NYU The Magazine of New York UniversiPhty School of Medicineysiciawinter 2010-2011n volume 62 • No. 2

E x p l ori n g t h e n e w f r o n t i e r gn e o mics com e s o f ag e

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Ja n Vilcek: A Man Richard Tsien secrets of aging of Many Gifts to lead and behavior New Neuroscience Institute Help Us Make Dreams Come True

Ev ery aspiring physician dreams of the day someone will Make a Gift Online call him or her “Doctor” for the first time. But getting there Please visit www.nyu.edu/alumni. takes a lot more than hard work and dedication—it takes resources. By contributing to the NYU School of Medicine Alumni Campaign, you help To discuss special ensure that our next generation of physicians will have access to the best giving opportunities, teaching and research, along with a competitive financial assistance package. call Anthony J. Grieco, MD, Associate Dean for Alumni Relations, When you make a gift, you help us guarantee that all of our students will at 212.263.5390. have the means to complete our rigorous education. One day, you may even have the privilege of addressing them yourself as “Doctor.”

Thank you for your generosity. The Magazine of New York University School of Medicine winter 2010-2011 volume 62 no. NYU Physician 2 New York University Cv o er Stories Martin Lipton, Esq. Chairman, 08 d i eliver ng on Board of Trustees the promise of John Sexton personalized medicine President Meet the scientists at the cutting Robert Berne edge of the burgeoning field of Executive Vice President bioinformatics. for Health 14 D iving deep Next-generation NYU Langone• sequencers reveal extraordinary Medical Center views of gene interaction patterns that may foretell the story of life. Kenneth G. Langone Chairman, 18 z eroing in RNAi, a powerful Board of Trustees new tool, is helping researchers Robert I. Grossman, MD rapidly discover the function of Dean and Chief thousands of genes. Executive Officer 22 sr ec ets of aging and Deborah Loeb Bohren Ant genomes may Vice President, behavior Communications and help solve some of the great Public Affairs mysteries of biology. • NYU Physician S teven B. Abramson, MD Anthony J. Grieco, MD Editors, Science Dep artments and Medicine Frank W. Lopez 02 Letter from the Dean “ whole-genome Managing Editor Transforming Technologies rnai screening Marjorie Shaffer 03 S upport Senior Editor technology Q&A with Dr. Jan T. Vilcek, Man of Many Gifts Rob Hewitt isen op ing Art Director 04 News from Medicine Sherry Zucker Subverting the Immune System the way to new Print Production Targeting Auditory Tumors Coordinator An Unorthodox Approach to Treating Severe Colitis: Worms? discoveries.” Nancy Sherman Boy or Girl? A Genetic Switch for Determining Gender Copy Editor 26 Faculty News • Dean’s Honors Day OnheC t over: Dr. Richard Tsien to Direct New Neuroscience Institute illustration by Dr. Joel Oppenheim Named AAAS 2010 Lifetime Mentor Emiliano Ponzi NYUThe Magazine of new York UniversiTYPhYsiciaN school of Medicine winTer 2010-2011 Medical Center Joins Malaria Vaccine Initiative volume 62 • No. 2 Plastic Surgery Becomes Full Department Dr. Nirav Shah Nominated as State Health Commissioner Dr. Evgeny Nudler Honored by New York

ExPloriNg thE NEw froNtiEr gENomics comEs of agE

PlUs Academy of Science JaN VilcEk: a maN richard tsiEN sEcrEts of agiNg of maNY gifts to lEad aNd bEhaVior NEw NEUrosciENcE iNstitUtE 30 Alumni Profile Rosalyn Scott, MD: Overcoming Barriers of Gender, Race, Tou O r Readers and Motherhood NYU Physician is available as an iPad App that 32 Obituary you can download free Keith Krasinski, MD from iTunes. photograph by rené perez

NYU Physician winter 2010-2011 1 Message from the Dean & CEO Transforming Technologies ten Years ago the first draft of the human genome was published and, in 2003, the sequencing of the roughly three billion letters of DNA that spell out the genetic code of our species was finally completed at a cost of some $2.7 billion. It was truly a revolutionary achievement. Since that time, the technology available to sequence DNA and RNA has advanced so rapidly that the same task now would take mere weeks and cost only $30,000. The ever-faster generating of DNA and other molecular data has created an enormous “this is just demand for bioinformaticians who can make the best use of this data. the beginning In these pages we feature some of the transformative technologies at work in recently established core facilities at NYU Langone of an entirely Medical Center. These facilities offer equipment and expertise that new era in enable scientists and physician researchers to perform experiments medicine.” designed to probe the biological information contained in the human genome. Until recently the most advanced equipment wasn’t widely available to investigators at academic medical centers. By pooling resources and distributing the costs of acquiring and managing new equipment, however, researchers at the Medical Center can now take advantage of the latest technology. In this issue you will learn about three of our pioneering facilities: the Center for Health Informatics and Bioinformatics (CHIBI), the RNAi Core Facility, and the Genome Technology Center, all of which offer invaluable services. We are justifiably proud of the great investment that the Medical Center has made in acquiring new genomics machines and advanced robotics and in recruiting faculty with the expertise in bioinformatics and health informatics to interpret the flood of data emanating from experiments with this sophisticated equipment. In a very short time, our Center for Health Informatics and Bioinformatics has become one of the world’s leading centers of its kind. I’m sure the investment that we have made today will bear great fruit in the years ahead, when we obtain a fuller understanding of the biological information contained in our own genome and in those of many other organisms. This is just the beginning of an entirely new era in medicine. •

Dean & Ceo robert i. grossman, md

NYU Physician 2 winter 2010-2011 Support

A Man of Many Gifts Q& A with Dr. Jan T. Vilcek

Jan T. Vilcek, MD, PhD, professor of microbiology, and his wife, Marica, recently pledged $21 million to NYU Langone Medical Center that will help purchase and renovate residence hall space on East 26th Street for students at NYU School of Medicine, create a merit-based full-tuition scholarship fund for medical students, and expand the couple’s fellowship fund for students in the Department of Microbiology. For the Vilceks, it was the latest in a series of extraordinary gifts they have made to NYU Langone flowing from royalties they earn from the anti-inflammatory drug Remicade. Used by over a million people worldwide to treat rheumatoid arthritis, Crohn’s disease, psoriasis, and other inflammatory disorders, the drug was developed from a monoclonal antibody generated by Dr. Vilcek and his colleague Junming Le, PhD, at NYU Langone. Dr. Vilcek joined the NYU Langone faculty in 1965 after he and his wife defected from communist Czechoslovakia. In 2005 they announced their intention to donate $105 million from their future royalties to NYU Langone. NYU Physician recently spoke with Dr. Vilcek at his office in the Smilow Research Center.

NYU Physician: You and your wife, Marica, new residence hall will help attract an even have pledged over $100 million to the Medical better group of students. Center, an unprecedented level of generosity by a faculty member of any institution. Most of the NYU Physician: Why did you decide to base the money is devoted to research, but this additional scholarships for medical students primarily on gift of $21 million mainly supports education- merit and not on need? related activities. Why? Dr. Vilcek: We decided to base the Dr. Vilcek: My goal in life has never been scholarships primarily on merit to become rich. Much of the royalty because my main goal is to improve the income from Remicade sales due to me competitiveness of our medical school as an NYU faculty member goes to fulfill and attract the most highly qualified and our 2005 pledge to NYU, but Marica and talented students. I still receive significant royalty income. What better way to spend it than to give NYU Physician: Over the last 10 years, you’ve it back to NYU School of Medicine? I’ve developed widespread philanthropic interests, always considered medical education including the Vilcek Foundation. What does the to be important, and it has become even Foundation do? more so over the last decade. Dr. Vilcek: The Foundation recognizes the contributions of immigrants NYU Physician: Why is that? to biomedical science—that’s my Dr. Vilcek: There is a stage in life—and background—and to the arts, which is I think I’ve reached that stage—when my wife’s background. Marica studied I’m no longer quite as active in research art history and worked for most of her as I once was, yet I feel that I can still professional life at the Metropolitan do something very useful in medical Museum of Art. Our main goal is to raise education. public awareness about the contributions of immigrants to science and the arts. NYU Physician: Why support a residence hall? Dr. Vilcek: We lost some good applicants NYU Physician: What makes you happy? to other schools because the physical Dr. Vilcek: Well, one thing that makes condition of our previous residence hall me happy is to see the Medical Center had deteriorated. The new residence hall is flourish under Dr. Grossman’s leadership. so much more comfortable and attractive! And I’m absolutely delighted that my and Those students who moved from our older my colleagues’ research has contributed facility to the new one are very, very happy. to this successful new life, so to speak, of We already have great students, but the the entire medical center. •

NYU Physician winter 2010-2011 3

News from Medicine

S ubverting the Immune System The nefarious TB bacterium’s surprising strategy Joel Ernst It is an all too common scenario these days in the developing world: A person is infected by Mycobacterium tuberculosis. The body’s immune system sends T lymphocytes to search out and destroy the bacteria but some of the intruders escape and take cover in the lungs, where they quietly go about their nefarious business for decades, multiplying and building strength. Finally, once they’ve mustered a new army, the bacteria mount a second, is offering a more audacious, radical the genes across different strains of the more vicious and successful assault. explanation. His work suggests that the bacterium would show variation. The An estimated 2 billion people, nearly bacterium may actually subvert T cells, more diverse the genes, the more diverse one-third of the world’s population, are turning them away from their protective the epitopes, thus providing the bacteria believed to harbor the bacterium that task and into allies in destroying a host’s with an ever-changing set of disguises causes TB, a disease that claimed the lives lungs and spreading the infection from from T cells. of 1.3 million people in 2008. person to person. To their surprise, however, they Scientists have thought that the The conclusion sprang from a found the opposite. The research, bacterium, like most other pathogens collaborative study led by Dr. Ernst and published in Nature Genetics, showed that have co-evolved with humans, Sebastien Gagneux, PhD, of the University that the genes and their epitopes were escapes immune detection by continually of Basel to study the genes that code for extremely stable. Indeed “the [DNA] changing its appearance so that the the peptides, called epitopes, that T cells sequences encoding for T cell epitopes defending T cells fail to recognize it. Joel recognize and lock onto before trying to were the most stable, least diverse in the Ernst, MD, director of the division of blast the bacteria away. genome,” says Dr. Ernst. In addition, he infectious diseases, the Jeffrey Bergstein Dr. Ernst and Dr. Gagneux expected says the bacterium carries a “remarkably Professor of Medicine, and professor of to find genetic evidence of the standard high number of known epitopes,” 600 pathology and microbiology, however, shape-shifting maneuver, that is, that versus about 50 for most pathogens. Taken together, these facts indicate that the bacterium is more likely to be The battlefield of a lung infected with M. tuberculosis (green). At the scene are recognized than to be missed by T cells. the immune system’s soliders, macrophages and dendritic cells (in red) and Thus, says Dr. Ernst, “M. tuberculosis must CD4+ T cells (in blue). be benefiting from being recognized by human T cells, and that is absolutely revolutionary.” He speculates that after the initial infection, bacteria that survive the first line of defense and lodge in the lungs somehow co-opt the T cells and get them to work to the bacteria’s advantage, eventually promoting lung damage and ñez

the coughing that transmits the infection u to other people. N The new findings have significant evejo-

implications for developing a vaccine r T against TB. The usual method is to target the epitope genes and stimulate T cell raldina

production, but in this case that may i actually exacerbate lung damage G and enhance the spread of infection. “What the bacteria want to do is infect, replicate, expand their population, and be transmitted to somebody else,” Dr. Ernst emphasizes. “We have to prevent that.” • —graciela flores image courtesy of

NYU Physician illustrations by 4 winter 2010-2011 peter oumanski

Matthias Karajannis

Jeffrey Allen

MRI of the brain of a patient with a vestibular schwannoma (in red). These slow-growing tumors, the hallmark of neurofibromatosis type 2, engulf the acoustic nerve, typically leading to hearing loss and other problems. T argeting Auditory Tumors An NYU Langone Medical Center–initiated clinical trial may open the way to medical treatment out as the most likely culprits. Intrigued by the association People with neurofibromatosis type 2 (NF2), a disease characterized between the gene and these receptors, by slow-growing tumors on nerves and other tissues in the brain and Dr. Karajannis obtained specimens from spinal cord, face an agonizing choice: Watch and wait and risk it all, or NYU Langone’s tumor bank and in undergo multiple surgeries that may very likely incapacitate you one 2008 confirmed that they were indeed faculty at a time. overactive in vestibular schwannomas. That scenario may change for the young adulthood, when the first of many Fortunately he didn’t have to search far for better if an oral medication that shows tumors engulf vital structures in the a drug to target these receptors. Lapatinib early promise in shrinking, or at least brain and spinal cord. Often, the initial (brand name Tykerb) was known to arresting the growth of, vestibular casualty is hearing, because vestibular inhibit both EGFR and ErbB2; moreover it schwannomas—the most common NF2 schwannomas attack the acoustic nerves. had already been approved by the FDA in tumors—continues to progress through Tinnitus, balance problems, facial 2007 as part of a combination treatment clinical trials. The drug, called lapatinib, paralysis, and total hearing loss may for metastatic breast cancer. c. n I is now undergoing a phase 2 clinical trial follow, depending on the size and location After further testing in the laboratory, at NYU Langone Medical Center, which of the growths. The Neurofibromatosis Dr. Karajannis and his colleagues moved initiated the study. Center at NYU Langone is one of many directly to a human trial when they “Having taken care of NF2 patients clinics formed internationally by CTF to received institutional and government searchers, e for decades without any effective medical create a shared patient registry and trials approvals. The trial, supported by R therapies,” says Jeffrey Allen, MD, the consortium for NF patients. The Making GlaxoSmithKline, makers of lapatinib, oto

h Otto and Marguerite Manley and Making Headway Foundation is a major sponsor was launched in late 2009. So far, 15 of the P / Headway Foundation Professor of of research and clinical initiatives to fight 17 trial slots have been filled. Nine patients LC L Pediatric Neuro-Oncology, professor of this disease at NYU Langone. are continuing on the medication without neurology, and a co-investigator on the Dr. Karajannis, a pediatric oncologist tumor progression, and three patients trial, “I am very excited about the prospect who also does basic research in cell have seen their tumors shrink by at least

terprises, of identifying active drugs against this signaling, began searching for a medical 15 percent in volume. n E debilitating disease.” therapy for NF2 after joining NYU Encouraged by initial results, t r

A Although it is still early, the Langone in 2007. In the early 1990s, the NYU Langone team, along with investigators are encouraged by the initial scientists had linked mutations in a researchers at Johns Hopkins University, ving i response to lapatinib. “Tumors have gene called merlin to the growth of NF2 Ohio State University, and the House Ear L shrunk in some patients, and several tumors. Subsequent research suggested Institute of Los Angeles, are also enrolling others have remained stable for more than that when merlin is disabled, cell-surface patients on a separate “phase 0” trial of 12 months,” says study leader Matthias receptors regulating a variety of cellular lapatinib. Patients who are scheduled Karajannis, MD, assistant professor of processes go haywire, taking the brakes to undergo tumor-removal surgery will pediatrics. off cell proliferation. Two closely related be asked to take the drug for 10 days NF2 affects about 1 in 25,000 people, receptors—epidermal growth factor preoperatively, and their tumors will be m I according to the Children’s Tumor receptor (EGFR) and epidermal growth analyzed to further understanding about mri Foundationage courtesy of (CTF). It typically begins in factor receptor 2 (ErbB2)—were singled the drug’s effects. • —gary goldenberg

NYU Physician winter 2010-2011 5

News from Medicine

A n Unorthodox Approach to Treating Severe Colitis—Worms? A case study reveals how worms may heal the intestine Can worms help relieve the symptoms of severe ulcerative colitis? According to a case study of a 35-year-old man from northern California P’ng Loke who infected himself, the tentative, stomach-turning answer is yes.

“The idea for treating colitis with production is often associated with severe three months later swallowed another worms is not new, but how this therapy symptoms. 1,000 eggs. The worms typically settle in might work remains unclear,” says P’ng The first clue that worms might be the lower intestine, reaching maturity in Loke, PhD, assistant professor of medical beneficial arose from the observation about three months. Females can produce parasitology, who led the study, published that most cases of colitis occur in North thousands of eggs a day, and the worms in the December 1, 2010, issue of Science America and Northern Europe, where can live for many years. Translational Medicine. He says the case helminth (parasitic worm) infections Within months, the man’s condition study, which analyzed the man’s gut tissue are rare. Yet the disease rarely occurs in improved dramatically, and he remained in when he had active disease and when he Asia, Africa, and Latin America, where remission for almost three years, says Dr. was in remission, suggests that infection worms are common. Some laboratory Loke. Curious about his own recovery, and with a particular parasite “increases or and clinical tests subsequently supported what would happen to him if he relapsed, restores mucus production in the colon, this observation: Worms suppressed the man contacted Dr. Loke, an expert in providing symptomatic relief.” inflammation in animal models of helminth biology, who was then at the Ulcerative colitis, characterized by autoimmunity, and helminth therapy University of California, San Francisco. open sores or ulcers in the lining of the helped heal colitis in clinical trials. Soon after, the man suffered another bout colon, affects some 600,000 Americans, Based on these findings, the of severe colitis and decided to reinfect according to the Crohn’s and Colitis California man in the case study sought to himself with worms; by last year he was in Foundation of America. The most infect himself with worms after he failed remission. Dr. Loke and his team were able common symptoms are abdominal pain to respond to steroids and feared losing to analyze the man’s gut tissue during his and bloody diarrhea. The cause isn’t his colon. In late 2004, he ingested 500 relapse and after he was again in remission. known, but studies point to defects in eggs of the roundworm Trichuris trichiura, The researchers discovered that immune regulation. Disruption of mucus which he obtained from Thailand, and when the patient had active disease, a type of immune cell (CD4+ T cell) that Scanning electron micrograph of a parasitic roundworm of the genus Trichuris. produces an inflammatory protein Deliberate ingestion of T. trichiura, which infects the lower intestine, is reported called interleukin-17 abounded. After to relieve the symptoms of ulcerative colitis, apparently by stimulating mucus exposure to the worms, when the disease production in the colon. was in remission, T cells that produce interleukin-22, a protein important in mucosal healing, multiplied. Thus the researchers suspect that to expel the worm, the immune system appears to c. n activate specialized cells that increase I mucus production in the entire colon. “In essence, the worms trigger a big sneeze of the gut, which may have a cr oscopy, i

beneficial side effect for ulcerative colitis,” M l

says Dr. Loke, who does not advocate e helminth therapy. The problem is that the k worms themselves can damage the gut,

and, he adds, it is impossible to predict nnis Kun e

who might be helped and who might be D harmed by infection. Studies under way using a worm (T. suis) that infects pigs to treat colitis should be less risky, he says. Alas, they will still be stomach turning. • —gary goldenberg m I age courtesy of c.

NYU Physician illustrations by 6 winter 2010-2011 peter oumanski

Boy or Girl? A genetic switch for determining gender is found

A person’s sex, it would seem, is a matter of Xs and Ys: Through a biological twist of fate, each of us ends up either female, with two X chromosomes, or male, with one X and one Y. Yet sometimes a child Harry Ostrer is born with an X and a Y chromosome and develops physically as a female, and her brothers and male cousins may have underdeveloped or ambiguous genitalia.

A new study, led by Harry Ostrer, as females, and had partially developed screening technique is already being used MD, professor of pediatrics, pathology, ovaries, overdeveloped clitorises, or in France to identify affected individuals. and medicine and director of the Human excessive hair, while others grew up as “Like it or not, biology is destiny,” Genetics Program at NYU Langone men and had urethral openings on the says Dr. Ostrer. These conditions Medical Center, describes a previously underside of their penises, small genitalia, “influence how people think about unidentified gene, MAP3K1, that may or infertility. By carefully analyzing their themselves and whether they consider play a critical role in orchestrating human DNA, Dr. Ostrer’s team and collaborators themselves male or female.” Better sexual development. The culmination from France, England, and Australia scientific understanding, he says, gives of nine years of research, the findings, uncovered several mutations in the affected families peace of mind, providing published recently in the American MAP3K1 gene and showed that they them an explanation of the cause and Journal of Human Genetics, could unlock affected pathways favoring ovarian helping clarify their options. the nuances of the genetic cascade that development. Dr. Ostrer plans to set up a national determines gender. Dr. Ostrer believes that the discovery consortium to sequence the entire genome Since the discovery 20 years ago will help scientists better understand of affected individuals and their families, of a “maleness” gene, SRY, on the Y normal development and provide an which he hopes will help researchers chromosome, a host of other gender- avenue for genetic screening, allowing identify related genes and eventually related genes have been found. MAP3K1, clinicians “to explain a given condition, to develop new therapeutic options for those located on the fifth chromosome, identify other families who may be at risk, affected by these conditions. • represents a “new molecular switch,” or to perform prenatal diagnosis.” A new —Joshua Feblowitz says Ostrer, which may “modulate the pathways between male and female development” and hold the key to In 1970 a family with a condition known understanding how these genes are as 46,XY disorder of sex development connected. was identified. By carefully analyzing This discovery, says Alexander the DNA of family members, the mutation responsible for the condition Pearlman, PhD, a postdoctoral fellow was recently discovered. This mutation at NYU Langone Medical Center and results from the replacement of the the first author of the study, addresses base A (adenine) by G (guanine). the delicate nature of human sexual ok o development. Even though a person C may have the genetic factors associated with being either male or female, he rdon o says, “a single base mutation could turn G everything the other way.” Researchers unearthed this potent gene by examining individuals with trer and s

O disorders of sexual development (DSDs). These conditions, previously called intersex disorders, affect approximately 1 in 1,000 people and can cause numerous abnormalities. Dr. Ostrer’s team studied one family from France, another from New Zealand, and several individuals with a condition known as 46,XY DSD. Though genetically

image courtesty of Harry male, some with the condition developed

NYU Physician winter 2010-2011 7 M eet the Scientists at the Cutting Edge of the Burgeoning Field of Bioinformatics Delivering on the Promise of Personalized Medicine

by bryn nelson

illustration by joe magee photographs by elizabeth weinberg

NYU Physician 8 winter 2010-2011 NYU Physician winter 2010-2011 9 imagine a long ribbon or a stretch of ticker tape tied into an elaborate series of knots or In the blink of an eye, a protein can likewise using computer-based mathematical strategies, or assemble within a human cell, transformed from algorithms, to recognize disease-linked patterns that bows. a string of amino acids into a precise combination might otherwise remain hidden. of knots, turns, coils, spirals, and other shapes that enable it to carry out a specialized task aiding M aking Predictions • CHIBI the well-being of the cell. A single wrong fold researchers are identifying the bits of molecular can destabilize the entire structure, leading to information that may reveal patterns known as devastating diseases such as cystic fibrosis or predictive signatures, which assess the risk of Alzheimer’s. diseases like leukemia, psoriasis, and epidemic The grand challenge of biomedicine is how to obesity; pinpoint the best medical studies; and convert such biological observations into targeted flag websites that promote dubious therapies, disease interventions that can correct or prevent among other projects. “It’s not a boring place, I can such mistakes. But until recently, few tools were tell you that,” says Constantin Aliferis, MD, PhD, available to help researchers delve into the details of associate professor of pathology, who was recruited how our biological mechanisms really work. from Vanderbilt University in 2008 to be CHIBI’s Five years ago, no computer had the power founding director. To help get the center off the to simulate the thousands of steps required ground, he brought along three members of his for a ribbon of amino acids to fold into a Vanderbilt team, biomedical informatics experts three-dimensional protein. Today, the fastest Alexander Statnikov, PhD, Lawrence Fu, PhD, and supercomputers would need about three years to Yin Aphinyanaphongs, MD, PhD. perform a simulation for each protein. Five years Perhaps the most promising capability of CHIBI from now, the best machines might complete researchers and other bioinformaticians is their the task in little more than a day. ability to focus the power of new analytic tools on As technology surges forward, gathering some of the most challenging issues confronting raw data is no longer the main barrier to physicians: the ability to predict the onset or course “ You want to realizing biomedicine’s lofty goals. Instead, of disease in a patient. CHIBI researchers have finding and interpreting the most useful developed several types of algorithms to look for learn how information within the rising flood of data telltale biomarkers within molecular data that to predict is becoming the overriding problem. The reproducibly indicate a patient’s health status and answer, in many cases, may be found within can help build predictive models of disease. “You events ,” says the expanding field of bioinformatics. want to learn how to predict events,” Dr. Aliferis Rooted in computer science, says. “Who’s going to respond to treatments? Who’s Dr. Aliferis. bioinformatics calls upon a diverse range of going to get well, with or without treatment?” Other “Who’s going other disciplines to help researchers discover algorithms suggest which molecular players are to respond to and make the best use of biological and causing a disease or condition and which are merely treatments? biomedical observations. Bioinformaticians tagging along—essential information for designing repeatedly dive into tidal waves of DNA, drug interventions. All told, he says, more than Who’s going RNA, and protein sequences and into 2,000 researchers in 50 countries use these and to get well, deep pools of other data detailing the other algorithms created by the center’s experts. with or without inner workings of a cell’s components. By Dr. Aliferis counts oil painting and an ancient treatment?” highlighting useful signals that point to a Greek martial art among his passions, but he normal or abnormal state, such as unusually is perhaps most animated when talking about active or inactive genes, researchers can CHIBI’s many projects and the need to strengthen retrieve pearls of wisdom from the murky depths. the scientific rigor of biomedicine. He first became One glittering pearl has been the advancing interested in bioinformatics-themed basic research knowledge of an overabundant protein called HER2/ when he entered medical school in 1984. At the time, neu. With the help of bioinformatics tools, learning bioinformatics was just taking off, fueled by new how this protein contributes to aggressive breast techniques for recombining and sequencing DNA cancer has helped clinicians develop effective drugs that allowed researchers to extract and compile like Herceptin that kill cancer cells containing excess genetic information more easily. The demand for copies of the protein. At NYU Langone Medical bioinformaticians increased dramatically with Center, researchers in the new Center for Health completion of the Human Genome Project in 2003. Informatics and Bioinformatics (CHIBI) are similarly The mammoth effort assembled the roughly three

NYU Physician 10 winter 2010-2011 Dr. Constantin Aliferis, left, director of the Cener for Health Informatics and Bioinformatics (CHIBI). billion letters of DNA that spell Dr. Stuart Brown, out our genetic inheritance right, head of CHIBI’s and spurred a gold rush of Sequence Informatics prospectors eager to find rich Group. veins of information stored in the biological code. The trend continues with the recent growth of RNA isolated from keloid-associated cells that of evidence-based medicine, which uses the best point to heightened or decreased activity among a scientific evidence to make clinical decisions, and subset of our estimated 20,000 to 25,000 genes. ever-faster methods for generating DNA sequences Unusually high or low gene expression, compared and other molecular data. “The discovery of to normal cells, could implicate genes involved in meaning is really what science is all about,” says the condition. Stuart Brown, PhD, an expert in plant molecular A second project is examining the mechanism biology who serves as a bioinformatics consultant behind fatty liver disease, a condition linked to and head of CHIBI’s Sequence Informatics Group. excessive drinking that can eventually lead to life- At a recent meeting with fellow researchers, threatening cirrhosis of the liver. With CHIBI, Dr. Dr. Brown pointed out that information in the form Cronstein’s lab is scrutinizing the livers of mice of RNA or DNA sequences is accumulating so exposed to high levels of alcohol. The collaborators fast that it’s now an easily obtained commodity. It are looking at the relative activity of 450 to 500 took researchers 13 years and some $2.7 billion to small RNA pieces, called microRNAs. Past research sequence the human genome, a job that would take has pointed to a key role for these molecules in only a few weeks and $30,000 today. “As things get the disease. Preliminary results obtained with cheaper,” Dr. Brown says, “more scientists can play,” the help of Dr. Statnikov, assistant professor of resulting in innovation but also greater need for medicine and director of CHIBI’s Computational computational data analysis. CHIBI’s specialized Causal Discovery Laboratory, suggest that 30 to ability to help researchers identify patterns in the 40 microRNAs may be primary agents of change, overflowing pool of data, he contends, offers a “huge perhaps by inhibiting the expression of critical growth area” for assisting medical studies. genes. A lexander Statnikov In one such collaboration with Bruce Cronstein, MD, the Dr. Paul R. Esserman T he Transcriptome • An ambitious Professor of Medicine, professor of pathology and joint effort with William L. Carroll, MD, the Julie pharmacology, and co-director of the Clinical and and Edward J. Minskoff Professor of Pediatrics, Translational Science Institute, CHIBI scientists professor of pathology, and director of the NYU are hoping to clarify the cellular mechanism behind Cancer Institute, has adopted a similar goal of keloids. These excessive and often disfiguring scar identifying critical players in the reemergence of tissue growths disproportionately afflict people of childhood leukemia and then discerning which African descent. “First, may offer the best targets why does that happen?” for medical interventions. Dr. Cronstein asks. The project is analyzing the atnikov, photographs of dr. aliferis by mike weymouth, of dr. brown by elizabeth weinberg t “Second, can we design entire transcriptome—the S a better therapy based full sequence of messenger upon an understanding RNA—from samples at Using bioinformatics exander l of what’s happening?” diagnosis and relapse from tools, researchers A Figuring out how a drug 10 children with acute can visualize and works might provide clues lymphoblastic leukemia sort highly complex to predict which patients (the most common form gene interactions. The would most benefit from of childhood cancer) to example to the left it, thereby personalizing find out hidden pathways illustrates the mapping their course of therapy. responsible for relapse. of a gene regulatory network in which To help bring that The collaborators individual genes are about, researchers will sequenced 280 million represented by need to pore over potential letters of RNA from the yellow boxes linked to

gene network map Courtesy of differences in the levels cancerous white blood many others.

black and white illustrations by NYU Physician p eter james field winter 2010-2011 11

although It’s possible to generate thousands of cells of each patient biomarkers chair of the Department of Medicine, has and compared these that may identify called upon Dr. Alekseyenko and other CHIBI transcriptomes to a those most likely researchers to help analyze the skin-based reference sequence to respond microbiome data. Early results have pointed compiled from toward a surprising association of several healthy individuals. to a given microbes with the skin condition psoriasis. The bioinformatics- treatment By comparing the genetic mix of microbes aided comparison —which do living on patients’ psoriatic lesions with discovered defects in we choose? unaffected patches of their skin and that of A lexander Alekseyenko a number of genes not healthy volunteers, the collaborators hope previously linked to to build the first diagnostic signature of the cancer and showed that these key differences in disease. “Like any census, it’s complicated,” Dr. RNA sequences are unique to individual patients. Blaser says. “You could say that we’re comparing Investigators are now using these observations to the census of New York and Chicago, or maybe identify shared pathways leading to disease. it’s New York and Indianapolis, or New York and With technology leading the way, scientists are Moscow. That’s what we’re going to find out.” moving well beyond the genome—the full set of The complex project, he says, would have human DNA—to analyze other molecular agents been impossible without a strong biomedical of health and disease. Proteomics, for example, informatics component. “This is very exciting identifies and studies the relative amounts and from my perspective,” Dr. Aliferis says of the interactions of our entire collection of proteins. microbiome census, “because our first results Epigenomics focuses on the physical and chemical clearly indicate that this technique could be modifications to DNA that can activate or used for diagnostic purposes and could point to deactivate genes. previously unidentified microbes that may have a Together the various disciplines enable causal role in the disease.” researchers to combine layers of information into Dr. Blaser has received federal funding for a complete picture of the disease process, says another microbiome project that could establish Jinhua Wang, PhD, research assistant professor an unexpected link between gastrointestinal flora of pediatrics, who likens his data-mining task and epidemic obesity. Due to changes in the human to finding hidden “dark matter” in the genome. lifestyle, he hypothesizes, an evolving community Dr. Wang, who comes from a background in of microbes may be fueling obesity by affecting computational biology and genomics research, how fat is metabolized, especially among children. is helping the NYU Cancer Institute integrate As a first step in the project, his team is exposing multiple sources of clinical and molecular data. mice to small doses of antibiotics that alter their “If you look at two-dimensional pictures, you composition of gastrointestinal microbes. Although don’t have information about the depth,” he says. still early in the collaboration with CHIBI, Dr. Looking at cancer through multiple layers or Blaser says it is already revealing significant different angles may offer a more accurate portrait differences both in the composition of microbial J inhua Wang of its inner workings and root causes. populations and the ensuing effects on the animals’ fat and lean mass. T he Microbiome • Another promising source of biomedical information has emerged S electing the Best data • Still, with the federally funded Human Microbiome the successful integration of bioinformatics Project, which is conducting censuses on the into medical studies is bringing new challenges. teeming microbial communities that live in or on Although it may be possible to generate hundreds us and outnumber our own cells 10 to 1. Many or even thousands of molecular signatures that of these microorganisms pass from parent to identify those patients most likely to respond to a child and can provide a wealth of genetic clues given treatment based on a genetic profile, which about diseases. “It’s like a whole other genome set of markers should researchers use, and are they that lives with us,” says Alexander Alekseyenko, necessarily any better than others? To resolve the PhD, a bioinformatician at CHIBI with training in issue, CHIBI scientists have invented a technology bioinformatics, phylogenetics (the study of how designed to scan data sets and extract all signatures organisms are evolutionarily related), and statistics. that meet two requirements: They must be as NYU Langone Medical Center researchers diagnostic or predictive as possible based upon received major funding to study the microbiomes— the data, and they must be as small in number as the entire genetic makeup of specific microbial possible. The result is a compact catalog of the most communities—within the upper gastrointestinal significant indicators. tract and on the skin. As part of the latter project, The same general problem confronts Martin Blaser, MD, the Frederick H. King Professor researchers trying to sift through the of Internal Medicine, professor of microbiology, and overwhelming hodgepodge of information online.

NYU Physician 12 winter 2010-2011

Dr. Fu, assistant professor of medicine, and Dr. and accounts for factors such as the track record of Aphinyanaphongs. assistant professor of medicine, the scientific journal and other papers by the same are using the tools of health informatics to retrieve authors. the most relevant information from existing studies To highlight less-than-reliable information, Dr. and assessing the overall value of that data. “We Aphinyanaphongs is developing a public health focus on trying to help researchers, doctors, and tool to help consumers steer clear of dubious patients search the scientific literature or the web websites touting unproven and even dangerous to find the best articles or the best websites,” Dr. therapies. With no reliable filter now to sort good Fu says. The goal, though, comes with a tricky websites from bad, desperate patients can fall prey L awrence Fu question, Dr. Aphinyanaphongs says: “Can you to commercial sites that pitch “miracle” cures and teach a machine to recognize quality?” bogus treatments. So far, the answer seems to be yes. A program For a pilot study, Dr. Aphinyanaphongs is called EBMSearch, which Dr. Aphinyanaphongs using key words as red flags to predict whether built in his Nashville garage while still at advertised cancer treatments are simply too good Vanderbilt, analyzes features such as a clinical to be true. With health informatics tools guiding study’s experimental design and ranks the best him, Dr. Aphinyanaphongs has found several traits of the bunch in the public PubMed archive of shared by sites investigated so far. “The language scientific papers. Researchers can type in search of a site that’s trying to cure your cancer is a very terms, choose the range of publication dates, nonscientific, pie-in-the-sky language,” he says, and decide which aspect of a clinical study to with words like “Nobel,” “discovered,” “amazing,” emphasize. “There is a pyramid of evidence, and “cure,” and “orthodox” frequently used. when a field matures and conclusive evidence is Although still a work in progress, the finally available, only the top of the pyramid really algorithm has performed better than a simple matters for medical decision making,” Dr. Aliferis Google rank and another online tool called The says. “It consists of well-designed clinical trials and Quackometer in predicting unreliable sites. ng a syntheses of the literature.” Purveyors of dodgy therapies could try to game the W Another popular way to assess a study’s value system by avoiding words identified as signatures is to count the citations it receives in subsequent of quackery, of course, but Dr. Aphinyanaphongs papers. But that method works only for older says wording that is muted to avoid detection may studies, Dr. Fu says, because newer ones simply fail to entice new consumers. haven’t had enough time to amass citations. His Ultimately Dr. Aliferis believes that well- solution: He designed the first computer model designed and carefully vetted bioinformatics and Y in Aphinyanaphongs

ng Courtesy of Jinhua to predict successfully which papers will receive health informatics tools must become routine i c the most citations in the future, a tool that should features of biomedical research for the field to likewise help researchers and physicians quickly deliver on its many promises. Several CHIBI find the most important papers. The model also projects and services may simplify that task, incorporates agreed-upon signposts of good studies including a user-friendly search program called dna sequen Find a Researcher that could help foster more in-house collaborations. Another tool helps medical This figure shows investigators choose the multiple runs of DNA best available software for sequencing from the recognizing patterns. “They white blood cells of can take a look at what’s a single leukemia patient, compared to under the hood of different the standard reference software packages,” Dr. sequence from the Cronstein says. “This will Human Genome Project make a huge difference in (shown in white). The our ability to analyze data.” position labeled “R” In turn, the push indicates a potential to fully integrate cancer-linked mutation. bioinformatics into Some of the white biomedicine may help blood cells have this change while others do redirect the incoming flood not, perhaps reflecting of information into the a mix of normal and clinical channels that make cancerous white blood the biggest impact in saving cells in the sample and improving lives.• selected for sequencing.

NYU Physician winter 2010-2011 13 by eric next-generation illustration by goldscheider joe magee sequencers reveal photographs by extraordinary elizabeth weinberg views of gene interaction patterns that may foretell the story of life.

D iving Deep into the genome

NYU Physician winter 2010-2011 15 JANE Carlton • Several at the genome years ago, Dr. Carlton sequenced the sexually transmitted human technology center pathogen Trichomonas vaginalis, at nyu langone which latches onto the lining of the urogenital tract, destroying epithelial medical center, cells and increasing susceptibility to HIV, the virus that causes the latest technology, called next-generation AIDS; she is now leading a team to sequencing, offers unparalleled views of the sequence the genomes of four more human genome and the genomes of other organisms, enabling parasites using the next-generation scientists to begin to understand how cells function and evolve. sequencing equipment at the Genome On another level, it provides a more effective and efficient means Technology Center. Such so-called of finding mutations in genes. “Mutations are the proverbial needle in the haystack,” says Jiri Zavadil, PhD, assistant professor of pathology, who directs the Genome Technology Center. “Now we can deconstruct the haystack. This is an example of the unprecedented power of deep sequencing. It is really revolutionary.” Identifying sequences of A, T, G, and C (the nitrogen bases adenine, thymine, guanine, and cytosine, the four-letter alphabet of DNA) is at the heart of genomics. Next-generation sequencing, commonly referred to as deep sequencing, enables the recording of an enormous number of reactions with a high degree of accuracy based on certain chemical characteristics of each base. Dr. Carlton The highly anticipated sequencers of the near future are expected to generate 10 times more data. “The field is moving so fast that yesterday is the olden days,” says Jane Carlton, PhD, associate professor of medical parasitology and director of genomics who chairs the faculty advisory board of the Genome Technology Center. Another tool offered at the Genome Technology Center is called a microarray, which Dr. Zavadil allows researchers to search a biological sample rapidly for de novo sequencing is a crucial first step in generating data for future The Illumina Genome Analyzer IIx, known base sequences. above, is one of the next-generation The complexity involved investigations aimed at seeing how sequencers in the Genome in capturing, storing, and similarities and differences between Technology Center. manipulating the huge genomes translate into observable phenotypes—traits, behaviors, amounts of data the high- or properties. Intriguingly, the throughput technologies yield demands collaboration among new sequencing techniques also

scientists with specialized skills. “You have to put together g

allow scientists to capture genetic a this holy triangle of IT [information technology] people, information from communities z bioinformaticists, and biologists,” Dr. Carlton says. “But in the of organisms, an approach called vid Zag end genomics is still just a tool really. It’s not the be-all and the metagenomics that Dr. Carlton is also a end-all, it’s the biological questions that keep driving what we using to study microbial interactions D do.” in the urogenital tract. “Metagenomics Taken together, deep sequencing and other technologies are is really powerful because not only do

we get to find out about that particular neider and now helping scientists understand the big picture, to connect h how genes influence cellular activity, to compare patterns of organism, but we can also see what c gene expression in healthy versus diseased cells, and analyze are all the other friends and foes in the interactions of gene products under varying conditions terms of microbes that it has in that over time. particular environment,” says Dr. Carlton. This multidimensional Here are some examples of research resulting from swath of information can yield clues collaborations between NYU Langone Medical Center about how organisms interact with investigators and the Genome Technology Center. each other or even how they may have

co-evolved. images Courtesy of robert s

NYU Physician 16 winter 2010-2011 ROBERT SCHNEIDER • MAX Costa • Max Costa, DAVID Zagzag • David Zagzag, MD, Robert Schneider, PhD, the Albert B. PhD, chair of the Department of PhD, professor of pathology and neurosurgery Sabin Professor of Microbiology and Environmental Medicine and and chief of the Division of Neuropathology, Molecular Pathogenesis, professor professor of environmental medicine studies the development of blood vessels—or of radiation oncology, and associate and pharmacology, wanted to find angiogenesis—in brain tumors. A strategy to fight director of Translational Research out if gene expression in healthy cells the growth of cancer is to inhibit blood flow to and co-program leader of the Breast transformed in his laboratory into malignant cells in order to cut off their nutrient Cancer Research Program at the cancer cells differed depending on supply, which also curtails their access to oxygen. NYU Cancer Institute, is looking for which known carcinogens they were Curiously, the gliomas he studies actually do better patterns of small pieces of regulatory exposed to. “One very interesting in a low oxygen, or hypoxic, environment, which RNAs known as microRNAs thing we found is that if we take undermines the full effectiveness of treatments that within breast tumors, as well as human bronchial epithelial cells and inhibit blood vessel formation. in the surrounding healthy tissue. Dr. Zagzag Specific microRNAs and patterns turned to genomics of microRNA expression may help to understand a predict whether breast cancer is transcription likely to spread. The equipment factor called HIF-1a at the Genome Technology Center associated with enables him and his team to address cells’ response the question of which cancers are to low oxygen. likely to remain in the breast and (Transcription which are likely to metastasize. The factors are proteins answer has implications for patients that latch onto whose underlying resilience would be sequences of DNA, damaged by unnecessary treatment, thereby regulating Dr. Zagzag as well as for overburdened healthcare Dr. Costa the activity of genes, systems globally where cancer care and Dr. Zagzag first is still considered a luxury, says Dr. make them into cancer cells with reported on the Schneider. Because of scarce resources chromium, all the resulting cancer presence of HIF-1a in many poor countries, doctors often cells have the same gene expression nearly a decade ago.) can’t provide treatment to patients pattern,” says Dr. Costa. “But if they Last June his team most in need. Genomics-based were transformed by nickel, it’s a published a paper in diagnostics, he says, may offer them the completely different pattern.” This the journal Molecular ability to focus their resources more kind of information can eventually Cancer, which used rationally in order to do the most good. give physicians an important microarray analysis diagnostic tool. Studies he is able to to measure gene do with next-generation sequencing expression in cancer technology in collaboration with the cells engineered to Genome Technology Center, he adds, be deficient in HIF-1a. “allow us to understand which factors His findings help interact with individual genes in elucidate how the response to environmental stressors.” factor influences the invasive potential of those cells, providing a piece of a puzzle that cancer researchers

ag are putting together z about gliomas. Dr. Schneider • avid Zag

D left: Expression patterns of above: The heat map microRNAs within breast identifies changing tumors may be useful to “ the field patterns of gene assess the likelihood that is moving expression induced hneider and by low oxygen in brain

ke Weymouth a breast cancer might i c M metastasize. Locally so fast tumor cells that are advanced breast cancers dependent on a key that spread five years after that regulatory gene, HIF-1a . Costa:

r treatment showed a similar D pattern to matched cases yesterday of

h of metastatic cancer.

p is the olden

1 2 3 4 days.” normal future future matched breast nonmetastasizing Photogra

images Courtesy of robert s metastasizing metastases LABC LABC

NYU Physician winter 2010-2011 17

by dan ferber photographs by rené perez zeroing RNA i, a powerful new tool, is helping researchers rapidly discover the function of thousands of genes.

Left: A liquid-handling robot in the RNAi laboratory at NYU Langone Medical Center. This type of automated equipment enables analysis of the entire human genome in a matter of weeks or months rather than years.

NYU Physician winter 2010 -2011 19 f o r decades, R n a had been thought to act a s D n a’ s lieutenant, dutifully carrying out the commander’s instructions to manufacture proteins in the cell. B u t recently, that thinking has changed, and scientists have discovered that there are a multitude of R n a cousins running around in our cells that play critical roles in human health. O n e of these molecules, small interfering R n a ( R n a i ) , is the foundation for a powerful tool that can rapidly screen whole genomes to identify genes involved in a host of specific biological processes.

Ramanuj DasGupta, PhD, assistant professor of pharmacology, is director of the RNAi Core Facility, a state- of-the-art laboratory at NYU Langone Medical Center that opened in 2008. Here researchers can simultaneously test the function of thousands of genes, using an array of advanced robotics, automated microscopes, and other highly specialized equipment. This new technology can help untangle complex biological pathways like those that lead to cancer or to the proper development of tissues and those that keep infectious microbes from invading our tissues. “The amazing thing is that you can systematically and comprehensively query the function of each and every gene in the genome in a matter of weeks. It is also highly cost-effective,” Dr. DasGupta says.

A Unique Resource RNAi screening is based on the Nobel Prize–winning discovery that when fragments of double-stranded RNA are introduced into animals or cells in culture, they effectively suppress the expression of the corresponding gene by destroying its Dr. Yun complementary messenger RNA. This form of RNA carries messages from DNA in the cell’s nucleus to the cytoplasm, where proteins are made. The need for an automated screening tool has never been that glowed much more or less than usual, Dr. DasGupta identified greater. Although genomicists have cracked the human genome 148 novel genes that seemed to regulate the Wnt pathway; later and decoded that of the roundworm, fruit fly, mouse, and other studies demonstrated that some of them actually did so. More than organisms, the function of thousands of genes remains unknown. half have human equivalents, and 21 had been linked to human And the old method of determining gene function—shutting down disease, the researchers reported in Science in 2005 and Genome a gene and then observing what happens to the mutated cells or Biology in 2007. organism—is inordinately laborious and time consuming. Dr. DasGupta’s team reported in the journal PLoS One in The RNAi Core Facility funds three full-time staff, including 2009 that they had used an RNAi screen to pinpoint a previously assistant director Chi Yun, PhD, who maintains RNAi libraries unresearched protein, dBili, that turns off a master switch of this for organisms commonly studied by biologists, such as humans, critical pathway in fruit flies, zebrafish, and cultured human cells. mice, fruit flies, and roundworms. She also coordinates the work And Foster Gonsalves, PhD, a postdoctoral fellow in the lab, further flow for the variety of whole-genome screens that are currently exploited this tool in a novel strategy of integrating RNAi with being performed at the facility. The lab is open to researchers chemical genetic screens to identify three small molecules that could everywhere, providing they agree to share their data with the be the basis for innovative therapies for colorectal cancer and other scientific community. diseases associated with misregulated Wnt signaling. Dr. DasGupta himself has employed RNAi to probe a crucial cellular signaling pathway—called the Wnt pathway— that regulates many aspects of development and disease. A S creening for Surprise malfunctioning Wnt pathway can lead to devastating birth defects To find essential genes, researchers need a cell-based assay—a or a variety of cancers. The pathway is complex and its regulation way to quickly detect the cellular process they’re examining— only partially understood, and whole-genome RNAi screening that can be used on the RNAi-screening lab’s automated “assay- technology provides Dr. DasGupta and others in the field the detection” equipment. A number of researchers at NYU Langone means to identify novel modulators of this pathway. Medical Center have used such assays to find a particular gene. To identify them, he took a modified version of a firefly gene Michael Garabedian, PhD, professor of microbiology and and engineered it into fruit fly cells so that they glowed when the urology, in collaboration with Susan Logan, PhD, associate Wnt pathway was activated. He mixed tiny samples of those cells professor of urology and pharmacology, worked with the RNAi with about 22,000 double-stranded RNAs, each corresponding facility staff to develop a screen that could identify potential to a potential gene in the fruit fly genome. By focusing on samples targets for new and better drugs for prostate cancer. Current

NYU Physician 20 winter 2010 -2011 drugs stem the action of male hormones, androgens, but they developed a sophisticated but counterintuitive test in which chemically castrate the patient, sometimes causing hot flashes, tiny stem-cell-like tumors form in the roundworm’s developing fatigue, sexual dysfunction, and other serious side effects. gonad, but only when RNAi blocks genes that spur cells to Cancer cells also frequently become resistant to these drugs. Drs. overgrow earlier in development. Then, using techniques Garabedian and Logan wanted to use RNAi to find new ways to developed by Fabio Piano, PhD, director of the NYU Center for block the androgen receptor, which turns on genes in the nucleus Genomics and Systems Biology, she and her laboratory team in response to testosterone. Such an approach, they reasoned, mixed an RNAi that targeted each of the worm’s 18,000 genes. might lead to therapies with fewer side effects and lessen the Some of the RNAi experiments obstructed the cell’s likelihood of resistance. response to an insulin-like protein, they reported in the journal The screen identified 80 genes that alter the activity of the Development in 2010, offering clues about how nutrition might

The RNAi screen above reveals genes that alter the activity of the androgen receptor, which turns on genes in the nucleus in response to testosterone. Each circle represents a well that contained an RNAi Dr. DasGupta corresponding to a gene in the cell. Red wells indicate the presence of genes that inhibited the receptor, while purple and blue wells reveal genes that helped it function. androgen receptor. Some were known, and others were newly affect tumor growth. “The real beauty of RNAi is that you can identified. Blocking one of these genes stopped the growth of screen the library fast,” Dr. Hubbard says. “Unlike conventional laboratory-cultured cells from late-stage prostate cancer patients genetic screens, you know right away which gene is responsible. who no longer responded to conventional therapy. “This is the If you get an interesting hit, you go with it.” kind of target gene that we were looking for,” Dr. Garabedian says. And Jennifer Philips, MD, PhD, assistant professor of E. Jane Hubbard, PhD, associate professor of pathology, is medicine, pathology, and microbiology, uses RNAi screens using RNAi screens to better understand the genes and proteins to identify human genes that make tissues vulnerable to that make cells proliferate in normal development and in cancer. Mycobacterium tuberculosis. The results of her initial screen, She works on a soil-dwelling roundworm called Caenorhabditis published in Science in 2005, identified 86 genes that promote elegans that serves as a model bacterial infection in fruit fly cells. Some belong to a cellular because it shares many pathway called ESCRT (endosomal sorting complex required for fundamental features with transport), which serves as a guide to the cell’s recycling center, other organisms, it is easy to “...you can the lysosome. manipulate at the molecular systematically In 2008 she and her colleagues reported in the Proceedings level, and its cells can be of the National Academy of Sciences that ESCRT proteins also steer tracked precisely under a and mycobacteria to the lysosome in mammalian cells. More recently microscope. Importantly, comprehensively they identified a protein from TB bacteria that interacts with the RNA interference is triggered query the ESCRT machinery; she suspects this interaction may help the when the worm eats bacteria function of TB bug survive in human macrophages. (In humans, TB bacteria engineered to produce a evade normal immune defenses by hiding out in macrophages.) specific double-stranded RNA. each and “Without RNAi screening, the role of that machinery would Dr. Hubbard knew that never have been identified. No one who works on TB would have tumors can develop from every gene in thought to look at it,” Dr. Philips says. malfunctions in genes that The appeal of the work lies in the unbiased nature of RNAi direct immature cells called the genome in screens; you never know what you may get, Dr. DasGupta says. stem cells to develop into a matter of With a clever genetic test, RNAi screens routinely open up the mature tissue or in genes that door to years of new discoveries. “You’re really limited only by direct cells to multiply. She weeks.” your imagination,” he says. •

NYU Physician winter 2010–2011 21 A worker of the jumping ant Harpegnathos saltator with sickle-shaped mandibles and large eyes used for hunting prey. Illustration based on a photograph by Jürgen Liebig.

by josie glausiusz

illustration by emily cooper photograph by Sasha Nialla Why do queens in ant colonies live five times longer than workers? What makes ants altruistic? Why do they live in rigid hierarchies? T swhe an ers lie in their genes.

s ecrets of aging and behavior

NYU Physician winter 2010-2011 23 a n nt colony is a monarchy ruled they sting, they fly, and their queens by a long-lived, egg-laying queen mate multiple times, making it difficult to analyze gene inheritance. served by scurrying, sex-sacrificing Ants are perfect, the researchers thought, not only because they do female workers and short-lived, not sting, but because different castes within the same colony, the queen expendable males. sometimes the and the workers, carry identical genes, yet give rise to individuals regime is overthrown—the queen dies, of differing size, behavior, and fertility. Clearly, some other mechanism—diet or pheromones, and workers battle to replace her, forming a powerful oligarchy for example—must influence the expression of individual genes of now-fertile pseudoqueens. Such is the world inhabited by and overall development of individuals. What’s more, both the Jerdon’s jumping ant, or Harpegnathos saltator, a primitive species Florida carpenter ant and Jerdon’s jumping ant are already well hailing from south India that preys on small insects. studied. Jürgen Liebig, a behavioral ecologist at Arizona State Not all ant societies conform to these rules however. The University in Tempe, spent years investigating social behavior wood-boring, territorial Florida carpenter ant, or Camponotus and chemical communication in these two species. In 2008 Drs. floridanus, lives in large complex colonies dominated by an egg- Reinberg, Berger, and Liebig received a generous grant from the laying queen, with day-to-day tasks performed by two infertile Howard Hughes Medical Institute to sequence the genomes of female worker castes: majors that guard the nest and minors that the two ant species; they published their results in the August 27, scavenge food. When the queen dies, so does the colony. 2010, issue of Science. Autocratic insect empires may seem of interest only to entomologists, but these two ant species are poised to reveal epige netic tags • Understanding epigenetic secrets of human development, aging, and behavior, thanks to alterations has been compared to reading a book. Once printed, the work of Danny Reinberg, PhD, professor of biochemistry, and the text—the genes or DNA—will always remain the same. But his colleagues. The Chilean-born Dr. Reinberg is an expert in the a reader may interpret the text differently, depending on the burgeoning field of epigenetics, alterations in gene activity that emotions he or she experiences while reading it or comments do not involve mutations to DNA, but are determined instead scribbled in the margins by previous readers. The classic view of by molecular “tags” that latch onto genes, turning them on or genetics is that mutations in DNA, or changes in gene sequence, off, or directing them to shout or to murmur. These changes are are passed on to future generations. By contrast, epigenetic tags typically inherited when cells divide. that turn individual genes on or off make no fundamental change Dr. Reinberg, a Howard Hughes Medical Institute to the underlying DNA, just as readers’ wisecracks in a book’s investigator who has co-edited an authoritative textbook margins may alter later interpretation, but not the basic text. on epigenetics, has spent 30 years studying how genes are In order to understand epigenetic alterations in the ants, the expressed in cells and ultimately translated into proteins, the research team first had to “print out” the original text, or genome, building blocks of life. Most significantly, he has discovered of these species—the first social insects, after honeybees, to have some of the key enzymes that control access to DNA in its their genomes sequenced. cellular form, where it is curled tightly around proteins called The project began with the arrival of 10 packages of frozen histones in a complex called chromatin. This access is crucial ants from Dr. Liebig’s lab. Then the team crushed the ants in to the development of specific cell types during embryonic liquid nitrogen using a mortar and pestle and extracted DNA development. A liver cell, which shares the exact same DNA from each caste in both species—for the carpenter ants, the with every other cell in the body, becomes a liver cell and gives queen, major and minor workers, and males; for the jumping rise only to liver cells because certain areas of that cell’s DNA are ants, the pseudoqueens (also known as gamergates), workers, exposed and expressed. and males. (Removing the queen from a jumping ant colony In the course of his research, “I started reading about triggers the development of gamergates.) They shipped the epigenetics, and I got fascinated,” Dr. Reinberg says. To truly DNA to the Beijing Genomics Institute in Shenzhen, China, understand how this process controls development where scientists chopped it up and and behavior, he realized he needed to study a whole sequenced the DNA with the aid of high- organism. And that’s when he hit upon ants. throughput genome analyzer machines. They then analyzed the results. the need for a model • The idea arose Some findings were during a long conversation with Shelley Berger, PhD, straightforward, says Roberto a fellow expert on epigenetics, on a traffic-choked bus Un derstanding Bonasio, PhD, a postdoctoral fellow in ride to a conference outside Mexico City five years epigenetic Dr. Reinberg’s lab who is supported ago. A biologist at the University of Pennsylvania, Dr. alterations by a fellowship from The Helen Hay Berger had recently returned from Costa Rica, where Whitney Foundation. The ant species she had observed fungus-farming leaf-cutter ants. ha s been share about 33 percent of their genes The two agreed on the need for a model organism in with humans, while 20 percent of them which an identical genome gives rise to individuals compared are unique. The carpenter ant has 17,064 of varying form and behavior. The honeybee was to reading genes and the jumping ant has 18,564. one option—a draft version of its genome had been The researchers, however, were just as sequenced in 2006—but bees are difficult to handle, a book. interested in epigenetic changes, since

NYU Physician 24 winter 2010-2011 Dr. Danny Reinberg (left) and Dr. Roberto Bonasio are investigating the role of epigenetics in brain function and behavior.

it’s clear that these must influence behavior, such as the jumping with neurological disorders such as Rett Syndrome, which ants’ switch from workers to pseudoqueens, resulting in both is characterized by severe language difficulties and lack of extended life span (queens typically live at least five times longer social engagement. Curiously, Dr. Reinberg and colleagues than workers) and a sudden ability to lay eggs. So the team also found that DNA methylation levels were lower in the primitive looked at the RNA levels in different ant castes, an indicator of jumping ants than in the more socially sophisticated and rigidly which genes were being expressed. organized carpenter ants. Two enzymes were overexpressed in the jumping ant pseudoqueens, telomerase and SIRT1, which are both involved cli nical applications • The role of epigenetics in aging, Dr. Reinberg says. In addition, the switch from worker in brain function and behavior is “a fascinating question,” to pseudoqueen brought about major changes in the biosynthetic says molecular biologist Vincenzo Pirrotta, PhD, of Rutgers pathways for complex chemicals involved in communication University, who calls Dr. Reinberg “perfectly positioned” to and social behavior. Dr. Reinberg also found intriguing chemical do this research in ants. “His work on epigenetics has been differences in the brains of the major and minor carpenter ant going on for many, many years, and he has made many major workers: The levels of certain neuronal receptors—the docking contributions,” Dr. Pirrotta says. “Now the question is how to go stations for neurotransmitters in the ants’ brains—varied. about applying that kind of expertise to try to understand how This observation suggests that these variations may influence epigenetics works in the nervous system.” behavior in the castes. Understanding epigenetic changes may also be key to curing Brain function in ants as well as in humans may also be diseases—an area of intense focus for Dr. Reinberg, who two affected by another epigenetic tag—DNA methylation. This is years ago started a new company, Constellation Pharmaceuticals. a common type of clamp comprising a methyl group, a carbon The company aims to develop novel drugs that combat miscues atom with three hydrogen atoms (CH3) that locks onto a gene, in epigenetic control of gene expression that can lead to cancer, typically preventing its transcription into RNA, which in turn autoimmune diseases, or mental retardation. It’s already known, directs the construction of proteins. DNA methylation may be for example, that DNA methylation can silence certain tumor influenced by the outside environment. For example, in one suppressor genes and lead to rampant cell division and cancer fascinating 2004 study, rat pups whose mothers spent more metastasis. time grooming them showed a specific pattern of methylation “I cannot predict what is going to happen,” Dr. Reinberg in the brain and were less anxious and more resilient to says. “But as long as the dedication to this kind of basic research stress. In humans, abnormal methylation has been associated continues, I am sure that the clinical applications will follow.” •

NYU Physician winter 2010-2011 25 Faculty News

School Honors On October 6, 2010, the School of Medicine honored three of Three Masters its most distinguished faculty and One Major members for embodying outstanding lifetime achievement Benefactor in the three missions of NYU at Dean’s Langone Medical Center: patient care, research, and education. Honors Day In ceremonies highlighting the School’s annual Dean’s Honors Day, Dean and CEO Robert I. Grossman, MD, cited the trio for their “powerful intellect, sustained effort, steadfast achievement, and greatness of spirit.”

Dr. Joseph McCarthy Dean’s Honors Day, established in 2002 to recognize faculty advancement and achievement over the previous year, added in 2007 the special categories of Master Clinician, Master Educator, and Master Researcher to honor those deserving of such distinction. This year, Joseph McCarthy, MD, the Lawrence D. Bell Professor of Plastic Surgery and director of NYU Langone Medical Center’s Institute of Reconstructive Plastic Surgery, was named Master Clinician. Benard Dreyer, MD (’70), professor of pediatrics, was recognized as Master Educator, and Rochelle Hirschhorn, MD (’57), professor emerita of medicine, cell biology, and pediatrics, was honored as Master Researcher. Dean Grossman lauded Dr. McCarthy as “a trailblazer who has revolutionized craniofacial surgery.” In his 35-year career at the Medical Center, Dr. McCarthy has specialized in reconstructive plastic surgery of the face. He developed the concept of craniofacial distraction and also introduced Dr. Benard Dreyer surgical reconstruction of the face as early as infancy to avoid or ameliorate future psychosocial problems. Dr. Dreyer was cited as “one of the nation’s premier experts in health literacy and a revered mentor who has shaped countless careers.” Over a 34-year career at the Medical Center, he has been a leader in developing the pediatrics curriculum for students and fellows. He has also taken a leadership role in his field outside the Medical Center and was recently voted president-elect of the American Pediatric Association. Dr. Hirschhorn, a member of the School of Medicine community since graduating in 1957, was described as “a pioneer in genetics, conducting seminal work on enzyme deficiencies and s joshua bright

gene mutation.” Her major work concerned the enzyme adenosine h deaminase (ADA) and its role in immune cells, which led to an p understanding of the role of ADA and its deficiency in individuals

with impaired immune systems. • Photogra Dr. Rochelle Hirschhorn

NYU Physician 26 winter 2010-2011 Faculty News

th e giants among us

The Valentine Mott Founder’s Award, named for the father of modern surgery and co-founder of NYU School of Medicine, is bestowed upon those who have shown exceptional support for NYU Langone Medical Center’s medical program. This year, the award went to Thomas S. Murphy, Sr., who served as the Medical Center’s chairman of the board from 1984 through 1997. The former chairman and CEO of Capital Cities/ ABC Inc., Mr. Murphy has been a member of NYU Langone’s Board of Trustees since 1972. He is also a member of the Urology Research Program Advisory Board, an honorary alumnus of NYU School of Medicine, and a life trustee and honorary vice chair of New York University. Together with his late wife, Suzanne, he endowed the Thomas and Suzanne Murphy Professorship in Neuroscience and has also generously supported the Medical Center’s biomolecular research program, Centers of Excellence, Trustee Annual Fund, and expansion of Tisch Hospital’s Dr. Robert Berne, executive vice president for health; Emergency Department. Kenneth G. Langone, chair of NYU Langone’s Board of “This day is about pausing to recognize the giants among us,” Trustees; and Dr. Robert I. Grossman, dean and CEO of said Dean Grossman, “and Thomas Murphy is a giant if ever there NYU Langone Medical Center. was one.” •

Thomas S. Murphy, Sr. (center), recipient of the Dr. Steven B. Abramson, senior vice president and vice Valentine Mott Founder’s Award, with Dean Grossman and dean for Education, Faculty and Academic Affairs. Kenneth Langone. Dr. Anthony J. Grieco, associate dean for Alumni Relations, led the faculty procession on Dean’s Honors Day. hs joshua bright p Photogra

Some of the faculty members who attended the ninth annual Dean’s Honors Day.

NYU Physician winter 2010-2011 27 Faculty News

Dr. Tsien Named Me dical Center Joins with PATH Malaria Director of New Vaccine Initiative Neuroscience Institute Richard W. Tsien, DPhil, an internationally Nyu Langone Medical Center is renowned scientist, has been appointed director of working with the PATH Malaria the recently established Neuroscience Institute and Vaccine Initiative and Merck to the first Druckenmiller Professor of Neuroscience, develop a vaccine to prevent the malaria effective January 2012. Dr. Tsien—a member of both parasite from entering the human liver. the National Academy of Sciences and the Institute Researchers from the three of Medicine and a former Rhodes Scholar—joins organizations will evaluate a vaccine NYU Langone from Stanford University, where he approach that targets a novel part of currently serves as the George D. Smith Professor of a major surface protein on the malaria Molecular and Genetic Medicine in the Department parasite. Malaria is estimated to kill nearly of Molecular and Cellular Physiology. 900,000 people each year with the majority In 2009, NYU Langone Medical Center received a $100 million gift from the of deaths occurring in children under the Druckenmiller Foundation to establish a state-of-the-art neuroscience institute and age of five in sub-Saharan Africa. to provide for the recruitment and support of the highest caliber neuroscientists. Dr. The circumsporozoite protein (CSP), Tsien’s appointment reinforces NYU Langone’s existing strengths and will enable it to identified in the early 1980s by Drs.R uth become a leader in translational neuroscience. and Victor Nussenzweig and Dr. Jerome At Stanford, Dr. Tsien was the founding chair of the Department of Molecular and Vanderberg at NYU Langone Medical Cellular Physiology. He helped establish the Stanford Brain Research Center and served Center, is the basis for many of the vaccines as its co-director from 2000 through 2005. He also served a 10-year term as director now in development. Blocking a critical at Stanford’s Silvio Conte Center for Neuroscience Research. Dr. Tsien studies how function of the protein may prevent invasion synapses contribute to neuronal computation and network function in both healthy of the malaria parasite into the liver, an and diseased brains. His research, supported by the NIH and private foundations, essential step in causing malaria. has contributed substantially to understanding how neurotransmitters, drugs, and “We think molecular alterations regulate calcium channels. we can improve Born in China, Dr. Tsien came to the United States as a child and later received both the way sub- undergraduate and graduate degrees in electrical engineering from the Massachusetts unit vaccines Institute of Technology. He was then named a Rhodes Scholar, graduating with his are designed doctorate in biophysics from Oxford University, England. He subsequently joined the by strategically faculty at Yale University School of Medicine and served there for nearly two decades targeting this before moving to Stanford. critical protein • function,” notes Elizabeth Nardin, PhD, Dr. oppenheim receives lifetime professor in the Department mentor award of Medical joel d. oppenheim, phd, senior associate dean for Biomedical Sciences, professor Parasitology at of microbiology, and director of the Sackler Institute of Graduate Medical Stud- NYU Langone ies at NYU School of Medicine, was recently awarded the 2010 Lifetime Mentor Medical Center. “Other vaccine Award of the American Association for the Advancement of Sciences. approaches targeting CSP have required The award honors an individual who has demonstrated extraordinary leadership in extremely high levels of antibody, which increasing the participation of underrepresented groups in the science and engineer- are difficult to elicit and to maintain.T his ing fields.I t especially recognizes an individual who has mentored significant numbers of approach has the potential to address abbott

these students to the completion of doctoral degrees. that problem.” n Since becoming director in 1994 of the Sackler Institute, Dr. Oppenheim has built Although this vaccine approach is

its doctoral program in the biological sciences into being tested primarily for use in children M: joh i e

a model of diversity. Approximately 15 percent of younger than one year of age, researchers h Sackler’s PhD graduates belong to underrepresent- believe it could be used to help prevent pen ed minorities—African Americans, Native Americans, disease in all populations. p . o

Hispanic Americans, as well as individuals with dis- PATH Malaria Vaccine Initiative (MVI) r d

abilities or from economically disadvantaged back- was established at PATH in 1999 through an f grounds—compared to only 7 percent to 8 percent initial grant from the Bill & Melinda Gates of bioscience PhDs awarded nationwide. Foundation. Merck is one of the world’s Dr. Oppenheim has been a member of the NYU largest pharmaceutical companies, faculty for 37 years. operating in more than 140 countries. • • h p otograPh o

28 photograPh of dr. oppenheiM: john abbott

p hotograPH of dr. shah: carl glenn; dr. nudler: mike weymouth S C health records andothermeanstoimprove andefficiencyofcare theeffectiveness expertise inusingsystems-basedmethodstoimprove patientoutcomesandelectronic Dr. S Dr. patients fromaroundtheworld. At Tisch innovative surgical treatments that attract celebrated forthedevelopment of of Reconstructive Plastic Surgery, Surgery continues tohousetheInstitute Langone forthepast 30years. Reconstructive Plastic Surgery at NYU of plastic surgery andtheInstitute of leadership asdirectorofboththedivision has provided chair. Dr. McCarthy department’s first 26), willserve asthe Honors Day (see page at last year’s Dean’s as Master Clinician who was honored of Plastic Surgery D. BellProfessor MD, theLawrence academic department. the status ofafull has beenelevated to aesthetic surgery, reconstruction, and surgery,facial microsurgery, breast renowned forleadership incongenital in theUnited States andinternationally Langone Medical Center, oneofthelargest The Plastic Surgery at Service NYU Department Becomesastic a Surgery P t l omm The new Department ofPlastic Joseph McCarthy, a to serveasthenewcommissionerofstate’sDepartment of cal Center Nirav t e h Heal R . a i S hah, MD,MP s , hasbeenselectedbyNewYork h s

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Depar U U ment by centered healthcare,” according tothe announce- to transitionthefuture oflower-cost,more patient- recognized thoughtleaderintheverymethodsneeded will servehimwellinhisnewposition. million inresearch funding. than 90peer-reviewed articlesandreceived over$4.5 received educationat hisundergraduate niversity andhisMDMP niversity i na o f G t S overnor Cuomo. overnor chool ofMedicine. e clinical facility. construction ofanew state-of-the-art $4 milliongrant toward thedesign and Foundation recently gave theInstitute a million sincetheInstitute’s inception.The Foundation hasprovided nearly $50 Reconstructive Surgery in1955; the to foundthedepartment’s Institute of Facial Reconstruction, which helped from theNational Foundation for one ofthemost competitive intheUnited surgery (with 24residents) israted as Its six-year residency programforplastic for itsoutstanding trainingprograms. its faculty, thedepartment iswell known surgical procedures, respectively. perform morethan2,500and1,300 affiliate, the Institute’sfaculty annually the School ofMedicine’s teaching primary Hospital andat Bellevue Hospital Center, d t m

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A Blava 2010 as revealed how dangerous bacteria such a breakthrough study in in numerous studies in diverse fields. members of his research team are involved careers. support promising scientists early in their in unrestricted funds, which is provided to and research. interdisciplinary achievements in science his highly innovative, distinguished, and S B A Dr. Dr. a project on aging, funded in part by these proteins in response to stress. Finally, the main factors that spur production of shock proteins, and the lab has identified protective cell components known as heat which creates critical cellular process of transcription, is investigating the mechanism for the can thwart antibiotics. anthracis, the causative agent of anthrax, production. the presence of various metabolites. control gene expression by directly sensing molecules, dubbed riboswitches, that can Caenorhabditis Caenorhabditis elegans. can affect the lifespan of the roundworm A eptember 2009, Dr. Nudler published lavatnik cademy of rtemyev, is examining how bacteria w Staphylococcus aureus and Currently Dr. Nudler and 12 A A ar nother research effort is focusing on separate project under his guidance N was awarded the New York Evgeny Nudler, PhD, the A nderson Professor of A u d war H d

S is lab has discovered cience’s prestigious 2010 T R d for Young l he award includes $25,000 N Faculty News er er A templates for protein t R n Science that e • ik ik S ceive cientists for B iochemistry, Bacillus J ulie Wilson R I N n T s A imur

29 Alumni Profile A Pioneering Cardiothoracic Surgeon Rosalyn Scott, MD, recalls the challenges of academic medicine and motherhood.

In 1977 Rosalyn Scott, MD (’74), became the first African Dr. Scott had her baby, finished her American woman in the country to start residency training in training, and went on to the University cardiothoracic surgery. During the interview at Boston University of Texas Medical School in Houston as School of Medicine, the department head offered her the job if she an assistant professor of surgery. In 1983 could start that July. Although she had a toddler at home and had she joined the University of California, just learned that she was pregnant again, and had still to complete Los Angeles, and the Charles R. Drew her general surgery residency, she took the job for a very practical University of Medicine and Science, where she spent most of her career as reason: “I didn’t want to lose this opportunity.” Later she found chief of the division of cardiothoracic and vascular surgery. out that if her boss had known she was pregnant, he would not At a recent interview, in dark slacks and a bright coral-red have hired her. jacket, umber beads at her throat, dark hair cropped short, Dr. “It was not so hard to do surgery when you are nine months Scott recalled the challenges of motherhood as a surgery resident pregnant,” Dr. Scott admits. “It turned out that the chair of and then later as an academic surgeon, when life was never surgery was equally rotund,” she adds with a wry smile. “People predictable. “When my girls were young, I’d never say no, but I’d asked if I could reach the operating table. I told them that Dr. always say, ‘Let’s have a fallback plan.’ ” Williams could and I didn’t think I would ever be as large as A consummate diplomat, Dr. Scott will not comment about Dr. Williams. I could always borrow his scrubs if necessary!” the demeanor of her colleagues when she was first starting out,

Dr. Rosalyn Scott in the medical simulation center at Dayton VA Medical Center in Ohio.

NYU Physician photograph by 30 winter 2010-2011 Robe rt ray kummer Signs of the Times: At NYU Langone, nearly half of new surgical faculty are women. Since becoming interim- chair of the Department of Surgery in 2005, now-Chair H. Leon Pachter, MD, has recruited 39 new faculty members, 18 of whom are women, shown surrounding him in a recent photo.

except to say that there was a lot more “throwing of instruments” wanted to be a physician. Her uncle, Arthur Falls, MD, was back then. Colleagues describe Dr. Scott—a founding member a thoracic surgeon, who, in the 1920s, worked at Provident of both the Association of Black Cardiovascular and Thoracic Hospital in Chicago, the only hospital in the city that accepted Surgeons and the Society of Black Academic Surgeons—as a African American physicians and patients. He later became fearless and thoughtful leader in a profession dominated by men. president of that hospital. Her father, Roy Proctor, DDS, had gone “I thought, here’s this field, heart surgery, which is to dental school at New York University College of Dentistry. “I’d absolutely male dominated, and she stands out in a second as always heard about NYU,” she says. He was 48 when she was being completely different and wonderfully creative, and always born and had his first heart attack when she was in the third wise beyond her years,” says Peter Greene, MD, of Johns Hopkins grade. But he lived long enough to see her go to medical school, School of Medicine, who got to know Dr. Scott in the mid-1980s urging her to become a heart surgeon because he believed that it through the Society for Thoracic Surgeons, when they were both was a good niche for his daughter. young heart surgeons. “Often the people who aspire “She’s used to going into a field like cardiothoracic to leadership do so in a bloodthirsty fashion—there’s a lot of stepping on one surgery, which is very old school another to advance—I never saw her do it and not diverse, and being comfortable there or heard anybody say or suggest it,” says herself and guiding it along a better path.” Dr. Greene. “She’s used to going into a field like cardiothoracic surgery, which is very old school and not diverse, and being comfortable there herself and guiding it along a better path.” Before attending NYU School of Medicine, Dr. Scott majored One of those she guided was trauma and critical care in chemistry at Rensselaer Polytechnic Institute in Troy, New surgeon Anthony Charles, MD, a Nigerian native, who, when Dr. York. “There were 5,000 men on campus and about 100 women,” Scott took him under her wing, had just arrived in Los Angeles she says. “I started in the first class that had a place for women to from the United Kingdom. “She facilitated my whole academic stay on campus. Now there’s a female president who is African career. She was incredible,” says Dr. Charles, now an assistant American.” professor of surgery at the University of North Carolina at Despite the increasing numbers of women in many medical Chapel Hill School of Medicine. fields cardiothoracic surgery remains an almost exclusively When Dr. Charles started his job search, Dr. Scott told him, male club. In 2009 women made up only 3.3 percent of the “I think you should look at North Carolina. I’m going to call up membership of the Society of Thoracic Surgeons. “I think it is the chair and tell him you’re coming.” At the time Dr. Charles clear that women have had a harder time in the field than men, wasn’t even considering North Carolina. “I already had two other though opportunities are a little better now,” Dr. Scott says. job offers,” Dr. Charles says with a laugh. “But she was right.” “Until you’re 20 to 30 percent of a field, you’re at a disadvantage.” A native of Newark, New Jersey, and the only child in a African American women cardiothoracic surgeons are rarer still, family of medical professionals, Dr. Scott always knew she with fewer than a dozen working in the U.S. today. continued on page 32

NYU Physician winter 2010-2011 31 Obituary

keith krasinski, md

Keith Krasinski, MD, professor University of Illinois School of Medicine of pediatrics and environmental and completed a pediatric residency and medicine, died October 2, an infectious disease fellowship at the 2010, after a two-year struggle with Children’s Hospital at the University of an especially aggressive type of skin Texas Southwestern Medical School. In cancer. He was 61 years old. Dr. Krasinski 1991, he co-founded and served as director dedicated his career to caring for children of the Lower New York Consortium, infected with HIV and to preventing a Ryan White and New York AIDS transmission of the virus from mothers Institute–funded network of providers to their newborns. In 1999, as a result in lower Manhattan and Staten Island of his groundbreaking work with that offered coordinated care and access Assemblywoman Nettie Mayersohn of to clinical trials for HIV-infected women, Queens, the state of New York established children, youth, and their families. A a screening program to detect newborns member of the New York State AIDS at risk for HIV and offer treatment to Advisory Council, he helped establish mothers and babies. guidelines for the care and prevention “Keith really fought hard for of pediatric AIDS. In 1997, he became the legalization of routine testing of director of NYU School of Medicine’s newborns,” says his longtime colleague Institutional Review Board, which and friend Robert Holzman, MD, monitors research ethics, a position he professor emeritus of medicine. Early held for 10 years. For 25 years he served in the AIDS epidemic, privacy concerns as deputy hospital epidemiologist for limited the testing of mothers and babies Bellevue Hospital Center, assuming the at risk, leaving many of them untreated. political process to achieve it.” top post after Dr. Holzman retired in 2007. “So it was not a popular position,” Dr. A native of suburban Chicago, Dr. Dr. Krasinski is survived by his wife, Holzman says, “but he saw what was Krasinski joined NYU School of Medicine Debra, and three daughters, Katie, Annie, needed and worked very hard in the in 1981. He earned his MD from the and Stephanie. •

A Pioneering Cardiothoracic Surgeon continued from page 31 R emarkably, Dr. Scott never viewed the renovations for a 17,000-square-foot Education. “Basically, I think cutting and her gender or her race as impediments. center at the VA, where she is also associate sewing should be a woman’s profession. “That’s not to say I’m naive about it. But chief of staff for medical education. She also It was really, to me, a natural extension of if you put that in front of everything you has a faculty appointment in the College what women do anyway. Men have to learn say or do, you probably become pretty of Engineering and Computer Science at how to cut and sew.” paralyzed. You just have to go do the best Wright State. Married to businessman Clarence you can do.” Besides the robotic “patients,” much Scott, Dr. Scott has two daughters, one of Two years ago she left California to has changed in medical education since whom is a lawyer in California; the other take the positions of chief of surgery at the her own training in the 1970s. “Today, here recently finished a postdoctoral fellowship Dayton VA Medical Center and professor in our [surgery] residency program, we’re in public health at the University of North of surgery at Wright State University very female friendly,” she says. “We have Carolina at Chapel Hill and now works at Boonshoft School of Medicine in Ohio. three or four babies a year.” the U.S. Health Resources and Services Today, as part of a nationwide team Indeed, she argues that surgery Administration in Washington, D.C. designing the most advanced medical is really women’s work. “Surgery is an What career advice did she give her simulation center yet for the national exercise in perfection and compulsion,” she own adult daughters? “I told them they Veterans Affairs in Orlando, Florida, said in the 1999 short documentary Women should do whatever they wanted to do, but Dr. Scott directs the Dayton VA Medical Are Surgeons, produced by the National make sure they get terminal degrees in Center’s simulation center and is designing Institutes of Health Office of Science their field!” • — aubin tyler

NYU Physician 32 winter 2010-2011

You, too, can make a difference at NYU Langone. To learn more, about how to create your own legacy and become a member of The John Revere Society, please contact Marilyn Van Houten at 212.404.3653 or email her directly at [email protected]. The Gift of a Lifetime

elping others is life’s driving force for HEugene Kalnitsky, MD,’54, a retired physician and air force officer, and his wife, Linda, a former teacher and coordinator of volunteers for local Florida charities. Eugene completed his medical degree and residency in internal medicine at NYU School of Medicine. He was especially affected by his classes with Samuel Standard, MD, who opened Eugene’s eyes to the value of patient- centered care.

Linda Kalnitsky and Eugene Kalnitsky, MD, `54

With the compassion they have shown throughout their lives, and in gratitude for Eugene’s medical education, Eugene and Linda made the gift of a lifetime through a charitable annuity. Legacies like theirs help transform the future of medicine.

You, too, can make a difference at NYU Langone. To learn more about how to create your own legacy, please contact Marilyn Van Houten at 212.404.3656 or email her at [email protected]. Nonprofit Org. U.S. Postage Office of Communications and Public Affairs PAID 550 First Avenue, New York, NY 10016 Permit No. 8167 New York, NY