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UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE | SUMMER 2012PITTMEDBEDTIMESTORIESTHE ASTOUNDING IMPORTANCEOF A GOOD NIGHT’S REST

OF NOTEDevoted to noteworthy happeningsat the medical schoolJOINING THE PARTYOF LINCOLNAbraham Lincoln established the National Academyof Sciences (NAS) in 1863 to provide counsel to thegovernment on matters scientific. In May 2012, threeUniversity of Pittsburgh School of Medicine facultymembers joined the roll call of luminaries.Among the 84 new members inducted this year areYuan Chang, Patrick Moore, and Peter Strick. Chang,an MD Distinguished Professor and American CancerSociety Research Professor of Pathology, and Moore, anMD/MPH Distinguished Professor and American CancerSociety Research Professor of Microbiology and MedicalGenetics, are husband and wife. He is also director ofPitt’s Cancer Virology Program. They have identified twoof the seven viruses known to cause cancer in humans.(For the latest one they identified—the Merkel cellvirus, which causes a rare skin cancer—they also quicklyfound potential therapeutic agents.) Strick’s workhas illuminated the way in which neural circuitry controlsvoluntary movement. He is a PhD, DistinguishedProfessor of Neurobiology, director of the SystemsNeuroscience Institute, codirector of the Center for theNeural Basis of Cognition, and a senior research careerscientist in the VA Pittsburgh Healthcare System.Chang, Moore, and Strick join Susan Amara, ThomasDetre Professor and chair of neurobiology, and AngelaGronenborn, UPMC Rosalind Franklin Professor andchair of structural biology, as active School of Medicinefaculty in the NAS. —Joe MikschCOURTESY DARREN SMITHAbout FaceAlthough all transplants are complex, a face transplant offers additionalchallenges, notably aesthetics and the fact that several kinds of tissuesare involved rather than just a single organ. But thanks to plastic surgeryresident Darren Smith, Pitt surgeons have a new tool to help themprepare for their first patient. (The University of Pittsburgh and UPMC’splastic and reconstructive surgery program was given the go-ahead todo face transplants in 2010 and has since screened potential patients.)Before coming to Pittsburgh, Smith (Res ’14) was spending hissummers in New York City as an undergrad and then a medical studentworking with Court Cutting, professor and surgeon in the Departmentsof Plastic Surgery and Surgery at New York University. In the program,Smith learned how to build computer-based models of craniofacialanatomy for teaching purposes.Shortly after arriving in Pittsburgh, Smith began to experiment morewith his interest: “[Pittsburgh’s] transplant program was huge. It wasan opportunity. . . . In Cutting’s lab, we built generic models of anatomyfrom image data to teach surgical techniques. Now, we are using similarprinciples to build anatomical models of specific patients to plan facetransplants.” —Shermi SivajiSUMMER 2012 3

Next GenerationA&QDarlene Zellers: Improving the lot of postdocsIt’s hard out there for a postdoc. You’re not quite a student any longer, and you’re not faculty. Youhave some idea where you want your career to go, but you might not know how to get there. To helpsketch out the career road map, Pitt’s schools of the health sciences recently established the Centerfor Postdoctoral Affairs in the Health Sciences, which is led by Darlene Zellers (shown above, center,flanked by staff members Tammy Dennis and Steve Wendell), associate dean of postdoctoral affairsin the School of Medicine. The office will help postdocs—there are about 650 of them in the healthsciences at Pitt, 90 percent of these in the School of Medicine—form concrete career goals by pairingthem with faculty supervisors and requiring that these mentors and postdocs work together.Why Pitt chose to formalize the postdoc experienceThere are guidelines for postdocs that the provost established in 2003. If you’re going to say, “Whatkind of progress are postdocs making on their research?” you have to understand what they weresupposed to accomplish. This is where the career development plan comes into play. It’s a preliminarydocument that then later serves as the baseline for the individual being evaluated. We areamong a handful of institutions to require a career development plan. Our process is unique in thatthere is so much structure to our template.On expected resultsA national survey of postdocs called “Doctors Without Orders” found that structured oversight ofpostdoc training correlated with increased trainee satisfaction, increased number of publications,higher rating of faculty-mentor relationships, and decreased conflicts between faculty and postdocs.So they found a very positive correlation between degree of structure and those positive outcomes.Her question for usI would be interested in other faculties’ reactions to putting a similar process in place. How adaptabledo they think our process is to other academic cultures? —Interview by Joe MikschCAMI MESAThe School of Medicine’s scholarlyproject requirement, an integral partof the curriculum since 2004, hasgiven students a taste of the research worldwhile they learn the physician’s arts.The Bert and Sally O’Malley Awards forOutstanding Medical Student Research recognizeespecially notable scholarly projectefforts with $500 prizes. (Bert and SallyO’Malley got their bachelor’s degrees at Pittin 1959; he went on to obtain his MD here in1963 and then enjoy a career as an innovativeendocrinologist. Bert O’Malley, a NationalMedal of Science winner, is chair of molecularand cellular biology at Baylor Collegeof Medicine.) The Class of 2012’s O’Malleywinners are Naomi Pitskel, Sameed Khatana,Adam Christopher, and the team of Hyun Kimand Mark Bernard. Pitskel’s work (performedunder the tutelage of Kevin Pelphrey of YaleUniversity) used functional imaging and neurogeneticsto study atypical gaze processingin people with autism. Khatana (working withWen-Chih Wu at Brown University) examinedthe association between certain antipsychoticsand metabolic syndrome in patients withmood and psychotic disorders. Christopherwas recognized for his project studying therole of cilia in complex congenital heart disease.(He was mentored by Cecilia Lo, a PhD,Dr. F. Sargent Cheevers Professor, and chairof developmental biology at Pitt.) And Kimand Bernard looked into ways to protect cellsfrom radiation damage. (The two worked withPitt’s Michael Epperly, a PhD and associateprofessor of radiation oncology, and JoelGreenberger, MD professor and chair of radiationoncology at Pitt.) —JM4 PITTMED

Partners with J&JMoney is tight. Federal funding of basicscience is lagging. The state has cut support forPitt’s School of Medicine and the University as awhole. So, the medical school is looking for additionalpartners. It’s embarked on a new venturewith the New Jersey–based Johnson & JohnsonCorporate Office of Science and Technology, hopingthat this symbiotic relationship will benefitresearch here and provide new commercial prospectsfor J&J.D. Lansing Taylor, director of the Universityof Pittsburgh Drug Discovery Institute andAllegheny Foundation Professor of Computationaland Systems Biology in the School of Medicine,is leading the effort on this end. J&J will fundfour research projects, expected to take 12 to18 months to complete, to the tune of $100,000each. “The idea is that while science is imperfect,out of the four, one or two may look reallypromising, and J&J will want to invest more,”Taylor says. The grants will be awarded in July.(The University’s Clinical and TranslationalScience Institute will also contribute funding.)“Hopefully this is just the first [partnership],”Taylor says. “We’re going to be aggressive ingoing after industry and getting our name outthere.” —JMCATHERINE LAZURETHE OWL, 1954FLASHBACKHis patients remember the late Richard Deitrick(BS ’54/MD ’59) as the man who helped care forthem and their babies (he served as head of ob/gynat UPMC Mercy). Pitt football fans remember him asthe man who, in 1952, helped the Panthers beat theOhio State Buckeyes on their home field for the firsttime since 1936. Quoth thePittsburgh Press: “Deitrick,a 215-pound end, caught theball on Ohio State’s 35-yardlineand stormed the rest ofthe way to the goal like anirritated bucking bronco, withseveral shifts of piggy-backriders having no success whateverat reining him in.” AfterDeitrick’s death in August2011, we learned that the gooddoctor (who also played onPitt’s basketball and baseballteams) was drafted by the LARams, but instead chose to goto med school.LONG LIVE MICE!It seemed like a simple proposition. The stem cells in mice bred to agerapidly (mimicking the rare disease progeria) show signs of degenerationlike those of naturally old mice. So Pitt’s Johnny Huard, a PhD and professorin the Departments of Orthopaedic Surgery and of Microbiology andMolecular Genetics in the School of Medicine and director of its Stem CellResearch Center, and Laura Niedernhofer, an MD/PhD associate professorin Pitt’s Department of Microbiology and Molecular Genetics and a memberof the University of Pittsburgh Cancer Institute, wondered how an injectionof stem cells derived from the muscles of a young mouse might affect therapid aging process.The results were beyond their wildest dreams. Not only did the miceinjected with stem and progenitor cells display healthier, more activebehavior, but they also lived two or three times longer than expected(sometimes as long as 66 days, instead of the 20- or 21-day lifespan seenin other mice bred to inherit progeria). Three sets of control groups demonstratedno change in life span.Further experimentation showed that the new cells had spread outbeyond the abdominal injection site to reside throughout the body, “buteven that doesn’t explain the benefit we’re getting,” says Huard. By placingaging and healthy stem cells side by side, Huard and Niedernhofer discoveredthat an as-of-yet unknown secretion of the healthy cells actuallyrescues the aging cells.“We really believe that, down the road, we can help to improve agingand delay aging-related disorders in people,” says Huard. “This is whatscientists dream about.” —Justin HopperDeitrick captained the Panthers4 PITTMED as a Pitt senior.SUMMER 2012 5

GO BUCS!Rocky Tuan holds a tiny terracotta–colored pirate ship. The realtreasure in the buccaneers’ boat isthe promise it holds in repairingknees, hips, and other joints ravagedby injury or disease.As director of the Center forCellular and Molecular Engineeringin Pitt’s Department of OrthopaedicSurgery, Tuan and postdoctoralassociate Hang Lin created theship with a 3-D printer, paid forby Pitt’s Clinical and TranslationalScience Institute, which they saywill one day create natural polymerimplants that contain the patient’sown living cells to repair joints.Tuan hopes to see the processbecome commonplace in his lifetime.Along with maintaining thepatient’s natural bone and tissue,the procedure would greatly reducethe amount of invasive surgery,recovery time, and cost involvedwith traditional joint replacement.And that’s plenty of reason to raisethe Jolly Roger.—Text and photo by John AltdorferAppointmentsJian-Min Yuan, an MD/PhD, will lead the Cancer Epidemiology,Prevention, and Control Program in the University of Pittsburgh CancerInstitute. He will also serve as professor of epidemiology in Pitt’s GraduateSchool of Public Health (GSPH) and associate director of cancer preventionand population science at the University of Pittsburgh Cancer Institute.Yuan is interested in how environment, diet, behavior, and geneticsinfluence cancer. His investigations have included the potential rolesthat green tea, incense, and volatiles released by Chinese home cookingmight play in the disease. Yuan is a principal investigator on four NationalInstitutes of Health–funded projects; he comes to Pittsburghfrom the University of Minnesota.One of the U.K.’s foremost ophthalmic surgeons is nowchief of the Division of Pediatric Ophthalmology at Children’sHospital of Pittsburgh of UPMC, director of Pediatric ProgramDevelopment at UPMC Eye Center, and visiting professor ofophthalmology at Pitt. Kanwal “Ken” Nischal came toYuanPittsburgh last fall from Great Ormond Street Hospital forChildren in London. In addition to his experience as a pediatriceye surgeon, Nischal has developed treatment algorithmsthat include innovative surgical techniques for children bornwith opaque corneas.Nathan Yates, a PhD, has been named associate professorof cell biology in the School of Medicine and scientificdirector of Pitt’s Biomedical Mass Spectrometry Center. Ascodirector of the University of Pittsburgh Cancer Institute’sCancer Biomarkers Facility, Yates will pursue research on the discoveryand measurement of protein biomarkers that may be usedto detect disease early and help doctors select the best treatments.Prior to joining Pitt, Yates was scientific director for theDepartment of Exploratory and Translational Science at Merck &Co., where he codeveloped differential mass spectrometry. At Pitt,Yates plans to collaborate with scientists from leading academicinstitutions to develop a groundbreaking cloud computing platformfor the storage and analysis of proteomics data.As of April, the McGowan Institute for Regenerative Medicinehas a new director and associate director. Professor of SurgeryWilliam Wagner, a PhD who takes over as director, is oneof the institute’s founders. Wagner’s research into cardiovascularengineering, focusing both on the monitoring of existingequipment and the development of new technologies, involvesgraduate and postdoctoral researchers from a broad range ofspecialties and has resulted in numerous patent filings and awards forinnovation. McGowan’s new associate director is Rocky Tuan (shownwith miniature ship above), a PhD and the Arthur J. Rooney Sr. Professorof Sports Medicine in the Department of Orthopaedic Surgery. Beforecoming to Pittsburgh in 2009, Tuan served as chief of the CartilageBiology and Orthopaedics Branch of the National Institute of Arthritis andMusculoskeletal and Skin Diseases. Tuan’s research has run the gamutfrom the development of the musculoskeletal system, to cell biochemistry,nanotechnology, and tissue-regeneration technology. —JHYatesWagnerNischal6 PITTMED

CLOSERRUB MY BELLY 101Nola, a muscular and squirmy Staffordshire terrier of an almost metallicgray hue, was lounging in the Cathedral of Learning on a winter Tuesdayevening. The wind blew cold outside, and as University of Pittsburghstudents made their way in from the chill Nola leapt into action—okay,lounged into action. As hand after hand petted her short, soft coat, shesmiled, kissed, and wiggled.Aaah . . . that’ll take the edge off a stressful day.It really does, too, says Dawn Marcus, an MD professor in the Departmentof Anesthesiology at the University of Pittsburgh. Marcus is a painresearcher and author of The Power of Wagging Tails: A Doctor’s Guide toDog Therapy and Healing (Demos Health, 2011). “[Therapy dogs] lowerheart rate, blood pressure, and respiratory rate. Endorphins go up. Thereare substantial and long-lasting physiological changes,” she says.So how do dogs get schooled for the clinic and other therapy environments?Here’s one way: Top off a rigorous certification program byallowing hundreds of students to canoodle with the pooches. The CollegeCanines have been visiting the Cathedral every Tuesday evening whenclass is in session for years now. Nola and her cohort of about 10 otherbeasties are accompanied by volunteers from the Western PennsylvaniaHumane Society, which sponsors the program. Students stop to kiss andpet and coo and snap photos to share with family. Some say they misstheir own hounds, and the College Canines help alleviate some homesickness.Marsha Robbins, an educator with the Humane Society, therapy dogtrainer, and all-around pooch pusher, says, “The students seem to findthis a very relaxing time. The dogs love it, too. They start to wiggle theirtails when they know they’re coming here.” —Joe Miksch—Photo by Martha RialSUMMER 2012 75

INVESTIGATIONSExplorations and revelations taking place in the medical school8 PITTMEDThe U.S. Department of Agriculturerecommends that about 66 percent ofdietary fat should be unsaturated. Butdon’t overdo it. An excess accumulationof these fats seems to be harmfulin obese patients with pancreatitis.

UNSATURATEDSOLUTIONRESEARCH INTO PANCREATITIS DEATHSYIELDS AN UNEXPECTED CULPRITBY MELINDA WENNER MOYERGETTY IMAGESVijay Singh was perplexed.The assistant professor inthe University of Pittsburgh’sDivision of Gastroenterology, Hepatology,and Nutrition was using rodents to studyacute pancreatitis, a rapid-onset illness inwhich the pancreas becomes swollen andinflamed. But time and time again, whatSingh learned from his average-weight animalsdidn’t explain what happened to peoplewhen the condition was severe: Theyoften died within days. The consensus basedon animal studies was that pancreatitis wascaused by malfunctioning proteins that ateup the organ; yet researchers had developeddrugs to tame these vicious proteins, and allhad failed miserably in clinical trials.“After being in the field for 10 years,one starts thinking, ‘What is going on?’”Singh says. To find out, he teamed up withhis wife, Pitt’s Sarah Navina, an assistantprofessor of pathology, who had accessto the postmortem bodies of pancreatitisvictims. Seventy-four autopsies and a handfulof lab experiments later, Singh and Navinapublished a paper in Science TranslationalMedicine uncovering a shocking new cause fordeadly pancreatitis: unsaturated fat.Obese people with pancreatitis are muchmore likely than lean people to succumb tomulti-organ failure. When Singh and Navinacompared the pancreases of lean and obesepeople who had died, they began to see why.Whenever Singh asked his wife to point outa pancreatic region that was necrotic—thatis, where cells had died a particularly violentdeath—“it would be around a chunk ofnecrosed fat,” Singh recalls. In other words,fat and dead pancreatic cells seemed to gohand in hand. They also found that thosewith severe pancreatitis were more likely to beobese and have considerably more pancreaticfat than were healthy subjects.Singh still didn’t know whether fat cellscaused pancreatic cell death. Their juxtapositionmight be a coincidence. When thepancreas’ pyramid-shaped acinar cells becomedamaged, as they do in pancreatitis, theirnormal processing fails and the cells beginspilling their powerful enzymes everywhere.Back in his lab, Singh placed acinar and fatcells side by side so that everything the acinarcells secreted came into contact with the fatcells and vice versa. The acinar cells soondied. Inside the shared liquid in which thecells were cultured, Singh found high levels ofunsaturated fatty acids—essential fats that weget through our food. But the cells survivedwhen Singh added a molecule called orlistat,which inhibits lipases that break down triglycerides.(Orlistat prevents the body fromabsorbing the fats and is sometimes prescribedfor patients so they don’t regain lostweight.)Singh surmised that the spilled digestiveproteins prompted the fat cells to releasetheir stored unsaturated acids. Then, lipases(also part of the cocktail of digestive proteins)broke down the unsaturated fats. But what hestill didn’t know was how the unsaturated fats’byproducts were harming the pancreatic cells.When he looked inside dying acinar cells,he saw that the byproducts were blockingtwo key steps in the cells’ energy-productionpathway. Unsaturated fat was literally starvingpancreatic cells of energy and killing them.This discovery explains how unsaturatedfats harm pancreatic cells. But how do theycause multi-organ failure? Because bloodtravels from the pancreas directly to otherorgans, including the kidneys and lungs,Singh believes that unsaturated acids reachthose organs and damage them, too. As thefinal piece of his puzzle, Singh gave orlistatto obese mice with pancreatitis. They did notdevelop multi-organ failure and die. “I wasvery, very, very surprised,” says Singh.The U.S. Department of Agriculture recommendsthat 66 percent of dietary fat should beunsaturated. Singh speculates that unsaturated fatsare only dangerous when we eat too many of themand they are stored. In smaller quantities, these fatsare used up rapidly.“The secret lies in the excess accumulation,”he says.Singh’s work was funded by the NationalCenter for Research Resources, Pitt’s Clinicaland Translational Science Institute, and others.His next goal is to determine whichpancreatic lipases break down unsaturatedfats and attempt to inhibit them with drugsto protect obese pancreatitis patients. (Whentaken as a pill, orlistat doesn’t get absorbedenought to inhibit pancreatic lipases, saysSingh.) But this work could apply to otheracute conditions, too: For example, burn victimshave higher-than-normal blood levels ofunsaturated fats.There are far more questions than answersat this point, but one thing seems certain:Unsaturated fats aren’t harmless. “What ischanted about unsaturated fats being verygood—we have to take that with a pinch ofsalt,” Singh says.■SUMMER 2012 9

SCHOOL OFFISHA NEW DIRECTION INPARKINSON’S RESEARCHBY JUSTIN HOPPERCAPTION T/KK. LOTHROPEdward Burton, an MD, looksforward to the day when the twosides of his work coalesce. As apracticing clinician in UPMC’s Departmentof Neurology, Burton spends a few dayseach week seeing patients suffering fromParkinson’s and other neurodegenerative diseases.As a research scientist in the University’sPittsburgh Institute for NeurodegenerativeDiseases (PIND) and assistant professor ofneurology and of microbiology and moleculargenetics, Burton spends the balance of histime with an unlikely subject—zebra fish.Unlikely, that is, for a practicing MD.Besides being home-aquarium favorites, zebrafish have long been found in labs studyingdevelopmental biology. In the early days of theirlives, zebra fish are transparent—a state madepermanent in the human-engineered speciescalled Casper zebra fish. This gives researchersthe opportunity to view physiological changesin a living, growing vertebrate. But in 2004,Burton looked at Pitt’s world-class zebra fishfacilities—aquarium tanks stacked 10 feet highfilling a football-field-sized room—and beganto think, “What could these animals tell usabout Parkinson’s disease?”“You can do things with zebra fish youcan’t do with other animals,” says Burton.“If we had a zebra fish model for Parkinson’s,because they’re transparent we could look atthe biochemistry [of the disease and potentialCOURTESY E. BURTONtreatments] in a living animal.”Before zebra fish can be effectively usedto study Parkinson’s, someone needs to createa model—to understand how the diseaseaffects a zebra fish’s behavior and biochemistryin ways that can be correlated with the sameeffects in a human. (Since 2004, several otherlabs around the world have begun working oncreating this model, often using Burton’s publicationsas groundwork.)Behavior is relatively easy: Zebra fi share active critters with fast-paced lives, andBurton can tell a Parkinsonian fish withintwo hours (that makes it possible to do quick,large-sample tests for drug effectiveness). Infact, Burton and others at PIND showed thatscientists could make a zebra fish observablyParkinsonian by knocking out its dopaminesystem.The biochemistry is tougher to sort out buthas come a long way recently, as evidencedby a paper Burton and colleagues publishedlate in 2011 in The Journal of BiologicalChemistry titled “Hypokinesia and ReducedDopamine Levels in Zebrafish Lacking -and 1-Synucleins.” This research has madean important advance towards establishingA 7-day-old zebra fish larva used to studyneurodegenerative disease swims in the wellof a plate in Burton’s laboratory.Burton’s zebra fish model for Parkinson’s bymapping zebra fish synucleins—proteins presentin neural tissue that are heavily implicatedin Parkinson’s research.“Synucleins are important in Parkinson’s.For example, rats lacking -synuclein becomeresistant to toxins commonly used to modelParkinson’s,” says Burton. “We wanted toknow, ‘Do zebra fish have -synuclein?’”The answer, it turned out, was no. Whichmakes it somewhat more complicated, but byno means impossible, to create the model. Hislab will attempt to genetically engineer a fishwith -synuclein.That fish is next on Burton’s to-do list. Hebelieves there will be a big payoff in terms ofthe ability of scientists to witness Parkinsonianbiochemistry and degeneration in a transparentmodel. “It’s a long road, because we’vegot to invent everything ourselves [in termsof techniques and reagents],” says Burton.“Creating an effective treatment for humanpatients is a multidecade process.” ■10 PITTMED

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COVER STORYTHE POWER TO MAKE OR BREAK OURHEALTH, FROM BIRTH TO ADULTHOODAND EVER AFTER | BY ELAINE VITONESLEEPING’SBEAUTYA sleep schedulegone askew can havedevastating effectsthroughout the lifecycle. Fortunately,sleep is a modifiablebehavior.Pick a piece of your physiology, any piece. Heart health,lung health, kidney health. Appetite and metabolism. Orconsider memory, learning, and emotion. Pain. Aging.The immune system. Neurological development. Fetal development.Heck, any cellular-level kick-starting or daily humming-along, period.Every single aspect of our health that’s been measured so far hasbeen directly linked to sleep. There are “clock genes” in every cell ofour bodies. How we operate in our 24-hour rhythms is central notonly to the quality of our lives but also how long we get to live. Thatcould make for a pretty scary bedtime story, given that we live in aculture that tends to squeeze in shut-eye between the 11 o’clock newsand breakfast.“Measuring sleep is like measuring temperature and blood pressure,”says David Kupfer, an MD and the Thomas Detre Professor ofPsychiatry and a professor of neuroscience and of clinical and translationalscience in the University of Pittsburgh School of Medicine.(Kupfer served as chair of psychiatry when that department, withWestern Psychiatric Institute and Clinic of UPMC, or WPIC, firstbecame known as a preeminent research center.)ILLUSTRATIONS | CATHERINE LAZURESUMMER 2012 13

When we lose step in our 24-hour rhythms andfeel the inevitable effects, it’s an outward sign thatsomething’s wrong, Kupfer says—or, many times, ifsleep problems are left untreated, something will be.A couple years ago, for the first time in its30-plus-year history, Healthy People—the marchingorders the U.S. Department of Health and HumanServices (HHS) issues as benchmarks for betterhealth—included an entire chapter on sleep. Butthe integral role of sleep in every aspect of medicinehas been a mantra at Pitt for decades now.It all started once upon a … okay, in 1973, whenKupfer came here from Yale as the first recruit of thelate, great head of WPIC, Thomas Detre, to set up achronobiology lab—one of the first four or five clinicsof its kind in the country. Kupfer was among thefirst to look at sleep as a biological marker of depression,and those observations were among a few thatprompted the biological revolution in psychiatry.Sleep research at Pitt helped bring psychiatry intothe realm of the biological science of the body. Andever since, Kupfer and Co. have urged Pitt’s medicalcommunity to (so sorry) wake up to sleep.“Now we have a third generation of sleep researchershere,” says Kupfer, addingthat Pitt has probably hadmore federal funding in thisarea than just about any otherinstitution—and is beginningto train more people.About five years ago, the50-some-odd sleep researchersscattered across the Universitybegan to organize more formallyunder what’s now calledthe Sleep Medicine Institute,which is based on the 11thfloor of WPIC. It’s a veritableWho’s Who of sleeppeeps: former presidents ofthe American Academy ofSleep Medicine and the SleepResearch Society, and authorsof the sleep-disorders section of the AmericanPsychiatric Association’s Diagnostic and StatisticalManual of Mental Disorders (DSM). (Kupfer menteeCharles Reynolds, UPMC Endowed Professor ofGeriatric Psychiatry and director of the Pitt/UPMCAging Institute, chairs the sleep-disorder group forthe forthcoming DSM-5. Kupfer himself chairs theoverall DSM-5 task force.)At sleep-medicine conferences, it’s hard not tonotice Pitt people; their colleagues call Pittsburgha “sleep mecca.” On these pages is a samplingof what these scientists—with support from theNational Institutes of Health, the Commonwealthof Pennsylvania, the Department of Defense, andPitt’s Clinical and Translational Science Institute,among others—are uncovering about sleep andhuman health.They’re finding that a sleep schedule gone askewcan have devastating effects throughout the lifecycle—but, fortunately, sleep is a modifiable humanbehavior. When we sleep better, we drift backto health, both in body and mind. Our zzz’s canbecome the stuff of a Disney happy ending ratherthan a grizzly Grimm fairy tale.DOWN WILL COME BABY“There is absolutely no excuse for watching the 11 o’clock news,” says Pitt’s Timothy H.Monk, PhD, DSc professor of psychiatry. “I always say that when I’m interviewed on TVprograms, and it ends up on the cutting room floor.”Monk, who has a sense of humor about just about everything except the importanceof a healthy sleep rhythm, has been studying the body clock since 1974, back whenpeople wouldn’t even use the term circadian rhythm without putting quotes around it. Heinvestigates what happens to sleep, performance, and mood when the biological clock isdisrupted—by jet lag, space travel, depression, age, what have you. Monk wrote some ofthe first studies showing disruptions in circadian rhythms experienced by night nurses,astronauts, depressed patients, and octogenarians. He also developed widely used toolsfor measuring sleep rhythmicity.Most of Monk’s work has focused on late adulthood, but in recent years, he has learnedthat a botched circadian cycle can be detrimental even in infancy (“something a millionmiles from your thoughts,” he says with a laugh, gesturing to this writer’s then-verypregnantbelly).Collaborating with researchers at the University of Wisconsin in the early ’90s, Monkenlisted new parents in a study of their 1-month-old babies’ daily routines, charting out theirsleep times as well as their time spent feeding, playing, diaper-changing, and cuddlingupfor comfort. Monk’s Wisconsin colleagues then revisited these families several timesthroughout the tykes’ school-age years.14 PITTMED

sabotage our emotional health?Franzen did a pilot study of teens in theirall-too-typical state—way more sleep deprivedthan their still-developing brains ought to be.He showed them photographs of emotionallycharged scenes and played for them recordingsof disturbing verbal exchanges, then asked theteens to control their emotional reactions tothese stimuli. Meanwhile, Franzen’s team measuredthe teens’ pupil-dilation responses: “It’ssort of an old-school measure [of emotional regulation],”he says, “but it’s cheap and easy to do,and it’s noninvasive.” (Pupil dilation also coincideswith cognitive function. So, just to be surethat wasn’t what was behind any changes in theirpeepers, Franzen also observed the kids discussingconflict with their friends and measured signsof emotional regulation or lack thereof.)Sure enough, when Franzen compared thesleep-deprived adolescents to controls, pupilswere about twice as big when the sleepy kidswere exposed to negative stimuli. (Their interactionswith their friends hinted at a similarpattern—dominance, aggression, general shortfusedness.)With a new National Institutes of HealthResearch Project Grant (a.k.a. R01 grant) in hand,this summer Franzen is launching a full investigationof these pilot-study results, hoping to finallyarrive at the first objective measures of impairedemotional control related to sleep deprivation.He’s comparing the results of the teen studies tohis previous work with young adults, probing thequestion of whether or not adolescents are morevulnerable to the ill effects of sleep loss. Andfurther down the road, he plans to tease out howexactly neural circuitry changes when people,especially adolescents, don’t get enough sleep.Even as kids are waking up early for the 8 a.m.school bell, they’re burning the midnight oil—because that’s what they’re hardwired to do, saysFranzen. “At puberty, the desire to stay awake atnight is not just social—there are biological influences,too.”The teen years are such a vulnerable time—“when kids are increasing their risk for developmentof substance abuse and depression,” saysFranzen. He hopes that by showing neural circuitryshifts at work, eventually he can make a case forscreening kids in the clinic and flagging the oneswho may be headed for trouble. “Adolescence isperhaps a unique opportunity to prevent a problemfrom happening in the first place,” he says.SNORING:THE CINDERELLA OF SLEEPThough still underdiagnosed, sleep apnea has gained attention as a seriouspublic-health risk. The evidence continues to pour in. For example, PatrickStrollo—professor of medicine and of clinical and translational science,medical director of the UPMC Sleep Medicine Center, and codirector of theSleep Medicine Institute—found a whole new reason these patients have suchpoor outcomes: They have higher levels of a particularly bad form of arteryhardeningcholesterol called LDL subclass B.But snoring? It’s the other sister, just sort of there, like background noise.We’ve always taken for granted that, yes, people who report snoring tend tohave health problems, but that’s just because they have sleep apnea, right? Infive decades of research on sleep disturbances and their devastating effect oncardiovascular health, we’ve never really monitored snoring.But a few years ago, when Tom Rice (Fel ’11) began working with Kim Sutton-Tyrrell, a cardiovascular epidemiologist in Pitt’s Graduate School of PublicHealth, he read an Australian study with a small sample of snorers verses nonsnorers.It suggested that sawing logs—or rather, the resulting vibrations inthe neck that rattle the carotid artery—might actually do damage, independentof sleep apnea.Piggy-backing on a cardiovascular-risk study of Sutton-Tyrrell’s, Rice studiedyoung adults who were overweight but who had not developed cardiovasculardisease, measuring the vibrations in the air flow in their noses as well as theircarotid artery wear and tear over time. The results were more impressive thanhe’d expected: Nonsnorers in the study had healthy, thin carotid walls. Peoplewith sleep apnea, as it’s long been known, have thick carotid artery walls. Butthe snorers in Rice’s study were somewhere in the middle.Snoring, it seems, could be part of a gradual progression to heart attacksand strokes.“We don’t know all the reasons sleep apnea leads to cardiovascular disease,”says Rice, who’s now assistant professor of medicine. He adds that fragmentedsleep and lack of oxygen explain some, but not all, of it. “[Perhaps] snoringdamages the arteries in the neck and then makes them more susceptible to thedamage from the low oxygen level.”Rice presented the findings from his ongoing, now-NIH-funded study at theInternational Symposium on Sleep and Breathing in Barcelona last spring.Assistant Professor of Psychiatry Wendy Troxel (PhD ’05), another one ofthe many Pitt people who trained here in sleep medicine and stayed to join thefaculty, has also made surprising discoveries regarding this Cinderella of sleepdisturbances. In the journal Sleep in 2010, Troxel published the first prospectivestudy showing that people who report snoring and insomnia complaintshad greater risk of developing metabolic syndrome, a cluster of factors thatincrease the odds of getting heart disease. These findings are the first to showthat commonly reported sleep problems, including snoring and difficulty fallingasleep, can predict the onset of metabolic syndrome over a three-year followupperiod.Some 40 to 50 percent of the U.S. adult population snores, and those arejust the ones we know about. If you sleep alone, or if your better half is sleepingsoundly, you could be a snorer and be none the wiser.16 PITTMED

Sawing logs—all in a night’s work? Evidence suggests that snoring may be part of a progression to cardiovascular disease.SUMMER 2012 17

MOTHER’S SLUMBER,SPOILED, SPELLS TROUBLEMichele Okun (Fel ’07) knows her preggos. She can even guess the exact gestationalstage of a Pitt Med writer just by looking at her (33 weeks at the timeI waddled into her office). “Glad I haven’t lost my touch,” she says. “I haven’tworked with third-trimester women in a long time.”For 10 years, Okun, a PhD assistant professor of psychiatry and psychologyand a psychoneuroimmunologist, has studied the impact of disturbedsleep on women’s health. The past few years her focus has been on weeks10 to 20 of pregnancy. This is when cells within the uterus begin to expandand remodel to conjure up that most crucial cauldron of baby-making magic:the placenta.Okun explains that throughout pregnancy, the immune system churns ina delicate balance, its demands constantly changing. Too little inflammationat the onset, and the blastocyst can’t implant properly. Too much immuneresponse at various points thereafter, and the woman’s body rejects the fetus.When the placenta is developing is the most precarious time. The mostdangerous outcomes of pregnancy—low birth weight, preterm birth, preeclampsia,you name it—are associated with heightened levels of cytokines,messenger cells that signal immune responses, during this critical interval.And what’s one common cause of climbing cytokine levels? Sleep loss,of course.Okun says that in common lore as well as in ob/gyn literature, everyoneassumes women are supposed to be cursed with crummy sleep pretty muchthe whole way through pregnancy. But in Okun’s ongoing, four-year study,which was funded by a K99/R00 grant from the NIH, she has found thatthis is, first of all, not true. (In fact, in the first trimester, about 30 percentsleep very well, and another 30 percent sleep poorly.) And secondly, it is apotentially pretty dangerous assumption. As she follows the outcomes ofthe women in her study, she’s finding that those who sleep poorly betweenweeks 10 and 20 are indeed having more complications. Eventually, Okunhopes her work will inform a new set of primer questions that ob/gyns canuse to screen for problems from the get-go—an idea that’s pregnant withpotential.HAUNTINGSleep affects health, which affects sleep. It’s a complicatedmess to sort out, which is why most academic medical centers’sleep programs have single-disease foci. But Pitt’s sleepthink tank is different, says Martica Hall, associate professorof psychiatry and psychology and of clinical and translationalscience. “I think it’s fair to say in Pittsburgh we’ve createdthe most diverse set of studies investigating the bidirectionalrelationship between sleep and health.”Hall, who came to Pitt for her PhD in biopsychology in1995, was the first of Pitt’s sleep peeps to study physicalhealth, and she’s proud to have fostered what’s now a verybig interest in this giant, sprawling family of researchers. “It’sa big sandbox, and we’re having a lot of fun.”Hall’s particular interest is how stress affectssleep, which, in turn, affects stress, and how thatwhole ugly cycle has a way of throwing our healthfor a loop. She’s studied how acute and chronicstress stymie sleep and health in a number of populations:adolescents, young adults, parents of sickchildren, people with insomnia or depression, caregivers,elders in bereavement. In measuring heartratevariability—a sign of a healthy ticker capableof adapting to a changing environment—Hall hasshown that everyone, even healthy young collegekids, do worse by this measure when they’re introducedto acute stress before they hit the hay. “I callit haunting,” she says.As principal investigator on the ancillary sleepstudy to the NIH’s Study of Women’s Health Acrossthe Nation, Hall conducted the first multisite studyto understand who develops sleep disturbancesduring menopause and why. So far, she and her collaboratorshave published numerous papers to thisend, on everything from the intricate dance betweenhormones, hot flashes, and brain activity duringsleep to how factors like marriage affect sleep.One factor that’s clearly accounting for significantdifferences is race. African American women havethe highest risk for persistent sleep disturbances,she’s found—even when you control for stress level,hot flashes, health complaints, medication, environment,depression, worries about money, and more.However, there’s something “very intriguing”going on that doesn’t yet add up, she says.“If you look at brain waves in African Americanwomen, they do not sleep as deeply as whitewomen, but their periphery tells a different story.Their heart rate variability during sleep is more idealthan that seen in whites. So now we are taking astep back to try and better understand more aboutrace differences in nocturnal physiology. Because weactually know very little.”18 PITTMED

A team of researchers is trying to understand whodevelops sleep problems during menopause and why.Imagine a truck lumbering down a dusty desert road. Out ofnowhere, there’s an explosion, an ambush, a threat that’s audiblewith terrifying clarity, but you can’t see it. The person in the seatbeside you is hurt, but you can’t tell how badly. You are scared,out of breath, and utterly helpless. And then you wake up.This scenario is all too typical among the nearly 2 million whohave served in the wars in Iraq and Afghanistan. For 90 percentof people with post-traumatic stress disorder (PTSD), the brainhas a terrible habit of replaying nightmares night after night. Thelack of sleep only compounds what they’re going through: feelinganxious, irritable, depressed, and frustrated as they struggleTURNING THE PAGEto reenter school, family, friendships, and work environments.Concentration suffers. Tempers rise. Isolation, despair, and alcoholand substance abuse often follow.Poor sleep is a risk factor for PTSD, depression, and substanceabuse. But this newest generation of foreign-war veterans hasgiven researchers the chance to, for the first time, study—and,more importantly, screen and intervene for—those returning fromcombat zones before a long descent into illness. “If we can fix thisone aspect, sleep, we may have a broad impact on mental health,”says Pitt’s Anne Germain, PhD associate professor of psychiatry.“And it’s one that people want. They want to sleep well.” InSUMMER 2012 19

PRECUNEUSAND CURIOUSERaddition, for many veterans, help with a sleep disorder—onemental health complaint that doesn’t carry a stigma—is a gatewaytreatment to addressing other difficulties they may have.Germain teaches veterans how to stop replaying their nightmares,which have become involuntary habits, default modes fortheir sleeping minds. Through writing and visualizing exercisesthat she’s developed, Germain trains veterans to finally turn thepage and dream about something else by focusing on a wholenew set of images of their choosing.She’s also fine-tuning and packaging the treatment so thatit’s easy for primary care providers, nurses, social workers—anynumber of people with even minimal training in mental health—to provide the treatment, as well.Germain is pressing on and digging deeper, trying to understandwhat happens in the sleeping brain of a person who’s beenexposed to traumatic events, in hopes of finding better treatments.In the past six years, she has studied some 400 veterans;one additional year’s work will complete the data-analysis portionof this U.S. Department of Defense–funded project.In imaging studies, Germain is showing that, in both wakingand REM/dream-sleeping, the brains of veterans who havePTSD light up in regions of emotional reaction and alertness: theamygdala, the hippocampus, the medial cortex, and the arousalregions of the brain stem.“Your brain is saying, ‘Something’s going on—better beready.’ You get stuck in this state of hypervigilance of threat, andyou never get a chance to get out.”Germain is studying veterans before and after a successfulcourse of treatment. She’s also looking at veterans with PTSDwho do not have sleep problems in hopes of figuring out whatmakes their sleep so resilient. These insights, she says, could beuseful in helping veterans and civilians alike.“These are people who are already more resistant to stress—Idon’t know about you, but I don’t think I could get through bootcamp—and they still aren’t immune to the impact [trauma] hason sleep or mental health. If we can understand how to treatcombat-exposed military veterans, we can generalize to anyonewho’s exposed to not just traumatic events, but milder stressors,too, and still have a big impact on sleep.”Trying—and failing—to fall asleep all night is exhausting.Typically, people with insomnia will sleep late whenever theyget a chance. Their circadian rhythms get so out of whackthat their bodies have no idea when it’s time to settle downfor the night.But usually, people with insomnia find that their sleepimproves once they learn a few basic principles: restrict thetime you spend in bed; establish a regular waking-up time;put off going to bed until you’re actually sleepy; and, if youfind yourself stuck, wide awake, get out of bed and go dosomething else until you’re tired.“It sounds pretty obvious,” says Daniel Buysse (Fel ’89,Res ’87), “but I can tell you, when you present these topeople with insomnia, their jaws often drop in amazement.They’ve often been doing exactly the opposite.”Buysse, professor of psychiatry and of clinical and translationalscience, director of the Neuroscience Clinical andTranslational Research Center, and codirector of the SleepMedicine Institute, is one of the world’s leading experts oninsomnia. (In the late ’90s, he spearheaded the now widelyused Pittsburgh Sleep Quality Index.) He explains that sleepscientists have shown again and again that behavioral treatmentsare more effective than going down the rabbit holewith sleeping pills, the side effects of which often proveto be too much for people. Here’s the problem: Behavioraltreatments typically take eight weeks of one-hour sessionswith highly trained clinical psychologists. “The prevalence ofinsomnia far outstrips supply of this treatment,” Buysse says.“I ran into this in my clinic. I just don’t have the time.”So starting in 2003, Buysse adapted and distilled the treatmentto a one-month course of two in-office counseling sessionsand two follow-ups over the phone that teach patients torealign their body clocks. They restrict their sleep at the onset,among other changes in their routines. They build sleep pressureso that when they finally hit the pillow, sleep comesquickly, and at the appropriate time.Buysse and his sleep-medicine cronies on the 11th floor ofWestern Psychiatric Institute and Clinic of UPMC have usedthis treatment, dubbed BBTI (Brief Behavioral Treatmentfor Insomnia), with great success for years. And clearly, it’sworking—they just don’t know why. That is, they don’t knowwhat makes the brain of a person with insomnia differentfrom the rest of the waking-when-we’re-supposed-to world,or what happens biologically to help people with insomniasnap out of it.Buysse may be closing in on the reason, though—and ithas to do with a particularly curious puzzle when it comes topeople with insomnia. They complain not just of sleeping too20 PITTMED

PEOPLE WHO GOBUMP IN THE NIGHTlittle, but also that the sleep they do get is lousy, likethey were never really asleep at all. And yet when youbring them into the sleep lab and measure their brainwaves, they seem to snooze no differently than the restof us.Using a brain-imaging technique called 18 F-FDG PETimaging, in conjunction with EEG sleep studies—atechnique that was developed in the ’90s by Pitt’sown Eric Nofzinger (Res ’91, Fel ’93), professor of psychiatry—Buyssemeasured metabolism in the brains ofpeople with insomnia. Buysse found that, both in sleepand wakefulness, these patients had unusually highlevels of activity in regions called the precuneus andthe posterior cingulate. These sites take over, essentially,when you put your brain in neutral—when youdaydream, tease out your what-ifs, and let your mindwander to the other side of the looking glass.But after sleep restriction (similar to what’s usedduring BBTI), it’s a totally different story. In Buysse’s preliminarystudies, he’s found that the precuneus actuallypipes down, allowing the person to sleep more deeply.Buysse laughs, a Cheshire Cat grinning over the possibilities.“Behavioral treatments often cause the personto have less sleep, yet people say that they’re feelingbetter. It just does not make sense! But maybe the thingwe need to do with our treatments is not to increasesleep, but to decrease the activity in this self-monitoringcenter of the brain during sleep. It could be that all thissleep monitoring we’ve been doing with EEG may be ahuge red herring. EEG tells us what the brain is doingglobally, but insomnia may be something that happenslocally in specific brain regions.“This is potentially really cool. If it really holds up, itcould be a pretty fundamental change in what we thinkof as insomnia.”Say your grandpa falls asleep in his La-Z-Boy while watchinga preprime-time episode of Wheel of Fortune. By thewitching hour, he’s already gotten most of the sleep heneeds for the night, so naturally, by 2 a.m., he’s wideawake. This becomes his habit, so he goes to the doctorand says he has insomnia. The doc then may prescribea bottle of sedatives—potentially dangerous stuff to have onboardwhen Grandpa inevitably gets up in the middle of the night to emptyhis bladder.Up to 10 percent of seniors have serious insomnia, and for thispopulation, it’s more than a nuisance. The wee-hour puttering of anelderly family member going bump in the night can be very disruptiveto the other family members, who have work and school anda 6 a.m. alarm to worry about. And knowing that is distressing forGrandpa, too.It all comes back to circadian rhythms, says Pitt’s Timothy Monk,who directs the Human Chronobiology Research Program at WPIC.“The circadian signal isn’t as strong as people get older,” he says,though some people fare better than others. To discover exactlywhy—and how the strengths of the superior snoozers might informbetter treatments for seniors with insomnia—he’s leading Pitt’ssleep dream team in AgeWise, a large, five-year study funded by theNational Institute on Aging. It’s an all-encompassing look at the roleof seniors’ circadian rhythms, sleep strength, stress reactivity, functionalbrain neuroanatomy, and genetics in these folks’ responses toa standard behavioral treatment of insomnia. (So far, a good portionof the seniors in the study are responding well.)If more and better therapies became available for seniors, thepotential public-health impacts could be huge. Between the stressof disturbing the family’s sleep and the very real threat of a hipsnappingtrip over the cat, sleep problems are among the biggestreasons people transition to nursing homes.Sleep makes or breaks us all, from cradle to La-Z-Boy. And it’sworth the investment of our time, says Monk.“You’ve got to think of sleep as something you do. It’s notsomething that just fills the time when you’re not doing things.It’s something you do.”Pitt’s sleep researchers are always looking for participants tovolunteer for their studies. Call 412-246-6413.SUMMER 2012 21

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FEATUREMIGHTY MITOCHONDRIA ENERGIZE THE CELL,AND MUCH MORE | BY JOE MIKSCHMEANING OF LIFE,TOLD WITH 13 POLYPEPTIDESMitochondria have beeninstrumental to thedevelopment of life aswe know it. Scientistsare just beginning tounderstand their importanceto our health.East Liberty’s Sharp Edge Beer Emporium, as one mightguess, has an awful lot of kinds of beer. Belgian brews are aspecialty. As are craft beers. As are imports. The beer list is anovella-length testament to the art of zymurgy. It’s a fine, homey place.Cheers with better beer and high-quality bar fare. A place with regulars.And on a fairly regular basis you’ll find University of Pittsburgh scientistsat the Edge—many from the nearby University of PittsburghCancer Institute—sipping a tasty beverage and talking shop, orrather, lab.A particularly spectacular spring evening finds Pitt’s Bennett VanHouten atop a stool. He might have been there anyway, maybewith his wife and sometimes-collaborator, wildlife biologist VictoriaWoshner, or Pitt colleagues and genial companions Michael Lotzeand/or Simon Watkins. But at this particular moment he’s there withan interested party to discuss mitochondria-related research at theSchool of Medicine.ALL IMAGES | COURTESY UNIVERSITY OF PITTSBURGH CENTER FOR BIOLOGIC IMAGINGSUMMER 2012 23

Mitos, in dark blue, dance aroundthe nucleus of a HeLa cell. Below,blue mitochondria comingle in thegreen cytoplasm of a rat liver cell.Mitochondria. It’s not going too far to saythat these energy-producing organelles—scatteredabout inside our cells and numberingup to thousands in each—are the reason we’rehere. Not just Van Houten and this reporter,but all of us and pretty much every otherliving thing that’s more advanced than a bacterium.One could write a book about theirevolution and purpose—British biochemistNick Lane did with 2005’s Power, Sex, Suicide:Mitochondria and the Meaning of Life. (Thetitle is not at all hyperbolic. Really.)The Dementedly Short Version in WhichDates and Occurrences Are Generally butNot Universally Agreed Upon: About 4.6 billionyears ago came the Earth. Then, about800,000 years later, life appeared on Earth inthe form of bacteria. Bacteria ruled for a long,long time. About 2.4 billion years ago, Earth’satmosphere became oxygenated. A billion orso years after that, an archaebacterium (whichcould live under extreme conditions such asthose found in geysers) without membraneencasedstructures developed a symbiotic relationshipwith a eubacterium (bacteria we aremore likely to come across today, which liveunder more conventional conditions). Theyeventually fused together and, more or less,became one. This “hopeful monster,” as Lanecalls it, became the first true eukaryote. Lots oftrue eukaryotes ganged up, diversified, specialized,and became the components of complexbeings, ranging from plants to humans. Andthat eubacterium that fused? Seems that ithelped create the mitochondrion and cellnucleus. Its own small genome stayed withthe mitochondrion, but it also shed many ofits original genes into the larger cell nucleus.It makes energy in the form of adenosine-5triphosphate (ATP). It persuades a cell to diein a quiet and peaceful way when the cell hasbecome damaged. The tiny little organelle hasbecome a big part of us.For us to thrive, mitochondria need tobehave themselves and work well, generatingthe energy our cells need to live. We’re in troublewhen mitos go bad. That can mean cancer,neurodegenerative diseases, devastatingendogenous mitochondrial DNA disorders,muscle wasting with age. Pitt investigatorsare part of a recent resurgence of interest inmitochondria, and they have a finger in everymitochondrial pie.Van Houten has long been a student ofDNA damage and repair in the cell’s nucleus,a field of study considered important to understandingaging and cancer. But throughout thepast decade or so, he has developed and actedon a hunch that the ability of the mitochondrionto repair its own DNA may be equallyfundamental to our health. Van Houtenbelieves that unrepaired insult or injury to themitochondria’s DNA (mtDNA) is the beginningof a nasty and self-perpetuating chain ofevents that may be responsible for the majorityof adult-onset diseases, including cancer.And work that began with a postdoc in hislab appears to reveal why many tumor cellscan be so tenacious (it has to do with theirfeeding habits) and could pay dividends in theform of a novel mitochondria-targeted cancertreatment.“The chemistry works,” he says of thisexperimental work. “We don’t know how, butthat’s okay. Nobody has ever shown this.”The buffalo bites come, and anotherbeer is ordered. Time to get down tobusiness. Van Houten, a PhD, theRichard M. Cyert Professor of MolecularOncology in Pitt’s Department ofPharmacology and Chemical Biology, was askedto think of a few promising mitoresearchersto be featured in this story. He opens a folder,pulls out two sheets of paper labeled “PittsburghMitochondriacs”—those who are maniacal formitochondria, of course. The list is 24 nameslong.Asking Van Houten to narrow down the listis fruitless. “He does great work!” “She does greatwork!” “Oh, he does great work, too!” “Her workis excellent!” He scribbles a few diagrams on thepages. An alphabet soup of proteins follows.Another “(insert name here) does great work!” Ashortened short list of Pitt research and researcherswe really should know about, according to VanHouten: A postdoc with a potential biomarkerfor Parkinson’s. A biochemist’s long-standingwork in mitochemistry. Mitos and the injury thatresults when blood supply is returned to oxygendeprivedtissue. An oncogene that actually controlsmitochondrial biogenesis. A new compoundthat protects mitochondria from radiation. Agingmice with signs of mitochondrial dysfunction.Mitos and exercise. Mitos and fruit flies. … VanHouten is infectiously enthusiastic about mostthings, but nothing more than science and thepeople, particularly those here at Pitt, who do it.Mitorelated research has become so fruitfulin recent times that last year Van Houten andLotze organized and executed the first RegionalTranslational Research in Mitochondria, Aging,and Disease Symposia. The second set of symposiais planned for Saturday, Oct. 20, at the UPMCCancer Pavilion. (For those who want to startstressing their mitochondria first thing, there’s anoptional 10K “fun run” at 6:30 a.m.)The buffalo bites are long gone, a plateof nachos has disappeared, and several pagesof notes later, the whirlwind introduction tomitochondria is over, for tonight anyway. Thiswriter’s head is swimming, not from the beerbut from mito info. So, with limited time andspace, we begin our journey to the center of themitochondria with Van Houten himself. (Thestories of some of the others Van Houten effusedover will be told in a future edition of the PittMitochronicles.)After earning his doctorate at the OakRidge Graduate School of BiomedicalSciences in Tennessee and completing afellowship at the University of North Carolina,Chapel Hill, Van Houten, in 1988, found himselfin New England, a young professor at theUniversity of Vermont. He had been hired to24 PITTMED

do research and teach graduate students aboutdamage to, and repair of, nuclear DNA. As heleft his course coordinator’s office, he was toldhe also needed to prepare and deliver a series oflectures on mitochondria.Back then, everyone knew that mitochondriawere the cell’s mighty ATP factories; but once theelements of energy production had been elucidated,the organelle just wasn’t a hot topic.“I said, ‘I don’t know anything about mitochondria,’”Van Houten recalls.“I guess you’ll learn,” the course directorreplied.Here’s what he learned. “As I was reading, Iwas like, Holy crap, nobody knows anything aboutmitochondria DNA damage and repair. I mean,zero! Zilch! ”Nothing could be cooler to the curiousmind.By 1999, Van Houten had invented andpatented a method that allowed himand many of his fellow mito-seekersacross the scientific landscape to study mtDNAdamage. Quantitative polymerase chain reaction(qPCR) allows for the amplification ofsmall amounts of DNA. It had been aroundfor some time, but Van Houten and colleaguesdetermined that if DNA is damaged it will notamplify. Lots of DNA damage, proportionallylittle amplification—and vice versa. Thoughmitochondrial DNA makes up only about1 percent of total cellular DNA, the VanHouten technique allows for both the amplificationof mtDNA and a way to quantify thedamage it has suffered.(We pause here, as we enter Van Houten’soffice at the University of Pittsburgh CancerInstitute in Shadyside, to ask why mitochondriahave hung on to their own genome,particularly after giving up almost all of theirDNA to the nucleus. The answer is, No oneknows for sure. There’s really not even muchagreement on why this may be the case. Thismuch is true, though: mtDNA encodes 13polypeptides, all of which are involved increating proteins vital to the electron transferchain, which generates energy for cells. VanHouten suggests that mtDNA is “kind of likethe canary in the coal mine. The idea is ifthere’s bad, toxic stuff in there, the canary willdie before the miner.” When mitochondriafreak out because their DNA is being damaged,and they can’t produce enough proteinsto make enough energy, the cell at large candedicate resources to the rescue or find waysto adapt. Sometimes, though, things can reallyget screwed up.)So, Van Houten has used this qPCR trickto study mtDNA damage and repair in morethan three dozen scientific papers. He positsthat unrepaired mtDNA damage can causemitochondrial dysfunction, which can increasethe quantity of dangerous free radicals floatingabout, which may cause irreversible and deadlydamage to the cell. This death spiral, thethinking goes, could be responsible for variousdiseases associated with getting older, such ascancer and Parkinson’s.Van Houten takes a few short steps acrosshis office to a bookshelf and grabs a whitebinder. He sits down—affably grumblingabout a lack-of-caffeine-induced headache—and flips to an illustration. “Okay, this isthe electron transport chain …” The lessonbegins. In brief, the electron transport chainmoves, well, it moves electrons down a chain inthe mitochondria. These electrons eventuallymeet with oxygen. As the electrons are passedalong to oxygen, enzymes use the energy that’sreleased to pump protons. The protons buildup in what’s called a proton gradient, whichis used by a special nanomachine that makesATP, which fuels our cells.The whole affair is called oxidative phosphorylation(OXPHOS), and when it workscorrectly, the waste products are water andcarbon dioxide. When OXPHOS is off, watchout, because here come the free radicals. Theynaturally occur during OXPHOS and, inA TERRIBLE DEATH“It has a horrible name,” says Michael Lotze. “HMGB1, High-Mobility Group Box 1.”Perhaps so, but this protein a) is vital for mitochondrial qualitycontrol, b) can promote cancer cell survival and DNA repair,and c) is responsible for winning Bennett Van Houten, who isPitt’s Richard M. Cyert Professor of Molecular Oncology, a largebottle of Belgian-style beer.Lotze, an MD, is a professor of surgery and of bioengineeringas well as vice chair of research for the Department of Surgeryat the University of Pittsburgh. He spends a lot of time thinkingabout the role inflammation plays in cancer and how to target aprocess called autophagy—literally “self-eating.” He imaginesthat finding a way to rein in the process could result in a noveltherapy for cancer.One of the primary perpetrators of inflammation, in his view,is the mitochondrion. Mitochondria promote inflammation whenthey are released as a result of tissue damage or trauma. Theright way for mitochondria to extinguish an ailing cell is apoptosis,or “programmed cell death”—the clean way to kill ailingcells without releasing signals that prompt an inflammatoryresponse. Cancer, though, features cells that are truly messedup monsters that should die through apoptosis but don’t.“Cancer cells just want to die, but they can’t because they’vecompromised their ability to do apoptosis,” Lotze says. Theycan eventually die if they run out of fuel or are subjected tochemotherapy. They can still perform autophagy, which isnot so clean and nice. “They die a terrible, awful, horrible,screaming-out-loud, blood-in-the-streets death,” Lotze says.This process puts all sorts of cell-junk into the bloodstream,causing further inflammation and perpetuating the diseasethrough increased autophagy. And it’s promoted, in part,by HMGB1. (Lotze, with the University of Pittsburgh CancerInstitute’s Van Houten and Daolin Tang, addressed the clinicalimplications of the process in the New England Journal ofMedicine’s March 22 edition.)“I call this ‘programmed cell survival,’” Lotze says. “All ofour anticancer treatments are designed to kill cancer, kill cancer,kill cancer. But if you don’t die the right way and releasefactors that promote the remaining cells’ survival, it’s likeadding fuel to the fire.”“As for the beer bet,” says Lotze, “that was kind of an asiderelated to how mitochondria make their energy. I suggestedthat HMGB1 was taking the mitochondria offline, and theyweren’t going to be able to do OXPHOS [the metabolic processmitochondria use to produce energy]. Ben said it was the otherway around, and he was right. ... Oh well!” —JMSUMMER 2012 25

small amounts, are helpful with cell signaling.But when the system goes haywire, and thereare too many radicals, reactive oxygen species—suchas superoxide, hydrogen peroxide,and hydroxyl radical—wreak havoc. This isoxidative stress. And it, in large amounts overtime, is very, very bad.Reactive oxygen species damage the mitochondria’sDNA. Damaged mtDNA hurts theelectron transport chain. When that’s screwy,the cell produces less ATP and more reactiveoxygen species, which, in turn, further damagesmtDNA. It’s a cycle, and it’s vicious.Otto Warburg won the Nobel Prizein 1931, having proven that cellsconsume oxygen. His investigationsinto cellular respiration—he thought thateven in the presence of oxygen, tumor cellschose to make almost all their ATP throughglycolysis rather than OXPHOS—led him topropose that cancer is caused by screwed upmitochondria.As he put it: Cancer, above all other diseases,has countless secondary causes. But, even for cancer,there is only one prime cause. Summarizedin a few words, the prime cause of cancer is thereplacement of the respiration of oxygen in normalbody cells by a fermentation of sugar.Warburg said the above during a lecturein 1924. Eighty-eight years later, Van Houtenbegs to differ. Or at least to add to the conversation.“Warburg showed that despite the fact thattumor cells have access to a lot of oxygen, theymake a lot of lactate (an indicator of glycolysis),”Van Houten says. “He didn’t understandwhy, but he thought that the mitochondriamust be broken because there was so muchglycolysis going on.”Warburg was right about glycolysis. But hemay have been wrong about the cell’s mitochondriabeing on the fritz. Not exactly right,anyhow. Perhaps the mitochondria aren’t brokenin cancer, Van Houten says. Perhaps theyget repurposed.Van Houten and collaborators ran an assayon cells bearing a known cancer-causing geneticmutation, wanting to see how the cells madethe energy they needed. “I expected glycolysisto go up, and it did, but OXPHOS did too,”Van Houten says. “What that tells us is thattumor cells are metabolically flexible.” So, themitochondria are working. Yet the cells are alsoproducing ATP through glycolysis, a much lessefficient method than OXPHOS.Van Houten and company then took astep back to look at the mitochondrion’s ownlittle metabolic lab, which does the chemistrythat drives OXPHOS and other cellular affairsmetabolic, including the manufacture of fattyacids and lipids. “So the idea is that ratherthan making ATP, the mitochondria are shortcircuited.… Maybe they aren’t broken but arebeing used to make precursors to fatty acidsand lipids,” Van Houten says.The upshot, Van Houten thinks, is thatcancer cells have turned to glycolysis to maketheir minute-to-minute energy because they’vepulled their mitochondria away from theirregular role on the ATP production line.Rather than making energy for the here andnow, maybe mitochondria are being used togenerate fatty acids that can be stored andlater synthesized—by them!—to make energydown the line.“This is all fresh data,” Van Houten says.“My idea is that fatty acids are like a battery.Glucose is taken up in excess by tumor cellsand converted to fatty acids and lipids andthen used later for the generation of ATPby OXPHOS. The prediction is that tumorcells have very active mitochondria. This iscool; but it also says that if we’re really goingto attack this problem, we have to be prettysmart, because tumor cells can switch [howthey feed themselves]. One anticancer agentis not going to be enough.” How about two?Van Houten is far from a lone wolf inthe lab. One day in the not-too-distantpast, postdoc Wei Qian came calling.Qian had a set of data showing that the breastcancer cells he was working with—he hadaltered them so they couldn’t make a proteinvital for mitochondrial dynamics—weren’t fissuringand fusing like they usually do. Theprocesses of fission and fusion allow the mitochondriato cut out damaged parts and againbecome functional organelles.As Qian and Van Houten delved moredeeply, they found that it wasn’t just themtDNA that was screwed up. Inhibitingmitochondrial division, it turned out, causednuclear DNA to become abnormal as well.The cells were going nuts and starting todie. How about that? Mitochondria, as VanHouten thought, not only function in cancer,but their health is also vital to the survival ofcancer cells.“So we thought we would use the knowledgethat [cancer] cells are using their mitochondriaagainst them,” Van Houten says.Qian’s cells had been treated with somethingcalled mitochondrial division inhibitor 1(mdivi-1), which inhibits small molecules. Itwas killing the cancer cells by stopping theirmitochondrial ability to undergo coordinateddivision, causing cell cycle problems and chromosomeinstability. That, of course, was good.But the inhibitor could also affect the mitos ofhealthy cells in vivo.“I don’t think we can ever kill a cancer cellby totally knocking down its energy production,because the side effects on other tissuewill be too hard,” Van Houten says. “But we dowant to cripple them. Keep them from goingas fast. Maybe if we combine [mdivi-1] withnormal anticancer drugs we’ll have a fightingchance.”So that’s what Qian and Van Houten did.They took cancer cells, then treated them withthe inhibitor and cisplatin (one of the moreeffective cancer drugs out there, cisplatin curedfamed cyclist Lance Armstrong’s metastasizedtesticular cancer). And they watched.“Look at this synergy!” Van Houten exclaimsat a figure in a draft paper. “Each of the drugsby itself isn’t doing much, but the combination!Holy cow! We’re really excited about this. We’vepatented the combination. This is really bad forcells, and it looks like tumor cells are especiallyinhibited. It looks awesome. This is synergy.What we’re trying to do now is understand howit’s actually working.”While that investigation is ongoing, Qian,Van Houten, and others plan to see whetherthe combination works as well in a mouseas it does in vitro. The preclinical trial willinvolve “nude mice” (those without immunity)injected with human cancer cells. Once theresultant tumors grow to a certain size, somemice will be given just the inhibitor, some willbe treated with just cisplatin, and others willget the patented combo.“If it works, we should see the tumors meltaway!” Van Houten says, grinning and satisfied.“Of course, we need money,” he adds, alittle less excitedly.Then, after a pause, the smile returns. “Wow!That’s a long journey from when I got asked toteach some lectures on mitochondria!” Up next in the Pitt Mitochronicles: What a pesticideand mitochondria tell us about neurodegenerativedisease, especially Parkinson’s. The modelfl y for mitochondrial disease. And the travails ofrestoring blood to oxygen-deprived tissue.26 PITTMED

THE GREATEQUALIZERFEATUREThe study of anatomyhas always been a milestonein a med student’scareer at Pitt—in termsof how they see medicine,their instructors,their future patients,and themselves. (SHOWNHERE: Students usedcolored pencils totrace neural pathwaysduring TryphenaHumphrey’s legendaryneuroanatomyclasses.)HOW TO TEACH ANATOMYBY JENELLE PIFERANATOMY NOTES COURTESYJAMES BONESSI (MD ’56)It was with resolve and optimism that, in the springof 1923, Davenport Hooker set out to changethe way medical students learned anatomy. Hewas a domineering man, a PhD gross anatomist withvast knowledge, unyielding expectations, and a speakingvoice that fell on first-years’ ears like cannon fire.SUMMER 2012 27

(His excessive volume, students said, was theresult of his training as an artillery officer duringWorld War I.)Hooker was 36 and just four years priorhad become the youngest chair of any anatomydepartment in the country. His ideafor remaking the subject at the University ofPittsburgh was bold, but not entirely new. Infact, the notion had been circulating throughthe minds of the anatomy staff for years: Wasit possible to teach the anatomical subjects—gross anatomy, microscopic anatomy, grossneuroanatomy, embryology, and organs ofthe senses—not as five courses that inevitablyoverlapped, but as one course, seamless andcomprehensive?In those days, Hooker was a giant in theUniversity of Pittsburgh School of Medicine.He’d arrived at Pitt in 1914 as assistantprofessor of histology and neurology after abrief stint teaching anatomy at Yale, his almamater. By 1919, he was appointed professorand chair in the Department of Anatomy,posts he held firmly for the next 37 years.A small man, Hooker had blue eyes, sandyhair, and a dramatic manner. He would sit onthe balcony in the anatomy lab and watch hisstudents (he knew them all by name) dissectcadavers below. They worked four to a table,and a good number of them, mostly men,chewed tobacco to mask the room’s odor.in biological research. He spentsummers in college recordingthe behavior of newly hatchedloggerhead turtles in Florida.As a graduate student, he studiedthe development of embryonicfrog hearts. (He noted,to his great interest, that theanimal’s heart not only beginsto beat before being reachedby the nerve fibers, but alsocontinues to develop normally,though still unconnected tothe nervous system.) This earlyinterest in nerve-muscle relationshipswould later informhis life’s greatest pursuit, aseries of groundbreaking reflexstudies at the University ofPittsburgh.But in the spring of 1923,seated in his top-floor officein the medical school, Hookerpercolated about a new and better way toteach his students anatomy—one that wouldalso challenge his staff and train its mostjunior members.“The best way to learn a subject,” hewrote, “is to bear the responsibility for teachingit to others.”The correlated course in anatomy was toDavenport Hooker led the department for37 years and fundamentally altered theway Pitt students learned anatomy.they would spend another 66 hours learningthe anatomy of the nervous system.Hooker did not gloat over the boldness,newness, or inherent advantages he saw insuch a course. Instead, he wrote, “This typeNATIONAL LIBRARY OF MEDICINEShould Hooker spot a mistake, he’d bellow the offender’s last nameand send the student racing up the stairs to face him.Should Hooker spot a mistake, he’d bellowthe offender’s last name and send the studentracing up the stairs to face him.Hooker’s insistence on time and punctualityearned him the nickname “HurryupHooker” among students. “The medicalstudent who arrived late for an eighto’clock lecture arose earlier thereafter,” wroteTryphena Humphrey, an MD/PhD colleagueof Hooker’s and eventually a professor of neuroanatomyin his department. “There was notolerance of the lazy or dishonest student, butevery effort to aid those in scholastic, financial,or other trouble. No one knows howmany students Dr. Hooker helped at criticaltimes in their lives, with encouragement,sound advice, a justly administered scoldingor financial aid,” Humphrey wrote in a profileof the doctor.At age 17, Hooker developed an interestbe offered for the first time in the fall of 1924.“The purpose of the course is to give the studenta more comprehensive and closely knitknowledge of the structure and developmentof the human body than was possible withthe older method,” Hooker wrote in notes onthe course. It was to occupy 704 class hoursduring the first year. As students dissected acadaver—from the head and neck to the thorax,abdomen, pelvis, and extremities—theywould encounter new organs and systems,studying at once gross anatomy, cell anatomy,and embryology. (“It was difficult teaching forthe anatomy staff since each instructor foundit essential to be prepared on all three phasesof anatomy rather than only one,” Humphreywrote.) Students hopped back and forthbetween the anatomy lab and microscopylab, towing pieces of tissue or organs recentlyharvested for study. During the second year,of course is merely a means to an end. As amethod it is valuable, but it is nothing more.”Still, the methodical doctor could notmask his growing anticipation that, in thisway, he might be able to teach his studentsmore, in less time.At the beginning of the school year,Hooker would issue his students awarning, says Perry Engstrom (MD’47), a former student later hired to teachin the department. “He would say, ‘Thereare medical schools where they accept 200students into a class with the idea that 100 ofthem are going to graduate. The Universityof Pittsburgh is different. In our class thereare 86 students. We expect every one of youis going to graduate, and we’re going to see toit that you do.” Engstrom says it was a threat,in a way, but the kind that a well-respected28 PITTMED

HIPPOCRATEANABOVE: During Hooker’s correlated course, first-year studentsspent several hundreds of hours in the anatomy lab. RIGHT:Using a piece of colored chalk in each hand, Humphrey madeintricate drawings of the brain and spinal cord.father might give a son.Hooker’s department was described by theAmerican Association of Anatomists as “a harmoniousone in which to work.” Prior to theconstruction of Scaife Hall, the medical schooloccupied Pennsylvania Hall, a modest buildingon top of Cardiac Hill where a residencehall of the same name now stands. Studentsand professors would trudge upwards usinga stairway carved into the steep hillside. Atlunchtime, it was a nuisance to head downthe hill into Oakland and back up again,says Engstrom. So Hooker hosted brown-baglunches for his staff in the anatomy library.“We’d sit around a table upstairs and havelunch, talking about events of the day, whatwas going on in the medical school, and whatstudents were having problems,” Engstromsays. “Hooker was so sharp. He’d say so-andsoneeded some special attention and ask ifone of us would look after him and bring himup to date.” To these lunches Hooker invitedprofessors, junior instructors, and administrativestaff alike. “Everybody came witha brown bag. Your rank had nothing to dowith it,” says Macy Levine (MD ’43B), whoworked in Hooker’s lab as a student.It was these interactions that lent anundercurrent of approachability to the giant.Colleagues trusted him and went to him withproblems. Hooker and his senior staff wouldconsider each issue with “cautious, carefulscrutiny” and then incisively implement asolution, Humphrey wrote. It was clear “thefinal decision was his,” she says, “but theevidence received careful thought, not lipservice.”In the summer of 1925, after the firstcorrelated class concluded, Hooker wasquick to admit that the program wasnot without its flaws. “The results of ourexperience with this type of course have beeninteresting and in some respects unforeseen,”he wrote in “The Teaching of Anatomy as aCorrelated Course,” an article published inMethods and Problems of Medical Educationin 1930. Several early blunders in planningled to discouraging results and slow progressamong students. These errors were later rectified,however, and students demonstrated amore lasting and thorough comprehension ofanatomy than ever before. What they lacked,though, was the same intimate knowledgeof the details of structure. “The reader isleft to judge which is the more important: agenuine working knowledge of the body, ora rather facile (and, we believe, temporary)grasp of relatively unrelated details,” Hookerwrote. “We prefer the former.”To his surprise, Hooker was also forced tonote no time had been saved. In consideringthis truth, the staff agreed it requires as muchmental effort for a student to grasp correlationas to study each component separately.On the whole, however, Hooker and histeam determined the experiment was a success.In the coming years, several other anatomydepartments attempted a similar teachingmethod, but “none so satisfactorily or forso long,” wrote Humphrey. The correlatedcourse would continue to be taught at Pitt forthe next 28 years.For the success of the course Hooker feltindebted to two colleagues: J.S. Nicholas,a PhD who worked with him for five yearsat Pitt and later returned to Yale to becomedirector and chair of the Osborn ZoologicalLaboratory, and John C. Donaldson, an MDwhom he had met in high school. Earlyand long-lasting friendships formed betweenHooker and both men.Donaldson and Hooker had become reacquaintedat Yale when Donaldson was a seniorand Hooker, then serving as an instructor ofanatomy, was helping teach a course in whichhe found his former high school classmate.Upon becoming chair at Pitt in 1921, Hookerpromptly invited Donaldson to join his staff.One of Hooker’s original hires, Donaldsonwas among the first at Pitt who taught studentsanatomy by making them see it.A tall, quirky man, Donaldson was wellliked by students. His office contained a largebookshelf of classic literature—specimens hereadily lent out to those who dropped by, saysLevine, who often took him up on the offer.During his evenings at home, the doctorwould gather cloth, wire, tubing, and clay andassemble anatomical models of the humanbody. One display demonstrated how thesmall intestine rotates during embryologicaldevelopment. “The intestine starts out as astraight tube but then develops rapidly andbecomes 25 feet long. He showed how itcoiled without tangling and knotting itself.“It was amazing,” says Engstrom. “You’dread about it in a book, and then you’d seehis model the next day in class. He’d showyou how it happens. My gosh, the book madesense after you saw the model.” After class thedoctor would make these tools available forSUMMER 2012 29

students to use. “He’d put his hand on yoursso you could do the twisting and moving ofthe model to get the pieces into place. He’d beright there helping you,” Engstrom says.Later in life, Donaldson developed a moderatestoop but could still be seen jogging afew steps in the lecture hall (in his youth hewas a track man), demonstrating how a reflexsignal travels the pathway of a nerve.Another beloved professor, Jacob Priman,would join the University in 1948. A nativeof Latvia, Priman arrived in Pittsburgh aftertreating refugees and displaced people inGermany. His English was poor at first, butit was no matter for anatomical terms wereuniversal. Priman received emeritus status atthe University and continued teaching intohis 70s.A correlated course in anatomy requireda certain muddling of the department’s hierarchy,which is why, Hooker wrote, “Theinstructional staff must be willing to cooperatewholeheartedly in the project.” It wasvital, he said, that each member act as chief insome parts and assistant in others, accordingto their specialties. This made even the chairmerely a helper at times, Humphrey wrote, “aLEFT: HIPPOCRATEAN, RIGHT: NATIONAL LIBRARY OF MEDICINEamong their favorites. (She received twoGolden Apple awards for her teaching.)Using both hands, Humphrey would createintricate drawings of neural pathways onthe blackboard and lecture at the same time.“We all carried a box of pencils—just like afirst- or second-grader,” says Engstrom. “Youhad to. Otherwise, you put 150 lines on apiece of paper, and you can’t sort them out.They cross and run parallel.”“There were very few [projectors] at thistime,” says Robert E. Lee (MD ’56), “and herlectures were unique. She was ambidextrous.God help [you] if you dropped the pencil youwere drawing with. By the time you foundit on the floor, she had switched to anotherleft: Jacob Priman, a native of Latvia, joined thefaculty in 1948 after serving as a physician forthe displaced in post-WW2 Germany. right: JohnDonaldson was Hooker’s right-hand man and afavorite among students for his colorful, interactivemodels, which he made by hand from clay and wire.of human fetal behavior ever made, accordingto Humphrey.Humphrey continued her research until latein life, by which time her glasses had grownthick after she’d spent decades peering intomicroscopes. She published numerous studieson the patterns of spinal nerve formation inembryos while at Pitt and traveled the worldDonaldson developed a moderate stoop but could still be seen jogginga few steps in the lecture hall (in his youth he was a track man), demonstratinghow a reflex signal travels the pathway of a nerve.procedure only possible in a truly democraticdepartment.”The course plan also offered, for a certainspan of the year, a staff member respite fromteaching. It was Hooker’s firm belief that anacademic department has three functions:the teaching of students, the training of staff,and research. For the lattermost, the courseoffered continuous time for thoughtful study,and soon, to the chairman’s great fortune, acolleague worthy of his partnership in the labwould join the University.Tryphena Humphrey, neuroanatomistand the Hooker chronicler quotedabove, arrived at the University ofPittsburgh in 1939. Among friends and colleaguesshe was known as “Trap.” Amongstudents, “Ma.” A short-statured woman,Humphrey came to class armed with a boxof colored chalk. Though students scrambledto keep up with Humphrey, her lectures werecolor,” he says.While Humphrey was still completingher doctorate at the University of Michigan(she studied under Elizabeth Crosby, aPhD neuroanatomist who later became herlife partner and won the National Medalof Science), Hooker purchased a 35-mmmotion picture camera. Having gained thetrust and permission of the obstetricians atMagee-Womens Hospital, Hooker was ableto observe therapeutically aborted fetusesremoved by Caesarian section. Upon stimulatingthe skin, he recorded the degree ofreflex development, and in January of 1933,created the first films ever made of humanfetal movement. Humphrey saw great importancein the study and later joined Hookerfor what she called “the momentous task” ofdocumenting how reflexes form.The records created, involving morethan 135 fetuses and 20 premature infants,amounted to the most extensive investigationgiving lectures. Colleagues noted her affectionfor the phrase: “Happy to meet, sorry to part,happy to meet again” during these whirlwindyears. She left Pitt to become professor of anatomyat the University of Alabama at Birminghamin 1963. She died eight years later.By the mid-1950s, Hooker was preparingto retire, and pressure was mountingwithin the department. An explosionin medical knowledge had begun (the doublehelicalstructure of DNA had been discoveredjust years prior), and the devotion, by then, ofmore than 800 hours to the study of anatomyseemed to some on staff overblown, Barbara I.Paull wrote in her book, A Century of MedicalExcellence.In 1956, a new chair of the department wasselected—Albert Lansing, a renowned scientistand PhD who used chemistry and electronmicroscopes to study cellular aging. Theschool soon changed the department’s name30 PITTMED

HIPPOCRATEANleft: Students gather in the anatomy lab (1957-58). Dissection has long been consideredone of the best ways to learn gross anatomy. right: Humphrey was known by students as“Ma” and earned two Golden Apple awards for her teaching.to Anatomy and Cell Biology to reflect anincreased emphasis on teaching at the molecularlevel. This name would shift a number oftimes before the word “anatomy” would bedropped entirely. The anatomical subjects wereagain compartmentalized, and the course ingross anatomy landed within the jurisdiction ofthe present-day Department of Neurobiology.Throughout the country, first-year medicaleducation evolved to cover ever more subjectsin less depth. As knowledge expanded in areaslike genetics, pharmacology, and molecularbiology, new curricula were added that pinchedthe time allotted for each course.With the recent explosion of knowledge inthe basic sciences, Pitt’s faculty have rethoughthow to best incorporate the “pure” sciencesinto the curriculum. In their fourth year, Pittstudents now revisit the basic sciences, selectingfrom a panel of integrated life sciencescourses. First-year gross anatomy, now taughtin approximately 150 hours, emphasizes radiologicalimaging and a clinical approach.“We want students early on to be able toapply basic principles to clinical scenarios,”says Cynthia Lance-Jones, associate professor ofneurobiology and lecturer for medical embryology.“That means overtly showing them how todo it from day one.” Students now interact withpatients in class and meet in groups to discussassigned cases.“There is something magical about takinggross anatomy when students first startmedical school,” says Lance-Jones, who alsocoordinates the first-year basic science core. “Itmeans being a doctor to them. And there’s anelement of that that extends to how they viewthe people who are teaching it.”The course continues to be “the greatequalizer,” notes Jack Schumann, a PhD andPitt’s current director of anatomy. “We havepeople who come with PhDs in biochemistryor PhDs in literature. None of the studentshave had any gross anatomy. It puts them ona level playing field.”When Lance-Jones arrived at Pitt in 1983,Nick Cauna, an MD/ScD anatomist andembryologist, headed the anatomy program.He, too, created models and drawings on theblackboard. (Like Humphrey, he was ambidextrous.)“To watch him lecture was unbelievable,”she says. “When I first started, I tried to drawthings on the board, and I would literally goto class ahead of time. With dotted lines,I would label it left to right to make sure Ididn’t mess it up.“This was a tradition. I bet [the anatomyinstructors] all did it, and none of us can doanything like that now.”On Schumann’s first day at Pitt, he walkedinto Cauna’s office to find the man partiallyconcealed behind a giant model of thehuman head. “So, you are the new anatomist?”Cauna said, “I am the very old anatomist.”He promptly broke into a wide smileand shook Schumann’s hand.With Cauna’s 1983 departure, traditionsof handmade models and black-board drawingscame to a close, but a fondness for suchcustoms was not lost. Before Cauna left Pitthe provided materials for a museum in theback room of Pitt’s anatomy lab. There,dissections are enclosed in cases, and hiscolorful-plaster models of the trigeminalnerve and embryonic development remainon display. Every year professors still lugcertain structures out for lectures, because asSchumann has noted, in bold, near the topof his syllabus, ANATOMY IS A VISUAL SCIENCE.Following his retirement from Pitt in1956, Hooker lived and worked inNew Haven, Conn., where a spacewas made available for him in the OsbornZoological Laboratory. There, he hung acolored print of Rembrandt’s “The AnatomyLesson of Dr. Nicolaes Tulp” and continuedruminating over the fetal films he’d made atPitt. Although he made extensive progressduring these years, Hooker was not able tocomplete a comprehensive account of thestudy before his death in 1965. Nevertheless,the research yielded more than 40 scholarlypublications. Hooker’s work was writtenabout in TIME and occupied three full pagesin the 1947 Encyclopedia Britannica. Hisfindings were printed widely in textbooks,and his films were made available to scientistsinterested in expanding the work.“Those who were privileged to workclosely with him are more conscientiousresearch workers and better teachers becauseof this association,” Humphrey wrote of hercolleague after his death. “Likewise the medicalstudents who passed through his hands… have become more valuable physiciansand more honorable and tolerant men andwomen because of his influence.”During Hooker’s last year at the University,the alumni association had his portrait painted.One former student, George Fetterman,MD ’30 (who later joined the faculty),recalled it hanging outside an elevator nearthe anatomy lab and the chairman’s formeroffice. Every time Fetterman got off thatdepartment elevator, he was met by the master’scareful gaze.SUMMER 2012 29 31

ATTENDINGRuminations on the medical lifeSheila Advento drew the tree above on Nov. 7, 2010,two months after a double hand transplant. She tookup painting several months later. ABOVE LEFT: “A ColorfulLife” (created May, 13, 2011). LOWER LEFT: “Fluidity”(Nov. 23, 2011). LOWER RIGHT: When Advento drew“Precious” (undated), she still had prosthetic arms.HARD BEAR WOMANTHE ART OF LIVINGBY ERICA LLOYDSheila Advento’s hands are not the hands she was born with.In 2003, at the age of 26, Advento was living with her mom in Hackensack,N.J., and working in patient billing at Quest Diagnostics while attending communitycollege. On July 4th, she came down with a devastating bout of meningococcemia anddays later fell into a coma. While Advento lay unconscious at Hackensack University MedicalCenter, her family held vigil at the hospital. Tita Sally, her aunt back in the Philippines, recitednovenas. Brother-in-law Hadrien, who had studied Native American healing practices, setup an altar in the ICU; he also called his mentor, Chief Phillip Crazy Bull, a Sicangu LakotaHoly Man, who proceeded to lead hundreds in a Sun Dance ceremony in South Dakota. Inrecognition of the healing powers of the bear, Advento would be offered the spiritual nameMato Suksuta Win, Hard Bear Woman.On the seventh day of her coma, the doctors called a family meeting: They couldn’treverse the young woman’s condition. It was time to consider ending life support. Advento’sfamily refused to give up hope. Her mother, a nurse at NYU’s rehabilitation center, directedthe intensivist to continue support but lessen intravenous sedation. Also: If her daughter’svital signs deteriorated, the doctors should not attempt extreme measures to save her.On the ninth day, Advento opened her eyes. Her family was jubilant. Advento was gratefulto be alive; while comatose, she had a vision that she was lost in Calcutta.32 PITTMED

98.6 DEGREESPeople and programs that keepARTWORK COURTESY ADVENTOBut as the days passed, it became clear thatAdvento’s hands and feet were infected andcould not be saved. They would have to beamputated. During those weeks in the hospitalas the amputations proceeded, there wasdespair but also love. At any given moment,a family member was by Advento’s side. Inthe months afterward, she learned to walk onprosthetic legs. She learned to use prosthetichands. She moved into her own apartment,with an assistant helping her in the morningsand evenings.Seven years later, an opportunity arose.Advento would become the first woman inthe United States to undergo a double handtransplant. On Sept. 18, 2010, four teams ofsurgeons at the University of Pittsburgh wentto work. Two teams removed hands from thedonor; two teams attached those hands toAdvento. The surgeons fixated bone from thedonor hands onto her forearms. They connectedand repaired tendons, arteries, nerves,and veins. After 12 hours and 17 minutes,they were done. Advento was put on thePittsburgh Protocol of immunosuppression.She recovered from the procedures with nosignificant medical issues, but she would haveto win back her independence. This meantsix hours of occupational therapy a day.Advento would attempt to influence and feelher surroundings through an intricate networkof 96 nerves and 56 muscles that oncebelonged to someone else. The simplest tasks,like turning a door knob, were formidable.One month after the transplant, Adventodrew the cartoon character Garfield. (She’dalways liked drawing.) Four months aftertransplant, she wove a bracelet. That samemonth, she played darts for the first time,even pulling off a few bull’s-eyes. She experimentedwith something else, too. At Hadrien’ssuggestion, she started painting.“I wanted to keep trying things,” she says.“Even if I was unsuccessful, at least I wouldknow I was successful in trying.”She’s back working at Quest and expectsto continue with hand therapy (two or threehours a day) for the rest of her life. She hasher own place again; about once a week anassistant comes by to help out.What’s been most rewarding about thejourney: touching others —holding a handor reaching out some other way. Advento hasbeen featured in national media and giventalks to amputees and other groups. It seemsto help people when she shares her story. ■BEYONDEXPECTATIONSthe school healthy and vibrantNEW SCHOLARLY PROJECTFUND HONORS LOREN ROTH“ IBY NICK KEPPLERdon’t think there’s anyone more willingto go not just the extra mile but where he organized the prison debateStates Penitentiary in Lewisburg, Pa.,the extra 10 miles,” says Pitt’s Ellen team and treated James Hoffa. Later,Frank, Distinguished Professor of Psychiatry he was the psychiatric leader forand professor of psychology, of her colleague several State Department delegationsLoren Roth. Now some School of Medicine to the Soviet Union, examining thestudents will reap benefits from Roth’s tireless,beyond-the-expected approach to patient care.Anonymous donors have made a $100,000Communist party’s practice of lockingup healthy dissidents in mental hospitals.On a previous visit to the U.S.S.R. in 1985,gift to honor Roth, a psychiatrist who has Roth was a member of a lay group that setheld a variety of leadership positions in his up medical clinics with the underground and38-year history at Pitt and UPMC (includingchief medical officer) and is now Pitt’s associatesmuggled in medications.At Pitt, Roth and colleagues created “Thesenior vice chancellor for clinical policy Basic Science of Care” course that was requiredand planning, health sciences. The donation for several years for second-year medical students.will fund the Loren H. Roth, MD, SummerResearch Program, which will help med studentspay for travel, books, lab materials, andother expenses related to work on the researchexperience known as the scholarly project.The donors, a husband and wife who havelong supported the University, say Roth helpedThe course taught about hospital safetyand how medical care is administered in theUnited States.The med school course was “quite propheticand ahead of its time,” says McDonald. (By theway, the scholarly project fund is not the firstprogram to recognize Roth; a UPMC annualorganize care for a loved one. His “breadth seminar on quality and patient safety also carrieshis name.)of experience allowed him to locate nationalresources, beyond what was available locally,”says one of the donors.Roth has a special appreciation for thescholarly project experience that the $100,000This does not surprise Frank, who has donation supports. The project was added toworked with Roth for more than 15 years atWestern Psychiatric Institute and Clinic, wherehe began his career at Pitt 38 years ago as directorthe School of Medicine’s curriculum in 2004and led to 18 fellowships, 22 awards, and106 coauthorships in research papers amongof the Law and Psychiatry program. She the Class of 2011 alone. Students work withsays Roth took notice of another WPIC patientwho needed help and stepped into a variety ofroles for her, even helping to fix her plumbingand arrange her finances.Pitt’s Margaret McDonald, a PhD and associatevice chancellor for academic affairs, healthmentors to research a topic of their choosing.The program was designed to spark curiosityand help students develop investigative skills.(Projects examining three broad subjects closeto Roth’s heart—medical ethics, psychiatry,and quality of patient care—will be given preferencefor funding.)sciences, has known Roth since the 1970s,when she was a science reporter and he wasone of her sources. McDonald calls him a manof “extraordinary intellectual curiosity who hastaken the course of his career into several interesting“Pitt has pioneered nationally by establishingthese medical student research projects,”Roth says, “lighting the fuse of discovery,thereby adding so much to student experiencesdirections.” Before he was a psychiatrist, analytically and attitudinally.” —Joe MikschRoth was a general practitioner at the United and Shermi Sivaji contributed to this story. ■RothSUMMER 2012 33

MATCH RESULTSCLASS OF 2012ANESTHESIOLOGYBentley, DouglasUPMC/University of Pittsburgh, Pa.Garringer, JulieJohns Hopkins Hospital, Md.John, EricaBeth Israel Deaconess Medical Center/Harvard University, Mass.Kolan, MichaelMcGaw Medical Center of Northwestern Univ., Ill.Le, GiangNewYork Presbyterian–Columbia Univ. Medical CenterMcGovern, DavidMcGaw Medical Center of Northwestern Univ., Ill.Okafor, DionneBrigham & Women’s Hospital/Harvard Univ., Mass.Tuomala, LumeiNewYork Presbyterian–Columbia Univ. Medical CenterWilde, JamesLoma Linda University Medical Center, Calif.Wise, EricUPMC/University of Pittsburgh, Pa.DERMATOLOGYAndrulonis, RyanGeisinger Health System, Pa.McGuire, SeanPenn State Milton S. Hershey Medical Center, Pa.Mirvish, EzraUPMC/University of Pittsburgh, Pa.Secrest, AaronUniversity of Utah Affiliated HospitalsEMERGENCY MEDICINEBehringer, TiffanyVanderbilt University Medical Center, Tenn.Chowa, PhindileBrigham & Women’s Hospital/Harvard Univ., Mass.Considine Courtelou, HonoraUniversity of California, Davis Medical Center,SacramentoDownie, StevenVanderbilt University Medical Center, Tenn.Fung, ChristopherUniversity of Michigan HospitalsGandhi, RuchitaMt. Sinai Hospital, N.Y.Gebhardt, KoryMcGaw Medical Center of Northwestern Univ., Ill.Hemerka, JosephDenver Health/University of ColoradoHughes, KatieUniversity of North Carolina HospitalsKralik, KevinMaine Medical CenterMo, LarryUniversity of Chicago Medical Center, Ill.Pfeiffer, AnthonyUPMC/University of Pittsburgh, Pa.Roche, BaileyUniversity of California Davis Medical Center,SacramentoSaunders, JasonYork Hospital, Pa.Shulman, JoshuaUPMC/University of Pittsburgh, Pa.Smiley, MarkVidant Medical Center/East Carolina University Brody, N.C.Tawa, LindsayAdvocate Christ Medical Center, Ill.Yang, FanBrigham & Women’s Hospital/Harvard Univ., Mass.FAMILY MEDICINEArchinal, ElizabethSumma Health/Northeastern Ohio UniversitiesCooper, MaryUniversity of MassachusettsRuff, JoyIn His Image (St. John Medical Center,other Tulsa and Claremore clinics), Okla.Shah, KarishmaSt. Joseph’s Hospital/SUNY Upstate Medical CenterTaylor, LauraUPMC St. Margaret/University of Pittsburgh, Pa.INTERNAL MEDICINEBednash, JosephUPMC/University of Pittsburgh, Pa.Berger, ChristopherUCSF Medical Center/Moffit-Long Hospital andAffiliates/University of California, San FranciscoBernard, MarkUPMC/University of Pittsburgh, Pa.Bonifacino, ElianaUPMC/University of Pittsburgh, Pa.Boyd, CaryUPMC/University of Pittsburgh, Pa.Chua, AbigailMontefiore Medical Center/Albert Einstein Collegeof Medicine, N.Y.D’Auria, StephenUPMC/University of Pittsburgh, Pa.Ellis, ShaneSAMHS Lackland AFB, TexasEngland, JamesVanderbilt University Medical Center, Tenn.Evankovich, JohnUPMC/University of Pittsburgh, Pa.Giridhar, KarthikUCSF Medical Center/Moffit-Long Hospital andAffiliates/University of California, San FranciscoHalevy, JonathanFletcher Allen/University of VermontHintz, LindsayBeth Israel Deaconess Medical Center/Harvard University, Mass.Jarido, VeronicaDuke University Medical Center, N.C.Khatana, Sameed AhmedBrigham & Women’s Hospital/Harvard Univ., Mass.Laux, TimothyBarnes-Jewish Hospital/Washington University, Mo.Lembeck, MeghanPenn State Milton S. Hershey Medical Center, Pa.Liu, TimothyKaiser Permanente Santa Clara Medical Center, Calif.Livesey, KristenUPMC/University of Pittsburgh, Pa.Lozano, JoseDuke University Medical Center, N.C.Mahmood, DeebaVidant Medical Center/East Carolina University Brody, N.C.Maurice, NicholasUniversity of Michigan Hospitals, Mich.Pishko, AllysonDuke University Medical Center, N.C.Sedighi Manesh, RezaUCSF Medical Center/Moffit-Long Hospital andAffiliates/University of California, San FranciscoShah, MiratVanderbilt University Medical Center, Tenn.Shoukry, AlfredUPMC/University of Pittsburgh, Pa.Suresh, TejasMontefiore Medical Center/Albert Einstein College of Medicine, N.Y.Tavares, RobertBeth Israel Deaconess Medical Center/Harvard University, Mass.Wan, XiaoUniversity of Chicago Medical Center, Ill.Zikos, ThomasStanford University Programs, Calif.INTERNAL MEDICINE/MPHWu, YouKaiser Permanente Medical Center at Oakland, Calif.INTERNAL MEDICINE—PEDIATRICSRamer, SarahUniversity Hospital & Hackensack University MedicalCenter/UMDNJ, N.J.Zipkin, JonathanPenn State Milton S. Hershey Medical Center, Pa.INTERNAL MEDICINE—PRELIMINARYWheeler, DavidAlbert Einstein Medical Center, Pa.INTERNAL MEDICINE—PRIMARYMurphy, JessicaHospital of the University of PennsylvaniaSilverman, GabrielMontefiore Medical Center/Albert Einstein College of Medicine, N.Y.INTERNAL MEDICINE—WOMEN’S HEALTHHamilton, AmyUPMC/University of Pittsburgh, Pa.MAXILLOFACIAL SURGERYLi, TonyUPMC/University of Pittsburgh, Pa.NEUROLOGICAL SURGERYBales, JamesUniversity of Washington Affiliated HospitalsNEUROLOGYHepner, SethBarnes-Jewish Hospital/Washington University, Mo.Kang, PeterBarnes-Jewish Hospital/Washington University, Mo.Kim, JosephUniversity of Southern California AffiliatesOBSTETRICS/GYNECOLOGYCondon, KarenAbington Memorial Hospital/Temple University, Pa.Lee, Jessica KarenUPMC/University of Pittsburgh, Pa.Napoe, GnankangBrigham & Women’s Hospital/Harvard Univ., Mass.Pettigrew, GaetanUniversity Hospitals Case Medical Center/Case WesternReserve University, OhioRyan, AudraAlbany Medical Center/Albany Medical College, N.Y.Thomas, SemaraUniversity of Virginia Health SystemOPHTHALMOLOGYZhang, MatthewVanderbilt University Medical Center, Tenn.ORTHOPAEDIC SURGERYSingh, KeeratVanderbilt University Medical Center, Tenn.Working, ZacharyUniversity of Utah Affiliated HospitalsJIM BURKE / CIDDE34 PITTMED

Students and their cheering sections at this year’s Match Day in March. Someone’s name must be called last, eh? This year it was Beth Papas. But she wasrewarded with the pot of gold (as her classmates learned of their matches, they each put a dollar in the kitty), as well as a residency at Children’s.OTOLARYNGOLOGYBeswick, DanielStanford University Programs, Calif.Vella, JosephStrong Memorial Hospital/Univ. of Rochester, N.Y.Wilson, CalebUniversity of Tennessee Health Science CenterPATHOLOGYBartholow, TannerUPMC/University of Pittsburgh, Pa.Chou, DavidMassachusetts General Hospital, Harvard Univ.Shyu, SusanUniversity Hospitals Case Medical Center/Case Western Reserve University, OhioPEDIATRICSBarreiro, AlessandraDuPont Hospital for Children/Thomas Jefferson University, Pa.Carey, ReganHarbor-UCLA Medical Center, Calif.Christopher, AdamYale-New Haven Children’s Hospital, Conn.Conway, SusanCincinnati Children’s Hospital Medical Center, OhioEllsworth, KevinChildren’s Hospital of Pittsburgh of UPMC/Universityof Pittsburgh, Pa.Kippelen, FannyChildren’s Hospital of Philadelphia/University ofPennsylvaniaLeibowitz, MichaelChildren’s Hospital Colorado,Denver Health/University of ColoradoLinakis, SethUPMC/University of Pittsburgh, Pa.McBride, JoshuaUpstate Golisano Children’s Hospital/SUNY Upstate Medical University, N.Y.Mistovich, KeiliUPMC/University of Pittsburgh, Pa.Otto, AlanaChildren’s Memorial Hospital/McGaw Medical Centerof Northwestern University, Ill.Papas (Baker), BethChildren’s Hospital of Pittsburgh of UPMC/University of Pittsburgh, Pa.Pichler, StephenChildren’s Memorial Hospital/McGaw Medical Centerof Northwestern University, Ill.Predis, ErinChildren’s Hospital of Pittsburgh of UPMC/University of Pittsburgh, Pa.Salimi, UmarFloating Hospital for Children/Tufts University, Mass.Thompson, MichaelNationwide Children’s Hospital/Ohio State UniversityPEDIATRICS/PSYCHIATRY/CHILD PSYCHIATRYGraham, KahlebRhode Island Hospital/Brown University, R.I.PHYSICAL MEDICINE& REHABILITATIONCassell, AndreJohns Hopkins Hospital, Md.Darrah, ShaunUPMC/University of Pittsburgh, Pa.Guirand, AlcintoSpaulding Rehabilitation Hospital/Harvard Univ., Mass.McClure, MatthewHospital of the University of PennsylvaniaNora, GeraldUPMC/University of Pittsburgh, Pa.Pinto, ShantiUPMC/University of Pittsburgh, Pa.PLASTIC SURGERYBykowski, MichaelUPMC/University of Pittsburgh, Pa.Lee, Jessica AnnUPMC/University of Pittsburgh, Pa.PSYCHIATRYCohen, DanielWestern Psychiatric Institute & Clinic,UPMC/University of Pittsburgh, Pa.Deo, AnthonyNewYork Presbyterian–Columbia Univ. Medical CenterLundblad, WynneWestern Psychiatric Institute & Clinic,UPMC/University of Pittsburgh, Pa.Israel, BenjaminUniversity of Maryland Medical Center,Sheppard and Enoch Pratt HospitalZanoun, RamiWestern Psychiatric Institute & Clinic,UPMC/University of Pittsburgh, Pa.PSYCHIATRY/ADULT & CHILDPitskel, NaomiYale-New Haven Hospital, Conn.PSYCHIATRY/FAMILY MEDICINEHuijon, RogerUPMC St. Margaret/University of Pittsburgh, Pa.RADIATION ONCOLOGYBoyer, MatthewDuke University Medical Center, N.C.Kim, HyunThomas Jefferson University Hospital, Pa.Olson, AdamDuke University Medical Center, N.C.RADIOLOGY—DIAGNOSTICChen, YinHospital of the University of PennsylvaniaHattoum, AlexanderRobert C. Byrd Health Sciences Center/West Virginia UniversityMawn, JohnUPMC/University of Pittsburgh, Pa.Mayercik, VeraTufts Medical Center, Mass.McGarry, WilliamMcGaw Medical Center of Northwestern Univ., Ill.Mehta, AjeetEmory University, Atlanta, Ga.Mehta, AmarUniversity of Chicago Medical Center, Ill.Ng, TimothyEmory Healthcare, Grady MemorialPinnamaneni, NivedithaNYU Langone Medical Center, N.Y.RESEARCHLonghini, AnthonyUPMC/University of Pittsburgh, Pa.(Vascular Medicine Institute)SURGERY—GENERALDyer, MitchellUPMC/University of Pittsburgh, Pa.Gabrielian, AnnaDanbury Hospital, Conn./University of VermontGoodman, LauraUniversity of California Davis Medical Center, SacramentoHuynh, CindyUniversity Hospital/SUNY Upstate Medical University, N.Y.Johnson, CarlUniversity of Toledo Medical Center, OhioKu, NatalieUniversity of California San Diego Medical CenterMurken, DouglasHospital of the University of PennsylvaniaSURGERY—PRELIMINARYGo, KristinaShands Hospital/University of FloridaSingleton, AlexUPMC Mercy/University of Pittsburgh, Pa.Wynkoop, AaronVanderbilt University Medical Center, Tenn.Zaccheus, OlulekeBeth Israel Deaconess Medical Center/Harvard University, Mass.UROLOGYPackiam, VigneshUniversity of Chicago Medical Center, Ill.VASCULAR SURGERYDomenick, NatalieUPMC/University of Pittsburgh, Pa.SUMMER 2012 35

ALUMNI NEWSCLASS NOTES’90s During his residency, DavidRosenberg (General Psychiatry Resident ’92, ChildPsychiatry Fellow ’92) wanted to learn as much as hecould about treating psychiatric disorders in youth:“I asked one of my attendings what textbook hewould recommend I use to learn more about pediatricpsychopharmacology. He told me there was notextbook.” Rosenberg’s response? Write his own. In1994, Rosenberg, with John Holttum (Child PsychiatryResident ’94) and faculty mentor Samuel Gershon,now Pitt emeritus professor of psychiatry, publishedPharmacotherapy for Child and Adolescent PsychiatricDisorders, which is still used by pediatric healthprofessionals today (the third edition was publishedin March). Rosenberg, now chief of psychiatry andpsychology at the Children’s Hospital of Michigan andprofessor of psychiatry and behavioral neurosciences atWayne State University, studies the genetics of childrenwith depression and obsessive compulsive disorder.A specialist in both minimally invasive spine surgeryand advanced scoliosis, Hooman Melamed (MD’99) treats some of the best- and worst-case spinalscenarios. With the Scoliosis Research Society’s GlobalOutreach Program, he has traveled to Colombia, wherehe says scoliosis in kids is often overlooked. Melamed,now spine consultant at Shriners Hospitals for Childrenin Los Angeles, describes seeing “horrible conditions” inteenage patients who should have been treated as toddlers.Both at home and abroad, the surgeon performscomplex osteotomies, where the spine is broken andreset. Conversely, much of his California-based practiceat DISC Sports and Spine Center treats less-severe disordersusing minimally invasive techniques. “People areshocked when they find out you can have spine surgeryas an outpatient and go home a few hours later.”’00s When Benjamin Davies (SurgeryResident ’02, Urology Resident ’05) learned he couldremove a kidney using one incision instead of three,he thought it was “crazy.” The technique, called alaparoendoscopic single-site (LESS) surgery, requiresDavies to manipulate traditional tools with his handscrossed. “It’s not something that comes intuitively. … Itjust takes a little getting used to,” says Davies, assistantprofessor of urology at Pitt. The surgery, which isoften used to remove healthy kidneys for donation, isnow being used by Davies to remove kidney tumors.Davies, a urologic cancer specialist, knew it wouldn’tbe an option for most of his kidney patients—becauseonly small tumors would fit through a single site—but hewanted to offer it to those who qualified. This March heperformed the first single-site kidney tumor removal inSouthwestern Pennsylvaia. He calls LESS surgery a “boutique”part of his practice but predicts it’ll become morecommon once robotic tools, currently in experimentalstages, are approved.Compared to traditional means of radiation therapy,the robotic CyberKnife system is extremely precise: Itdelivers multiple, pinpoint, high-dose beams of radiationwith submillimeter accuracy. “This allows us to focus radiationdoses more precisely so that critical structures surroundingthe problem remain unaffected,” says SarahgeneGillianne DeFoe (MD ’06, Intern ’07, Radiation OncologyResident ’11). DeFoe trained extensively on the techniqueduring her residency at Pitt, and in November she joinedthe Cape Fear Valley Health System in North Carolina tojumpstart a CyberKnife program there. DeFoe recentlyconducted a study demonstrating CyberKnife’s efficacyin treating rectal cancer. She also specializes in treatingpatients with cancers of the breast, brain, and lung.In 2010, cleanup crews and animal welfare expertsscrambled to prevent massive ecological damage afterthe BP Deepwater Horizon oil spill. And in the midst ofDeFoe starts a CyberKnife program in Fayetteville, N.C.LIVE WITH NANCY SNYDERMANDoctors’ offices are full of devices and instruments particular to each specialty,but they don’t typically include a microphone and professional cameracrew. As chief medical editor for NBC News, Nancy Snyderman (PediatricsResident ’79, Otolaryngology Resident ’83) regularly discusses health-relatedissues on Today and produces medical reports for programs like Dateline NBC,NBC Nightly News, and Rock Center with Brian Williams. Though her roles as physicianand journalist may seem worlds apart, Snyderman says that she’s a “perpetualstudent” in both positions. And she notes that her approach to communicatingdifficult scientific and medical concepts to patients and viewers is always the same:“My job is to take [complex medical] information and present it in a way that isn’tcondescending to people.”Snyderman’s television appearances broadcast her medical expertise to millions;yet she doesn’t believe that her views have more weight. “I don’t think myopinion matters any more than [that of ] someone’s personal physician,” she says.“As a journalist, I’m not necessarily supposed to have an opinion anyway.”In 2011, Snyderman received the School of Medicine’s William S. McEllroyAward, which honors a resident alumnus each year. She was also awardedthe Albert C. Muse Prize for Excellence in Otolaryngology from the Eye and EarCOURTESY SNYDERMAN36 PITTMED

chaos, they relied on an outdated,paper-based recordingsystem to track the speciesaffected and tag animals. That gotJonathan Lustgarten (BiomedicalInformatics MS ’06, PhD ’09)thinking: Why would veterinariansrely on a system that’s unreliable,easily damaged, and almostLustgarten with apenguinimpossible to share long distance?Last year, he thought about developing a softwaresolution, and he won the $100,000 Student InspirationAward from the University of Pennsylvania, where he isa veterinary medicine student, to do so. Lustgarten says,“The software will help veterinarians and researchersmanage information and provide the best care to animalsin a variety of disasters and beyond.”’10s It’s not surprising that, as afamily medicine doctor and Pitt associate professorof medicine and pediatrics, Brian Primack (Clinicaland Translational Science PhD ’11) is concernedabout tobacco propaganda. But what he found in arecent study is surprising: In the American Journal ofPreventive Medicine, Primack reported that of the hookahtobacco Web sites his team surveyed, more thanhalf didn’t include the word “tobacco.” “We expectedthat hookah Web sites might de-emphasize tobacco,but we did not expect that many would leave out theword altogether,” says Primack, who notes that noneof the sites required age verification and less than 1percent included a tobacco-related warning. Hookahtobacco, which comes in a variety of fruity flavors, isoften wrongly perceived as less harmful; but Primacksays studies show it exposes users to large amounts oftar, nicotine, and carbon monoxide.—Jenelle Pifer and Shermi SivajiTHE WAY WE ARECLASS OF ’02In the winter before their graduating year, pianist Mark Lazarev (MD ’02, Gastroenterology,Hepatology, and Nutrition Fellow ’08) and violinist Amanda Pong (MD ’02) took the stageto perform a sonata movement by Sergei Prokofiev in the School of Medicine’s annual talentshow. He’d decided to study medicine after years of studying classical piano in the Oberlin CollegeConservatory of Music. The talent show was, for him, a night of personal transition. “[Music] wasdefinitely something I was doing seriously,” he recalls from his office at Johns Hopkins University,where he is now assistant professor of medicine. But his overriding interest in science (he also studiedneuroscience as an undergrad at Oberlin) led him to pursue a path where he could “really reallyhelp people.” Now, he focuses his research on inflammatory bowel disease, specifically Crohn’s diseaseand ulcerative colitis. Because inflammatory bowel disease usually develops early, in the teensor 20s, there’s a real opportunity to improve quality of life over the long term, he says.Suzanne Atkinson (MD ’02) remembers hearing Lazarev play. “He was excellent. … Hereally had a depth to his personality that went beyond the typical stereotype of a med student,”she says. But atypical students were the norm at Pitt, it seemed to Atkinson. She herself turnedto medicine after years spent teaching and practicing wilderness sports. During a mountaineeringexpedition in Mexico, she met Jim Withers (MD ’84), a UPMC internist who inspired her tostudy medicine. Withers, who founded Operation Safety Net to bring medical care to people livingon Pittsburgh’s streets, taught Atkinson that physicians could practice medicine in uncommonways. “I saw … the way that medicine can allow someone to communicate with another humanin a way that otherwise wasn’t possible,” she says. Now a clinical instructor of emergency medicineat Pitt, Atkinson serves as a medical command physician with STAT MedEvac and also trainstriathletes (she is a triathlete herself). “In both activities, you really need to have a connectionwith the human being,” she says, “In the emergency room, it has to happen in a very compressedamount of time.”Bill Hobbs (Molecular Virology and Microbiology PhD ’00, MD ’02) performed at the talentshow the same year as Lazarev. His band—which cycled through a number of names, including FattMan and Billy Hobbs Band—played “loud and obnoxious rock and roll,” Hobbs says from his labat the Puget Sound Blood Center in Seattle. There, he studies adult sickle cell disease, an interesthe developed at Pitt while shadowing Timothy Carlos, then director of the school’s Adult SickleCell Program. These days, Hobbs’ research investigates a particular plasma protein (von Willebrandfactor). “People who don’t have enough [of theprotein] have bleeding disorders, but we thinkpeople with sickle cell disease have too much,”says Hobbs, who is also acting assistant professorof medicine in the Hematology Division atInstitute and Foundation for her significantcontributions to the medical field. “I wasblown away by receiving those awards,” shesays. “I owe Pittsburgh so much. I startedmy journalism career there, and I’ve stayedvery close to Pittsburgh and my mentorsthere.” (Snyderman is also a clinical associateprofessor of otorhinolaryngology at theUniversity of Pennsylvania.)Snyderman spoke at the School ofMedicine’s graduation ceremony this May,stressing that it’s important for new physiciansto focus on the compassionate fundamentalsof patient care. “A lot of it is gettingback to basics,” she says. “There is a basicneed for humanity in medicine and science.And there is nothing more important than thehuman touch.” —Dennis Funkthe University of Washington.“It was a stressful time,” Hobbs says of theMD/PhD program. The students still crammedin trips to Oakland bars and restaurants,but they’d study “before, during, and after.”Ilan Kerman (Neuroscience PhD ’99, MD’02) says that about sums it up. Duringhis time at Pitt, Kerman explored how thebrain maintains a stable internal environment,research he’s now building on as assistantprofessor of psychiatry and behavioral neurobiologyat the University of Alabama atBirmingham. Specifically, he’s looking intothe causes of the physical symptoms associatedwith depression. “There is a significantmedical comorbidity with depression, includingheart disease and diabetes. But in terms ofcauses, we don’t really know,” he says. —JPSnyderman in HaitiSUMMER 2012 37

ACHIEL L. BLEYAERTJUNE 23, 1931–OCT. 30, 2011JAMES SHAVERJAN. 21, 1935–APRIL 13, 2012GERHARD WERNERSEPT. 28, 1921–MARCH 26, 2012BleyaertIn the 1970s, AchielBleyaert investigatedbrain function andischemia after resuscitationat the InternationalResuscitation ResearchInstitute, now the SafarCenter for ResuscitationResearch in the University ofPittsburgh School of Medicine. His animalstudies showed that barbiturates after cardiacarrest protected the brain, says Ake Grenvik,an early colleague of Bleyaert’s and physicianat UPMC from 1968 to 2009. Though thefindings could not be confirmed in repeatedstudies and the treatment was not as successfulin humans, says Grenvik, “It was a big step—an important step—in research toward brainimprovement after cardiac arrest and resuscitation.”Bleyaert’s initial inquiries sparkeddecades of research in this area, Grenvik adds,which eventually led to the current practice ofusing hypothermia to protect the brain fromdamage after cardiac arrest.Bleyaert, a Pitt professor of anesthesiologyand critical care medicine from 1980 to1985, died in October at Clearfield Hospital,in Clearfield, Pa., where he had been a staffanesthesiologist since 1992. He was 80.Grenvik remembers Bleyaert as an intelligentman who was easy to get along with.Though quiet, he was a diligent worker anda positive mentor. “He was a good teacher inthe operating room for anesthesia residentsand medical students.” —Dennis Funk’40sHARRY S. HARTMANMD ’43ADEC. 8, 2011’50sPETER P. STAJDUHARMD ’52DEC. 3, 2011EDGAR S. HENRY JR.MD ’53APRIL 4, 201238 PITTMEDJames Shaver, directorof the Division ofCardiology in Pitt’sSchool of Medicine for morethan two decades and mentorto many, died in April.In the 1960s, ShaverShaveropened and directed the firstcardiac catheterization laboratory at what wasthen Presbyterian University Hospital. Hisclinical and research interests included valvularheart disease, adult congenital heart disease,hypertrophic cardiomyopathy, and the physiologicbasis of heart sounds and murmurs. Buthe may be remembered best for his teaching.As a Pitt faculty member for more than 40years, Shaver trained hundreds of cardiologists.William Follansbee, who teaches in theDivision of Cardiology, says he will rememberShaver for his remarkable ability to teachmedical students and cardiology fellows. “Itwas probably his greatest strength,” Follansbeesays. “I think the fellows in general who havegone through the program over the last coupledecades all saw him as an important mentor.”For many years, Shaver designed and ranthe fundamental cardiovascular course forsecond-year students. “An extensive amountof work goes into the course,” says Follansbee.“The syllabus just for that course is two volumesthick.”A spirit of eternal optimism was part ofwhat helped Shaver shape the curriculum andguide students in their careers, Follansbeesays. He notes that in later life Shaver wouldn’tlet his own medical issues get him down, andthat he still went skiing and traveled to conferences.“He was dedicated and motivated untilthe very end,” he says. —DFIN MEMORIAMMARTIN ARISTARKMURCEKMD ’58MARCH 16, 2012’60sEDWIN DELROYSTUTZMAN JR.MD ’61APRIL 12, 2012ROBERT EMERSONCAVENMD ’64JAN. 15, 2012LOUIS D. METAMD ’67MARCH 15, 2012’70sALAN JOHNKUNSCHNERRES ’72MAY 2, 2012’80sJEFFREY S. GIBSONMD ’89APRIL 9, 2012’90sAMY C.MASZKIEWICZSOBIESKIMD ’97MARCH 4, 2012FACULTYANTHONY H.VAGNUCCIAPRIL 19, 2012PATRICK G. LAINGMARCH 28, 2012Gerhard Werner, an MDand former dean of Pitt’sSchool of Medicine, wasan avid reader: He devouredbooks of philosophy and literatureand encouraged his studentsto do the same. Werner’s inquisitivenesswas an essential part of him,Wernersays William de Groat, a former colleague.“Werner was excited about research and wasalways thinking of something new to do,” says deGroat, Distinguished Professor in the Departmentof Pharmacology and Chemical Biology. In the1960s, de Groat joined Pitt under Werner, thenthe department’s chair.An innovative neuroscientist, Werner publishedmore than 100 scientific papers and developeda muscle relaxant (succinylcholine), his firstmajor invention; it’s still used by anesthesiologiststoday. With a keen interest in computer science,Werner, while at Pitt, helped devise an early artificialintelligence-driven medical expert system.“He was visionary, but also urbane and cultured,”says de Groat, noting that Werner’s worldlinesswas particularly evident in the classroom.Hoping to enliven lectures, he often shared wittystories about his extensive travels. (He graduatedfrom the University of Vienna’s medical schooland worked in India and Brazil before emigratingto the United States in 1957.)In 1974, he was appointed dean of the medicalschool. Although he was a basic scientist, oneof his most lasting administrative contributionswas a practice plan system that would prove keyto turning the school’s financial situation aroundduring difficult times, Barbara I. Paull notes inA Century of Medical Excellence (1986).Werner was honored with the U.S. SeniorScientist award from the Alexander von HumboldtFoundation in 1985.After retiring from Pitt in1989, he became an adjunctprofessor of biomedical engineeringat the University ofTexas at Austin. There, he stayedactive in such research areas asartificial intelligence and neurodynamics.—Dana Yates

DAVID MADOFFREGENERATE,WITH PRECISIONBY SHARON TREGASKISWhen it comes to cancer, the lastthing a patient wants to hear is, “I’msorry, it’s inoperable.” Interventionalradiologist David Madoff (MD ’95) hates foranyone to deliver such news. So he has dedicatedthe past decade to refining a pre-operativeprocedure known as PVE (portal vein embolization)that makes more patients with liver cancereligible for surgery.Unlike such organs as the kidney, lungs, orheart, the liver responds to severe injury witha growth spurt. It’s like a starfish sprouting anew arm after a predator’s attack: Remove aportion of the organ, and the remaining piecewill regenerate to full capacity within months.But there’s a catch: Take too much, and what’sleft shuts down, flooding the body with toxinsand bacteria.“People can die after surgery if they havea very small liver,” says Madof f, now chiefof the Division of Interventional Radiologyat NewYork–Presbyterian Hospital and WeillCornell Medical College. Without intervention,he says, just 25 percent of patients whoneed extensive resection would qualify.Enter PVE, pioneered by Japanese surgeonMasatoshi Makuuchi in 1990 and since refinedby Madoff, who’s traveled throughout the worldteaching the procedure. Like most techniquesdeveloped by interventional radiologists, it’sBRIAN KLATT (MD ’97)PresidentJAN MADISON (MD ’85)President-electMARGARET LARKINS-PETTIGREW (MD ’94)SecretaryPETER FERSON (MD ’73)TreasurerROBERT E. LEE (MD ’56)HistorianSUSAN DUNMIRE (MD ’85)Executive DirectorMEDICAL ALUMNIASSOCIATION OFFICERSCOURTESY MADOFFMadoff helps make diseased liversstrong enough for resection.minimally invasive. Using imaging technologyto reveal the portal vein, the radiologistthreads a catheter into the blood vessel to beembolized and then injects either a chemicalsolution or beads that block blood flow to thepart of the organ slated for removal. Much asan arborist prunes diseased limbs to ensureenough sunlight and nutrients make it tohealthy branches, PVE reduces blood supply tothe portion of the liver slated for removal andconcentrates resources in the rest of the organ,spurring liver regeneration before surgery. Fourweeks later, after a CT scan confirms that therest of the liver has gained volume, the patient,previously inoperable, is eligible for resection.In 1991, the then-future radiologist Madoffdiscovered his love of imaging as a first-yearmedical student at Pitt, where he did independentresearch with faculty at the nascentPET Center. “I saw all of this new technologyDONALD MRVOS (MD ’55)CARL ROBERT FUHRMAN (MD ’79)GREGORY M. HOYSON (MD ’82)SAM TISHERMAN (MD ’85)JOHN F. MAHONEY (MD ’90)ADAM GORDON (MD ’95)CHARISSA B. PACELLA (MD ’98)HEATHER HEINRICHS WALKER (MD ’99)BRETT PERRICELLI (MD ’02)Members at LargeM-200k Scaife HallUniversity of PittsburghPittsburgh, PA 15261tel 412-648-9090; fax 412-648-9500medalum@medschool.pitt.eduas the future of diagnosis and treatment,” saysthe 44-year-old, who won a research awardfrom the medical school’s summer researchprogram. “Pitt ... created a milieu where Icould get excited about doing research and anacademic career.”It wasn’t until Madoff was a fellow invascular and interventional radiology at theUniversity of Texas M.D. Anderson CancerCenter that he came across PVE, then relativelyunknown in the United States. His mentorhad assigned him to present a case involving apatient whose PVE had led to complications.Madoff was hooked. “I wanted to make theprocedure easier,” he says, “with fewer complications.I realized there was a whole avenueof research just at its infancy.”Last year, Springer published a textbook,Venous Embolization of the Liver: Radiologicaland Surgical Practice, which Madoff editedwith three others, including Makuuchi, nowpresident of the Japanese Red Cross MedicalCenter in Tokyo.Madoff has focused his PVE-related investigationson analyzing which patients are thebest candidates and refining the devices andtechniques involved to improve regenerationand reduce the risk of complication. He hasalso demonstrated that the procedure canbe used with other tactics to starve out livertumors while promoting function in healthytissue, allowing some patients to avoid conventionalsurgery entirely.“We’ve developed a safe technique over thecourse of years, where we’ve had very few complications,”he says. “But some patients don’tregenerate; we’re still working on the predictorsof who regenerates and who doesn’t.” ■SUMMER 2012 39

LAST CALLTHE GIFT NO PHYSICIAN EVER FORGETSOn the first day of anatomy lab in the School of Medicine, the entire first-year class gathersin groups of six, each with a cadaver they will carefully study for the next seven weeks.Here, they will learn the fundamentals of biology shared by all people, as well as theinherent quirks of individual anatomy. They will witness the scars, injuries, and evidence ofhow this person spent her days on earth. For budding physicians, the experience inspiresawe and humbles. Medical anatomy becomes personal and profoundly human.Every day in the anatomy lab is a reminder that men and women—perhaps when ailing,perhaps in the prime of life—decided to donate their remains to further medical education.To honor these people and to express gratitude, first-year med students gather in Pitt’sHeinz Memorial Chapel annually.On a brilliant spring day, families of donors fill the front chapel pews; white-coatedstudents take the pews in the back. During one of many musical tributes, the congregationsits in stunned silence as eight students mesmerize with an a cappella performanceof Palestrina’s Sicut cervus, one of the greatest examples of religious choral art to emergefrom the Renaissance. Seventy-one donor names are read aloud; a candle is lit for each.Class of 2015 president Lauren Zammerilla makes a pledge: With every patient they see, sheand her classmates will repay these profound offerings with humility, respect, and compassion.As Loren Roth, associate senior vice chancellor for clinical policy and planning, healthsciences, and a physician himself, notes, “These honored dead have made a gift that noyoung man or woman who becomes a physician ever forgets.” —Chuck StaresinicPHOTOS BY JOSH FRANZOS40 PITTMED

C A L E N D A ROF SPECIAL INTEREST TO ALUMNI AND FRIENDSWHITE COATCEREMONYAUGUST 53 p.m.Scaife Hall, Auditorium 6MUSGRAVELECTURESHIPOCTOBER 12–13J. William Futrell, MD, Speaker2013 WINTER ACADEMYFEBRUARY 15, 2013Ritz-CarltonNaples, Fla.For information:Pat Carver412-647-5307cpat@pitt.eduwww.winteracademy.pitt.eduMEDICAL ALUMNIWEEKEND 2013MAY 17–20, 2013Reunion Classes:2003 19981993 19881983 19781973 19681963 1958UPCOMINGHEALTH SCIENCESALUMNI RECEPTIONDATE TBASan Francisco, Calif.St. Augustine, Fla.For information:Pat Carver412-647-5307cpat@pitt.eduFor information on an event, unless otherwise noted, contactthe Medical Alumni Association: 1-877-MED-ALUM, 412-648-9090,or medalum@medschool.pitt.edu. Or go to www.maa.pitt.eduTO FIND OUT WHAT ELSE IS HAPPENING AT THE MEDICAL SCHOOL, GO TO www.health.pitt.edu

UNIVERSITY OF PITTSBURGHSCHOOL OF MEDICINESUITE 401 SCAIFE HALLPITTSBURGH, PA 15261CHANGE SERVICE REQUESTEDNONPROFIT ORG.U.S. POSTAGEPAIDPITTSBURGH, PAPERMIT NO. 511THE OWL, 1959THE GIFT THAT GIVES BACKWhen you establish a charitable gift annuity (CGA) with theUniversity of Pittsburgh School of Medicine, you receive an incometax deduction and an annual payment for life. Deferred CGAs giveyou the option to defer the income payments so that you receive agreater fixed income later. At the time of your death, the funds youcontributed when you established the CGA will benefit the schoolor a specific program you have designated. The examples below arebased on a gift of $10,000.If you would like to learn more about theways in which you can arrange for yourlegacy to the School of Medicine, contact:Lisa J. SciulloForbes Tower, Suite 80843600 Forbes Ave.Pittsburgh, PA 15213412-647-0515slisa@PMHSF.orgwww.pitt.planyourlegacy.orgDue to varying restrictions, Pitt is notable to offer gift annuities in some states.AGE RATE YEARLY ESTIMATEDINCOME DEDUCTION55 4.0 $400 $1,85160 4.4 $440 $2,23165 4.7 $470 $2,95670 5.1 $510 $3,69175 5.8 $580 $4,26880 6.8 $680 $4,79185 7.8 $780 $5,50290 9.0 $900 $6,190