NYUTHE MAGAZINE OF NEW YORK UNIVERSITYPHYSICIAN SCHOOL OF MEDICINE FALL 2015

Unlocking the Potential of Cannabidiol A new extract offers controversial hope for uncontrolled seizures

PLUS SUGAR-LOVING FRUIT FLIES AND THE RIDDLE OF OBESITY / RETHINKING OXYTOCIN / GROWING CARDIAC CELLS Help Us Make Dreams Come True

EVERY 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 nyulangone.org/give 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 fi nancial 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 FALL 2015 NYUPHYSICIAN

New York University Martin Lipton, Esq. Chairman, Board of Trustees

John Sexton President “They are hedonic flies,” Robert Berne says Dr. Suh. “They only Executive Vice President for Health care about the sweet stuff.” • NYU Langone Medical Center Kenneth G. Langone Chairman, Board of Trustees

Robert I. Grossman, MD The Saul J. Farber DEPARTMENTS Dean and CEO 02 Dean’s Letter Kathy Lewis Nature’s Pharmacy Senior Vice President, Communications and Marketing 03 News from Medicine • • Fresh Hope for Treating a Devastating NYU PHYSICIAN Pediatric Cancer Steven B. Abramson, MD • Antibiotics: Too Much, Too Early? Anthony J. Grieco, MD • The Purkinje Puzzle Editors, Science • Mother Love and Oxytocin and Medicine COVER STORIES • Chop Shop: Ridding the Brain of Dangerous Plaques Nicole Dyer Unlocking the Potential Editor of Cannabidiol 24 Faculty Conversation Thomas A. Ranieri 10 A nonpsychoactive ingredient of Q & A with Dr. Cheryl Pegus, clinical Marjorie Shaffer marijuana has been hailed as a professor of medicine and population Contributing Editors miracle cure for intractable pediatric health and associate director for clinical epilepsy. Dr. Orrin Devinsky puts the Sherry Zucker innovation at NYU Langone claim to the test. By Kenneth Miller Print Production Coordinator  26 Faculty News The Sweet Life of a Fruit Fly • Dr. Thomas Einhorn, renowned Segal Savad Design Why do we crave sugar? Banana- orthopaedic surgeon, joins NYU Langone Art Direction 18 loving fruit flies are yielding • Ruth and Victor Nussenzweig receive • intriguing clues. By Josie Glausiusz ON THE COVER: prestigious Alpert Foundation Award ILLUSTRATION BY GABY D’ALESSANDRO 27 Around Campus Building Stronger Bridges to Fight Parkinson’s Disease

28 Obituary Martin S. Nachbar, MD ROBERT NOONAN / SCIENCE SOURCE

NYU PHYSICIAN FALL 2015 1 MESSAGE FROM THE DEAN & CEO

Nature is a master pharmacist.

Its unrivaled genius is the inspiration for more than 120 medications on the market today. We are all familiar with salicylic acid, better known as aspirin, which was once harvested from the bark and leaves of the willow tree. Penicillin was first discovered in a moldy petri dish. Then there’s sweet wormwood, a fern-like plant native to Asia whose prized ingredient, artemisinin, is a potent treatment for malaria. It’s not surprising that medicine should seek to harness the therapeutic properties of marijuana. For the cover story of this issue of NYU Physician, we visited with Orrin Devinsky, MD, professor of neurology, neurosurgery, and psychiatry at NYU Langone Medical Center, and one of the country’s leading epilepsy specialists. Dr. Devinsky has launched the first large- scale trial of cannabidiol, marijuana’s main non-psychoactive chemical, for the treatment of the most severe forms of pediatric epilepsy. Early data are encouraging. The compound, delivered as a purified liquid extract, has already improved the lives of many children for whom conventional seizure medications have failed. It has also given parents a safer alternative to untested medical marijuana. Whether we are researching new ways to treat intractable epilepsy, cure a devastating form of pediatric cancer, or elucidate the molecular drivers of obesity—you will read about all of these efforts on the following pages—uncompromising science is at the heart of everything we do. At NYU Langone, it’s the foundation of our world-class patient care, and our commitment to it has never been stronger.

DEAN & CEO ROBERT I. GROSSMAN, MD

NYU PHYSICIAN PHOTOGRAPH BY 2 FALL 2015 JOHN CARNETT NEWS FROM MEDICINE Nature is a master pharmacist. FALL 2015 ADVANCES IN PEDIATRIC CANCER, THE MICROBIOME, HEART DISEASE, AND MORE

Antibiotics magnified beneath a microscope.

“We have been using antibiotics as if there was no biological cost.” MARTIN BLASER, MD PAGE 5  DE AGOSTINI PICTURE LIBRARY / SCIENCE SOURCE PICTURE LIBRARY AGOSTINI DE

NYU PHYSICIAN FALL 2015 3 NEWS FROM MEDICINE

growth and progression in mice. The “Every single mouse unexpected finding, if verified in human clinical trials, could point toward a in which we had powerful new approach for treating the deleted CXCR4 childhood cancer. The research, published in the journal was alive and Cancer Cell, yielded dramatic results running around the in mice that were afflicted with the cage,” says Susan equivalent of T-ALL and stripped of the CXCR4 protein. “When 100 percent of Schwab, PhD. the mice with the wild-type leukemia had died, every single mouse in which we had deleted CXCR4 in the leukemia cells was alive and running around the cage,” says Susan Schwab, PhD, assistant Meanwhile, the leukemia continued professor of pathology and an investigator unabated in the untreated mice. SUSAN SCHWAB, PHD in the Skirball Institute of Biomolecular Coauthor Iannis Aifantis, PhD, Medicine, who co-led the study. professor of pathology and chair of the FRESH HOPE FOR A second set of experiments, in Department of Pathology at the Laura TREATING A which the collaborators transplanted and Isaac Perlmutter Cancer Center leukemia cells from humans into and an Early Career Scientist at the DEVASTATING immune-deficient mice, led to similarly Howard Hughes Medical Institute, says PEDIATRIC CANCER surprising effects. Two weeks after researchers have only begun to explore some of the mice received a drug the microenvironment, or physical Researchers discover a way to designed to block CXCR4, the therapy niche, of cancer cells. reverse T-ALL in mice. effectively halted leukemia progression. “It is actually the first study

ESPITE GREAT strides in treating pediatric cancers, doctors have D long known that one in four children diagnosed with a devastating form of cancer known as T-cell acute lymphoblastic leukemia, or T-ALL, will relapse within five years and face a grim prognosis. Even those who do respond to treatment often suffer serious long-term side effects from the drug and radiation therapies, underscoring the need for more effective and less toxic treatments. Now, there is fresh hope. Researchers from NYU Langone Medical Center found that a protein on the surface of infection-fighting T-cells, named CXCR4, is essential for T-ALL survival. Blocking its activity, they discovered,

can halt and even reverse the leukemia’s A leukemia cell at 8,000x magnification. THEA BRINE. PORTRAITS: STEVE GSCHMEISSNER / SCIENCE SOURCE,

NYU PHYSICIAN 4 FALL 2015 that shows there are specialized CXCL12, which is secreted by blood been well tolerated, though researchers microenvironments where leukemia vessels and attracts other cells to create caution that the medication’s safety cells reside,” Dr. Aifantis says. “We T cell–supportive niches in the marrow. must be evaluated in children, as well. are now able to visualize these The researchers suspect that T-ALL The NYU Langone researchers plan microenvironments even in a living exploits this same signaling pathway to study next-generation inhibitors of organism, using microscopy.” By better to attract blood cells and nutrients to CXCR4 that may be even more effective. understanding these physical niches places where it can thrive instead. Some of these drugs are already in within the bone marrow, he adds, Without the guidance of CXCR4, “the clinical trials for other conditions, researchers may be able to target them leukemia just essentially melts away,” meaning that tests of their application with antileukemia interventions. Dr. Schwab says. The study showed for T-ALL could proceed quickly. The How do cancerous cells co-opt that depleting CXCL12 itself also stalls exciting potential, Dr. Aifantis says, CXCR4? The protein normally acts like T-ALL progression. CXCR4 may play owes much to the multidisciplinary a homing beacon to recruit blood cells a key role in human development but exploration of leukemia’s unexplored to the bone marrow and help T-cells seems to be less important later in life. niches. “We’ve just approached it from mature. Among its partners, the protein In adults, drugs that block the protein’s different angles,” he says. • binds to a signaling molecule named activity in targeting other diseases have —BRYN NELSON

VERY YEAR, up to 10 bigger bones, and had more disruptions million U.S. children in the microbial communities in their guts receive antibiotic than untreated mice. E prescriptions that are Although the implications for humans unlikely to do them are still unclear, multiple studies in rodents any good, according to the American and children by Dr. Blaser and other Academy of Pediatrics. A new study of researchers have suggested that early-life antibiotic use in mice by NYU Langone antibiotic exposure can indeed alter the Medical Center researchers suggests why bacterial landscape of the gut and increase the dangers of repeated and potentially the risk of obesity and other metabolic MARTIN BLASER, MD unnecessary antibiotic use, especially disorders. Dr. Blaser, who was recently early in life, may extend well beyond appointed chair of the Presidential ANTIBIOTICS: immediate side effects and eventual Advisory Council on Combating bacterial resistance. Antibiotic-Resistant Bacteria, says the data TOO MUCH, “We have been using antibiotics as if could help improve guidelines for pediatric TOO EARLY? there was no biological cost,” says senior antibiotic prescriptions to minimize the author Martin Blaser, MD, the Muriel potential harm. New mouse study links G. and George W. Singer Professor of For the study, female mouse pups overexposure to antibiotics Translational Medicine and director of received three short courses of tylosin, in infancy to lifelong the NYU Human Microbiome Program. an antibiotic used in veterinary medicine metabolic disorders. “Our latest experiments are yet another that represents an increasingly popular piece of evidence suggesting that class of pediatric antibiotics called the overexposure to antibiotics indeed has macrolides; amoxicillin, a commonly long-lasting effects.” used broad-spectrum antibiotic in the The study, published in Nature beta-lactam class; a mixture of both drugs; Communications, found that mice treated or no drugs at all. To mimic the effects of with two classes of antibiotics in doses standard pediatric prescriptions in the proportional to those commonly used in U.S., the researchers gave mice the same children gained more weight, developed proportional dose that the average child

NYU PHYSICIAN FALL 2015 5 6 NEWS FROM MEDICINE a high-fat diet,themicrobiomes ofthe researchers moved six-week-old miceto changes, such asanew diet.When the be lessadaptable toenvironmental antibiotic-exposed microbiomes may Microbial Ecology, alsosuggested that the DianeBelferProgramforHuman maturity ofthemicrobiome.” suggest that thedrugs are“stunting the maturation. The results, Dr. Blaser says, and specific markers linked tonormal both theoverall microbial diversity the intestinal tract, by markedly reducing the trillionsofmicroorganisms inhabiting development ofthegutmicrobiome, or that bothantibiotics disrupted the sequencing, theresearch alsoshowed on bonegrowth. Basedonextensive DNA that amoxicillin had thebiggest impact three tosixweeks old,thestudy found effect onweight gainoncethemicewere when theywere just 10days old. receives. The micereceived theirfirst dose conduction cells. method ofgeneratingcardiac- Researchers create a new PUZZLE THE PURKINJE GLENN FISHMAN, MD The study, supported inpartby While tylosin had themost pronounced R of Medicine. instructor inNYULangone’s Department coauthor Laura M.Cox, PhD, anadjunct dietsuntilfat months later,” says lead of themicrobiomes didn’t adapt tohigh- weeks. “In thetylosin-treated mice, some shifted inoneday, while otherstooktwo mice onamoxicillin, somemicrobiomes linked metabolism. tofat Amongthe by increasingtheproportionofmicrobes untreated micealladapted withinaday Medical Center. Division ofCardiologyat NYU Langone H.Charney and directoroftheLeon Medicine intheDepartment ofMedicine MD, theWilliam GoldringProfessorof contractions,” explainsGlenn I.Fishman , of cardiac muscle cellstosynchronize like atreeroot,interfacing withmillions impulses. “Purkinje fibersbranch out transmitting life-sustaining electrical within theheart’s muscular walls, cells formacriticalbutdelicate network Stem Cell Reports, Dr. Fishman anda FALL 2015 NYU PHYSICIAN Antibiotics arevitallyimportant for In astudy recently published in heart. These specialized vital toahealthy, beating fibers arenonetheless 1% ofheartcells,Purkinje EPRESENTING less than less than widely usedinchildren. Crystals ofamoxicillin,anantibiotic other heart conditions. other heartconditions. therapies forcardiac arrhythmias and discovery opensthedoor tonew of thesespecialized cells.Their exciting technique forgrowing large numbers Medical College, announcedanew in collaboration withtheWeill Cornell team ofresearchers at NYULangone, in life. potential downsides ofoveruse early stewardship, andscrutiny ofthe more targeted therapies, antibiotic the new study highlights theneedfor however, Dr. Cox andDr. Blaser say courses ofthedrugs by theage oftwo, With theaverage child receiving three treating seriousbacterial infections. Me th k team ultimately zeroedino mo substance that would helptra n th by theWeisfeldFamilyProg i n C now e at itelevated levels ofc e researchers scouredali arly 5,000 chemicals, hunti A use stem cellsinto Purki dicine andtheKorein Fo ardiovascular Regenerative s partofthestudy,suppor n assodium nitroprusside, • —BRYN NELSON yclic AMP, a n a br nje cells.The u ra ndation, ary of ary nsform ng chemical te m d

finding for a

ANTONIO ROMERO / SCIENCE SOURCE, multi-functional signaling molecule that heart rhythms. Current antiarrhythmic appears to promote the differentiation drugs are fraught with side effects of Purkinje cells. By exposing mouse because they target the entire heart. stem cells to sodium nitroprusside, “Now that we have a way to isolate researchers found it was possible to Purkinje cells, we can screen them with generate populations of cardiac cells that candidate antiarrhythmic drugs and include nearly 40 percent Purkinje cells. perhaps identify those that specifically The finding holds important clinical target the biology of the Purkinje cell,” implications. Damage to Purkinje says Dr. Fishman. cells due to cardiovascular disease or Next up, the researchers hope to apply congenital disorders can disrupt the the same methods to coax Purkinje cells ROBERT FROEMKE, PHD electrical signals that regulate heart from human cardiac stem cells. • beats. By inducing stem cells to become —JOSHUA FEBLOWITZ MOTHER LOVE Purkinje cells, it may be possible to reconstruct the Purkinje network anew AND OXYTOCIN rather than implanting a pacemaker, the The researchers A new study reveals the brain standard solution. “The ultimate goal scoured nearly region where oxytocin exerts is to create artificial Purkinje fibers and 5,000 chemicals its remarkable effects. reconstruct part of the heart’s original conduction system,” says Dr. Fishman. for one that would In addition to acting as a patch for a transform mouse damaged conduction network, artificial HOUGHT TO be the Purkinje cells could also be used to stem cells into hormonal glue that develop new drugs to treat abnormal Purkinje cells. binds mother and infant, T oxytocin is often referred to as the “love hormone.” In mice, this chemical messenger, synthesized deep in the hypothalamus, attunes mothers to the ultrasonic distress calls of lost pups, enabling them to find and return their helpless newborns to the safety of the nest. Where and how does oxytocin work in the brain to facilitate this lifesaving social behavior? Robert Froemke, PhD, assistant professor of otolaryngology and of neuroscience and physiology at NYU School of Medicine, and his team at the Skirball Institute of Biomolecular Medicine tackled this question in a recently published study in Nature. “We know a lot about how oxytocin works in the body, but not in the brain,” Dr. Froemke says. Ordinarily among mice, only veteran The branched mothers respond to the squeaky, high- extensions of pitched cries of a lost pup. Males and Purkinje fibers (yellow) females without offspring simply tune sustain the heart’s out the pleas. But nonmoms cohoused PETER GARDINER / SCIENCE SOURCE, PORTRAITS THEA BRINE PORTRAITS / SCIENCE SOURCE, PETER GARDINER conduction system.

NYU PHYSICIAN FALL 2015 7 8 NEWS FROM MEDICINE Implanted fiberopticsallowed the technology known as optogenetics. the brain,courtesy ofanemerging to expresslight-sensitive proteins in third group was genetically engineered group received salineinjections. A to each testing session,while asecond systemic injections ofoxytocin prior retrieval behavior. Onegroup received veteran mothersandobserved forpup- without offspring were cohousedwith which threegroups offemalemice researchers setup anexperiment in this remarkable transformation, the the nest.” can pick them up andreturnthemto lactating, she can’t feedthepups, butshe says Dr.mom,” foster Froemke. a “She isn’t female without offspring beginstoact like them learnitfaster. “With oxytocin, the injections ofoxytocin canhelp that shows behavior, andDr. Froemke’s new research with veteran momscanlearnthematernal Crystals ofoxytocinat50xmagnification. To study how oxytocin facilitates

behaves inliving animals.” understand how thenative circuitry release ofoxytocin internally toreally with optogenetics, we canstimulate the inject adrug,” says Dr. Froemke, “but release ofoxytocin. “It’s onethingto the engineeredcellsandstimulate the researchers to flash bluelight onto the ability torescuelost pups and faster even nonmomshousedalonecanacquire experiment, theresearchers showed that as theveteran mothers.In aseparate rescuing pups at the samerate andspeed the oxytocin-enhanced non-moms were more pups. Remarkably, after threedays, the salinegroup, buttheyalsoretrieved groups beginretrieving pups earlier than injections. Not onlydidtheoxytocin pups thanthemicethat received saline stimulation, beganretrieving distressed oxytocin, eitherby injection orviaoptical more ofthenonmomsthat received habitat withtheveteran mothers, FALL 2015 NYU PHYSICIAN Within 12hours ofsharing thesame “ of those things.” don’t think it’s either Dr. Froemke. “But I love hormone,” says as atrustdrug, a buzz around oxytocin there’s beenalotof In the past 10years,  “That’s thenextbigquestion.” cortex thantheright, Froemke says, active intheleftside oftheauditory based therapies couldprove therapeutic. social cueshasbeenmuffled, oxytocin- disorders inwhich theability to“hear” autism, schizophrenia, PTSD,andother to relevant socialcues.For peoplewith it up allows us topay moreattention a sortofchemical volume control: turning Instead, hebelieves oxytocin ismorelike I don’t thinkit’s eitherofthosethings.” a love hormone,” says Dr. Froemke. “But of buzzaroundoxytocin asatrust drug, social information. may alsounderlie ourability toprocess important roleinspeech recognition, that thisbrainregion,which plays an with andwithoutoffspring, suggesting of theauditory cortexinfemalemice receptors concentrate intheleftside Their findings revealed that oxytocin the temporal lobe that facilitates hearing. the auditory cortex,abrainstructurein to andilluminates oxytocin receptorsin developed anovel antibody that binds answer thisquestion, theresearchers responding totheoxytocin andhow? To than withoutit. more efficiently withan oxytocin boost As forwhy oxytocin appears most “In thepast 10years, there’s beenalot But which brainregionswere

—NICOLE DYER •

PASIEKA / SCIENCE SOURCE therapies for this disorder without removal process instead of a building understanding the molecular block for beta-amyloid construction. mechanisms of the disease,” Dr. Ghiso Given the shortage of good biomarkers says. Until recently, for example, many for Alzheimer’s disease, Dr. Ghiso says, investigators overlooked the potential his lab is exploring the potential of the ability of protein-digesting enzymes, or 16-amino acid piece as a better indicator proteases, to prevent the accumulation of disease progression. of disease-linked molecules. “By making Dr. Ghiso cautions that the the molecules smaller, perhaps it is easier “promiscuous” proteases have many to get rid of them,” he says. functions and can be harmful in high JORGE GHISO, PHD The new study, published in The amounts. “So, simply increasing their Journal of Biological Chemistry, found concentration in the brain may have CHOP SHOP that the MMP-2 and MMP-9 proteases damaging consequences since these begin chopping from the tail end of the molecules will degrade other things,” In a boost for Alzheimer’s main beta-amyloid proteins, which are he says. The proteases can target the research, scientists reveal either 40 or 42 amino acids in length. brain’s network of blood vessels, for how two enzymes chop up The proteases initially pare the proteins instance, and cause hemorrhaging. toxic plaques in the brain for down to exactly 34 amino acids. That Nevertheless, he says, the new data easier removal. shorter version, in turn, is trimmed to may better illuminate the beta-amyloid 30 amino acids, and finally to only 16 disposal process and lead to experiments amino acids. on whether carefully calibrated enzyme OUGHLY 700,000 This last remnant, the study found, is levels can improve clearance of the toxic people in the U.S. will nontoxic and relatively stable, suggesting protein without triggering unwanted die from Alzheimer’s that it may be an important part of the side effects. • —BRYN NELSON disease in 2015, R making it the sixth leading cause of death. A hallmark of the degenerative brain disorder is the buildup of a small protein called beta-amyloid, which forms the main constituent of clumplike plaques. Based on recent research, many scientists believe that these potentially toxic aggregations throughout the brain may be caused by errors in the brain’s disposal process rather than by excess protein production. A new study led by Jorge Ghiso, PhD, professor of pathology and psychiatry at NYU Langone Medical Center, suggests that two enzymes in the brain may play a vital role in chopping up the dangerous beta-amyloid protein into smaller, nontoxic pieces that can be safely removed. The apparently beneficial actions of these two enzymes, known as MMP-2 and MMP-9, may point to new targets for therapeutic interventions that help disrupt the disease process. Beta-amyloid molecules, shown here as a computer animation, form

LEONARD LESSIN / SCIENCE SOURCE, PORTRAITS: THEA BRINE. PORTRAITS: LEONARD LESSIN / SCIENCE SOURCE, “Researchers are trying to develop clumplike plaques in the brain associated with Alzheimer’s disease.

NYU PHYSICIAN FALL 2015 9 UNL KING The Potential of Cannabidiol A nonpsychoactive ingredient of marijuana called cannabidiol has been hailed as miracle cure for intractable pediatric epilepsy. Now Dr. Orrin Devinsky of NYU Langone Medical Center’s Comprehensive Epilepsy Center and colleagues are putting the contentious claim to the test in the first large-scale study of the compound.

BY KENNETH MILLER

NYU PHYSICIAN 10 FALL 2015

epilepsy and had received UNTIL HE WAS TWO YEARS OLD, little benefit from conventional Liam O’Brien was a typical toddler—happy, treatments. But the girl’s seizures seemed to have been active, and curious about the world. all but banished by a highly He would trot around his family’s home unconventional remedy: an extract of cannabis. Along on Staten Island, leaving a trail of toys and with a handful of other exercising his growing vocabulary. children with similar conditions, she used a strain that was high in cannabidiol (CBD), the THEN, ONE DAY in June 2011, Liam did targeted medications. Although they plant’s main nonpsychoactive chemical something strange: He walked into the reduced the frequency of the seizures, component, and low in intoxicating kitchen, dropped his chin to his chest, and new problems arose. Liam began having tetrahydrocannabinol (THC). thrust one of his arms in the air. He stood atonic seizures, suddenly losing all Karyn knew there were reasons to be motionless for several seconds before muscle tone and crashing to the floor. He wary. Possession of marijuana was a felony continuing on his way. also developed tonic seizures, in which under federal law, and though Colorado In the weeks that followed, such episodes his entire body stiffened; often, he stopped had legalized medical marijuana, New became more frequent. Liam also began breathing for 30 seconds or longer. “It was York had not yet done so. But she was losing his language skills. His worried so scary,” Karyn recalls. “I never knew if willing to try anything. “We can’t live like parents, Karyn and Kevin, took him to a he was going to start breathing again.” this anymore,” she told Dr. Devinsky’s pediatric neurologist, who diagnosed him As the months wore on, Liam was nurse practitioner, Erin Conway, RN. “I’m with autism. An electroencephalogram given more than half a dozen medications, ready to move to Colorado.” showed that he also had epilepsy, a but none eased his symptoms. Moreover, Conway suggested a less radical move. condition in which abnormal bursts of the drugs brought troubles of their own, Dr. Devinsky, she said, was about to launch electrical activity interfere with normal making him floppy limbed and sleepy. the first large-scale study of CBD as a brain function. The resulting seizures can The combined effects of the drugs and treatment for severe, treatment-resistant take many forms, from a brief dimming of the seizures, which disrupt learning and epilepsy, and Liam might be eligible. consciousness to body-racking convulsions. may cause brain damage, added to the Liam was experiencing a type known as developmental delays associated with his myoclonic seizures, which sometimes cause autism. By age four, Liam could speak involuntary movements in just one area of fewer than 10 words and was unable DR. DEVINSKY had begun looking into the body. to use a toilet. To avoid injury, he was CBD after another patient’s father asked The neurologist started him on an forbidden to climb stairs unassisted or sit him about reports in the national media anticonvulsant medication, but it had in a chair without arms. He had to wear a of supposed miracle cures wrought by little effect. A second drug was added, helmet at all times to prevent concussions extracts containing the substance. While but the seizures multiplied. They came in when he fell. there was very little in the literature about clusters, totaling 50 or 60 a day. Liam’s condition took a toll on his marijuana’s anticonvulsant effects in Seeking a team of specialists who parents as well. His nighttime seizures humans, the neurologist was encouraged could handle Liam’s complex case, his left them perpetually sleep deprived. Any by the research in animals. Data showed parents brought him to NYU Langone family outing could turn into an ordeal. that two of the most plentiful of the plant’s Medical Center’s Comprehensive Epilepsy Letting him play unsupervised was 80-plus unique compounds, known as Center to meet with its director, Orrin unthinkable. Kevin worked as a computer cannabinoids, could quell seizures—THC Devinsky, MD, professor of neurology, programmer, but Karyn’s full-time job in 61 percent of animal studies, and CBD neurosurgery, and psychiatry. One of the was making sure their son survived in 81 percent. THC interacts primarily country’s leading epilepsy specialists, Dr. each day. with the endocannabinoid system, a Devinsky has led many major studies of In July 2013, a TV documentary gave neurological network that helps regulate novel treatments. He ordered a thorough her a sliver of hope. Its subject was a little physiological processes including sleep,

workup and prescribed a regimen of girl in Colorado who suffered from severe memory, mood, appetite, inflammation, BY KARSTEN MORAN PHOTO

NYU PHYSICIAN 12 FALL 2015 By studying the potential of cannabinoids for treating epilepsy, researchers hope to separate truth from rumor.

immune function, and bone growth. (The body makes chemicals, known as endocannabinoids, which transmit messages through the system by binding to two types of receptors—CB1, found largely in the brain, and CB2, found mainly in other organs. THC fits into those receptors like a key into a lock.) CBD, meanwhile, works mainly with other signaling systems. Its anticonvulsant effects seem Liam O’Brien with Dr. Orrin Devinsky, one of the country’s leading epilepsy specialists. to involve receptors that help regulate the excitability of brain cells by altering the balance of calcium ions, and unlike THC, it doesn’t deliver a high. a conference room at the Medical Center’s a defect in one gene. Other varieties Dr. Devinsky was intrigued enough by Comprehensive Epilepsy Center. Together, can be triggered by brain injury, stroke, CBD to begin exploring his own study. But they hatched a plan for a multicenter trial tumors, or substance abuse. Population there was one big catch: the compound was of a purified CBD extract. studies indicate that heredity is a factor, available only in the form of homemade but in most cases, the underlying cause is oils and tinctures, with little control over unknown. In about half of those affected, consistency or purity. Then Dr. Devinsky the disease can be controlled by a single heard about GW Pharmaceuticals, a EPILEPSY IS NOT a single disorder, medication. (More than two dozen types British company that manufactured a but rather a group of disorders of anticonvulsants are available.) Around cannabis-based medication, Sativex, which characterized by recurrent seizures that 30 percent of patients continue to have was approved in 22 European countries have no immediate cause. The condition, seizures, however, even when taking two for relief of multiple-sclerosis spasticity. which afflicts about 1 percent of the or more drugs at once. Up to 25 percent The firm’s manufacturing processes were population, occurs when the brain’s experience adverse effects that limit cutting-edge, and its product—an extract electrochemical balance is disrupted, treatment options. For some patients with standardized to 50 percent THC and 50 allowing neurons to fire excessively severe epilepsy who don’t respond to any percent CBD—met strict pharmaceutical and for too long. In a seizure, a group of treatments, removal of malfunctioning standards. Dr. Devinsky called the overexcited brain cells begin firing in brain areas, though a last resort, is a company’s CEO in London to explain what an abnormally synchronized way. This viable option. Another is implanting a he had in mind. sets off a storm that can involve just part pacemaker to stimulate the thalamus (a Soon afterward, GW representatives of the brain (a partial seizure) or both structure deep within the brain) or vagus sat down with researchers from NYU hemispheres (a generalized seizure). nerve. Such surgical procedures, however, Langone and several other institutions in Some rare types of epilepsy result from can also lead to serious complications.

NYU PHYSICIAN FALL 2015 13 Liam O’Brien, with his parents, Kevin and Karyn, at NYU Langone Medical Center.

NYU PHYSICIAN 14 FALL 2015 Caring for a child with a severe, chronic disease is always difficult, but because intractable pediatric epilepsy is usually FROM 40 SEIZURES A DAY TO 3 associated with cognitive and behavioral A MONTH: NICOLE CANO’S STORY problems, the challenges can be particularly daunting. Kids with epilepsy also have a four fold higher risk of death, When Nicole Cano had her first seizure in 1998, at 10 weeks old, few according to the Centers for Disease would have imagined that her best hope for relief would come from the Control and Prevention. Yet parents cannabis plant. Nicole was born with Aicardi syndrome, a rare genetic desperate for alternatives to conventional disorder in which the corpus callosum—the bundle of fibers that connects treatments will sometimes expose their the brain’s hemispheres—fails to develop. Along with developmental children to other kinds of dangers. “They delays, patients suffer from seizures called infantile spasms, which often may try remedies they’ve seen on the progress to severe epilepsy. news or on the Internet but that haven’t Nicole’s spasms initially resembled stomach crunches; soon she was been objectively proven to be helpful,” having hundreds a day. A neurologist prescribed phenobarbital, a observes Judith Bluvstein, MD, assistant powerful sedative. When that stopped working, she was given another professor of neurology and codirector medication, and then another—up to three at a time. None helped for of Pediatric Special Procedures at NYU long. Over the years, surgeons implanted several pacemaker-like devices Langone. “In some cases, such treatments to stimulate nerves associated with seizures, but they had a limited effect. may actually do more harm than good.” By her teens, her whole body would go rigid for 20 minutes or more, By studying the potential of sometimes leaving her unable to breathe. She often required rescue cannabinoids for treating epilepsy, medications which made her sleep all day. Occasionally, she had to be researchers hope to separate truth from rushed to the ER. “Her seizures took control of our lives as well,” says her rumor and to develop new treatments mother, Laura. “It was horrible watching her suffer.” that are safer and more reliable than any Then, at 16, Nicole entered NYU Langone Medical Center’s clinical do-it-yourself nostrum. Yet the hurdles trial of cannabidiol—a nonintoxicating component of marijuana—for facing scientists who wish to study patients with intractable epilepsy. Over the next year, she went from 40 cannabis and its active ingredients remain major seizures a day to a mild one every three months. Although Nicole discouragingly high. The U.S. Controlled remains too intellectually disabled to speak, her mother sees significant Substances Act, first enacted in 1970, improvement in her alertness and mood. “She’s happier, and so is the stipulates five “schedules,” or levels of rest of the family,” says Laura, who also has two younger children. “It’s restriction, based on a drug’s degree of changed our world.” danger and medical value. Cannabis is classified as Schedule I—a category for drugs such as heroin and LSD, with a high potential for abuse, no accepted medical use, and no standard for safe use. bluntly. In recent years, the American that marijuana is also used for getting Possession of the plant or its byproducts, Medical Association and more than high “does not obviate its potential for except by specially licensed individuals, is 30 other mainstream medical groups medical product development.” punishable by prison and heavy fines. have asked the government to consider Nonetheless, researchers continue to Since 1996, when California became the reclassification. They cite cannabis’s navigate a grueling legal obstacle course. first state to legalize medical marijuana, relatively low addictive power (9 percent In addition to FDA approval, researchers 22 others have followed. (New York’s of users get hooked, versus 32 percent must get permission from the Drug statute, passed in July 2014, is more of cigarette smokers) and demonstrated Enforcement Administration and state restrictive than many but includes ability to ease symptoms stemming from drug-control agencies. Marijuana must be epilepsy among conditions legally chemotherapy, HIV, and other serious obtained through the National Institute on treatable with cannabis.) Meanwhile, the conditions, as well as growing evidence Drug Abuse, which grows a small crop at drug’s outlaw status on the federal level that cannabinoids could help control—or the University of Mississippi. As mandated has increasingly been called into question. even cure—many ailments. (See box.) As by law, the plant and its derivatives—

PHOTO BY KARSTEN MORAN PHOTO “Schedule I is crazy,” Dr. Devinsky says the AMA’s position paper puts it, the fact even nonpsychoactive CBD—must be

NYU PHYSICIAN FALL 2015 15 stored in an extra-heavy safe with an elaborate alarm system. “Federal oversight essentially handcuffs cannabis researchers CANNABINOIDS: A VERSATILE NEW in the U.S.,” explains Dr. Devinsky. “Other SOURCE OF MEDICINE countries are far ahead of us.” Despite all this, Dr. Devinsky and colleagues managed to launch the Research into the medical potential of cannabinoids, marijuana’s unique 10-center study in January 2014, using chemical constituents, is still in its infancy. But some of these 80-plus a new GW Pharmaceuticals product compounds show signs of promise as disease-fighters. As a recent clinical called Epidiolex, an orally administered study led by NYU Langone researchers suggests cannabidiol (CBD), the extract containing 99 percent CBD. The plant’s main nonpsychoactive component, may help control epileptic initial report, released in March of this seizures. In other laboratory studies, CBD has also been shown to kill tumor year, provided data for 123 patients who cells from cancers of the breast, brain, and skin, and protect mice from had been treated for at least 12 weeks. The diabetic retinopathy, a leading cause of blindness. results were promising: Total seizures Meanwhile, tetrahydrocannabinol (THC), the ingredient responsible showed a median reduction of 46 percent. for marijuana’s “high,” has been shown to slow the growth of lung For patients with Dravet syndrome—a tumors in mice by 50 percent; mixture of THC and CBD delays the onset devastating and often treatment-resistant of Huntington’s disease in rats; a cocktail of five cannabinoids kills MRSA form of epilepsy—the reduction was 52 bacteria in vitro. percent. Overall, 10 percent of patients— Cannabinoids are highly versatile: They can act as chemical triggers, and 22 percent of Dravet’s patients—were forcing cancer cells to self-destruct, or as antioxidants, shielding healthy seizure-free. Adverse effects compared cells from harm. They also interact with the body’s endocannabinoid favorably with many conventional system and other signaling networks, which regulate a wide range of epilepsy medications: 21 percent of physiological functions. Much more research will be needed before these patients experienced sleepiness, 17 percent complex molecules can be turned into lifesaving medications, but several diarrhea, 17 percent fatigue, and 16 percent pharmaceutical companies are already investing in the field known as loss of appetite. “cannabis biotech.” Does that confirm CBD’s growing reputation as a miracle drug? Hardly. The study was mostly intended to establish parameters for further research. It was placebo-controlled study of Epidiolex 8, he had three seizures, the following “open label,” meaning that everyone for children with Dravet’s and another day, none. There were several seizures on involved knew what patients were genetic form of severe epilepsy, Lennox- February 10 and 11, none on February 12, getting, and there was no control group Gastaut syndrome. He hopes that CBD and one each day on February 13 and 14. receiving a placebo. Nor does CBD will eventually improve the lives of large He hasn’t had a seizure since. appear to be strikingly superior to other numbers of epilepsy sufferers—adults as Liam is six years old now, a round- anticonvulsants, aside from its relatively well as children. Meanwhile, he’s pleased cheeked boy with a blond crew cut and benign side-effect profile. “There are some that that the drug has helped at least a lively blue eyes. Those terrifying episodes patients who benefited, some who didn’t, few of his patients. “Nothing makes me of falling to the floor, unable to breathe, and some who actually worsened,” notes happier than seeing people get better,” he are gone. His autism hasn’t vanished, epileptologist Daniel Friedman, MD, who says. “It’s very gratifying.” but he’s far more engaged with his helped lead the study. Because so little is Liam O’Brien was among the lucky surroundings. He finally mastered the known about CBD’s effects, all patients in 10 percent, though it took a week for potty. He can say more than 100 words, the study continued taking their existing the results to become clear. He got his including his name, and form short medications, leading, in some cases, to first dose of Epidiolex on February 7, sentences (“I want iPad” is a favorite). problematic drug interactions. 2014, and remained at NYU Langone’s He no longer needs a helmet for most Still, the prospect of having another Comprehensive Epilepsy Center for three activities. He even learned to ride a bike. weapon in the antiepileptic arsenal is hours afterward to be monitored for “I can relax a little bit,” says Karyn encouraging to many. Dr. Devinsky’s adverse effects. None appeared, but he O’Brien. “I can actually sit down and just team recently began a double-blind, had a seizure later that day. On February let him be a kid.”•

NYU PHYSICIAN 16 FALL 2015 TIME LINE

CANNABIS TH IN MEDICINE 2737BCE 7CENTURY BCE First recorded reference to medical First documented use use of cannabis, in treatise by of cannabis for epilepsy, Chinese Emperor Shen-Nung. by ancient Assyrians.

1621 CE 1839 1840s Cannabis mentioned in The Irish physician William O’Shaughnessy publishes Medicinal cannabis extracts gain Anatomy of Melancholy, by English first modern medical paper on cannabis, widespread acceptance in the clergyman Robert Burton, as citing its use in India for conditions including pain, West, becoming part of standard treatment for depression. nausea, spasticity, and convulsions. pharmacopoeia in Britain and the U.S.

1937 1970 1986 U.S. Marijuana Tax Act passed, U.S. Controlled Substances Act The Food and Drug Administration approves effectively outlawing possession classifies marijuana (along with Marinol, a synthetic version of THC (the and sale of cannabis. heroin and LSD) as a Schedule I drug, active ingredient in cannabis), for treating the highest level of restriction. anorexia in AIDS patients.

1996 2009 2015 California voters pass Proposition U.S. Department of Justice declares that Obama administration streamlines 215, making their state the first to “it will not be a priority” to prosecute medical approval process for cannabis research, legalize medical cannabis. marijuana patients or caregivers. eliminating requirement that proposals undergo review by Public Health Service.

NYU PHYSICIAN FALL 2015 17 The Sweet Life of a y Fruit Why do we crave sugar?Fl Why do we overeat? In the laboratory of Dr. Greg Suh, banana- loving fruit flies are yielding intriguing clues.

BY JOSIE GLAUSIUSZ Drosophila melanogaster,

ROBERT NOONAN / SCIENCE SOURCE a common fruit fly, snacks on a wedge of rotted fruit. 2015 meeting of the Association for Chemoreception Sciences, FOR GREG SUH, PhD, Dr. Suh was honored with the Ajinomoto Award for Young it was a humble yet Investigators in Gustation. He was, to his surprise, the first “fly hungry little fruit fly that person” to win the $3,000 prize. first convinced him of the

universal allure of sugar. orn in the city of Busan in South Korea, In one simple experiment, conducted in 2010, Dr. Suh offered Dr. Suh personifies playful scientific fruit flies a choice presented in a multiwell teriyaki plate: a curiosity. In conversation, he cites a wide dropper full of caloric sugar solution and a near-identical B range of influences, from Steve Jobs to his sugar with zero calories. The flies had no preference when mentor, the late, legendary Dr. Seymour Benzer, “the father of they were sated but preferred the caloric sugar when they neurogenetics,” who pioneered the study of how genes control were starved. Later, he and his collaborators tethered flies the development of the nervous system and hence behavior. in place with wax and offered the same choice. It took just Dr. Suh first became interested in the feeding habits of 30 seconds for the flies to decide. Starved flies lapped up the fruit flies in 2003, while he was a joint postdoctoral student caloric sugar, but when offered the empty-calorie alternative, in the labs of Dr. Benzer and David Anderson at Caltech. On they drank for a mere 20 seconds and then stopped. “That a whim, he decided to see what would happen if he fed fruit was really surprising,” says Dr. Suh, associate professor in the flies bananas. He quickly discovered that fruit flies willingly Department of Cell Biology at NYU Langone Medical Center. eat banana paste when starved but avoid it if they are sated—a “It is an innate behavioral response, because these flies were typical response among mammals, as well. not previously exposed to pure sugars: They know right away That set Dr. Suh off on a quest to understand how hunger that this is good stuff.” and satiation are encoded in the brain—one that he’s continued An award-winning neurobiologist, Dr. Suh studies the ever since setting up a laboratory at the Skirball Institute in biochemical mysteries of feeding and appetite by probing 2008. “It’s not easy to study feeding behavior,” he says. “There the genes and nervous systems of Drosophila fruit flies. He are many factors that influence feeding. You eat because you are and his research team at NYU Langone’s Skirball Institute of hungry. You eat because the food tastes good. I thought perhaps Biomolecular Medicine have identified sensors in the fruit- there is a way to uncouple these two pathways.” Though the fly brain that trigger sugar cravings. Complex interactions average adult fruit fly is only about three millimeters long between genes, neurons, and hormones, Dr. Suh believes, (about a tenth of an inch) with a brain only 100 microns wide can explain how these insect brains respond to hunger or (the diameter of a human hair), they are good model organisms satiation—and what happens when the balance goes awry. for studying human appetite, because they are “cheap, easy “We can learn a lot by studying fruit flies,” Dr. Suh says, “and to grow, and are genetically malleable,” Dr. Suh says, sharing we can learn a lot about us, about our feeding preferences, by about 77 percent of their disease genes with humans (see “A studying these small organisms.” Brief History of the Fruit Fly in Science,” page 23). By scrutinizing fruit flies, which carry some of the same In 2011 Dr. Suh and a postdoctoral student in his laboratory, disease genes as humans and can even get fat, Dr. Suh hopes Monica Dus, genetically engineered a fly in an attempt to to determine the role sugar plays in our propensity to overeat. uncouple pathways to hunger and taste. Their model insect The question has never been more relevant. While sugar carried mutant genes for sugar-detecting receptors located on consumption has actually declined since 1999, primarily due its mouthparts. Publishing their work in the Proceedings of the to reduced soda consumption, the average American still National Academy of Sciences, the researchers found that the fly consumes more than 75 pounds of the sweet stuff each year, was unable to taste sugar, yet if starved for 15 hours, it would and that consumption is thought to contribute to an escalating still choose to consume sugar over tasteless agar gel. obesity epidemic. According to the latest figures, almost 75 The implication of the finding was clear: Flies and other percent of men and 67 percent of women in the United States animals must possess a fail safe mechanism—one that is are now overweight or obese. fundamental to their survival—for detecting energy-laden but That’s one reason why the National Institute of Diabetes bland foods. “In ancient times, we lived in a world that was and Digestive and Kidney Diseases recently awarded Dr. Suh very scarce of food,” explains Dr. Dus, who left NYU Langone a $1.9 million grant to investigate the causes of obesity. He in late 2014 to head her own lab at the University of Michigan, is also funded by the National Institutes of Health and has Ann Arbor. “It was important for our ancestors, and animals

received accolades from a wide range of sources. At the spring in general, to be able to quickly get a handle on whether the BY SASHA NIALLA PHOTO

NYU PHYSICIAN 20 FALL 2015 Dr. Greg Suh holding a device that offers fruit flies a choice between caloric and non-caloric sugar.

NYU PHYSICIAN FALL 2015 21 food was good or not. Flies, if you think about how they feed, they just land in a patch of food that might have trash next to “ I always say that flies are little it, or there might be a really great food source. It’s important people. By studying flies, you for them to be able to recognize whether the food is edible, as can understand human nature well as the quality.” In their research, which was generously supported in a little better,” says Dr. Suh. part by the Irma T. Hirschl/Weill Caulier Trust, Drs. Suh and Dus had also found that starved flies without taste stimulates the neurons in the brain to trigger feeding: the receptors prefer a form of sugar that can be digested and flies extend their mouthparts, or proboscis, to suck in more metabolized, called D-glucose, over a calorie-free artificial food. They also excrete more often, which indicates that their sweetener (sucralose) or a nonmetabolizable form of sugar, gut is moving. This positive feedback loop increases the flies’ called L-glucose. A mystery neural pathway was enabling consumption of energy-rich sugars—the sort found in the the taste-blind flies to identify caloric foods when they were fermenting fruits. “When they nibble, they know that this is hungry—possibly by detecting a rise in sugar levels in the caloric sugar and go, ‘Oh, wow, this is the good stuff. I better insects’ blood after the sugars get absorbed by the gut. But start feeding,’” Dr. Suh says. Mutant flies with silenced Dh44 what form did it take? neurons, by contrast, can’t tell the difference between caloric In 2013, the team published new results in the journal and noncaloric sugars. Nature Neuroscience identifying a gene that they dubbed In humans, the homologous hormone CRH is released by Cupcake, both for its action—it is a “hunger sensor” that the brain’s hypothalamus in response to stress and has a role enables the flies to gorge nutritionally valuable sugars—and in a range of stress responses, from food intake to the timing an homage to Dr. Dus’s dog, of the same name. (It’s a tradition of birth. The researchers are now investigating the possibility for fruit-fly researchers to choose offbeat names for the genes that CRH neurons in mammals can sense glucose, allowing that they identify.) Starved flies with theCupcake mutation them to respond to the stress of starvation. could no longer distinguish between nutritional and Understanding how CRH helps detect the caloric value of nonnutritional sugars; they simply preferred the sugars sugar is crucial, because animals with an inactive nutrient with the most concentrated sweetness, even if they were sensor will keep on eating; they are not satiated, leading to calorie free. obesity. Overactivation of the gene could have the opposite The human analog of Cupcake is called, with slightly effect, inhibiting feeding. Sequencing the human genes less pizzazz, SLC5A11. It encodes a transporter protein that and unraveling their role could therefore help researchers enables cells in the small intestine to absorb glucose. But determine the causes of both over-and-under eating. the Cupcake gene in flies is expressed only in a specific set of “He really has been the pioneer on this range of nerves, called R4 neurons, in a structure called the ellipsoid Drosophila studies,” says Yale neurobiologist Ivan de Araujo body within the insect brain. The researchers speculate that DPhil, whose own research focuses on nutrient-sensing the neurons within the ellipsoid body monitor the insects’ and feeding behavior in mice. “Usage of flies is an extremely internal energy status, triggering feeding behavior if they are powerful tool from a genetic point of view,” he says. starved. But how? “You can play with their brains.” Screening fly genes for Last July, Dr. Suh and his team announced that they nutrient detection and selection that have homologs in the had discovered a crucial piece of the puzzle. In findings mammalian genome, “can help us understand how exactly published in the journal Neuron, they identified six neurons we choose foods and whether we can intervene in some within the Drosophila brain that release a hormone that, in way to reduce effective intake.” turn, is activated by nutritive sugars within the insects’ Delving into the roots of human motivation is Dr. Suh’s blood. The hormone, a nutrient sensor called Dh44, or goal, ultimately. It’s a habit that dates back to his early Diuretic hormone 44, is a homolog of a mammalian childhood years. On train trips with his family, he recalls, hormone named CRH, or corticotropin-releasing hormone. “my parents didn’t have to babysit me. I would go to other Starved Dh44-deficient flies in which the activity of these passengers, and I would ask all kinds of questions, about six neurons was disrupted could not sense caloric sugar. him or her, about the universe, about the fourth dimension, Instead, these pleasure-seeking insects lapped up only the UFOs.” That thirst for knowledge still extends far beyond sweetest sugar—artificial or genuine. “They are hedonic fruit flies. “I am a curious person in general,” Dr. Suh flies,” Dr. Suh says. “They only care about the sweet.” says. “I’m mostly curious about human behavior. I always In wild-type, nonmutant flies, the rise in caloric sugar say that flies are little people. By studying flies, you can

levels within the insects’ blood activates Dh44, which, in turn, understand human nature a little better.” • PHILLIPS / SCIENCE SOURCE M. DAVID

NYU PHYSICIAN 22 FALL 2015 A BRIEF HISTORY OF THE FRUIT FLY IN SCIENCE

n 2008, as Dr. Greg The fruit-fly brain offers an Suh, PhD, was equally valuable window into establishing his human biology. Its constellation I laboratory at the of more than 100,000 neurons Skirball Institute of direct complex behaviors such as Biomolecular Medicine, Republican learning and memory, sleep, and vice-presidential candidate Sarah courtship. By analyzing fruit flies that Palin made a speech in which undergo nerve degeneration in she cited research on fruit flies as larval or adult stages, researchers having “little or nothing to do with have modeled neurodegenerative the public good.” The scientific brain diseases impossible to study community begged to differ. In fact, in humans, including Alzheimer’s the contribution of the humble fruit disease, Parkinson’s, and fragile X fly to medical and genetic research mental retardation. Fruit-fly mutants is hard to overstate. “The fruit fly has also serve as model organisms for led to an astounding number of studying cancer, diabetes, and discoveries in our understanding of heart disease. human health and disease,” says Dr. Among the many benefits of Suh, assistant professor of molecular studying fruit flies, beyond the neurobiology at NYU Langone from how to map genes on a enormous potential to improve Medical Center. Dr. Suh’s own chromosome to mutant Methuselah human health, is the long-standing, research on fruit flies, for instance, is flies with an extended lifespan. playful tradition of assigning odd casting much-needed light on the Perhaps the most pivotal moment names to the genes that one biochemical riddle of obesity. in fruit-fly research came in 2000 discovers. This practice has led to The fruit fly, known more formally when a team of scientists decoded such quirky labels as the Ken and as Drosophila melanogaster, the insect’s entire genome, a Barbie gene, mutations that lead emerged as a champion model monumental accomplishment to lack of external genitalia (as in organism in 1910, when embryologist that gave scientists the technical the dolls); hunchback, which aids Thomas Hunt Morgan of Columbia knowledge needed to sequence in the development of the fly’s University found sex-linked genes the human genome. We now know thorax; swiss cheese, which causes in mutant white-eyed male flies. that Drosophila’s four chromosomes hole-pocked brain degeneration; His discovery confirmed the encode more than 14,000 genes, the creepy Halloween family chromosomal theory of inheritance three-quarters of which have of genes (disembodied, shade, and, by extension, launched functional analogs in humans. With shadow, shroud, phantom), which the field of classical genetics. the aid of mutant forms of Drosophila trigger embryonic death before the Morgan’s “Fly Room” at Columbia (some of which sprouted legs from exoskeleton has formed, giving these spawned not just thousands upon their head in place of antennae, mutant embryos a spooky look; thousands of flies (one mating or two pairs of wings) researchers and then there’s Dr. Suh’s personal can yield hundreds of offspring) have discovered so-called homeotic contribution, the cupcake gene, but generations of Drosophila genes, which direct the process of which lets fruit flies do what they do scientists who discovered everything embryonic development. best: sense sugar. •

NYU PHYSICIAN FALL 2015 23 FACULTY CONVERSATION

A Focus on Prevention Cheryl Pegus, MD, the new associate director for clinical innovation in the Department of Medicine at NYU Langone Medical Center, is devoted to breaking down barriers to wellness. BY RICH MALOOF

CHERYL PEGUS, MD, has enjoyed Cardiac disease is the number one cause “It’s critical to have an unusually wide-ranging career in of death not just in the U.S. but globally. healthcare. She has served as medical It kills more people annually than all a buy-in from the director of the Cardiovascular Risk cancers combined. Why is it still such a patient and mutuality Factor Group at Pfizer, Inc.; national problem? Partly because we’ve spent a medical director and clinical product lot of time focusing on the later stages of in achieving health head for Aetna, Inc.; and chief medical the disease, treating a group that already goals. That’s a shift officer of Walgreen Co. In October has it. We’ve made great progress with from the past.” 2014, she was appointed director treatment and decreasing deaths from of the Division of General Internal heart disease, but we haven’t focused Medicine and Clinical Innovation and enough on the earlier years when risk named associate director for clinical factors like diabetes and obesity begin innovation in the Department of to develop. Medicine at NYU Langone Medical Who else should be involved? Center. In her new position, Dr. Pegus How do we integrate wellness earlier in I’ve found it very humbling to work is focusing her skills on preventing patients’ lives? with and learn from experts outside of chronic conditions and dismantling Managing wellness is a team sport. the health sector who engage patients in barriers to wellness, pursuing a vision The physician is the captain when it their own self-management. Look at a forged in childhood. She recently comes to managing patients throughout tech company like Fitbit. They are not a shared her thoughts with NYU Physician. the disease process, from the earliest traditional healthcare company, but they phases and beyond, but there are know how to engage people with digital What made you become a crusader for many important players. Parents health tools and programs, and the preventive medicine? teach the first important lessons personalization is excellent. Partnerships Growing up in Trinidad, I was raised about diet and exercise, and they need with areas with different competencies by a family that encouraged me to their communities to help support are necessary to prevent people from try new things. My grandparents let lifelong healthy habits in children. developing chronic diseases. me climb coconut trees, and that was Grocery stores need to provide healthy something most girls didn’t do. Then, food options, and schools should be When you look at demographic factors my grandfather passed away when I instituting lessons about nutrition and such as ethnicity, gender, and age, which was 12. He could not afford healthcare the importance of physical activity. has the greatest impact on health? and didn’t really know enough to trust Employers are great partners for There is a lot of data on this, and that you should go to the doctor before wellness and prevention of chronic income plays a very large role. Health you got really, really sick. We cared for diseases. Programs that can engage and systems in our poorest areas are the him at home. That stuck with me, and incentivize employees are also helpful. most pressed to improve quality, I decided back then I was going to be a Healthy workplaces have been shown regardless of the population’s race. In doctor when I grew up. in studies to have positive results. areas where you are concerned about Some of this is policy driven, but the life’s basic necessities, your health Despite all the information and care available bottom line is that many partners takes a backseat. The income level of today, Americans are still dying of preventable must be at the table to improve the a community defines its resources,

conditions like most heart disease. Why? health of populations. prioritization, and health. BY SASHA NIALLA PHOTO

NYU PHYSICIAN 24 FALL 2015 That seems like an especially Is the relationship between patients and How does your position at NYU Langone intractable problem. primary care physicians changing? fulfill your broader ambition to improve People go abroad and succeed in Patients now have to understand wellness and prevention? improving health dramatically in places co-pays, deductibles, formularies, I’m fortunate to be working with great people where there is sometimes a great deal whether a prescription is generic right in my own sweet spot, where changing of poverty. The solutions are targeted to or not—issues that are new. They healthcare markets and data analytics the community and its health resources, also have mobile health tools and meet great clinical care. There aren’t many and are personalized to improve lots of information and data at their institutions that are ready to address all selected areas. This is where the policy fingertips. In response, we physicians the big questions about changing a medical piece comes in. Recently I was elected are modeling shared decision making. curriculum, integrating cost, quality, and as an advisory panel member in the It’s critical to have a buy-in from the access, and doing innovative research. NYU Addressing Disparities program at the patient and mutuality in achieving Langone is. In my role, we are developing PCORI [Patient-Centered Outcomes health goals. That’s a shift from the care management programs across Research Institute], where the focus is past. NYU Langone is leading in this populations, utilizing data information on evidence-based research to improve area, with changes to the medical systems, and integrating e-health. We are the accessibility and effectiveness of curriculum, focusing on value, participating in collaborative research care in communities. Multiple utilizing electronic medical records, across population health, basic science, and stakeholders will be looking at cost- and undertaking many new avenues innovation, and we are also educating the effective solutions. of research. next generation of doctors. •

NYU PHYSICIAN FALL 2015 25 FACULTY NEWS

THOMAS A. EINHORN, MD, an and supported by the National Institutes Renowned internationally renowned expert in adult of Health. His research has been featured Orthopaedic Surgeon hip and knee reconstructive surgery, in more than 230 peer-reviewed journals. Joins NYU Langone to whose award-winning research has He has also authored six textbooks, included the study of novel biologic more than 70 book chapters, and dozens Lead Research Efforts techniques to treat joint ailments, has of monographs. He previously served been appointed director of clinical and as chair of the Department of Ortho- translational research development for paedic Surgery at Boston University the Department of Orthopaedic Surgery Medical Center, a position he held since at NYU Langone Medical Center. In 1997, and professor of orthopaedic this role, Dr. Einhorn will oversee the surgery, biochemistry, and biomedical department’s translational and clinical engineering at the Boston University research efforts, which contribute to School of Medicine. the understanding, treatment, cure, and An alumnus of Rutgers University, prevention of musculoskeletal diseases. Dr. Einhorn earned his MD from Cornell Dr. Einhorn, professor of orthopaedic University Medical College. He completed surgery at NYU School of Medicine, is his residency at St. Luke’s–Roosevelt currently the principal investigator of a Hospital Center, and his fellowship at The

multicenter research project sponsored Hospital for Special Surgery. • ANDREW NEARY BY PHOTO

Ruth and Victor she overturned the widely held belief that malaria was too complicated to vaccinate Nussenzweig Receive against, and launched a decades-long Prestigious Alpert effort to create a malaria vaccine. In Foundation Award 1980, Dr. Victor Nussenzweig, research professor of pathology and professor SINCE JOINING NYU SCHOOL emeritus of pathology, collaborated with OF MEDICINE more than 50 years his wife on the discovery of a sporozoite ago, Ruth S. Nussenzweig, MD, PhD, protein called the CS protein, showing and Victor Nussenzweig, MD, PhD, have that antibodies against it conferred partial emerged as two of the most prominent immunity to malaria. This important researchers in the field of tropical insight laid the groundwork for the RTS,S medicine. Adding to their long and vaccine, the most promising malaria illustrious list of accolades, the husband- vaccine in clinical trials today. wife duo have received the prestigious During her tenure at NYU Langone Arts and Sciences. Together, they have Warren Alpert Foundation Prize in Medical Center, Ruth Nussenzweig authored over 500 scientific papers. recognition of their groundbreaking has served as head of the Division of The Warren Alpert Foundation research on malaria, a disease that kills Parasitology in the Department of honors innovative biomedical researchers nearly 600,000 people every year, mostly Microbiology and the first chair of the dedicated to understanding and curing children in Africa. Department of Medical and Molecular disease through groundbreaking research, Dr. Ruth Nussenzweig, research Parasitology. She holds the distinction scholarship, and service. Since 1987, the professor of pathology and professor of becoming the first woman to chair a foundation, in partnership with Harvard emerita of microbiology and pathology, department at NYU School of Medicine. Medical School, has awarded the Warren made her first big contribution to malaria Victor Nussenzweig, meanwhile, has led Alpert Foundation Prize to many of the research in 1967 when she immunized the Michael Heidelberger Division of the world’s foremost physician-scientists and mice against malaria by inoculating Department of Pathology at the Medical researchers. Each fall, Harvard Medical them with irradiated sporozoites, the Center since 1987. Both researchers are School hosts a scientific symposium in parasites that cause malaria. In doing so, members of the American Academy of October in honor of the recipients. • WEYMOUTH BY MIKE PHOTO

NYU PHYSICIAN 26 FALL 2015 AROUND CAMPUS

Building Stronger Bridges to Fight Parkinson’s Disease $25 million grant establishes international institute based at NYU Langone

THE PAOLO AND MARLENE FRESCO FOUNDATION has donated $25 million to NYU Langone Medical Center to establish the international Marlene and Paolo Fresco Institute for Parkinson’s and Movement Disorders (the Fresco Institute) to advance the understanding and treatment of Parkinson’s disease and movement disorders. In honor of the gift, NYU Langone’s Parkinson’s and Movement Disorders Center will be renamed the Fresco Institute. The center has been a designated a National Parkinson Foundation Center of Excellence since 2009, and it will retain From left: Dean Grossman, Kenneth G. Langone, and Paolo Fresco this designation. The gift will help establish a fully integrated Parkinson’s center in Italy that coordinates efforts to care for problems), while cognitive and behavioral Dr. Tsien, the Druckenmiller Professor patients. It will also create opportunities for problems may arise in advanced stages. of Neuroscience, chair of the Department early-career scientists and researchers in According to the Centers for Disease of Neuroscience and Physiology, and Italy through a fellowship program. Some Control and Prevention, complications director of NYU Langone’s Neuroscience of those fellows will train at NYU Langone from Parkinson’s disease are the 14th Institute. “It will also build vibrant for two to three years. leading cause of death in the United States. connections between scientists in the Jointly led by a clinician and a “Treatment for Parkinson’s is not one size United States and in Italy working neuroscientist—Executive Director fits all,” explains Dr. Di Rocco, the Founders on disorders of the brain. The vision, Alessandro Di Rocco, MD, and Professor of Neurology and director of leadership, and generosity of Paolo and Scientific Director Richard Tsien, the Division of Movement Disorders in Marlene Fresco have made this possible.” DPhil, respectively—the institute, in the Department of Neurology. “People “Dr. Di Rocco and his team have this respect, is believed to be the first of associate Parkinson’s with tremors and slow cared for some of my dearest loved ones, its kind devoted to Parkinson’s disease. movement, but it goes far beyond that. There for which I am profoundly grateful,” Afflicting an estimated 4 to 6 million are literally dozens of potential symptoms. says Paolo Fresco. A trustee at NYU people worldwide, including some 1 The longer someone has it, the more Langone since 2013, he operates the million Americans, Parkinson’s is an intricate and individualized their symptoms Fresco Foundation and is involved in incurable, progressive neurological become. Its progression also varies—slowly various charitable initiatives in Italy. disorder that destroys the brain cells in some people and quite rapidly in others.” He was previously chairman of Fiat that produce dopamine, an essential “The Fresco Institute will establish and executive vice chairman at General neurotransmitter. Early symptoms of the stronger bridges between clinical science Electric, where he worked for more than disease are movement related (shaking, and basic science of movement disorders, 35 years. Mr. Fresco received a law degree

PHOTO BY KARSTEN MORAN PHOTO rigidity, slowness of movement, and gait particularly Parkinson’s disease,” notes from the University of Genoa. •

NYU PHYSICIAN FALL 2015 27 OBITUARY

Martin S. Nachbar, MD

MARTIN S. NACHBAR, MD (’62), “He was unfailingly a passionate and dedicated teacher and mentor who early on grasped the supportive, curious, enormous potential of computers in and inquisitive—an medical education, died on May 16. He was 78. incredibly powerful In the 1980s, Dr. Nachbar brought to presence.” NYU School of Medicine an entirely new field—educational informatics—by creating the Hippocrates Project, the School’s first computer-based learning program. Educational Informatics, established “He handed us each a Phillips head in 2007. The division, now under the screwdriver and told us to take apart umbrella of the Institute for Innovations what was in this box. We looked inside, in Medical Education, created e-learning and it was one of the very first personal tools like the Virtual Microscope and the computers,” recalls Adina Kalet, MD, WISE-MD surgical modules used by Martin S. Nachbar, MD professor of medicine and surgery. medical schools and health professions Dr. Nachbar, she notes, taught them schools nationwide. In 2012, in to program the computer and create partnership with a biomedical computer tools to care for their patients—for graphics company, the division introduced example, to graph blood pressure and an online virtual cadaver with 3D images MD; and award-winning author Lewis list medications—that are all part of of the human body. Dr. Nachbar also Thomas, MD, who served as dean of NYU chronic disease management and clinical cofounded the Consortium on Medical School of Medicine. informatics today. Education and Technology, a partnership Dr. Nachbar completed a residency in Over the next decade, the Hippocrates of medical schools that share computer internal medicine at Bellevue in 1966. He Project pioneered innovations in computer learning technology. subsequently joined the Department of simulation, 3D modeling and animation, “He really was one of the fathers of Microbiology as an NIH Basic Science and online learning, creating essential an entirely new field,” says Marc Triola, Training Fellow. In 1970, he accepted a resources for the School’s curriculum. MD, associate dean for educational joint appointment in the Departments of Dr. Nachbar was attracted to medicine informatics, and director of the Institute Medicine and Microbiology. for its “admixture of humanism and for Innovations in Medical Education. Dr. Nachbar received numerous science,” he said. In 1993, he and his wife, “He was unfailingly supportive, curious, educational honors and awards. He was Felice Aull, PhD, who taught physiology and inquisitive—an incredibly powerful named a Sackler Distinguished Lecturer, at NYU School of Medicine, founded the presence.” Tel Aviv University (1996). He won the Literature, Arts and Medicine Database, Dr. Nachbar was born 1937 in the Bronx, Distinguished Teacher Award, NYU an online public resource for annotated the son of first-generation Americans School of Medicine (1997); New York works of literature, fine art, music, and the of Russian and Hungarian ancestry. He University’s Distinguished Teaching performing arts related to the science of attended Bronx High School of Science. Award (2005); and the Master Teacher healing. It has become the largest medical He entered NYU School of Medicine in Award, NYU School of Medicine (2007). humanities website in the world. 1958, at a time he described as “electric” In 2009, he became director emeritus of In 2001, Dr. Nachbar became director with the presence of giants like Severo the Division of Educational Informatics. of the newly created Department of Ochoa, MD, whose groundbreaking work Dr. Nachbar is survived by his wife, Advanced Educational Systems, a on the synthesis of RNA won him a Nobel Felice Aull; a daughter, Nancy; and a forerunner of the current Division of Prize; father of nephrology Homer Smith, grandchild, Simone. •

NYU PHYSICIAN 28 FALL 2015 Change Change Change Change Change Change Change Change Change the world…

One patient at a time. When you include a bequest in your will to NYU Langone Medical Center you help us deliver outstanding health care to the many patients and families who rely upon us to improve their lives. Superb physicians, an award-winning nursing staff and internationally ranked scientists make the difference. Join our community, and create your legacy today. To learn more about making your planned gift to NYU Langone, please contact Marilyn Van Houten at 212.404.3653 or [email protected]. Sasha Nialla Moses V. Chao, PhD, professor of cell biology, neuroscience and physiology, and psychiatry, is a distinguished researcher at NYU Langone, and former president of The Society for Neuroscience.

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