for cancer. of the American College of Surgeons that School of Medicine faculty members result. However, mirroring J.D.’s By the end of September his tumors tells the story of the sleuthing that were conducting highly classified re- response to radiation treatment, the had completely regressed and no can- uncovered J.D.’s medical record, and search projects to support the Allies’ tumors recurred, and subsequent cer cells were detectable in a biopsy of also clarifies and corrects many of the effort in World War II. Pharmacolo- treatments with nitrogen mustard his lymph nodes. Unfortunately the specifics of his case. gists Louis S. Goodman, m.d., and were less and less effective. tumor returned by mid-October, and J.D.’s hospital admission re- Alfred Gilman, ph.d., were search- Nonetheless, the tumor regres- just as Goodman and Gilman had ob- cord, written up by a Yale medical ing for antidotes to mustard gas, the sion in the mice had been dramatic served in animals, the newly emerged student, fills in the detail that had chemical warfare agent that had been and had significantly increased their tumor displayed increasing resistance until now been missing by describ- used to such devastating effect in survival time. Goodman and Gilman to nitrogen mustard, which was also ing the patient’s management, the World War I. were eager to test nitrogen mus- found to be toxic to white blood cells. events that led to the use of nitrogen In studies of nitrogen mustard, a tard clinically, and they approached On December 1, 1942, after 96 days in mustard for treatment, the patient’s relative of the poison gas, Goodman Gustav E. Linds­kog, m.d., then an the hospital, J.D. died. social and personal history, and how and Gilman observed that lymph assistant professor (he would ulti- Fenn and Udelsman say that J.D.’s the decision to attempt chemotherapy cells in animals were particularly mately go on to chair the Department case was immensely important be- emerged. The student’s drawings in sensitive to the compound’s toxicity, of Surgery), about attempting an cause it revealed three aspects of che- the medical record are “beautiful,” which led them to wonder whether experimental nitrogen mustard treat- motherapy—tumor regression, tumor Udelsman says. “This was the birth it would also kill lymphoma cells. ment of J.D.’s terminal cancer. resistance, and toxic side-effects—that of medical oncology.”

8 www.medicineatyale.org