A glimpse of what's happening at the Grad School

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Fifth-year neuroscience graduate student Siobhan Pattwell is doing herPhD dissertation on how mice ofvarying ages remember painful stim-uli—work that may offer insight into

how humans process trauma. She is conducting herresearch under the mentorship of psychiatry and phar-macology professor Francis Lee, MD, PhD, but herfocus has also been influenced by a rotation in the labof professor BJ Casey, PhD, at Weill Cornell’s SacklerInstitute for Developmental Psychobiology. And whenshe needed a collaborator with particular expertise, shelooked farther south in Manhattan, teaming up withan electrophysiologist at NYU who recorded synapticactivity in the mice’s amygdala, the brain regionresponsible for fear behavior and learning.

With rankings and student metrics onthe rise—and the new Medical ResearchBuilding under construction—theGraduate School of Medical Sciences ispoised for another quantum leap inresearch and education

By Beth SaulnierPhotos by John Abbott

Brain trust: Neuroscience professor TeresaMilner, PhD (center), with members of her lab(from left to right) Helaine De Brito Pereira, EliTownsend-Shobin, Danielle Robinson, MeganFitzgerald, and Tracey Van Kempen

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“What I like the most about WeillCornell is that it’s a very collaborative envi-ronment,” says Pattwell, a New Jerseynative whose increasing interest in clinicaltopics has her pondering an MD. “I neverfeel secluded in my own little lab. If I havea question I just walk down the hall andask someone—and it’s not only within thewalls of Cornell itself, but also in New YorkCity. Plenty of my mice went for taxi ridesdown to NYU.”

That sort of collaboration—both withinWeill Cornell and with its peer institu-tions—is one of the hallmarks of theGraduate School of Medical Sciences. Theschool is itself a cooperative effort betweenWeill Cornell and the Sloan-KetteringInstitute (SKI), a unique partnershipbetween a medical school and a researchinstitution that began in 1952. “I don’tknow any other pair of institutions in thecountry that functions quite this way,” says

Thomas Kelly, MD, PhD, a molecular biolo-gist and director of SKI. “It has been terrificfor both institutions, and it’s great for thestudents, who benefit enormously fromhaving such a wide range of mentors tochoose from. We want to teach people howto do creative, rigorous science—to educatestudents who are going to make a differ-ence, who will do the kind of work thatchanges scientific directions.”

Over the past decade and a half, the


student ratio, currently at 250 professors for 550 students.“Even though you’re working with world-class facultyhere, they’re accessible,” says Silver, a professor of physiol-ogy and biophysics. “There’s great mentoring; you’re not anumber. This is an intimate atmosphere and everyone’sdoor is always open. You see us in the lab—you don’t needto make an appointment three months in advance to seeyour P.I. And mentoring is a very important aspect ofgraduate education. Part of a student’s training is watchinghow a P.I. works, how you write grants, how you put apaper together.”

In addition to its cooperative efforts with peer institu-tions in New York City, the Graduate School has strength-ened its ties to the Ithaca campus—a priority of PresidentDavid Skorton, MD. Efforts include tri-institutional pro-grams in computational biology and chemical biologyamong Cornell, SKI, and Rockefeller University; increasedcollaborations among Weill Cornell scientists and Ithaca-based biomedical engineers; and video-conferenced cours-es through the Clinical and Translational Science Center.Almost an entire floor of the new 480,000-square-footMedical Research Building—which will double the dedi-cated research space at Weill Cornell—will be devoted tolabs for visiting Ithaca faculty. “There has been a big moveto link up the two campuses,” Silver says. “We’re all start-ing to collaborate more with each other.”

When the Medical Research Building opens in 2014, itwill allow for the recruitment of up to fifty new faculty—many of whom will take on graduate students—and DeanHajjar envisions a 25 percent increase in enrollment. Theschool has already stepped up recruitment efforts, includ-ing a revamped admissions website and increased efforts to

draw underrepresented minorities and students from beyond theNortheast; Silver has visited campuses as close as Hunter College andas far away as India. “We prepare our students to be academic scien-tists in any realm in the world,” she says. “That’s a great thing tooffer a young person. Being an academic scientist in this day and ageis very competitive and very difficult. Every time you walk into thelab, it’s like an Olympic event. You need to hit home runs, and weprepare our students to be golden—to be the best.” Clearly, thevision of Dean Hajjar to develop the seven graduate programs from asmall school to a major player in New York, if not the United States,is coming to fruition, as many leading scientists now recognize.


Graduate School has been on the rise, both quantitatively and qual-itatively. Dean David Hajjar, PhD, notes that when he took office in1997, there were about 220 students; now there are more than 550.The average GPA of the incoming class has risen from 3.1 to 3.7,and GRE scores have increased from percentiles in the 60s and 70sto the mid- to high 80s. “We’re considered a hot school, and topstudents want to come here,” Hajjar says. “We’re one of the biggestschools in New York in the biomedical sciences, and people knowwe’re a school to be reckoned with.”

Nationally, the Graduate School now ranks Number 26 in U.S.News& World Report, up from Number 38 in 1997. Students apply fromall over the world, and Dean Hajjar encourages these opportunities.Recently named a Fulbright Scholar/Specialist, he and AssociateDean Randi Silver, PhD, have made a concerted effort to reach outglobally to recruit outstanding students.

The Graduate School is divided into seven programs of study forPhDs: biochemistry and structural biology; cell and developmentalbiology; molecular biology; immunology and microbial pathogene-sis; neuroscience; pharmacology; and physiology, biophysics, andsystems biology. In addition, it offers three master’s degrees: clinicalinvestigation, clinical epidemiology and health services research,and health sciences for physician assistants. “You don’t apply to theGraduate School, you apply to a program,” explains Silver. “Wedon’t have a core curriculum—you specialize from the minute youcome in the door. Although we have a lot of flexibility and you canwork with any faculty member, your education is tailored to yourscientific interests.”

Among the school’s strengths, Silver says, is a “superb” faculty-

Dean David Hajjar, PhD

Associate DeanRandi Silver, PhD


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Gender EqualityTeresa Milner, PhD, Professor of Neuroscience

Historically, pharmaceutical research has been skewed toward half the population—the male half. Neuroscience professor Teresa Milner aims to correct that. “Certaindrugs work better in females than males, but most of the time it’s the reverse—drugs work better in males than females. Most of the research that had been doneup until the last fifteen years has been focused on males. But we’re finally starting—not just in my lab but in many labs—to make headway in understanding what’s dif-ferent between males and females, so perhaps we can design better therapies.”

Since women have higher rates of drug addiction than men, one focus ofMilner’s work is the role that the opioid system of the hippocampus plays in allow-ing an addiction to take root. “We’re trying to understand the mechanisms, withthe goal of designing therapies that would be helpful in preventing relapse,” shesays. Milner is also exploring the role of hormones in women’s health—how theyaffect plasticity in the hippocampus, as well as their effects on the cardiovascularsystem. “We’re particularly interested in what happens over the life cycle, whenfemales hit menopause, so we’ve been developing mouse models of menopause,”Milner says. “We’re looking at changes in the brain that happen during menopausethat could affect hypertension, depression, learning, and memory.”

One goal is to develop improved hormone replacement therapies. To that end,Milner is exploring the window of opportunity—between the onset of menopauseand five years after the final menstrual period—when hormone replacement is mosteffective. “We want to design therapies so we can get the positive effects of reduc-ing depression and memory loss,” she says, “but not the negative effects like hyper-tension and cancer.” Her work encompasses myriad avenues of investigation, fromelectron microscopy to physiology and behavior. “I like that approach of under-standing the whole body, but I like a lot of the technical aspects, too,” she says. “Ienjoy working with my hands, and it’s a very hands-on type of science.”

The following are profiles of eight scientists—four faculty and four PhD students—whoexemplify the depth and breadth of research atthe Graduate School of Medical Sciences.

In FormationPhD student Jason Gray

Working in the lab of M. Elizabeth Ross,MD ’79, PhD ’82, professor of neurologyand neuroscience, seventh-year PhD can-didate Jason Gray is using mouse modelsto study the genes that cause birthdefects—and how environmental factors,like levels of folic acid, can affect them.Gray is primarily focused on a gene calledLRP6, encoding a receptor that plays aleading role in a developmental pathwayimportant in cell proliferation and differ-entiation, known as Wnt signaling.

“Some of the genes that we study areimportant for development, because ifthey get turned off or mutated you end upwith neural tube defects such as spina bifi-da,” says the Baltimore native. “We partic-ularly study several membrane receptorsthat allow cells to communicate with eachother as the embryo develops. But if anembryo is carrying two defective copies ofthe gene, when the neural tube is sup-posed to close—in mice, around embryon-ic day nine—the folds won’t properlyappose in the embryo. They’ll fail to curveand flip over correctly, and you end upwith a defect like spina bifida.” Gray is alsostudying how this gene is involved in pat-terning, telling the various cells of anembryo what they should become andwhere they should go, and how a simplenutrient—the vitamin folic acid—impactsLRP6 function to promote neural tube clo-sure. “The embryo needs to know whichend is up so that it can properly close theneural tube,” says Gray, who plans to do apostdoc and then work in academia. “Andit seems that may be getting disruptedwhen this gene is turned off.”

Gray has recently reported strikingevidence that folic acid influences Wntsignaling and that the optimal amount offolic acid for healthy birth outcome dif-fers according to the gene variations car-ried by the embryo. “There’s no onedose that fits all,” he says, “and supple-mentation that is good for some geno-types can be too much for others.” That’simportant, because currently prenatalfolic acid is the only clinically effective

measure known to reduce the occur-rence of spina bifida in humans.

Gray’s research and stipend arefunded through a National ResearchService Award, an NIH grant that goes to less than 15 percent of applicantsnationwide. In addition to his own work,he has hosted visiting medical students

from the Qatar campus, training them intissue culture techniques. “I find thiswork exciting because it’s directly transla-tional,” Gray says. “It has potentialimpact for developing genetic screens tohelp identify people at risk for neuraltube defects, as well as offering possibletreatments and enhancing prevention.”

Jason Gray



Fear FactorPhD student Siobhan Pattwell

Adolescents have one foot in childhood, the other in the adult world. Fifth-yearneuroscience PhD candidate Siobhan Pattwell has been using animals with fourpaws to explore how the adolescent brain is designed to make the transition.Under the mentorship of Francis Lee, MD, PhD, associate professor of psychiatryand pharmacology, and BJ Casey, PhD, director of the Sackler Institute forDevelopmental Psychobiology, Pattwell has been studying fear learning in a mousemodel through childhood, adolescence, and adulthood.

Using classical principles of Pavlovian conditioning, Pattwell puts the mice in achamber and gives them an electric shock paired with an auditory tone, then stud-ies the animals’ subsequent fear of the box and tone, measured by how long theyfreeze. “If you fear-condition an adult mouse and test them the following day, theirfear response is high,” Pattwell says. “They’re scared of being in the box; theyremember it as being a bad place. But when I started looking at this across devel-opment, I realized that the adolescent mice showed no fear response at all. Wewondered if they just weren’t learning, because there was nothing about their

Siobhan Pattwell

behavior that indicated they rememberedeven being in the box, let alone that theywere shocked.”

The researchers investigated variousangles and ultimately discovered differences inmolecular signaling in the hippocampus, theregion of the brain known to be responsible

for picking up contextual clues inducing fear.The adult mice showed increased signalingwhen reintroduced to the chamber; the ado-lescents didn’t. Then, during routine testing ofsome new software, Pattwell accidentally dis-covered something else: when those adoles-cent mice grew up, they did remember theshocks they’d received as teens. “So they didlearn the memory,” says Pattwell. “They werejust not capable of retrieving it at the time.”

Even when adolescents lacked the abilityto retrieve these specific context-based fears,Pattwell says, they had normal responses todirect fear stimuli. In evolutionary terms, shesays, that makes sense. “Adolescence is a timewhen you’re leaving your environment, yourhome, the safety of your mother,” says Pattwell.“You can’t be afraid of everything, or you’llnever leave—you won’t find food or a mate. Soyou need this exploratory, thrill-seeking periodwhere you venture out. But at the same time, interms of the mouse world, you do need to beafraid if you hear a hawk overhead.”

In addition to offering insight into theadolescent brain, the work underscores theimportance of timely intervention; the devel-opmental period in which fear is suppressedseems to double as a window in which treat-ment may be effective in keeping the memoryfrom ever cropping up later in life. SaysPattwell: “The broad implications of thesefindings suggest that if children have experi-enced trauma, even if they seem OK at thetime, they may benefit from treatment to pre-vent something bad from happening downthe road.”

‘Adolescence is a time when you’releaving your environment, yourhome, the safety ofyour mother.’


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At First SightPhD student Nathan O’Connor

As physiology and biophysics grad student Nathan O’Connornotes, the AMA has projected that within the next three or fourdecades, the number of people going blind or suffering visionloss due to diabetic retinopathy will triple—and that’s a conser-vative estimate. In the lab of physiology and biophysics profes-sor Randi Silver, PhD, O’Connor has been using a rodent modelto study the early stages of the degenerative eye disease, whenits most prominent characteristic is vascular leakage. “One of thefirst things that we discovered was that cells not normally foundin retinal neuronal tissue, called mast cells, are showing upthere,” says O’Connor, who holds undergraduate and master’sdegrees in engineering from Rensselaer Polytechnic Institute.“That was striking. The next thing was that these cells are inclose apposition to vessels, a potential hotspot for early diabeticretinopathy.”

This discovery points the way to a potential—or even a pre-ventive—treatment using an existing class of drugs, called mastcell stabilizers, used to treat asthma and conjunctivitis. ButO’Connor notes that there are delivery issues; the medicationsare now available only in nebulized form or as eye drops. “Therats have a pump delivering the drug to the peritoneal space,but you can’t do that with a person,” says O’Connor, who’s con-templating a career in industry. “You can give drops, but withhumans most of the drug would drain into the nasal cavity.”Ultimately, diabetic patients would likely get an injection, eitherdirectly into the eye or next to it; with a sustained-release formu-lation, it could be given annually as a preventive measure.“Diabetics know that even with tight glucose control, they’relikely to develop some form of retinopathy after a given numberof years—and it seems that once it starts, it’s hard to get it undercontrol,” O’Connor says. “The idea that a simple drug that couldsave people from going blind—almost like aspirin therapy in thecardiovascular realm—is pretty exciting.”

Great CommunicatorTimothy Ryan, PhD ’89, Professor of Biochemistry

For the past seventeen years, biochemist Timothy Ryan has beenstudying the synapse—the organelles that allow the brain’s 10billion neurons to communicate with each other. “What we do ispretty basic science,” he says, “trying to understand how thismachinery works.” That basic work has broad implications—everything from treating depression to curbing drug abuse topreventing neurodegenerative diseases like Alzheimer’s. “Itbehooves us to know what these proteins are normally doingand what the mutated state is—what is going wrong,” he says.“In the long term we need a repair manual in place. We have tounderstand how these things work if we hope to fix them.”

Ryan notes that the synapse is believed to have some 1,000constituent parts. And while science has known about synapticactivity for decades, only recently have researchers begun to geta look inside. “It’s as if you’re trying to understand somethinglike the combustion engine of a car, where you are handed adetailed parts list and everything is shrunk to tiny levels,” saysRyan. “Now we have a parts list, and it’s reasonably complete,but we know there are many things involved in this process.They’re very complicated machines, and they’re designed to lasta lifetime. That alone is an incredible challenge—how thesethings are built and maintained and how they fix themselves, andalso how this overlaps with disease processes.”

About half of his lab’s time is devoted to developing thetechnology to address those fundamental questions. “Neurons,of course, are already small things, and synapses are even small-er—individually, they occupy only a cubic micron, a volume often-to-the-minus-fifteen liters, or a femoliter. These small struc-tures contain a huge number of parts, and we use opticalapproaches that allow us to reveal the function of the synapticcommunication as it’s going on, as well as tell us somethingabout where and when a particular protein is participating. Sowe design optical tools that can work inside synapses and tell usabout the biochemistry that is going on. In my lab, we know wealways have to push the technology as far as possible, becauseyou’re only as good as the tools you use.”

Nathan O’Connor

Timothy Ryan, PhD



Acid TestPhD student Crystal Darby

There are many fronts in the battleagainst tuberculosis. One tactic is toexplore how Mycobacterium tuberculo-sis survives within the harsh environmentof the human body—and try to deviseways to thwart it. Fifth-year biomedicalsciences grad student Crystal Darby isfocusing on Mtb’s ability to resist theacid stress it encounters within activatedmacrophages inside the host. Darby andher colleagues in the lab of Carl Nathan,MD, chairman of the Department ofMicrobiology and Immunology, havefound that pH homeostasis is vital toMtb’s survival—and they hope thatknowledge could point the way to newdrugs to combat the disease.

To that end, Darby designed a high-throughput screen to identify small mole-cule inhibitors of pH homeostasis in Mtb.In a collaboration with the InfectiousDisease Research Institute sponsored bythe Lilly TB Drug Discovery Initiative, shetook the screen to Seattle and conductedsuccessful experiments using the Insti-tute’s equipment. “Then they screened acollection of Lilly’s compounds on theirown, and the assay worked for them as ithad for me,” she says. “For me, that wasan accomplishment.”

Darby notes that when she startedthe project, little had been done on theeffect of acid on tuberculosis, beyondthe work of a previous graduate studentjointly supervised by Nathan and profes-sor Sabine Ehrt, PhD, who had identifiedseveral Mtb mutants unable to recoverfrom acid stress. “There were so manyopen-ended questions that needed tobe answered,” she says. “It was exciting,because it could have taken any differentturn and path.” For Darby—living in adeveloped nation where TB is relativelyrare—it has been challenging to makethe connection between her work andthe disease’s global scope. “We don’toften see the face of the disease here inAmerica,” she says. “Attending confer-ences where we meet doctors fromChina, Southeast Asia, Africa, EasternEurope, and Haiti who work with TBpatients all day has opened my eyes tohow important this research is.”

Motor Trends

Many human diseases are associatedwith changes in the localization of oneor several proteins on the surface ofepithelial cells. In cystic fibrosis, forexample, a chloride channel protein ofthe lungs’ epithelial cells gets mislocal-ized—essentially, sending salt pumpingin the wrong direction and leading toaccumulation of thick mucus in the air-way. “A minor change in the localizationof one particular protein on the cell canaffect the whole function of the organand contribute to disease,” says cell anddevelopmental biology associate profes-sor Geri Kreitzer. “What we study arenano-motors, known as kinesins, andhow they carry these proteins to theirappropriate destination in cells.”

Kreitzer’s lab is devoted to epithelialbiology—exploring how epithelial cellsbecome epithelial, how they developtheir characteristic shape and function.“Epithelial cells cover all your body sur-faces—your airway, gut, genital tract,kidney, colon—and when they stop func-tioning properly, you end up with severephysiological defects,” Kreitzer explains.“Epithelial cells form the barrier be-tween the outside world and the sterileenvironment inside your body. Ninety

percent of all cancers arise from eithersubtle or dramatic changes in epithelialcell shape and function, and it’s thoughtthat their contact with the environmentmakes them a prime target for numerouspathogenic agents.”

Using cultured epithelial cells andhigh-resolution, time-lapse imaging,Kreitzer and her group are exploring howtiny nano-motors that move along thecells’ cytoskeleton help form and main-tain epithelial cell shape and function.“They literally are motors—they movearound on these cytoskeletal networksthat are like train tracks,” she says.“We’re trying to understand how theyrecognize and control the delivery of spe-cific proteins to appropriate sites on thesurface of these cells.” Kreitzer studiesboth normal and pathologic cells, tryingto understand how the protein-depositingsystem can go awry, leading to diseaseslike cancer and polycystic kidney disease.“Science gets me out of bed in the morn-ing,” Kreitzer says. “What I love aboutbeing a scientist is that every day youhave to incorporate what you learned theday before into what you’re going to donext. I find that constant intellectual stim-ulation very exciting.”

Geri Kreitzer, PhD, Associate Professor of Cell and Developmental Biology

Geri Kreitzer, PhD


Thin Is In

Could severe calorie restriction offer a fountainof youth? In scientific studies of animals andother creatures, a calorie-restricted diet hasbeen found to promote longevity. “If you putyeast on low glucose, they replicate moretimes,” says pharmacology associate professorAnthony Sauve. “If you put worms like C. ele-gans or flies like Drosophila on low-caloriediets, they have longer life spans. Work doneat Cornell in the Thirties showed that if you putmice and rats on low-calorie diets, they alsolive longer—and not just a little bit, but 50 per-cent longer.” The same is thought to hold forprimates; a study on rhesus monkeys has beengoing on at the University of Wisconsin formore than two decades. But, Sauve notes, “wedon’t know yet whether calorie restrictingwould work on humans, because it looks as ifyou would have to do it for a major part of alifetime, so we don’t have any data.”

While researchers still have much to learnabout how and why calorie restriction affectslifespan, they know that a class of enzymescalled sirtuins plays a role. Sauve’s lab is investi-

‘ What it boilsdown to in thebig-picturesense is thatthese enzymeslook as if theycontrol agingprocesses, orare fundamentalto them.’

Anthony Sauve, PhD

gating sirtuins, and their relationship to themetabolism of a form of vitamin B-3 known asNAD. “What it boils down to in the big-picturesense is that these enzymes look as if they con-trol aging processes, or are fundamental tothem,” Sauve says. “We also know that thingslike low-calorie diets, which activate theseenzymes and also up-regulate NAD metabo-lism, can improve health profiles in humans. Soat the end of the day, we would like to under-stand how these enzymes and NAD metabolismslow down the aging process, confer longevitybenefits, and improve health—and then take apharmacologic approach, to give people thera-peutics that tap an ancient pathway.” Such adrug, known as a CR mimetic, could not onlyretard the aging process but protect againstneurodegenerative diseases such as Alzheimer’s.“What is really cool is that in 2000, we did notknow sirtuins were enzymes—this is a wholenew field that has blossomed in the last tenyears,” Sauve says. “It has exciting downstreamimplications, and every day there are new ques-tions and discoveries.” •

Anthony Sauve, PhD, Associate Professor of Pharmacology

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A glimpse of what's happening at the Grad School