UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE | SUMMER 2009 PITTMED

CARING FOR KIDS THE LIFE AND TIMES OF A GREAT CHILDREN’S HOSPITAL OVER THE TRANSOM

PAVING THE WAY POSTER DOG We gladly receive letters (which we may Thank you for running the announcement Some people (probably not many Pittsburghers edit for length, style, and clarity). [Spring 2009] about the recent death of my this year) watch the Super Bowl for the commer- Pitt Med mother, Ruth Masters (MD ’35). I thought you cials; apparently some of our readers appreciate 400 Craig Hall might enjoy seeing this photograph and knowing Pitt Med’s ads, as well. In his note below, Scott University of Pittsburgh a little bit more about her. She was one of very Kennedy refers to the front and back cover ads Pittsburgh, PA 15260 few women who became doctors in those days. In in our Fall 2008 issue, including one for Pitt’s Phone: 412-624-4152 1933 there were only 650 members of the Medical Winter Academy—featuring Shirley, a black Fax: 412-624-1021 Women’s National Association. By dog in a Pirates hat—and one for planned E-mail: [email protected] 1941, the number of women phy- giving opportunities—featuring former nurse/ http://pittmed.health.pitt.edu sicians in the country had climbed fl ight attendant, current sports-car afi cionado to a mere 7,500 compared to Mildred Danch. For address corrections: almost 200,000 male doctors. Pitt Med Address Correction My mother graduated during Your magazine [Fall 2008] is truly outstanding, M-200K Scaife Hall this time. She had no resentment from the black lab up front to the fl ight attendant University of Pittsburgh about her treatment, she just said sans red Corvette on the back. Pittsburgh, PA 15261 that by working twice as hard as In truth, I tore off the cover to cut out the E-mail: [email protected] everyone else, she found that she lab shot before perusing the rest. So, if possible, was not looked down upon as a I would appreciate a replacement copy to put on RECENT Ruth (Snyder) Masters woman. In her 1935 Pitt medical our offi ce coffee table. Please? MAGAZINE HONORS c. 1934 school class of more than 60 stu- Carnegie Science Center Journalism Award dents, there was only one other woman. F. Scott Kennedy, PhD (J. Miksch) My sister Dr. Carol Rumack, who fol- Assistant Dean of Admissions lowed in Mother’s footsteps, wrote this about LSU Health Sciences Center CASE District II Accolades her: “Ruth Masters, MD, was born at home Shreveport, La. Gold, Periodical Staff Writing September 28, 1913, and raised and educated in Pittsburgh. Dr. Ruth won a The pup’s companion, CASE District II Accolades scholarship to the University of Pittsburgh, associate editor Joe Miksch, Gold, Best Article which she entered at age 16 after winning responds: (J. Miksch, “The Investigator’s Path”) a mathematics competition. She entered medical school at 18 years of age and I’m pleased that you’re CASE District II Accolades graduated at 21. (Her mother marched charmed by the photo of Silver, Covers (Summer 2008) in the women’s suffrage movement.) She my dog, Shirley. I feel com- married a classmate, the late Dr. Raymond pelled though (for reasons I IABC Golden Triangle Award of Honor Masters, in 1936, during their intern- Shirley can’t fathom) to point out Magazines ship at the University of Pittsburgh. that the lovely little miss They opened an offi ce in his father’s home on is primarily of pit bull and shar-pei extraction, IABC Golden Triangle Award of Honor November 1, 1936, and practiced there for though doubtless many other breeds (including lab, Magazine Design (E. Cerri) 64 years. She practiced family medicine and possibly) lurk in her checkered family background. delivered more than 3,200 babies, including IABC Golden Triangle Award of Honor 200 home deliveries. She says she always prayed Feature Writing during a delivery that “God would bless me to (E. Vitone, “What Possessed You?” ) give me the strength and talent to do it.” She FLU: READ MORE arranged adoptions of babies from mothers who ABOUT IT CASE Circle of Excellence did not want to choose abortion. Dr. Ruth was Gold, Covers (Winter 2007/8) • Edwin Kiester’s 2003 story for this elected the fi rst woman president of the medical magazine on the Influenza of 1918: staff at University of Pittsburgh Medical Center CASE Circle of Excellence http://pittmed.health.pitt.edu/ (UPMC) at McKeesport Hospital, serving from Bronze, Special Interest Magazines Jan_2003/DrowingBlood.pdf 1979 to 1980. She retired from active practice in 2001 at the age of 88 and remained a mem- • Chuck Staresinic’s story on the Pittsburgh Black Media Federation ber of the hospital’s ethics committee.” evolution of flu: Robert L. Vann Media Award The other Dr. Masters—Raymond E. http://pittmed.health.pitt.edu/ Magazine Features, Third Place Masters, my father—was a physician who pio- Winter_2006/evolutionofflu.pdf (C. Zinchini, “Twins”) neered atomic safety methods. Both of my parents had wonderful and productive lives. • UPMC’s Center for Biosecurity’s updates and original articles: Sara Masters www.upmc-biosecurity.org/ Pittsburgh, Pennsylvania PITTMED

UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE MAGAZINE, SUMMER 2009 (MAY/JUNE/JULY) VOL. 11, ISSUE 2

DEPARTMENTS OF NOTE 3 Emergency medicine abroad. Making sense of medical records in Malawi. Separation without anxiety.

CLOSER 7 Practice makes perfect in the move to the new Children’s Hospital.

INVESTIGATIONS 8 Preparing for the fallout. Function at the neuromuscular junction.

ATTENDING 32 Alumnus Jim Withers on taking medicine to the streets.

MATCH RESULTS 35 The Class of 2009 marches onward.

ALUMNI NEWS 36 19 Probing preeclampsia. FEATURES Is there a (Pitt) doctor in the (White) House? For the Good of the Child 12 LAST CALL 40 In 1951, Esther Bubley came to Children’s Hospital with a slew of cameras. Hands and minds and hearts. The scenes of caring she documented never made it to the pages of Life magazine as intended, but they are now the foundation of a documentary by filmmaker Ken Love and his wife, pediatrician Barbara McNulty (MD ’75). PHOTO-ESSAY BY ESTHER BUBLEY AND BARBARA MCNULTY

Welcome to the Dark Side 19 Cured meats, beets, and a bit of olive oil could be on the menu for cardio- protection. Could nitrates and nitrites be the secret to the Mediterranean diet? CONTRIBUTORS Pitt docs defend the honor of maligned molecules and look to new therapies. Portraits by painter/illustrator FRANK HARRIS regularly grace the pages of Pitt Med’s Alumni BY CHUCK STARESINIC News section (see p. 37). Harris describes these illustrations as having a “loose, painterly style” consistent from one issue to the next. Rather than being realistic, he paints in bright colors and “breaks the lines a bit.” For a feature article in this issue [“Welcome to the Dark Side”], he worked mainly in collage. Harris’ clients include Harvard Magazine and Vanity Fair, for which he produced caricatures of the presidential candidates. He is currently illustrating the program for Major League The Heart of the Matter 24 Baseball’s 2009 All-Star Game. Cecilia Lo–founding chair of Pitt’s new Department of Developmental Biology– Senior Editor CHUCK STARESINIC [“Welcome to the Dark Side” and other stories] is a six- is on an exhaustive search for the mutations behind congenital heart defects. year veteran of Pitt Med. His work has netted him several individual writing awards, including the top prize from the Association of American Medical Colleges for his profile of transplant great BY SHARON TREGASKIS Thomas E. Starzl. In this issue, Chuck takes us on a tour behind the mysteries of the healthful Mediterranean diet. His own wellness regimen includes a lot of running these days. This spring, Chuck finished first in his age group in Pitt’s Student Leaders in International Medicine and Kenya Pediatric HIV Project 10K race. Last year, he and his wife, Danielle, tried to have their third child, but instead had their third and fourth in rapid succession: twins Juliet and Edward. In the Shadow of a Stroke 28 Jun Chen and Peter Vosler may have found a way to limit the damage caused COVERR by stroke by leading cells back from the brink of death. Pediatrician Arthur Coddington has some company while he makes a phone call at Children’s Hospital of Pittsburgh in 1951. (Cover: Esther Bubley. © 2007 Children’s Hospital of Pittsburgh of UPMC.) BY JOE MIKSCH DEAN’S MESSAGE

PITTMED

he Simple Life is not a simple life.

PUBLISHER —Mason Cooley Arthur S. Levine, MD Two critical components of health care reform EDITOR IN CHIEF T Erica Lloyd are more complex than perhaps fi rst imagined.

ART DIRECTOR I’m glad to see the Obama Administration Elena Gialamas Cerri is tilting health care reform toward prevention.

SENIOR EDITOR We know that much of the burden of the cost of Chuck Staresinic care relates to potentially avoidable, chronic dis-

ASSOCIATE EDITOR eases—obesity and type 2 diabetes, COPD, lung JOSHUA FRANZOS Joe Miksch cancer, cirrhosis, and the like. And we suspect

PRODUCTION COORDINATOR that many illnesses outside the realm of those so closely linked to lifestyle choices are also Chuck Dinsmore avoidable. If under health care reform we are going to extend access widely, then we not

STAFF CONTRIBUTORS only have to keep the cost of health care under control, we need to reduce it. So preventing Eric Donato, Meaghan Dorff illness becomes critical.

OBITUARIES CONTRIBUTOR How do you do that? If you’re going to prevent illness, it helps to be able to predict it. Macy Levine, MD ’43 That’s where genomics comes into play. Just a few years ago, we thought that once we mapped

CIRCULATION MANAGER the human genome, we’d be well on our way to understanding the origin of most conditions Crystal Kubic that affl ict us. The next step would be targeted therapies. I’m simplifying what the thinking was here, of course. Yet, the reality of decoding disease turns out to be much more compli- CHIEF EDITORIAL ADVISOR cated. As it turns out, the results of genome-wide association studies are disappointing. With Kenneth S. McCarty Jr., MD, PhD the exception of diseases like sickle cell anemia that are caused by a mutation in a single EDITORIAL ADVISORS gene, common chronic diseases are very complex genetically. Obesity and most cancers seem Paula Davis, MA to involve many genes, each with a small effect. Many other common conditions, including Susan Dunmire, MD ’85, Res ’88 Jonathon Erlen, PhD schizophrenia and autism, may as well. Beyond that, diseases may involve single nucleotide Joan Harvey, MD polymorphisms (small genetic variations at the nucleotide level, nicknamed “snips”) in ways John Horn, PhD that are very diffi cult to understand. And some of what we were calling “junk DNA,” now Steven Kanter, MD Joan Lakoski, PhD known to encode untranslated microRNAs, turns out to have a critical role in suppressing Margaret Larkins-Pettigrew, MD ’94, Res ’98 messenger RNA. Contemporary genomics offers a window to learning about the wonders of David Lewis, MD the bodies we inhabit, yet the fi eld isn’t necessarily a quick ticket to new therapies. Margaret C. McDonald, PhD And what the administration deems a $20 billion problem is equally intricate—the digi- Ross Musgrave, MD ’43 David Perlmutter, MD tizing of medical records. There’s no standard in the United States for medical records. So Kevin Proctor, Class of ’11 those electronic records we do have aren’t interoperable in this country, never mind with Gabriel Silverman, Class of ’11 our European or other counterparts. Such a system could be enormously valuable. Yet as we Peter Strick, PhD Bennett Van Houten, PhD sort this out, we should be mindful that being wired doesn’t intrinsically mean better care. Gerard Vockley, MD, PhD As Pamela Hartzband and Jerome Groopman cautioned in The New England Journal of Simon Watkins, PhD Medicine, we don’t want each record to become a mystifying and unintelligible data dump of Marshall Webster, MD, Res ’70 lab results (as they are in some systems). Nor do we want to create a cut-and-paste approach Julius Youngner, ScD to care in which physicians copy the diagnoses of others rather than take time to think inde- OFFICE OF PUBLIC AFFAIRS pendently about the patient when writing a history. And wouldn’t it be nice if physicians Robert Hill John D. Harvith, JD were able to spend more time interacting with the patient during an exam, and less time with a computer screen? As educators, we need to put forward a holistic approach to care that does not substitute electronics for the doctor-patient relationship. And we will need to train physicians regard- ing prediction and prevention as we prepare them for the next chapter—personalized medicine—once we do make sense of our genomes in all of their complexity.

Pitt Med is published by the Offi ce of the Dean and Senior Vice Chancellor for the Health Sciences in cooperation with the alumni and public affairs offi ces. It is produced quarterly for alumni, students, Arthur S. Levine, MD staff, faculty, and friends of the School of Medicine. PR 6706 Senior Vice Chancellor for the Health Sciences The University of Pittsburgh is an affi rmative action, equal opportunity institution. © 2009, University of Pittsburgh Dean, School of Medicine

2 PITTMED OF NOTE

Devoted to noteworthy happenings

at the medical school

NEW LEADER AT STARZL INSTITUTE

Abhinav Humar has come to the University of Pittsburgh to take on the clinical directorship of the Thomas E. Starzl Transplantation Institute. The former director of the Liver and Living Donor Programs at the University of Minnesota Medical Center also serves as chief of the Division of Transplantation in the Department of Surgery. The surgeon said he was attracted to the job by the Starzl Institute’s stellar reputation, a reputation he plans to burnish. “If you ask people around the world about transplant, Pittsburgh would be at the top of the list,” Humar says. “I appreciate that reputation and the opportunity to improve it.” Humar made his own reputation as an expert in abdominal COURTESY CHILDREN’S OF PITTSBURGHCOURTESY OF UPMC HOSPITAL transplantation but plans to be hands-on in advancing all the institute’s programs. “We’re going to reach out to the community Congrats! and make sure that people know we are the place for transplant It’s a Bouncing Baby Hospital care from step A to step Z,” Humar says. —Joe Miksch On March 4, David Perlmutter moved into his digs in the recently completed John G. Rangos Research Center building, part of the new Children’s Hospital of Pittsburgh of UPMC. Two months later, patients arrived next door at the new nine-story, 296-room hospital building on a 10-acre, $625 million campus (the former site of St. Francis Hospital in Lawrenceville). Perlmutter, the chief physician and scientific director at Children’s FOOTNOTE and the Vira I. Heinz Professor and chair of pediatrics in the University of Acharya Yashovijaysuri, a guru of Jainism and Pittsburgh School of Medicine, described the view from his perch: “It’s beautiful. I’m looking at the hospital and the river and the North Shore and spiritual leader to millions, only travels by foot so the neighborhood of Lawrenceville. It’s just spectacular.” that he may avoid harming even insects. But desperate Almost as spectacular as the hospital itself. Perlmutter says that more than 90 percent of patient rooms are private and that they are considerably times call for desperate measures, and he was going blind. larger than those in the Oakland facility. “The design of the rooms is ideal for The guru fl ew to Pittsburgh from India after doctors in families, and we believe that has everything to do with how children handle illness,” he says. Mumbai found a golf ball-size tumor pressing on his optic The hospital boasts a 100 percent paper-free record system, has many nerve. They deemed it too risky to operate through the more intensive care beds, and it concentrates particular kinds of care on specific floors. (Cancer patients are on the ninth and cardiac patients on cranium. His followers convinced him that minimally the third, for example.) The research facility follows the open-lab model invasive brain surgery through the nose—a procedure used in Pitt’s Biomedical Science Tower 3 and offers investigators a great developed at Pitt—was an option. Days after surgery, deal more space. “This will enable us to continue to recruit great pediatric scientists,” he says. —JM the guru began to regain his vision.

SUMMER 2009 3 —Christina Rouvalis Veronica Ortiz, medi- second-year a Veronica in pathology at the University of Pittsburgh of Pittsburgh in pathology at the University

he aging brain loses volume, leading to leading to loses volume, he aging brain moments” and debilitating diseases “senior is an MD/PhD Raji Cyrus such as Alzheimer’s. A child who grows up in poverty may experience may experience up in poverty A child who grows the chaos of violence and drugs in her neighbor- family bonds, and poor nutrition. hood, strained to been linked have Those childhood stressors and other changes in health later in life. depression MD/PhD student at a third-year Horenstein, Jeffrey to write his dis- Pitt, studied MRIs of adult brains sertation status socioeconomic on the link between who and mental and physical health. Horenstein, Service the from Award a National Research received Health Sciences, National Institute of Environmental to suicide and plans to apply his lab research Service. with the Indian Health alcohol prevention adviser is Sheldon Cohen, Carnegie Horenstein’s Robert E. Doherty of Professor Mellon University’s at Pitt. who has adjunct appointments Psychology, Next Generation T student injury brain is a leading cause of death in Traumatic tried to improve have and neurosurgeons children, by maintaining oxygen children the odds for injured to the brain. cal student, received a Dean’s Summer Research Summer Research a Dean’s cal student, received brain different how to investigate grant Program The in that organ. affect oxygen temperatures at the annual congress which she presented study, Medicine, found that of the Society of Critical Care cause small varia- temperature changes in brain not likely but they are levels, oxygen tions in brain Ortizplans to keep study- to be clinically relevant. injury brain ing traumatic children. to help injured Her advisers include Michael Bell, an MD assistant associate medicine and of critical care professor in Pitt’s care of pediatric neurointensive director and Patrick Research, Safar Center for Resuscitation medicine of critical care MD professor Kochanek, of the Safar Center. and director working with James Becker, a PhD professor of of a PhD professor working with James Becker, of an MD professor and Oscar Lopez, psychiatry, diseases, vascular studies whether Raji neurology. lead to brain diabetes, and high blood pressure paper for best neuroscience a prize He won atrophy. the American Academy by a medical student from imaging from used brain That paper of Neurology. heart link between the MRIs to explore and brain to studying his career plans to devote health. Raji us of the dementia robs “I think the aging brain. he says. are,” fundamental aspect of who we

CAMI MESA —Interview by Joe Miksch rst graduate of the University of of of the University rst graduate nancial support, and departmental approval—despite culty getting buy-in, initial fi

c accidents and trauma are becoming the leading cause of death in [developing nations], nations], becoming the leading cause of death in [developing are trauma c accidents and

epidemiology and ask, “Are you willing to support you our research and our clinical efforts?” epidemiology and ask, “Are Q the fact that international emergency medicine was new and unproven. I think that the Department was new and unproven. medicine the fact that international emergency willing to take chances, to try Medicine has always been of Emergency new things, and this was and unorthodox is himself an innovator Paris, Paul certainly true in our case. Our chairman, Dr. to is afraid department. think that anyone and he has set the tone for the entire I don’t thinker, as reputation to try what is behind Pittsburgh’s This is really speak up, new things, or to take risks. medicine. leading centers for academic emergency one of the world’s PITTMED His question for the world of this chang- upon them the urgency impress the heads of funding agencies to really like to talk to I’d ing On the future of the fellowship On the future always looking for options and opportunities are to go People a huge amount of interest. There’s very important for folks to spend some time seeing It’s which I think is valuable. and study, abroad majority of the world. in the vast medicine is truly practiced how On the nature of international emergency medicine of international emergency On the nature traffi Road managed to deal with things like getting older because we’ve seeing that patients are and we’re coming in with heart malaria and diarrhea in many parts now are attacks and of the world. Patients you looking to make a dent in mortality, and those kinds of things. If you’re diabetic emergencies to start have deal with time-critical disease. focusing on things like ambulance systems which can We had no diffi We On the birth of Pitt’s international emergency medicine fellowship international emergency On the birth of Pitt’s Marc-David Munk (Res ’06, Fel ’07), shown above, worked as a paramedic, earned a master’s earned a master’s worked as a paramedic, above, ’07), shown ’06, Fel Marc-David Munk (Res an MD. He was the fi and, subsequently, in public health, degree worked as the he medicine. After graduation, in international emergency fellowship Pittsburgh’s in Qatar and trained project development medicine emergency for UPMC’s EMS medical director assistant director program’s he is the fellowship Today, EMS workers in the Caribbean and Africa. medicine in the School of Medicine. After returning of emergency and clinical assistant professor Flying Doctors service a stint with the from challenges of Munk spoke about the out of Nairobi, outside the United States. care updating emergency

&

4

Marc-David Munk: Emergency Medicine Abroad Medicine Marc-David Munk: Emergency A Learning to Educate The latest crop of residents sat watching the video. It showed a peer delivering a presentation regarding a patient. The content was fi ne, medi- cally speaking, but some of the terms the young doc employed could be considered pejorative and judgmental. “We use this video to show the types of sce- narios commonly seen in medical education,” says Jamie Johnston, MD professor of medicine in the renal-electrolyte division in the School of Medicine. A postvideo conversation reinforced ideas of professionalism and communication skills in the entering residents of 2008. The video is one project of Pitt’s Academy of Master Educators, which was formed in 2006 and recently announced its new class of 18 fac- ulty members. The academy not only recognizes teaching excellence, Johnston says, it concen- trates the teaching experience of faculty mem- bers and shares dos and don’ts with the medical school at large through programs like faculty development seminars, mentoring programs, and the new resident orientation mentioned above. “When I network with my colleagues at other institutions, they’re very jealous of what

we have,” Johnston says. CATHERINE LAZURE The newest members of the academy can be found at www.ame.pitt.edu/. —JM

FINE FELLOWS HONORING TRANSLATORS

The American Association for the Advancement of Science has asked its Four University of Pittsburgh School of Medicine faculty members to recognize standouts among their own since 1874. This year, members now augment the ranks of two groups dedicated the organization bestowed the honor of fellow status on three profes- to honoring scientists who convert basic science into clini- sors from the University of Pittsburgh School of Medicine. cal practice. The AAAS lauded Bernie Devlin, a PhD associate professor of psy- Michael Fine, MD professor of medicine and direc- chiatry and human genetics at Pitt, for his work modeling and analyzing tor of the VA Center for Health Equity Research and statistical data. His methods for analyzing genetic data have advanced Promotion, and Mark Gladwin, MD and chief of the such disparate fields as DNA forensics, genetics of IQ, genetic epidemi- Division of Pulmonary, Allergy, and Critical Care Medicine ology, and cancer biology. and director of the Hemostasis and Vascular Biology The organization also honored Herbert Needleman, an MD professor Research Institute (see story p. 19), are among the newest of psychiatry and pediatrics, and George Michalopoulos, an MD/PhD, the members of the Association of American Physicians. Each Maud L. Menten Professor, and chair of the Department of Pathology. was nominated by his peers to join the 1,000-member Michalopoulos is known for his work in liver regeneration. In 1989, organization. Only 60 physicians are invited to join annu- his lab identified hepatocyte growth factor, which stimulates liver cell ally. With the addition of Fine and Gladwin, Pitt boasts 17 proliferation. (Two other labs independently came across the protein at AAP members. the same time.) David Hackam and Satdarshan Monga were recog- Needleman’s studies, starting in the 1970s, showed that lead expo- nized by the American Society for Clinical Investigation, sure in children results in brain damage, made evident by lower IQs and which honors standout physician-scientists who are 45 or an increase in behavioral problems. His work eventually convinced offi- younger. Hackam is an MD/PhD with appointments in sur- cials at federal agencies to ban lead from paint and gasoline and lower gery, as well as cell biology and physiology. Monga is an the blood-lead standard for children. —Eric Donato MD associate professor of pathology and medicine. —JM

4 PITTMED SUMMER 2009 5 COURTESY CHILDREN’S HOSPITAL OF UPMC COURTESY OF PITTSBURGH CHILDREN’S

TWINS BECOME TWO Catherine Nickson was told she couldn’t get preg- nant again, but then a doctor told her she was. Then he told her she was carrying twins. Then he told her the twins were conjoined. “I thought it was a joke, that someone was playing a trick on me,” says Nickson. Finding Malawi Nickson and the twins—Dagian and Danielle Canadian-born Gerry Douglas didn’t even know where Malawi was back in 1996 when he was Lee—came to Children’s Hospital of Pittsburgh of assigned to the country as a member of Voluntary Services Overseas (VSO), a UK-based inter- UPMC from their Cleveland home with the hope national volunteer organization like the Peace Corps. that doctors here could separate the girls. It would Today, Douglas is so devoted to this Southern African nation that he owns a home in Malawi be the first such surgery performed in Pittsburgh. so he can run Baobab Health Partnership, a nonprofi t medical informatics organization. Dagian and Danielle were joined from the sternum Malawian medical records are in a state of disarray, which is something Douglas fi rst to the groin, shared a colon, and had individual, noticed as a VSO volunteer. Paper records were often incomplete or nonexistent or inaccurate. but connected, livers. If a new patient had been treated for high blood pressure, diabetes, or HIV, a doctor often On Dec. 13, two days before Dagian and wouldn’t know it. “It’s a total mess,” he says. Danielle turned 2, a team of 50 doctors and nurses Douglas, a 46-year-old PhD student in the University of Pittsburgh’s Department of led by Joseph Losee, MD associate professor of Biomedical Informatics, is changing that. A desktop touch-screen workstation appliance he surgery and pediatrics in the School of Medicine developed lets overworked doctors input medical records. Doctors have used the system to and chief of the Division of Pediatric Plastic issue identifi ers to more than 800,000 patients, and 18,000 received HIV care facilitated by Surgery at Children’s, began a 24-hour operation to BART, the Baobab Antiretroviral Therapy system. separate them. The operation took place after the For his efforts, Douglas received a Technology, Entertainment, Design (TED) fellowship. girls had undergone scores of earlier procedures in Douglas is one of 40 innovators selected from a pool of international fellowship applicants. He preparation. (The girls are shown above—pre-op, presented his work on Baobab Health to the fellows group during the TED Conference in Long with tissue-expanding balloons beneath their skin. Beach, Calif., in February. Dagian is on the left; Danielle is on the right.) Michael Becich, chair of biomedical informatics at Pitt, noted in a press release that “TED Two months later, the twins, looking hale and fellowships are given to the super-brilliant and rising talents across multiple scientifi c and cre- hearty in their Terrible Towel-draped hospital beds, ative disciplines.” had begun a long period of rehabilitation. And they With his wife and Baobab cofounder, Thuy Bui, whom Douglas met in Africa, Douglas is com- were looking forward to going home. Nickson said: mitted to working in Malawi for another 20 years. The couple—Bui is an MD and medical director “We’re going to have a big party.” —JM of Pitt’s Program for Health Care to Underserved Populations—brings their 7-year-old son, Ben, to Africa in the summer. Baobab employs 25 Malawian software developers, technicians, and other support staff. Douglas himself has not yet drawn a paycheck, but he hopes to receive a salary eventually from the organization, which is funded through the Centers for Disease Control and Prevention and other granting organizations. —CR

6 PITTMED CLOSER

MOVING FOR DUMMIES On a chilly Saturday in February, the brand-new Children’s Hos- from throughout the Pittsburgh area—about 200 people, all told. pital of Pittsburgh of UPMC campus in Lawrenceville receives its For four hours, they work in teams—one nurse and one or two very first patients, closed-lipped kids who handle their ailments EMTs per ambulance—to carefully move 23 mannequins from in stride. (To protect their privacy, they’ve been assigned num- patient floors on the Oakland campus to the new hospital three bers.) Seventeen has a low white-blood-cell count. Twenty-five miles away. has a bacterial infection. Forty has a broken arm—and, for some Not every trip goes without a hitch. “There are a few dead spots reason, looks suspiciously like … a Cabbage Patch Kid? for radio communication,” says David LaCovey, EMS coordinator. They’re not real patients, dummy. They’re CPR mannequins “But that’s the idea behind the drill—to identify things like that.” (and at least one doll)—stand-ins for the children during a dress Wheeling the gurney out of 17’s room, EMT Terry Salay nods rehearsal for the hospital’s big moving day on May 2. with the assurance of someone who does nothing but transport “I’ve been planning this for two years,” says RN Jennifer patients year round. “[Patients] do throw curveballs at you,” he Iagnemma, the patient coordinator for the move. “It’s exciting says, looking at Dummy No. 17. “But if there is one, we’re ready.” seeing our group come together to do this.” —Elaine Vitone Her group includes Children’s staff and volunteers, plus EMTs —Photo by John Altdorfer

SUMMER 2009 7 INVESTIGATIONS

Explorations and revelations taking place in the medical school CORBIS/ DRAWING OF TWO FIGURES AND INCENDIARY BOMBS BY DA BOMBS LEONARDO VINCI INCENDIARY AND OF TWO FIGURES DRAWING CORBIS/

Five hundred years ago, Leonardo da Vinci drew this sketch of incendiary bombs. In case someone else is sketching a bomb today, in particular a dirty bomb or other radioactive weapon, a team at Pitt is developing experimental protective therapy. 8 PITTMED NIGHTMARE MITIGATION DIRTY BOMBS AND DAY-AFTER DRUGS BY JOE MIKSCH

t’s as alarming as it is plausible to the effects of ionizing radiation. directly to the mitochondria, Greenberger Joel Greenberger: He believes that The Biomedical Advanced Research says, it disrupts the chemical signals caused at some point in the next decade or and Development Authority of the U.S. by radiation that lead to DNA damage and so,I someone will detonate a fi ssion bomb, Department of Health and Human Services cell death. a dirty bomb (in which radioactive material awarded a second grant of $2.7 million in Greenberger and colleagues are now in the is dispersed by conventional explosives), or 2008. This grant can be renewed for up to process of testing JP4-039’s safety and effi cacy. release radioactive material into the wind. three years and $9.8 million. They’ve begun animal testing. Shortly after “When I go around to meetings, I carry That money is intended to help Greenberger the results are in, Greenberger hopes to begin around a briefcase with a 25-pound barbell and colleagues develop and deliver drugs that a phase I trial in nonirradiated people to show plate in it,” Greenberger says. Twenty-fi ve combat radiation exposure. His collabora- JP4-039 is safe for humans. pounds of fi ssionable material is all that’s tors include Valerian Kagan, a PhD and In another avenue of study, a Pitt research needed to build a Hiroshima-type bomb. DSc professor in Pitt’s Graduate School of team led by Greenberger found in 2004 that “I put it in the back of the room, and I Public Health; Peter Wipf, a PhD University resveratrol, an antioxidant in red wine and have someone open it. Then I explain that, Professor in Pitt’s Department of Chemistry; many plants, also offers effective protection essentially, if it went off in this building, it and John Lazo of the School of Medicine, against radiation exposure. Researchers are would be enough to wipe out Oakland, and a PhD who is the Allegheny Foundation investigating whether it can be used clinically. there would be a good million people who’d Professor in the Department of Pharmacology Greenberger says a drug like JP4-039 experience some degree of fallout.” and Chemical Biology and codirector with could be distributed at an earlier point in the Obviously, some people would be beyond Wipf of Pitt’s Drug Discovery Institute. testing cycle if the situation requires it. “Let’s help in such a grim scenario, but Greenberger This journey began, as many things do say we’re in the middle of a phase I trial, and is looking for a way to reduce or eliminate in science, with a different intention. In we’ve given the drug, and people aren’t getting the deleterious effects of fallout for those 1993, Greenberger was investigating ways to sick [from it]. A bomb goes off someplace; the who’d survive. With others, he’s testing new improve cancer care by selectively protecting FDA could fast-track production of what’s in therapies that seem to offer protection from normal tissue from radiation therapy. the pipeline.” radiation exposure. Ionizing radiation harms cells by creat- Work is progressing on delivering JP4-039 Greenberger, an MD who is chair and ing superoxide, which causes DNA damage through a transdermal patch, similar to how professor of radiation oncology in the and leads to cell death. Greenberger found some birth control medications are admin- University of Pittsburgh School of Medicine, that overexpressing manganese superoxide dis- istered. Safety is especially vital in this case, has about $13 million in federal grant mutase (MnSOD), an enzyme that all cells Greenberger says, because there won’t be time money set aside for the job. possess, converts superoxide into hydrogen to determine who has been exposed to radia- In 2005, the National Institute of Allergy peroxide. Other molecules then come along tion in the wake of a nuclear incident. The and Infectious Diseases bestowed $10 mil- and turn the hydrogen peroxide into water. drug would be given to everyone who seeks lion, with which Pitt established a Center for Removing superoxide prevents DNA damage. treatment. “A lot of people who come in to Medical Countermeasures Against Radiation. Wipf, the chemist, has engineered a drug emergency rooms 24 or 48 hours after a bomb Greenberger, the grant’s principal investiga- called JP4-039 that functions like MnSOD. won’t need anything, but they won’t know tor, was charged with developing and testing Both target the mitochondria—the cell’s they don’t need anything, and they’re going to small molecules that can be used to mitigate power plant. When MnSOD is delivered be scared,” he says. ■

SUMMER 2009 9 TRIGEMINAL GANGLION SLEEPER OPHTHALMIC BRANCH MAXILLARY BRANCH CELLS MANDIBULAR BRANCH

HOW THE BODY KEEPS HERPES AT BAY BY REID R. FRAZIER

HSV COURTESY KIRA LATHROPCOURTESY KIRA erpes is Greek for “crawl” or tissues, vexing its host with HSV1 hides near the brain and spreads along the facial nerves “creep,” referring to the way cold sores or “fever blisters” when awakened. its lesions spread across the on the mouth and lesions on Hbody. Known to science since the Greeks, it’s the cornea, which can lead to blindness. with faulty lytic granules, the other normal lytic creepy in another way. It hangs around the Until about 10 years ago, scientists assumed granules. Knickelbein and Hendricks expected body in a latent state, often going years with- the immune system had nothing to do with the groups to have the same incidence of reac- out causing any symptoms. At certain times keeping the virus in a latent state because the tivation. They didn’t. Neuronal cells were more and under certain conditions, the virus reacti- latent virus didn’t emit any telltale proteins. likely to reactivate if their T cells were defi - vates, causing infections and collateral damage But in the 1990s, Hendricks and colleagues cient in lytic granules. “Jared went ahead and the immune system exacts on the body’s own at Pitt were among the fi rst to document the showed us we were wrong,” Hendricks says. tissues. Why the virus reactivates, or remains immune system’s role in keeping the virus They looked closely at the neurons. The lytic latent, has been a major source of interest to dormant. The researchers found a class of granules weren’t killing the host cell. immunologists and virologists for decades. lymphocytes called CD8T cells conspicuous- The Hendricks team had found something The University of Pittsburgh’s Robert ly clustered around latently infected neurons, new—lytic granules that attacked the virus but Hendricks has been fi xed on this question for like guards around a “high-value” prisoner. kept the host cell alive. Kill the soldiers, save almost 20 years. Hendricks, a PhD, and his But what is it about these CD8T cells the building. team recently found out how the body keeps that prevents the virus from reactivating? But how? these virus sleeper cells at bay, through what These cells can work in one of two ways—by The group focused on a common and amounts to an immunological commando raid. scrambling the viral replication sequence or potent lytic granule component, granzyme B, Hendricks is the Joseph F. Novak Professor and by killing the host cell. This latter function which is a protease—an enzyme that cleaves vice chair for research in ophthalmology; he’s is performed by cytotoxic molecules called proteins. also a professor of immunology, as well as lytic granules. The granules are more or less “We thought, ‘What if this protease was microbiology and molecular genetics. His lab immunological grenades. This is a common cleaving a viral protein essential for the virus studies herpes simplex virus type 1. HSV1, as way CD8T cells kill viruses. Mice defi cient in to replicate?’” Knickelbein recalls. With help it’s called, is the lesser-known, “above the belt” lytic granules, for instance, are inordinately from bioinformatics software, Knickelbein and cousin of HSV2, or genital herpes. susceptible to Ebola and HIV infection. The Hendricks examined the amino acid sequence HSV1 typically hides out in the trigeminal method works relatively well in muscle and of potential target proteins—cleavage sites, in ganglion, a bundle of nerves just underneath skin cells, but neurons are another matter: scientifi c argot—and found one sequence with- the brain at the top of the brain stem. These They don’t grow back, at least not as easily. in an important protein in viral replication, nerves innervate the cornea and parts of So the investigators assumed the CD8T ICP4 (infected cellular protein 4). This seemed the mouth and face, offering a convenient cells were scrambling the viral DNA to pre- to solve the puzzle—granzyme B cleaved ICP4 portal through which the virus spreads. The vent replication. Jared Knickelbein, an MD/ early on in the viral replication process, stop- viral DNA migrate into the cellular nuclei of PhD student in the Medical Scientist Training ping the process inside the neuron, with mini- neurons in the ganglion, where the virus goes Program and a member of Hendricks’ lab, mum damage to the host cell. into a latent state. When reactivated, it travels tested this theory. He gave one group of This discovery, published in Science in 2008, down the axons from the ganglion to the outer latently infected neuron cultures CD8T cells could pave the way toward a herpes vaccine. ■

10 PITTMED A CRITICAL PROTEIN IS HOOKING UP NERVES AND MUSCLES ALL DAY In healthy rat muscles, BY ELAINE VITONE critical receptors cluster together. Z.Z. WANG AND J. LINNOILAZ.Z. NEUROMUSCULAR JUNCTION, HOW’S THAT FUNCTION?

hen MD/PhD student right where they’re needed. Because of this MuSK and Tid1 in wedded bliss. She showed Jenny (pronounced Yenny) “clustering,” the AChRs can work together that if you knock out Tid1 in a model of neu- Linnoila began her PhD to relay the message to the muscle, causing it romuscular development, clusters never form. studiesW at the University of Pittsburgh in 2003, to contract. When these clusters can’t form, And if you knock out Tid1 at a later stage in her adviser, Zuo-Zhong “Z.Z.” Wang, then an the junction loses function, and the muscle the life cycle, the clusters fall apart, the AChRs associate professor of neurobiology, invited her weakens. scatter, and the muscle weakens. to investigate one of the great unknowns of the “Say you have a nerve injury,” says Linnoila. Wang accepted a faculty position at the neuromuscular junction—the place where, as “When the nerve degenerates, all these recep- University of Southern California in 2005, so the name implies, nerves and muscles meet. tor clusters spread out with no direction and Linnoila moved to Los Angeles to continue But fi rst he warned her that it wouldn’t be just go anywhere on the muscle-cell surface.” her work. (She continued to meet regularly a walk in the park. “Do you want to do some- Wang posed to Linnoila a fundamental with her Pitt PhD committee.) Wang shep- thing that the world hasn’t fi gured out yet?” question about what puts bodies in motion: herded her through the exhaustive process she recalled him saying. “It’s really exciting, What causes clusters to form during develop- of getting a paper on her studies accepted in but it isn’t easy.” ment and to hold their ground throughout our Neuron. It was published in November 2008. After decades of research, neurobiologists lives? MuSK seemed a likely party to it. For Then, last summer, Wang died in a hiking learned that as a fetus develops, the motor neu- one thing, MuSK is a kinase, a class of pro- accident. “It was horrible,” says Linnoila. ron secretes a protein called agrin, which binds teins known to be great communicators. For Like any scientifi c father and child, they’d to a receptor on the muscle surface called mus- another, MuSK isn’t found anywhere else in grown close. She spoke at Wang’s funeral and cle-specific kinase, or MuSK. If anything keeps the body besides the neuromuscular junction. dedicated the paper to him. She marvels at agrin and MuSK from getting together—for So what does MuSK talk to? the skills he demonstrated as a scientist and example, an autoimmune disease that can At Wang’s suggestion, Linnoila did a bio- as a mentor. damage MuSK—the lines of communication logical assay to hunt for proteins that bind to Now Linnoila is about to begin her resi- between nerve and muscle become disrupted, MuSK; if any proteins did, he reasoned, they dency in neurology at Harvard University. and the junction cannot function. were likely to be involved in clustering. Once she fi nishes, the young physician-scientist Normally, the brain’s messages to get mov- “Lo and behold,” says Linnoila. “In par- looks forward to resuming her research, excited ing travel down the spinal cord and through ticular, one protein called Tid1 bound very by the patient populations that might eventu- the motor neuron. When a message reaches strongly to MuSK. Basically, you put those two ally benefi t from it, among them people with the neuromuscular junction, the nerve releases together, and they’re married.” myasthenia gravis and muscular dystrophy. onto the muscle a neurotransmitter called Linnoila believed strongly in the hypothesis And when she talks about these possibili- acetylcholine. In a healthy muscle, clusters of and spent the next four years building the ties, she looks up and smiles. acetylcholine receptors (AChRs) are already case. Studying nerves and muscles in rats from “It’s like Z.Z. said, ‘It isn’t easy.’ But it’s formed along the neuromuscular junction, embryo through adulthood, Linnoila found worth it.” ■

SUMMER 2009 11 TOP: Through the years, one of the keys to Children’s Hospital of Pittsburgh’s success has been the attitude that permeates the place—children are not just little adults, they need to be nurtured and loved in the hospital as much they are at home. 2ND ROW, FROM LEFT: In 1951, orthopaedic surgeon William Donaldson (MD ’43, Res ’50) teaches pediatric residents about treatments for clubfoot. • Parents, volunteers, and “play nurses” all played a part in caring for sick children in the ’50s. • Back then, doctors did everything from sharpening needles and drawing and analyzing blood to lifting their patients, as Arthur Coddington does here, with a teenage cancer patient. BOTTOM/LEFT: Medical director Edmund McCluskey at the bedside. OPPOSITE PAGE: Entering the hospital.

12 PITTMED COVER STORY

THE LIFE AND TIMES OF A GREAT CHILDREN’S HOSPITAL PHOTOGRAPHY | ESTHER BUBLEY INTERVIEWS | BARBARA MCNULTY FOR THE GOOD OF THE CHILD

ediatrics was a young specialty in 1951. But the University of Pittsburgh–affi liated Children’s Hospital of Pittsburgh had a medical director in Edmund McCluskey determined to build a pediatric teaching facility of the highest caliber. He recruited top-notch physicians to help him. It became a memorable time for Pittsburgh pediatrics—when doctorsP like Albert Ferguson, Paul Gaffney, and Benjamin Spock (down the street at Western Psychiatric Institute and Clinic) were looking after Pittsburgh’s children. Pediatric residents lived at the hospital. The work was hard, but the trainees were met with an infectious culture of caring and dedication, says one now-retired pediatrician. One day in 1951, a photographer arrived to document the life of the hospital. She was an unas- suming woman from Wisconsin with dark hair and bulky cameras dangling from straps around her neck. Her name was Esther Bubley. She was only 30 years old, but she had a wealth of experience. She’d worked for Ladies’ Home Journal and Life magazines. In 1942, she was hired by the Office of War Information, which was a successor of sorts to the renowned Farm Security Administration’s photographic unit. Later, she’d traveled the world shooting for Standard Oil. In Pittsburgh, she was on assignment for the Pittsburgh Photographic Library, an enormous civic documentation project run out of the University of Pittsburgh’s Cathedral of Learning. She photographed every sort of event that might happen in a children’s hospital—admissions, surgeries, residents trying to catch some sleep, and painful discus- sions with worried parents. Although Bubley is known as one of the great documentary photographers of the mid-century, the Children’s Hospital photographs received scant attention. Life had planned to do a piece with Bubley’s shots, but cancelled when King George VI died. Instead the magazine covered Queen Elizabeth II’s coronation. Bubley’s photos were never published. She died in 1998. Her prints were boxed and stored in no particular order at Children’s. They later came to the attention of documentary fi lmmaker Ken Love and his wife, pediatrician Barbara McNulty (MD ’75). That’s Pediatrics, their fi lm that was inspired by these images, won a 2008 CINE Golden Eagle Award. What fol- lows are photos and interview excerpts from the fi lm. We offer a glimpse of the hospital’s rich history as it moves to its new, cutting-edge Lawrenceville home. (© 2007 Children’s Hospital of Pittsburgh of UPMC. Used with permission.) —Introduction and captions by Chuck Staresinic

SUMMER 2009 13 14 PITTMED Angelo Runco (MD ’50, Pediatric Resident ’51–’54, Chief Resident ’53–’54, Clinical Professor of Pediatrics): There probably were no more than 15 pediatricians in the whole city of Pittsburgh. We all [the resi- dents] lived at Children’s Hospital, in the residents’ quarters. It was like one big fam- ily. The camaraderie was great.

Andrew Gursky (MD ’49, Pediatric Resident ’51–’54): We were few in number, and we also were operating a hospital of approximately 300 inpatient beds. We not only typed and cross-matched the blood, we also took the blood to the patient and then administered it to the patient. Starting IVs—that used to be a very diffi cult procedure. It wasn’t unusual for us to try veins anywhere we could fi nd them, be they scalp veins … We would try wrist veins, leg veins.

Pascal Spino (Assistant Chief Resident ’50–’52): Drawing blood—which was so ter- rible at that time, you had to do that—and we drew it from the jugular vein, believe it or not. The nurse would put the patient over the table and have the baby cry, and this jugular vein would become prominent, and you would draw blood from that.

William Sieber (MD ’41, Res ’50, Pediatric Surgeon ’50–’90, Retired Clinical Professor of Surgery): Appendectomies and hernia operations were commonly done. But by far the greatest number of patients had infec- tions and required drainage of abscesses. The primary risk in those days was the OPPOSITE PAGE: Two boys learn to give anesthetic. It was administered primarily by insulin shots to themselves. nurses. It consisted primarily of open-drop CLOCKWISE FROM TOP: Nurse Virginia Anderson ether. In most cases, the nurse would monitor feeds an infant. • A bucket of water and the pulse by feeling the pulse. It was, what I some plastic sheeting serves as a humidifier. would consider, the most dangerous part of • A sick boy rests his head on the knee of an adult. • Doctors handled injections and the operation. intravenous lines. • They also were known to draw blood from the jugular. • (Two OR photos) Masked nurses administered open- drop ether and monitored pulse by touch during surgery.

SUMMER 2009 15 16 PITTMED OPPOSITE PAGE: Nurses and volunteers greatly Albert Ferguson (Pediatric Orthopaedic he saved many blue babies and Rh babies. influenced the mood of the hospital. Surgeon, Pitt Chair of Orthopaedic Surgery The blue babies were just children born TOP: Children and staff gather for a party. 2ND ROW: A girl listens to her doctor, ’53–’86): I fi rst came to Children’s Hospital with a heart defect—a bad valve couldn’t Coddington, on the phone. • McCluskey in 1950 or 1951, and it was at the invitation pump blood through to the lungs in suf- (hands in pockets) was both a workaholic of Ed McCluskey, who was one of the great- fi cient quantity to keep them going. I medical director who inspired fear in some est physicians that I have ever known. He remember one of his patients whose lips young physicians and a caring pediatrician was really the inspiration for bringing fi rst- looked like he had just eaten huckleberry who inspired devotion in the families for class medicine to Pittsburgh. pie; he turned into a lipstick ad right after whom he cared. • Paul Gaffney (in dark suit) When Ed McCluskey made rounds, he [treatment]. on rounds with residents. He is remembered by generations of Pittsburgh-trained pediatri- was teaching from the bedside. The kids Al Ferguson was also one of my heroes cians as an influential mentor. loved him, and he was able to evoke in at Children’s Hospital. He concentrated on them a feeling that they were being well straightening out children with curvature taken care of. of the spine. It would take weeks to do Gursky: This was on a Sunday, and we were this, but it was marvelous, because the in our lunchroom, when we got a call that Runco: One of our outstanding teachers children would be so happy getting ready there was an extremely ill youngster [Patty was Dr. Bill Donaldson. He gave us many, to walk straight. And he kept visiting them. Clark] in the emergency room, a fl oor above many lectures on pediatric orthopaedics, Each day he would crank the spine, and us. She had severe respiratory distress. She especially dealing with clubfeet. then as he did so, fi ll in open spaces with was gasping for air at that point. slivers of cartilage and bone about the size Sieber: Dr. Gaffney was one of the outstand- of matchsticks to stabilize the spine. And Spino: In certain cases of diffi cult breath- ing pediatricians at Children’s Hospital. As the children, well, they were told they’d ing, the infection affects the epiglottis. a diagnostician he had no peers. be able to go to high school prom, and (The epiglottis is the valve that covers the they did. trachea.) And in Patty’s case the epiglot- John Troan (Science Editor, Pittsburgh tis was so infected that it could not stand Press ’45–’57): Paul Gaffney was one of upright. And that’s often hard to diagnose. my heroes at Children’s Hospital because And when you see a person like that, they’re often turning blue. You have a few minutes only to save their life.

SUMMER 2009 17 LEFT, TOP AND BOTTOM: Andrew Gursky deliv- ers news to the guardian as 3-year-old Patty THE PHYSICIAN’S TOUCH Clark requires an emergency tracheotomy right: in a hallway. Pediatrician Lee Bass The photographs reproduced on these pages were plays with a boy he nicknamed “Ike.” found in an Oakland dumpster. Norman Rabinovitz, director of the medical photography department at Gursky: We were about to perform a tra- and play nurses. You don’t hear much Children’s Hospital of Pittsburgh until the offi ce was cheotomy, even though we were not surgi- about these people in the history of eliminated years ago, saved them from destruction. cally trained, when Dr. Silverblatt came Children’s Hospital, but I thought it was He shared them with documentary fi lmmaker (and in. He said there was no time to obtain one of the great highlights. his former intern) Ken Love, who brought the photos anesthesia, or there was no time to play home to see whether a story might emerge. games. Essentially, we held the youngster Spino: There was so much love generated The fi rst thing pediatrician Barbara McNulty (MD in the proper position, tilting her neck, by what they did. I think you knew that ’75), Love’s wife, did when she looked through the head back, so that he had exposure for the main aim in life there was for the photographs was to search for herself. She would the tracheotomy. Then immediately Dr. child and the good of the child. have been just 1 or 2 years old in 1951 and perhaps in Silverblatt made an incision. Thereafter, a full-body cast. McNulty was born with dislocated she stabilized. She was rather ill through- hips—shallow hip sockets that did not embrace the out the course of that day—being lethar- Hare: I think the important thing to real- rounded tops of her femurs. Nobody noticed until she was already walking. Surgery to repair the dam- gic, being tired, and even not being very ize is that Esther was recording that age did not work. alert. But I recall going to the fl oor on the human relationship that makes getting Thumbing through the images, McNulty became following day, at which time she was an well a successful thing in a hospital. enamored with Bubley’s project. It reminded her that entirely different youngster. She was sit- Whether you have high technology or the most important thing she knows about her own ting up inside her oxygen tent. She was low technology, a lot of it depends on the work has always been true: Nothing is more important alert. There was a difference in the young human relationships between doctors and than the bedside exam. A doctor must listen closely lady’s behavior and performance. patient, nurses and patient, parents and and lay hands on the patient. Even with high-tech patient. It’s the human relationships that tests, there is no replacement for the human touch. are liable to make the difference between Because of her childhood experience, McNulty Clyde Hare, Pittsburgh Photographer: You getting well and not getting well. and her practice partner James Romberger are par- look at Esther’s pictures of the nurses and ticularly sensitive to congenital hip dysplasia today. the children and the parents and you think, Spino: When you see a case like Patty In fact, a faint clicking clued Romberger in to the Boy, that’s exactly what I’d want to have at Clark—where you’ve accomplished so condition in this author’s newborn daughter (now a a hospital. much, where you had a child where the well-aligned, and speedy, 3-year-old). result might have been horrible—and McNulty never did fi nd her childhood self Runco: The length of stay was much lon- you see a happy, healthy, wholesome through Bubley’s lens, but as a pediatrician, she was ger at Children’s Hospital back in the ’50s, child leaving the hospital, you feel very able to interpret and order the jumbled photos in a and the needs of these children who had overwhelmed with happiness and satis- way that Love and fi lm editor Jodi Wu could not. long stays were many. They needed to be faction. And that’s pediatrics. ■ “Ken and I wanted to give this film to the hospi- educated, and they needed recreation. We tal,” says McNulty, the film’s director and producer. “We recognized that at this juncture with the new had the people who could do that. They Watch That’s Pediatrics online at did a wonderful job. We had a great many hospital, it’s important to look back as you look www.chp.edu/ThatsPediatrics forward.” —CS volunteers at that time—the gray ladies

18 PITTMED FEATURE

WELCOME TO THE DARK SIDE

MAYBE WE SHOULD INGEST ark Gladwin is a scientist with something to leverage: a fundamental biological discovery. MORE NITRATES AND NITRITES And that is why he is here in Pittsburgh. BY CHUCK STARESINIC M“We think we may have stumbled upon the active ingredient ILLUSTRATIONS BY in the Mediterranean diet,” he reports in his offi ce on the sixth FRANK HARRIS fl oor of UPMC Montefi ore. Gladwin says this calmly, without much fanfare, despite the magnitude of such a discovery. He is a youthful guy, with a head of hair just long enough that it might send another sci- entist to the barber. He wears snazzy shirts. He’s outgoing, and some of his colleagues wonder where he gets his energy. “There are mysterious cardioprotective qualities to the Mediterranean diet,” he continues. “And everybody has looked

SUMMER 2009 19 Mark Gladwin believes maligned molecules are the cardioprotective secret to the Mediterranean diet.

20 PITTMED at the vitamin E and the vitamin D and the vita- few ingredients that every lab already has lying Freeman himself may have unintentionally min C, and none of those things has panned out. around or can cheaply and easily get. provided us with a name for this dish: One- But what everybody has ignored is the one mol- Start with an ounce of oil. Nothing exotic, Pot Synthesis. You are the pot. Forget the fl ask ecule that is the richest but that is the bad one.” just regular oleic acid. (The olive oil in your and the hours of stirring—why not simply Gladwin, an MD who came to Pitt in 2008 kitchen is probably 55–80 percent oleic acid, slosh it around in your gut? as a professor of medicine and chief of the by the way.) Next, mix in some sodium nitrite, Division of Pulmonary, Allergy, and Critical Care which is common enough around the lab and n 2007, Freeman and Gladwin were Medicine, stumbled upon the power of this “bad is really just a type of salt used to cure meat. featured speakers at a conference at the molecule” when he was at the National Institutes Stir. That’s it. You’re done. IKarolinska Institute’s Nobel Forum in of Health. He describes the NIH as the sort of That’s the Reader’s Digest version. The rec- Stockholm. In the place where the Nobel place that enabled this discovery. It provided him ipe is actually more complicated and detailed, Committee announces the annual Nobel with a steady level of support without the need to but it’s nothing a careful and competent Prize in Physiology or Medicine, these two reapply for grants every cycle. By the same token, chemist can’t manage. The instructions (“lipid scientists were part of a program called it offered little hope for leveraging more funding phenylselenation/nitration protocol”) run fi ve “Frontiers in Medicine: The Emerging Role for his lab after a major discovery, such as a key pages long. A chemist adds reagents at vari- of Nitrate and Nitrite in Biology.” element of the Mediterranean diet—nitrate. ous stages to encourage particular molecular How is it that such common, mundane, Nitrate has long been seen as belonging to interactions and to discourage others. He stirs and purportedly deleterious stuff could turn the dark side of biochemistry. the clear yellowish liquid for several hours out to be so biologically important? To under- It is considered a pollutant in this country, with a spinning magnet dropped into the stand the research of Freeman and Gladwin, and the federal government tightly regulates the fl ask. Then he follows up with standard puri- you have to go back to the story of the 1998 amount of nitrate in drinking water. Your bot- fi cation measures, such as fi ltering the mix- Nobel Prize in Physiology or Medicine, which tled water is most likely nitrate-free. Municipal ture through a plug of silica gel. End result: a was awarded to three scientists who discovered water suppliers have become adept at limiting 99 percent pure solution of a fatty acid with a the role of nitric oxide in basic physiology. our exposure to nitrate. Over a recent fi ve-year nitro group (NO2) added in the middle. Nitric oxide was mainly known as a pol- period in Pennsylvania, for example, only a rela- Bruce Freeman, a lanky runner, cyclist, lutant, because it is present in automobile tive handful of communities in the state—with a and the UPMC Irwin Fridovich Professor and exhaust and cigarette smoke. It’s a free radical total population of less than 70,000—had nitrate chair of the Department of Pharmacology and was therefore thought to be a danger- levels in their drinking water that exceeded the and Chemical Biology in the School of ous thing to have running loose in the body, national health-based limits. Medicine, calls it “one-pot synthesis.” His where it would initiate uncontrolled reactions The negative press that nitrates receive actu- description makes it sound as though it were with cells and important biological com- ally pales in comparison to that of its sibling mixed in the break room while he munched pounds. Nitric oxide—NO, for short—was molecule, nitrite. Both molecules have been on a sandwich and scanned the latest issue trouble, so the experts said. indicted because they can lead to the forma- of Runner’s World, though he later notes that The 1998 Nobel recognized the dramatic tion of carcinogens called nitrosamines; yet it’s his lab’s method for adding a nitro to a lipid new understanding that NO protects the unclear if nitrosamines from food or beverages in this way is a “tour de force in organic heart, stimulates the brain, kills bacteria, and actually lead to cancer in humans. chemistry” that postdoctoral associate Steven dilates vessels to draw blood to wherever the Our bodies convert dietary nitrate into nitrite. Woodcock managed to pull off. body needs it. Most signaling molecules work And it’s the nitrite that is biologically active and, And what does this drug—this nitro-fatty through specifi c receptors in the cell mem- Gladwin believes, cardioprotective. acid—do? brane. NO, however, proved to be unusually Yet, parents are routinely told to avoid giving Experiments in Freeman’s lab in mice and powerful. Because of its small size and the fact children hot dogs because of the nitrites they tissue culture suggest that it might signifi - that it is soluble in fat, it easily traverses cell contain. cantly protect your heart from damage before, membranes to regulate cell activity. They are encouraged to lobby school boards during, and even after you’ve had a heart Nitric oxide is so unstable in the body that to remove nitrite from school lunches. There are attack. It looks promising for diabetes, too. it is natural to ask what compounds might act petitions one can sign to encourage the FDA to Freeman’s nitro-fatty acid occurs natu- as stable sources. That’s still an open question, ban nitrite. rally in low abundance in living tissue, and it and one that will ultimately have many cor- Gladwin insists that he isn’t advocating thera- appears unlikely to have dramatic, toxic side rect answers. (Nitroglycerin, for example, has peutic or even routine hot dog consumption. effects. Quite the opposite: It appears to be been prescribed to alleviate heart conditions “But the truth is that if you were about to have safe, stable, and simple to make. for more than 100 years. Now we know the a heart attack, and you ate a hot dog,” he says It sounds so simple that one might ask drug works by releasing NO.) with raised eyebrows, “based on all our data, you why we shouldn’t simply take some nitrite- At Pitt, Freeman and Gladwin are on to two should have cardioprotection.” cured meat—a nice Italian sopressata, for big pieces of the NO puzzle, both of which are Welcome to the Dark Side. example—and drizzle it with olive oil. Better likely to lead directly to therapy for patients. yet, toss with some cooked beets and serve hat follows are the instructions for on a bed of spinach—both rich sources of n 1990, eight years before the Nobel whipping up a potential wonder nitrate, which the body quickly converts to Committee recognized the importance W drug. You don’t need much—just a nitrite. Sounds tasty, doesn’t it? Iof NO, Freeman was at the University

SUMMER 2009 21 of Alabama, Birmingham, where he and oth- fatty acids have a benefi cial, clinically relevant rest of the body because it was unstable in the ers hammered out a landmark paper for the effect in treating sick mice,” he says. “That blood and would be instantaneously destroyed Proceedings of the National Academy of Sciences paper is cooking right now, in the peer-review by reactions with hemoglobin. (PNAS) describing a confounding observa- process.” “We started looking at the possibility that tion about nitric oxide. In the lab, NO com- In a small room off Freeman’s main lab, there were some subtle peripheral effects. We bined with highly reactive oxygen radicals to the air hums with the activity of two power- called it the ‘endocrine effect of inhaled nitric generate very toxic byproducts. Clearly, if this ful mass spectrometers, machines capable oxide’ because it was carried in the blood, dis- were happening in the body, it would be part of detecting and identifying molecules in tally.” They were looking for a blood-borne of an infl ammatory event. But that’s not what minuscule amounts. Here, researchers learn NO pathway. Freeman found. He says: what other molecules are created along the Gladwin and colleagues used an inhibi-

“When I tried to replicate those test-tube NO2FA pathway, what tissues contain them, tor to block NO production in the arms of chemistry-based observations in cell or ani- and how much is found there. healthy volunteers. Then they gave inhaled mal models, we observed that nitric oxide, At a table in the main lab, Volker Rudolph, NO gas and showed that NO was still reach- rather than being pro-infl ammatory, had anti- an MD and a visiting research associate in ing the arm. Next question: What was the infl ammatory properties.” pharmacology and chemical biology, gives a source of NO in the blood?

At this time, Freeman was about to embark, heart-disease/NO2FA briefi ng. He says that “So then we started rounding up the sus- courtesy of a Fulbright Scholarship, on a when someone experiences a blockage in the pects,” Gladwin says. “What could this spe- monthslong stint in the lab of one of his for- coronary artery—a myocardial infarction— cies be? And I was looking at all these strange mer trainees in Uruguay. There, while trying blood supply to part of the heart muscle is things like nitrosated albumin.” to fi gure out these anomalous anti-infl amma- cut off. A cardiologist can then remove the For bookkeeping purposes, Gladwin would tory effects of NO in living tissue, they stum- blockage and open the artery with a stent, always measure nitrite in the blood because it bled upon an unusual fatty acid byproduct. drugs, or a balloon. As the affected area of was an oxidation product of NO. Everyone When they looked at a fatty acid that included the heart muscle is reperfused with blood, the knew that nitrite was an inert waste product a long chain of 18 carbons, for example, they cells there suffer further damage. More than that appeared in the blood when you breathed discovered a nitrogen compound branching half of the cells that will die as a result of the NO gas. So measuring nitrite was a way of off from one of the carbon bonds—something heart attack will die upon reperfusion. The demonstrating that your healthy volunteer never seen before. patient will then live with a damaged heart; was, in fact, breathing NO gas exactly as you For nearly 20 years now, these nitro- the rest of the muscle will have to compensate intended.

fatty acids (NO2FAs) have been a focus in for this dead muscle tissue—the infarct. The “I even had a technician doing the nitrite Freeman’s lab. On any given day, as many as a heart may grow larger to compensate, too; measurements because they weren’t impor- dozen people—postdocs, students, and early- and this comes with its own negative health tant,” Gladwin says. “I spent day and night career scientists—attack this problem in his consequences. working on these complicated molecules that lab from multiple angles. In a mouse model of such heart attacks were really hard to measure, and my techni-

Two postdocs, for example, administer in Freeman’s lab, Rudolph injects NO2FA cian was breezing through all the nitrites.”

NO2FA to mice that have elevated blood glu- into mice just before the coronary artery But a telling sign showed up when he cose levels—the same problem that plagues is reopened—sometimes just three minutes looked at the technician’s measurements: gra- humans with diabetes. This follows an impor- before, mimicking the sort of intervention dients. There was more nitrite in the artery tant paper that Freeman and colleagues pub- that a cardiologist could someday perform on delivering blood to the arm than there was in lished in Nature Structural & Molecular Biology a human. In his experiments, the mice treated the vein leaving the same arm. The nitrite was

in 2008, showing that NO2FA was perhaps a with NO2FA always have smaller infarcts than being consumed. safe and natural alternative to the diabetes the control mice. “So we published a paper in 2000 say- drug Avandia. The drug lowers blood glucose In other words, they have cardioprotection. ing, ‘Look, we have this endocrine effect in levels by activating a receptor on the surface It’s as if they had just sidled up to the Dark the arm, and the only species we’re seeing is of the cell—the receptor is like a socket that is Side Café and ordered a spinach salad and a nitrite, and there are gradients suggesting it’s confi gured to fi t only a molecule with a specif- round of hot dogs. being used.” ic shape. When a molecule binds to the recep- Is it possible, Gladwin asked, that this low tor, it initiates a series of anti-infl ammatory ark Gladwin will never forget the concentration of nitrite is a source of NO for events. No one knew of a naturally occurring time that he, as a young NIH sci- dilation of these blood vessels? molecule that fi t this receptor until Freeman’s Mentist, presented some of his early This is the question that Gladwin posed to group showed that NO2FA does. Avandia’s work on nitrite at a conference. “Ridiculed” is a gathering of other scientists. And he recalls annual global sales total in the billions, but it too strong a word, he says, but it’s worth not- that a very famous scientist, of whom Gladwin has lately been associated with elevated risk of ing that he can’t come up with a better one. was a bit in awe, stood and said, “Mark, very bone fracture in women, as well as with heart In the late 1990s, Gladwin was investigat- nice work. You’re doing really nice work. I just failure, heart attack, and death. ing a mysterious property of nitric oxide gas: have one question: I use nitrite as a control in Freeman says the seminal paper in this area You can breathe it, and it will lower blood my aortic ring experiments. So how could this is yet to come. “The real relevance is when pressure in the lung. Yet, according to the pre- be active?” we are able to publish the observation that vailing wisdom, the gas would not reach the And the room went silent. Gladwin strug-

22 PITTMED ment in nine new people, and they might be useful—heart attacks, high blood got the same result. pressure of the newborn,” Gladwin says. “And “Whoa!” says Gladwin. “So then in all these preclinical models, the nitrite is we dropped the concentration by two working. So coming to Pittsburgh is very logs—from 200 micromolar in the exciting for me because now I have the oppor- arm to 2 micromolar. We repeat that, tunity at UPMC to move this discovery into and it dilates 10 of 10 people.” clinical practice. We’re limited at the NIH in patient population. Also, one of the ideal lot has happened since then, targets for nitrite is going to be solid organ including the 2007 Nobel transplantation, and Pittsburgh is obviously A Forum conference on the the center of the universe for that. emerging role of nitrate and nitrite “In solid organ [transplants], you essen- in biology, where both Gladwin and tially take a healthy organ, and you remove Mark Gladwin (left) and Bruce Freeman with Alfred Nobel at the Freeman spoke. Also, the famous sci- it, and you block its blood fl ow for hours. Nobel Forum in Stockholm. entist who used nitrite as a control, We think the nitrite—well, we’ve shown that gled to come up with an answer on the Gladwin reports, now says that he nitrite—essentially can stabilize organs in the spot. Maybe it only works at low oxygen, he always knew nitrite was a vasodilator. setting of blocking blood fl ow. We joke that suggested, whereas your aortic ring experi- Gladwin published in 2005 that low doses we’re turning an organ into a hot dog, but it’s ments probably use 100 percent oxygen. (This of nitrite prevent heart attack. a state of suspended animation where that tis- turned out to be true, Gladwin says, but at the “It was repeated by people all over the sue is protected from damage.” time, he was just “hand waving” and trying to world,” he says. Gladwin and Pitt colleagues Working with the Pittsburgh Life Sciences not look like a fool.) have proposed a heart attack trial to the Greenhouse, Freeman has started up a biotech

Gladwin relishes telling this story. National Heart, Lung, and Blood Institute. company to help bring NO2FA out of the lab, “So then what happened was a paper was What about the idea of nitrates and nitrites where it has only been tested in animals, and published in PNAS saying we were completely being toxins or carcinogens? into clinical trials in humans. The potential wrong,” he says with glee. One scientist who viewed Gladwin’s early market is signifi cant. “They claimed to have infused nitrite into papers harshly had been convinced for years “There are [University of Pittsburgh] pat- three people, and it didn’t do anything,” that nitrite was harmful. He had a hard time ents covering composition of matter, method

Gladwin says. “And that actually set us back believing Gladwin’s results, and data from his claims, and using [NO2FA] to treat spe- a year. … We were going to infuse nitrite into own lab showed that nitrite was toxic. But he cifi c disease conditions,” confi rms Hank normal volunteers, but when that paper came administered doses hundreds of times higher Safferstein, CEO of Complexa, the fi rm he out,” he pauses and throws up his hands. “This than Gladwin’s. Both Freeman and Gladwin launched with Freeman. was a really good lab that published, too, so we agree that there is at least the potential, with “We’re going to focus probably our initial thought they couldn’t make a mistake.” large doses of these compounds, for genotox- work on metabolic disease, in particular type 2 The nitrite experiment went to the back icity and DNA damage. diabetes. Obviously, this is a big area in terms burner. A year later, the lab had a surgeon Like all good things, nitrite is only good of unmet medical needs.” as a research fellow, and he needed a project. in the proper amount, says Gladwin, and the Is it also possible that a newfound aware-

He was an MD, so he could do all the blood same probably holds true for NO2FA. He cau- ness of these nitric oxide pathways might work, as well as analyze the results. tions that these are reactive nitrogen species simply encourage dietary changes that would “We start the experiments, and with the that cause powerful reactions. Gladwin thinks lead to healthier hearts? fi rst infusion [of nitrite], the hand turns red, the sweet spot for nitrite and nitrited lipids is “Look at the Mediterranean diet. It’s loaded and blood fl ow goes up 170 percent. It was in very low concentrations. with prosciuttos and salamis. It’s hot, so you as if we were infusing a vasodilator drug like At Pitt, Gladwin is the fi rst director of the have to cure your meat,” notes Gladwin, point- nitric oxide.” Gladwin and his colleagues Hemostasis and Vascular Biology Research ing out that such a diet also includes vegetables repeated this with nine patients, and they Institute. In his career, he has made major like beets—rich in nitrates, which the body called the lab that authored the paper assert- contributions to understanding the role of converts to nitrite. “Also, in the Mediterranean ing that nitrite was inert in the blood. These lung complications such as pulmonary hyper- diet, you live on well water—nitrate every- were good scientists and friends. Gladwin says: tension in sickle cell patients, and he has where. In the U.S., we tightly regulate nitrate “Even though their paper kind of slammed us, advanced the study of nitrite-based therapies in our water. If a well has nitrate, you can’t use it was good science.” for alleviating the vascular complications of it. Then the American diet: uncured meat and These scientists suggested the nitrite in sickle cell disease. In 2008, he coauthored a potatoes, pastas, bread, carbs. Zero nitrate. the IV bag was converting to NO. Perhaps review of the mechanisms of sickle cell disease We have a nitrate-defi cient diet. Is it possible they were actually infusing NO into the for The New England Journal of Medicine and that part of the cardiovascular disaster of the patients’ arms. a review of the nitrate–nitrite–NO pathway Western diet is that we’ve depleted this essen- Gladwin’s team buffered the nitrite solu- for Nature Reviews: Drug Discovery. tial mineral from our diet?” tion and measured the NO in the bag—a “What we’re doing is thinking of any To Gladwin, that sounds like a rhetorical negligible amount. They repeated the experi- disease where oxygen is low and nitric oxide question. ■

SUMMER 2009 23 THE HEART OF THE MATTER

CECILIA LO STALKS THE MOLECULES THAT SHAPE A VITAL ORGAN BY SHARON TREGASKIS PHOTOGRAPH BY STEPH HOOTON

24 PITTMED FEATURE

n the adult human, healthy function of the respiratory tract peutic,” she says. “I’m excited that we are at relies, among other things, on the rhythmic wave action of that boundary.” Much like seating assignments at a state hair-like cilia lining the airways. Their coordinated beat, dinner, the relative arrangement of organs in like fi elds of grain undulating in the wind, clears excess mucus and the chest and abdomen of a human embryo I matters enormously: heart to the left, liver to airborne contaminants from the lungs. In the fallopian tubes, cilia the right, stomach and spleen to the left, gall usher mature eggs from the ovaries to the uterus. In the ear, their bladder to the right. dance transmits vibrations to auditory nerves that we ultimately Occasionally, however, the whole assem- register as sound. In the brain cavity, they circulate cerebrospinal blage develops in mirror image, a condition known as situs inversus totalis. Providing that fl uid and prevent overaccumulations that might compress the the organs are otherwise normally conformed, skull’s precious cargo. Kids in grammar school learn about cilia in the condition may go undetected for a life- tandem with the dangers of smoking: Nicotine temporarily para- time and even supply an elegant plot twist, as in Dr. No. In that story, the fi ctional James lyzes our pulmonary street sweepers—and smoker’s cough results Bond lives another day when a would-be from their return to work after a few cigarette-free hours. assassin misses the spy’s right-sided heart by a few vital inches. First described by microscopists more than Fold, turn, divide, repeat, and the neural tube Far more worrisome, however, and associ- a century ago, cilia appear in nearly every yields a brain and spinal cord, the protean ated with myriad congenital deformities, is the cell type of the vertebrate organism and in heart splits into quadrants and migrates to the class of deformities Lo studies known as situs such simple organisms as mollusks and algae. left of the chest, four limb buds differentiate ambiguous, or heterotaxy. In heterotaxy, some Their ubiquity—even in organ systems where into a pair of arms and a pair of legs. organs are fl ipped while others occupy their wave action seems irrelevant—once led biolo- Most recently, Lo has begun to home in on standard location. Ultimately, the problem gists to dismiss the organelle as a vestige of the role of cilial motion during the fi rst few boils down to bad plumbing. With the organs evolution. That attitude refl ects oversight or, weeks following conception in the formation themselves out of place, the valves, veins, arter- perhaps, lack of vision. Previously, scientists of the cardiovascular system. ies, and chambers of the heart that normally could observe the cilia in action only in “You never know where the discoveries move oxygenated and deoxygenated blood in single-cell organisms, or within the fi rst few will come from that will benefi t a patient, discrete circulatory loops develop with quirks hours after the death of more complex crea- whether it’s developing diagnostics, medica- and malformations that can be fatal. tures. In the past decade, however, scientists tion, or some other therapeutic tool,” says Many genes are implicated in heterotaxy, armed with advanced imaging equipment Lo, who heads the National Heart, Lung, and which comes in multiple iterations of varying and an enhanced view of their microscopic Blood Institute’s Developmental Biology and severity. Even so, the condition is rare—fewer targets—alive and at work—have reconcep- Genetics Center in Bethesda, Md., as well as than 2 in 10,000 live births involve cardiac tualized the cilia as elaborate microsensors, its Laboratory of Developmental Biology. She defects associated with left-right asymmetry scanning their environment and generating set out to catalogue all of the genes responsible malformations of any kind, and a diagnosis and responding to the molecular signals that for congenital heart defects in mice. In the generally means a fast track to the operating convey information from cell to cell, maintain process, her lab revealed a link to a syndrome room. Although milder cases often end hap- cellular homeostasis, and even pattern the known as primary ciliary dyskinesia (PCD) pily, some infants with heterotaxy weather growing embryo. that affects the respiratory system in humans. the open-heart surgery only to spend the rest Research scientist Cecilia Lo, soon to be Lo now heads a study at Children’s National of their lives tethered to a ventilator. Worse, founding chair of the University of Pittsburgh Medical Center to investigate the relationship others undergo multiple operations and still School of Medicine’s new Department of between PCD and heart disease, a project die before their fi rst birthday. Because no one Developmental Biology, has spent the past 30 she plans to continue at Children’s Hospital has catalogued all of the genes involved or years investigating the mechanisms of com- of Pittsburgh of UPMC when she arrives in detailed the specifi c conformation of organs munication between cells in the developing Pittsburgh this July. each mutation yields, pediatric cardiologists embryo. Her quest: to understand how con- “When basic science impinges on clinical have lacked reliable indicators to predict a genital heart defects emerge during gestation. medicine, it behooves us to really pursue it baby’s odds before wielding a scalpel, leaving Like origami, much of embryonic develop- and bring that science to benefi t the clinical parents and doctors with little clarity about ment depends on the infl uence of patterning: population, whether it’s diagnostic or thera- how to proceed.

SUMMER 2009 25 “Cecilia has a big vision,” says longtime damage is so profound that by the time they cism,” says Vanderbilt University Medical collaborator Linda Leatherbury, a pediatric reach early adulthood, lung transplantation is Center chief of pediatric cardiology Scott cardiologist at Children’s National Medical the only viable treatment. Clinicians already Baldwin, who investigates vascular forma- Center who oversees imaging of Lo’s mice and knew that some kids with PCD have situs tion in mammalian embryos and worked conducts the study on children with hetero- inversus totalis. with Lo when both were on the University taxy and other congenital heart diseases. Based on the JCI fi ndings, Lo hypothesized of Pennsylvania faculty in the ’90s. “She’ll “It’s not like she wants to work on one that infants with heterotaxy whose open-heart often send her work to say, ‘What do you model, one specifi c defect, for the rest of her surgery leaves them ventilator dependent have think of this? Are we missing something?’ It career. She wants to fi nd all of the genes that undiagnosed PCD—“respiratory complica- goes both ways.” cause congenital heart disease.” tions in such patients are unfortunately attrib- As the group disperses to go off to their If Lo succeeds, one day clinicians will be uted to the heart disease,” she says. labs and computers, Lo stops to ask staff able to test for specifi c mutations associated The genetic link also validated Lo’s hypoth- scientist Biswanath Chatterjee about the sta- with heterotaxy and other complex congenital esis: She suggested that at the earliest stages of tus of a litter of mutated mice in the team’s heart diseases and help parents understand embryonic development, ciliary-wave action animal facility, a 15-minute walk across the the treatment options for their babies. programs the pattern and formation of the NIH campus. In its facility at the National Institutes of cardiovascular system. When the cilia don’t Chatterjee has known Lo since he spent Health, Lo’s team injects mice with a chemi- work properly, the organs form out of place. four years as a postdoctoral fellow in her lab cal that causes random genetic mutations, Effectively, PCD is a secondary outcome of at Penn in the late ’80s. then uses echocardiography to identify fetal the same genetic anomaly. “Science is in her blood,” says Chatterjee, mice with heart defects. The team details noting that he’ll often receive a series of e- the genome of every single affected mouse, n a swank, wood-paneled conference mails from Lo as she reviews literature from then compares it with the genome of a room on the seventh fl oor of the fl ag- home, long after her family has gone to healthy mouse to narrow in on anomalies in Iship National Institutes of Health facility bed. “Sometimes the e-mails just keep com- the mutated genome. In 2007, The Journal that houses her laboratory, Lo gathers with ing—1 o’clock, even 2 o’clock at night, and of Clinical Investigation (JCI ) published the her research team for their weekly journal the next at 5 o’clock in the morning. She team’s description of a recessive lesion in club meeting. On this late winter morning, a really enjoys this thing.” Dnahc5—an analog to the genetic glitch that junior associate presents a pair of 2008 Science Lo’s enthusiasm drives the lab forward, in humans causes primary ciliary dyskinesia. papers investigating the role of three proteins says Chatterjee, and she balances rigorous “That was a big surprise, because usually implicated in embryonic development and in expectations with acknowledgment that not when you think of patients with PCD, it’s ciliary action. Lo sits quietly, a can of diet cola everyone can maintain her pace. She also generally thought that [the] heart is normal,” on the table in front of her, fl ipping between makes a point, he says, of cultivating and says Lo. “No one really thought of PCD as a pages of the papers and intent on the slides protecting the junior scientists in her group. disease that could cause structural heart dis- of data projected on the screen at the front of Late last year, a researcher called Lo after a ease. We initially identifi ed this mouse model the room. Finally, as the colleague describes postdoc presented the group’s preliminary as a mutant with complex structural heart the authors’ conclusions, Lo breaks in. “The identifi cation, using massive-parallel DNA disease. When we identifi ed the gene, it was a point is to show specifi city,” Lo says, glancing sequencing, of a heterotaxy-inducing muta- complete surprise.” again at the manuscript in her hands and back tion of the gene Megf8. The other scientist Stanford University surgical intern Serena to the screen, “but they haven’t done the con- was also working on Megf8, he said, and if Tan was fi rst author of the JCI paper. At the trol. I’d like to see a parallel where they didn’t Lo’s group would hold their fi ndings for a time, she was a second-year Duke University get the result with the original sequence.” year, the two groups could collaborate and medical student with 12 months of funding The critique sparks a minidebate between then publish simultaneously. Lo called a from the Sarnoff Foundation. the dozen grad students, research techs, and meeting of the 18 scientists working with “Dr. Lo was committed to giving me a fellows in the room about how the authors her and the postdoc and presented the project,” says Tan, whose fi rst project ate up could have done better. The study examines opportunity. Everyone had a chance to voice six months and terminated in a dead end. the response of the proteins to antibodies, an opinion, says Chatterjee, a member of “She gave me the most exciting project going and part of the problem, says Lo, is that the the team. “She protected everyone who was on. She’s very hands-on, oriented to detail, best antibody to serve as a control in this case working on this project.” and very thorough in her investigation. [In isn’t widely available—its creator has closely There were too many questions about the her lab], you can’t just be swept away by guarded distribution. Soon the session is over, value of the collaboration for her group, says current trends. My paper, I think, was pub- but Lo has made her point: Claims by scien- Lo, and the team opted to stay the course. lished partly because no one has made such a tists aren’t the same as scientifi c proof from a Their fi ndings appeared in the March 3, detailed study on the phenomenon.” well-designed experiment, and collaboration 2009 issue of the Proceedings of the National People with PCD have compromised cil- can mean the difference between a so-so study Academy of Sciences. ial function in their respiratory tracts. In and one with the power to convince. “The human element is really impor- time, mucus and bacteria accumulate in “I send Cecilia a paper to read, and tant,” she says. “It’s not just my career, and the lung, leading to recurrent infection and she’ll say, ‘You haven’t proved this,’ or ‘You it’s not just the science. People’s lives and compromised pulmonary function. Often the haven’t done that.’ Likewise, she’ll take criti- careers are at stake. It’s my job to do the best

26 PITTMED J. ROSENTHAL, AL. BIRTH C) 72:213-223 (2004) ET DEFECTS RESEARCH (PART Lo and her colleagues can’t afford to capture only a fraction of the information needed for heart- defect research, which is what they get with 2-D images. Using a technique known as EFIC, they’ve the health sciences. Lo’s job will be to provide created digital, 3-D atlases of both human and mouse embryonic development that allow research- direction, says Arthur S. Levine, dean of the ers to view samples from any vantage point, including cross-sections of the heart. The fetal mice School of Medicine and senior vice chancellor above were each imaged at a different stage of maturity and are shown from different angles. for the health sciences. I can for the people in my lab.” Some mentors just give you a protocol to “What’s been needed in my view has been Beyond performing their wide-ranging follow, but not Dr. Lo. She’s always teaching. a senior developmental biologist of wide genetic analyses, Lo and her team have also And if I run into a problem, she has 30 dif- repute and recognition to bring together and refi ned and automated the technology to ferent solutions to try.” coalesce the theme, crystallizing what we generate a pair of three-dimensional online This spring, Samtani assisted a cardiology already have,” says Levine. “Adding Cecilia to atlases of human and mouse embryonic fellow developing a digital video of human the mix will accelerate our momentum—give development based on a technique known as cardiac development. “Viewers, other scien- it shape and form and visibility.” episcopic fl uorescence image capture (EFIC), tifi c researchers and clinicians, can go through At Pitt, Lo will have a joint appointment now a cornerstone of Lo’s documentation of the entire embryo,” he explains. “But it may in pediatrics, and the proximity of her lab complex structural heart defects. Using EFIC, be hard to orient.” The challenge is easy to get in the John G. Rangos Research Center to the group creates 3-D, digitized renderings around in still images. A simple compass icon the children’s hospital (next door instead that can be viewed in any plane. does the trick. Samtani suggested that incor- of a 25-minute drive away, as in Bethesda) EFIC provides an elegant work-around porating a comparable strategy into the video will promote the synergy she craves. She has to a basic problem in conventional histol- would enhance its value. “Dr. Lo said, ‘Go for already begun exploring partnerships with ogy, in which thin slices of paraffi n-embed- it,’ and now we’re trying to label everything, Pitt pediatricians who treat congenital car- ded samples go under the microscope. Of and we’ve got some new software. If I have an diovascular and renal disease. course, the heart functions and develops in idea and voice my opinion, everyone in the “This offers a whole new area of research three dimensions; when sectioned into thin lab, especially Dr. Lo, is so open.” to what we’ve traditionally studied,” says slices, critical information gets obscured or More recently, a late-night e-mail exchange Steven Webber, medical director of pediatric destroyed. And though each slice retains its with Lo about the possibility of combin- heart and heart-lung transplantation and an integrity in two dimensions, stretching and ing EFIC with confocal microscopy (which associate professor of pediatrics whose work compression caused by the slicing itself makes allows scientists to create a sharper image by with heterotaxic infants makes him particu- a 3-D reassembled composite impossible. illuminating one point of a specimen at a larly interested in Lo’s arrival. Structural anomalies aren’t replicated across time) had Samtani’s adrenaline running high. “From an intellectual standpoint on our specimens, and Lo’s team can’t afford to cap- He barely slept. “I was so excited to get to end, clearly [Lo’s appointment] broadens the ture only a fraction of the information needed work,” he says. scope of what we do.” from each heart. Using EFIC, they image the Lo’s fi rst recruitment effort, to bring a block face that remains, instead of the slice or Lo, the give-and-take of study stem cell biologist into the fold, got a boost they’ve removed. design and execution is precisely what this winter when President Barack Obama Premed student Rajeev Samtani joined Fmakes science a rewarding pursuit. “If rescinded the Bush Administration’s funding Lo’s team in 2007 as a freshman in biological you can’t discuss what you have,” she says, restrictions on embryonic stem cell research. engineering at George Washington University, “you’re missing a big part of the fun of doing “I hope that in building the department in D.C. Lo’s use of EFIC captured Samtani’s science. we can take an approach where you have basic imagination, and today the 20-year-old has “I feel like you can go a lot further in your scientists pursuing very fundamental issues developed some expertise in the technique. work, faster, by sharing resources, informa- related to how development is regulated and “Dr. Lo is the best mentor I’ve ever had,” tion, working with others. To me, being a translational component with investigators says the Maryland native. “It may take twice generous with your colleagues is a good thing. trying to relate those fi ndings to disease pro- as long to do a gross necropsy with me, but Ultimately, it’s a win-win.” cesses in children,” she says. “I really feel like Dr. Lo stops every second to make sure I At Pitt, junior developmental biologists the time is right to integrate the two. I don’t know what she’s doing—what she’s imaging. populate multiple departments throughout think you can do one or the other alone.” ■

SUMMER 2009 27 28 PITTMED FEATURE

A MENTOR AND STUDENT TRY TO KEEP DYING CELLS ALIVE | BY JOE MIKSCH

IN THE SHADOW OF A STROKE

bout five years ago, 59-year-old Randy Zotter was hav- ing some trouble with his knee. So much so, that he arranged to have an X-ray taken at UPMC Passavant in APittsburgh’s North Hills. No big deal, he thought, just a small diver- sion ahead of his plans to take his wife, Leslie, out that night for their 25th wedding anniversary. The X-ray completed, Zotter got into his car. “My left hand goes like this,” he says, fl opping it off a table. “It wouldn’t move. Immediately, I went into a state of denial.” He started the car and drove off. His left arm still wouldn’t move, and recalling that his father had a stroke when he was 39 prompted Zotter to turn around and head back to Passavant. He parked about 100 yards from the emergency room—“I didn’t want to block the entrance,” he says, laughing—and hobbled to the door. “I told a woman out there smoking that I was having a stroke. She ran away,” Zotter recalls. Once inside, he was taken in for a CT scan. Doctors confi rmed Zotter’s self-diagnosis. A cerebral artery had collapsed, they told him. For the next two weeks, Zotter rested in the hospital. For months afterward, he went through round after round of physical and occupational therapy.

Neural cells not immediately killed by a stroke can suffer from a deadly inability to synthesize proteins. Jun Chen and Peter Vosler have found that a protein called eIF4G, vital to synthesis, is torn apart by calpain, COURTESY P. VOSLER a protease, in the wake of a stroke. By inhibiting calpain, the two think they may have found a way to save such cells and perhaps have acquired the tools for an exciting new therapy. (The first image, in red, is a neural cell stained to show the expression of eIF4G. The second, in green, is a normal neuron. The third, at right, is an overlay of the two images.) SUMMER 2009 29 However, Zotter says, his doctors told him blood fl ow in the brain. After that window Biomedical Science Tower offi ce, the pair recount there was nothing to be done to save the brain closes, tPA isn’t effective and increases the risk the history of their nascent partnership. cells injured by the stroke. of brain bleeding. “When Peter came to my lab, and we sat Jun Chen and Peter Vosler, of the University “Only about fi ve percent of the 800,000 down to discuss what he wanted to do, I said, of Pittsburgh School of Medicine, are trying to stroke patients a year in the U.S. can get tPA ‘Peter, we have a major mystery in the [stroke] build a brighter future for patients like Zotter and benefi t from it,” says Vosler. fi eld, and it’s a big challenge,’” Chen recalls. ‘Do who make it to the hospital within a few hours That’s because of the small time window you want to take it on?’ He said, ‘Yes.’” of experiencing a stroke. They have found a and a host of other factors excluding patients “I was a young, naïve student,” Vosler adds, way to halt neuronal cell death caused by lack from tPA therapy. before both he and Chen dissolve into laughter. of blood fl ow, or ischemia. The therapy wasn’t an option for Zotter, Chen leans back and lets his student tell the Chen is an MD professor of neurolo- for instance, who didn’t have a blood clot but story. gy and pharmacology and chemical biology. did suffer from what’s known as an ischemic Regaining a bit of composure, Vosler says He holds an endowed chair and directs the infarction. seriously, “I thought that this work might be Cerebrovascular Research Center at Pitt. Vosler Chen and Vosler anticipate they’ve hit upon risky, but I was sure I was going to learn under is an MD/PhD student who recently complet- a molecular mechanism that, if translatable Dr. Chen no matter what I did.” ed his PhD work in neuroscience and begins into a drug, could limit the damage done in The reason for Chen and Vosler’s laughing his third year of medical school in the fall. such cases. Their work is predicated on a dis- fi t is that researchers have been poking around Stroke is the third-leading cause of death in covery European researchers Paul Kleihues and the question of how to rescue stroke-damaged the United States and the second worldwide. Konstantin-Alexander Hossmann made in the cells for decades. And though Chen discovered About 80 percent of those cases are consid- early 1970s. Using animal models of stroke, that protein synthesis disruption is probably ered ischemic—brought on by a lack of blood Kleihues and Hossmann determined that the responsible for the death of neuronal cells fl ow. When a stroke strikes, the halted blood brain uniformly shuts down protein synthesis present in the penumbra of a stroke, getting fl ow decidedly and immediately kills cells at in all ischemia-affected areas. Hossmann later into the nitty-gritty of protein synthesis could its epicenter. The damage eventually spreads found that brain regions that recovered protein be considered a bit much for a “young, naïve to the penumbra, the area surrounding the synthesis lived, whereas regions where protein student.” dead cells. According to Chen and Vosler, stopping the death of neuronal cells in the penumbra His doctors told him there was nothing to be done of a stroke can curtail the long-term physical to save the brain cells injured by the stroke. and emotional damage caused by this seri- ous insult to the brain. These cells don’t die immediately in a stroke’s wake. But when they synthesis inhibition persisted died. Vosler’s charge? First, create a credible model do die, the area of the brain affected is greatly Chen and Vosler posit that the neuronal of protein synthesis in the lab. The process expanded, leading to more problems for a cells in the penumbra of a stroke might be sal- of studying the causes and effects of stroke is stroke survivor. vageable if the disruption of protein synthesis complicated enough that the additional vagaries Zotter regained use of his arm—only after can be remedied. introduced by studying it in vivo are excessive months of physical therapy. He recalls trying “[Neuronal cells affected by ischemia] lose and confounding. So Vosler took the petri dish to refi ne his motor skills by attempting to over 90 percent of their capacity to synthesize path. screw a nut onto a bolt. The frustration, he proteins, and if protein synthesis is ineffi cient Vosler took primary cortical neurons from says, was overwhelming. “But I told myself, and persists, the neuron will die,” says Chen. rats, cultured them, and was able to mimic ‘Yes I can, and yes I will.’” That situation is not remedied by tPA or any ischemic conditions in culture dishes. He also Though he suffers no speech impediment, other current stroke therapy, including cerebral succeeded in reproducing persistent protein syn- Zotter says that he has to concentrate much angioplasty and surgery. thesis inhibition. “What he did was establish a more when speaking. And he’s more emotional “The question is,” adds Chen, “‘What model system to replicate the condition seen in now: “I tear up during ‘chick fl icks.’ I never causes the persistent protein synthesis defi - vivo,” Chen says proudly. “Now we can study did that before,” he says. ciency?’ That question has been pestering the the mechanism in a very tightly controlled situ- Although Zotter has recovered well over- fi eld for years.” ation.” all—thanks, he thinks, to the fact that he was He adds: “We believe that if we are able to Chen adds that he’s also impressed with very close to a hospital when he suffered his identify the molecular mechanism underlying Vosler’s feat because though the steps by which stroke—few treatment options were available persistent protein synthesis defi ciency, we may cells make proteins are understood, there is less to him when he entered the emergency room. be able to develop a new therapeutic strategy familiarity with how the whole business gets One of the most exciting advances in to prevent cell death after stroke.” started. Thanks to advances in molecular biol- stroke therapy in recent history came in the Perhaps, Chen says, they’ve completed the ogy, neuroscientists now know that there are early 1990s, when doctors began using a fi rst step and are now on their way to achieving 36—read: a whole lot of—proteins involved clot-buster called tissue plasminogen activa- the second. with initiating protein synthesis. “That’s before tor, or tPA. If delivered within three hours The effort started with Vosler looking for you get any translation, any elongation, or any of a stroke, tPA breaks up the clot that limits a PhD project and mentor. In Chen’s Starzl amino acids being added,” Vosler says.

30 PITTMED Earlier in vivo studies indicated that during Volser says he tried a new reagent that was blood-brain barrier. The process uses an 11- ischemia there is a decrease in the presence of supposed to ease the transfection process. “It amino acid sequence of HIV that does not a scaffolding protein called eukaryotic growth was touted to work in primary neurons,” he contain the pathogenic domain of the virus. factor 4G (eIF4G), which is responsible for says. But it didn’t. Eventually he settled on Earlier this decade, Chen was the fi rst to pro- transporting messenger RNA (mRNA)—pro- using a lentiviral vector, a kind of “neutered” vide neuroprotecion in an animal model of tein-making instructions—to a cell’s ribosome. virus that can’t reproduce but can carry stroke using a protein connected to this HIV Ribosomes are cells’ protein factories, the seat and insert cargo into cells. Vosler feared the amino acid sequence. of protein synthesis. If there’s a problem with size of the cargo might gum up the works. A nanoparticle might also serve as a deliv- eIF4g, mRNA messages cannot get to the ribo- (Lentiviruses can typically carry a 10 kilo- ery vehicle for the therapy. Nanoparticles are some, dooming protein synthesis. With that, base load; Vosler had 12 kilobases of stuff he tiny, inert bubbles that, like the HIV protein the cell dies. wanted to put into them.) segment, can cross the blood-brain barrier. Enter calpain. Calpain is a protease that “At this size, we expected that either there They’re particularly attractive for drug delivery cleaves, or breaks down, eIF4G. As Vosler would be no expression of eIF4G or there because they can be directed toward specifi c explains, calpain depends upon calcium in order would be very little,” he says. “Much to our neuronal receptors. Kind of like a GPS system to be active. In the wake of ischemia, calcium surprise, the virus was able to transfect pri- for stroke therapy. rushes into neurons and stirs up a calpain storm, mary neurons with approximately 75 to 90 The Randy Zotters of the world, Chen and with the calpain cutting up eIF4G and block- percent effi ciency.” Vosler hope, will someday be able to receive an ing normal mRNA activity. Chen and Vosler So with the technical issues solved and injection in the wake of a stroke that will halt thought, if calpain-mediated eIF4G cleavage after collecting and interpreting their data, and reverse the slow cell death caused by isch- and the resultant inhibition of synthesis are a Chen and Vosler felt confi dent that they had emia-related protein synthesis cessation. direct consequence of ischemia, perhaps inhibit- established a direct relationship between isch- The researchers are far from monitoring ing calpain could restore the process. emia, eIF4G, calpain, and the untimely end of safety trials, yet they are hopeful that they can Experiments conducted by Vosler inspire protein synthesis in neuronal cells. This, Chen avoid the risks related to conventional tPA confi dence that this hypothesis is correct. Vosler says, is a very big deal: “This is the fi rst time it therapy, such as brain bleeding. Chen imag- tried to calm down calpain by introducing a has been shown that protein synthesis inhibi- ines a prospective new therapy coming out of load of its inhibitor, calpastatin. Doing so, he tion and cell death are directly related.” their studies that—unlike with tPA and other found, stopped eIF4G cleavage, restored pro- With publication of the work pending— treatments—wouldn’t just restore blood fl ow tein synthesis, and increased the viability of his Chen hopes the results will see print in the to the brain, it would redeem neural cells in cultivated rat neurons. And by maintaining the Proceedings of the National Academy of Sciences the penumbra of a stroke, limiting damage proper level of eIF4G, Vosler was able to sustain this spring—Vosler has been on a bit of a and making a patient’s recovery easier. these gains. speaking tour, presenting the fi ndings at the Time will still be a factor in the treatment, Don DeGracia, a PhD associate professor of American Heart Association’s Fellows Research however. “The median time of arrival [to a physiology in Wayne State University School Day and at a conference at Cold Spring hospital after a stroke] is six hours,” Vosler of Medicine in Detroit, calls Chen and Vosler’s Harbor Laboratory on Long Island, N.Y. says. At this point, Vosler and Chen are work “impressive.” DeGracia is an author of a “That I was able to get a platform presenta- unable to pinpoint a required time frame for 1994 paper that implicated calpain as an enemy tion [at Cold Spring Harbor] in front of all any therapy arising from their work. of eIF4G. these big-time protein synthesis researchers was Vosler is unsure whether he’ll be travelling “What Pete and Jun have done is prove great,” Vosler says. “Postdocs through senior along with Chen through the intensive lab beyond a shadow of a doubt that calpain scientists said it was very interesting work. And work and lengthy clinical trials necessary to degrades eIF4G,” DeGracia says. “There were the fact that it’s related to disease directly and bring a calpain inhibitor–based therapy to some possible scientifi c doubts with our origi- has the potential to really help means a lot.” stroke patients. Come fall, he’ll resume the nal methods. Pete and Jun have used foolproof “Their work is one thread in a tapestry pursuit of his MD and, after that, the future methods to prove it.” that is being woven by many labs right now is unwritten. Also, DeGracia adds, “They’ve shown that recognizing how important it is that brain “I want to fi gure out how I can do clinical by preventing calpain from degrading eIF4G, cells recover their ability to make their own and lab work at the same time,” Vosler says. “I they not only recover the cell’s ability to make proteins,” Wayne State’s DeGracia says. “It’s the really enjoy research, but I haven’t decided on protein, the cells don’t die, either.” overall picture coming out of this tapestry that a fi eld. Surgery is enticing but would limit the The process leading to these discoveries will offer a new way to understand stroke and amount of time I could have in the lab. I really wasn’t particularly simple, Vosler says. may help us to prevent neurons from dying.” haven’t fi gured out what I want to do.” The eIF4G protein, at 220 kilo daltons And that’s what will mean the most to In a way, Chen says, it doesn’t mat- (that’s equivalent to the mass of 220,000 hydro- Chen and Vosler—translating lab-generated ter much what discipline Vosler ultimately gen atoms), is pretty huge as these things go. knowledge into a clinical application. chooses to pursue. The size, Vosler says, makes it diffi cult to syn- “We can develop a way to deliver the [cal- “The purpose of the MD/PhD program is thesize its DNA—a process that becomes harder pain] inhibitor to the brain, and that’s the way to train scholars, to train physician-scientists,” to do without errors the longer a sequence is. to attack it,” Chen says. Chen says. “Regardless of the area he goes into, Neuronal cells, he adds, are notoriously diffi cult They envision attaching the inhibitor to he is going to be outstanding. What he’s doing to transfect—to introduce DNA into a cell. a segment of HIV protein that can pass the is very rare, to be honest with you.” ■

SUMMER 2009 31 ATTENDING

Ruminations on the medical life DEREK WAHILA DEREK

Every winter, Operation Safety Net holds a vigil for the homeless who died on the 32 street that year. The organization’s founder, alumnus Jim Withers, is shown far right. CASTING A SAFETY NET

HOW PITTSBURGH’S STREET DOC GOT STARTED INTERVIEW BY TERRY GROSS

n November 17, 2008, tell the hospital for the fi rst nine months what I think is why within the medical fi eld this National Public Radio I was doing because I wasn’t sure how they is very timely. We need to learn to let our featured University of would accept it. Then I fi nally confessed that patients and those populations that are in OPittsburgh School of Medicine alumnus I was doing this work, and I would like some need teach us. So as time went by, I saw people Jim Withers (MD ’84) on Fresh Air with sort of support. At that time, they were able who—they had prescriptions that were melt- Terry Gross, produced in Philadelphia by to give us a small grant, which allowed me ing in the rain that some emergency room WHYY and distributed by NPR. Withers’ to hire some of the homeless guys, formerly had given them. They were coughing and ill, Operation Safety Net started as an out- homeless guys, as outreach workers, and then but they couldn’t afford [medicine], and they reach program under the auspices of UPMC get a secretary to sort of organize it all. The weren’t going to tell anyone. So, I realized that Mercy; it’s now a nonprofi t organization. record-keeping is a challenge—people that I needed to start taking some medicines out to What follows are excerpts of the interview. gave you different names on different days. the street. The police were kind of skeptical at (© 2008, WHYY, printed with permission.) Acquiring supplies—we used to sort of steal fi rst about me, so I worked on that relation- things from a hospital early on, and then that ship as well. And also, there was, in the very TERRY GROSS: My guest, Dr. Jim Withers, worked itself out a little better later on. beginning, a certain individual on the street has practiced medicine in dark alleys and GROSS: So, during those fi rst few months, that I think would have taken advantage of me under bridges as he’s traveled the streets when you were dressing like a homeless per- if I had anything that was of any great street treating the homeless. In 1992, he founded son, was that helpful? value. So I began fi lling little Ziploc bags with Operation Safety Net to treat homeless WITHERS: I think so. But it was amusing, medicines that could be very useful—antibi- people in Pittsburgh. It’s one of the nation’s because after I got established on the streets, otics, pain medicines that weren’t addicting, fi rst full-time street-medicine programs and they called me Doc Jim. And from one bridge bandage material. has inspired similar programs in other cit- to the next they would sort of refer me to GROSS: You said initially the police were ies. Last month, Dr. Withers established the someone else that needed help. And then one skeptical of you. What were they skeptical of? Street Medicine Institute, a nonprofi t dedi- day a guy said, “Doc, why do you dress so WITHERS: Well, they didn’t really believe I cated to helping communities throughout poorly?” And I realized maybe I should dress was a physician. I certainly wasn’t dressed like the world develop street-medicine programs. up a little bit. So then I just got more practical one at that time. And it was at night. We were Withers is a doctor of internal medicine. in my outfi t. going into places that—actually we were prob- Dr. Withers, welcome to Fresh Air. Being GROSS: So what do you wear now? ably trespassing in a few instances. So, they among the fi rst people to set up a street WITHERS: Just dark clothes, cargo pants, would stop and ask. And I particularly remem- medicine program, what are some of the and I have a backpack, which has gotten much ber, a guy came up to me, and he handed me obstacles you faced in getting something bigger; it has a lot of medical supplies and a handful of heroin and needles and things like that off the ground? Or maybe, like, the things in it. and just said, “Doc, I want to get off drugs.” I rules are established now, but they weren’t GROSS: What do you keep in your back- looked down the street; there was a policeman when you started? pack? watching us. And so, there really wasn’t any JIM WITHERS: There really wasn’t anyone WITHERS: Well, the street really has to precedent for them. But I got to know some of to ask, in terms of guidance, even if this was teach you how to do this sort of thing. And the police pretty quickly. I actually went to the a very good idea. Early on, I think I didn’t that’s really the underlying philosophy, which station and talked to them and acknowledged

SUMMER 2009 33 the hard work that they were doing and made it was just me and a formerly homeless per- WITHERS: It is a little challenging. I work partnerships with them. So that worked out son. I was quite concerned about my safety. with a lot of other cities throughout the United pretty well. We’ve been at this for over 16 years, and States to help them start programs or to improve GROSS: So what happened? Did you take no one has ever been assaulted or hurt by the programs that they’re doing in street medi- the heroin? any homeless person. But the fi rst year was cine, and one of them had an interesting term. WITHERS: I gave it back. I said, “You’re probably a little bit more up for grabs. I had Instead of calling it “case management,” he going to have to get rid of this yourself.” three people point guns at me. I had someone called it “chase management.” There’s a lot of GROSS: What are the typical problems threaten to cut my throat. It really became effort that’s put into keeping tabs on people and you’ve seen on the street—medical problems— obvious to me after time that we had become knowing where they are. Our electronic medi- since you started doing this work? part of the street culture and vice versa, and, cal records allow you to put a name in and fi nd WITHERS: Well, we live in a part of the if anything, we were well respected and cared out who’s likely to know where that person is. country that’s cold, and so we do see people for in the street. We work with the morgue. We work with the who suffer from frostbite, the loss of toes, and GROSS: So when people held guns to you, libraries. And then the street has its own sort trench foot. There’s a lot of trauma. People were they other homeless people, or not? of network of knowing where people are and are injured a great deal on the streets just by WITHERS: Well, one was a fellow that we what’s going on with them. living out there, but also people are victim- came up on the wrong way, and there’s a lot GROSS: Dr. Withers, I understand you start- ized by nonhomeless people, actually more of street etiquette and ways of doing things. ed a wall in memory of homeless people whom often and [more] seriously than by other (You really need someone who knows the you’ve worked with who have died. Would you homeless people. But for the vast majority street. And I would say anyone who is going describe the wall? of people, it’s medical conditions that we all to do this needs their own ambassadors to WITHERS: Years ago, I was in a People suffer from but just go untreated due to the the street—formerly homeless are great types Magazine article, and Sidney Sheldon sent living circumstances. of folks to do that.) And that person we just some money. It was very kind of him, and I GROSS: Many homeless people are men- surprised. thought, “I know what this money should go tally ill and are suffering with delusions and One guy, I also surprised, he knew me for.” There were people dying on the streets, hallucinations. How do you treat someone well, but he pulled a shotgun out, and another and no one was remembering them. So I used

There were people dying on the streets, and no one was remembering them.

in that condition? You don’t have their medi- former homeless guy was able to redirect the money to buy 10 plaques, and I was going cal records; there’s no family members to tell that—it didn’t go off. One was a policeman to drill them into the sidewalk or wherever that you about pre-existing conditions; they’re not who pointed the gun at us, and that frightened person had slept. Slowly they would accumulate, going to be able to accurately communicate me more than anything because I knew their and they would make a—almost a political— their symptoms or their, you know, long-term aim was good, and I didn’t move a muscle. So statement about how many people are dying. medical problems. So what do you do to get those are the kinds of things. You just have to Well, it turns out that that’s illegal. So oriented to their problems and to communi- be careful how you approach people in remote we negotiated with the city, and we found a cate to them what they need to do? campsites and things like that. compromise of a wall. Every street person that WITHERS: Oftentimes you ask them, GROSS: You said, “You have to be care- we can account for [since 1989] has a plaque “What medicines have you been on?” And ful not to do it the wrong way.” What’s an on that wall, and it’s become one of the focal they’ll mention some psychiatric medicines, example of the “wrong way” that got you into points for a sense of community. The homeless so you know that’s probably part of the his- trouble? anticipate their friends’ names appearing there tory. But you have to be very indirect, because WITHERS: There was a guy who was nod- when they’ve died. Family members come, and it’s very threatening to people to go right to ding [off], and for whatever reason, he was it’s a place of healing and of acknowledging mental health issues. against a wall, and we came at him in a sort also the reality of what’s going on. Each year, So I found that even if a person is quite of a horseshoe pattern. So he was surrounded. as in other cities, we have a homeless memorial paranoid, delusional, and afraid, they still have You know, there are a lot of predators out there service on December 21st. It’s a candlelight a rich emotional life, and they do understand that take advantage of the homeless. I guess service, and it has great meaning for all of us. that you care about them, that you’re consis- that would be the way that they would assault GROSS: Sounds like those plaques are part tent, that you’re respectful. These are things someone. obituary, part tombstone. that send powerful messages. GROSS: Is it diffi cult to work with people WITHERS: That’s right. GROSS: Did you worry about protecting over an extended period of time? Do the home- GROSS: Well, I want to thank you very your own safety when you’re on the street? less people that you see stay in one place? Can much for talking with us. WITHERS: Well, when I started, basically you fi nd them after their fi rst treatment? WITHERS: Thanks for raising awareness. ■

34 PITTMED MATCH RESULTS CLASS OF 2009

ANESTHESIOLOGY Luan, Chih-Chen Busch, Ryan Lancaster General Hospital/Temple University, Pa. University Hospitals Case Medical Center/ Swanier, Brandi Case Western Reserve University, Ohio Memorial Hospital of Rhode Island/Brown University Gauvin, Jean Thomas, Stephanie Johns Hopkins Hospital, Md. University of Colorado School of Medicine Lai, Yvonne Turner, Andres

Massachusetts General Hospital/Harvard University UCSF Medical Center, Calif. KAPELEWSKI / CIDDE Lao, Veronica University of Virginia Hospital INTERNAL MEDICINE Patience paid off as the Class of 2009 learned of their residency matches; Atri, Prashant Olutunmbi, Yetunde there were many happy and relieved faces in the crowd. University of Pennsylvania Health System Washington University Medical Center, Mo. Peperzak, Katherin Bryk, Jodie University of Pittsburgh Medical Center University of Pittsburgh Medical Center Rohrbaugh, Max Cai, Xiao NEUROLOGY Ewan, Lindsay University of Pittsburgh Medical Center University of California Davis Health System Bledsoe, Ian Cincinnati Children’s Hospital Medical Center/ Shah, Pranav Caprio, Timothy Stanford Hospital and Clinics, Calif. University of Cincinnati, Ohio University of Pittsburgh Medical Center McGaw Medical Center/Northwestern University, Ill. Linnoila, Jenny Goldberg, Brittany Telford, Charlotte Ceyrolles, William Massachusetts General Hospital/Harvard University Children’s Hospital of Wisconsin/ University of Pennsylvania Health System University of Pittsburgh Medical Center Magge, Rajiv Medical College of Wisconsin Tsai, Annie Fridman, Yaron Massachusetts General Hospital/Harvard University Pires Ervoes, John UCLA Medical Center, Calif. University of Michigan Hospitals and Health Centers Van Laar, Amber McGaw Medical Center/Northwestern University, Ill. Iyer, Sunil University of Pittsburgh Medical Center Shinozawa, Yohko DERMATOLOGY University of Pittsburgh Medical Center Zhang, Fan University of Texas Medical School at Houston Brown, Patrick Kearney, Kathleen McGaw Medical Center/Northwestern University, Ill. San Antonio Uniformed Services Health Education University of Washington Affi liate Hospitals PLASTIC SURGERY Center, Texas Larochelle, Marc OBSTETRICS/GYNECOLOGY Irwin, Chetan Hawryluk, Elena Johns Hopkins Bayview Medical Center, Md. Foley, Carolyn UCSF Medical Center, Calif. Massachusetts General Hospital/Harvard University Mak, Yinchong University of Minnesota Michelotti, Brett Pillemer, Brendan UCSF Medical Center, Calif. Makaroun, Sami Milton S. Hershey Medical Center/ University of Pittsburgh Medical Center Marsh, Tara Yale—New Haven Hospital, Conn. Pennsylvania State University Volker, Kirk Duke University Medical Center, N.C. McSorley, Meghan Naran, Sanjay University of Maryland Medical Center Martin, Elizabeth University of Washington Affi liate Hospitals University of Pittsburgh Medical Center University of Wisconsin Hospital and Clinics Nieto, Maria EMERGENCY MEDICINE Ojeifo, Oluseyi University of Massachusetts PSYCHIATRY Baca, Justin Massachusetts General Hospital/Harvard University Parrott, Meredith Balsamo, Dalia Brigham & Women’s Hospital/ Oman, Hilary University of Pittsburgh Medical Center Jackson Memorial Hospital/University of Miami, Fla. Harvard University, Mass. University of Michigan Hospitals and Health Centers Pfaendler, Krista Carl, Kevin Barr, Scott Proverbs-Singh, Tracy University Hospital/Univ. of Cincinnati, Ohio University of Pittsburgh Medical Center University of Virginia Health System Mount Sinai School of Medicine, N.Y. Ramgopal, Sheila Keary, Christopher Brooks, Deborah Saghafi , Ramin University of Pittsburgh Medical Center Massachusetts General Hospital/Harvard University University of Pittsburgh Medical Center Emory University, Ga. Salati, Jennifer Rao, Sukumar Frank, Virginia Salerno, Amy University of Pittsburgh Medical Center New York–Presbyterian Hospital/Cornell University University of Pennsylvania Health System Emory University, Ga. Semel, Mara Small, Jonathan Henning, Daniel Shah, Megha Strong Memorial Hospital/ New York–Presbyterian Hospital/Cornell University Beth Israel Deaconess Medical Center/ New York University Lagone Medical Center University of Rochester, N.Y. Striebel, Joan Harvard University, Mass. Shirsalkar, Advayanand UCLA Medical Center, Calif. Hilton, Michael Loyola University Medical Center, Ill. OPHTHALMOLOGY Woldu, Hiwot University of Pittsburgh Medical Center Song, Christopher Gushchin, Anna Mount Sinai School of Medicine, N.Y. University of Pittsburgh Medical Center Jones, David New York University Lagone Medical Center RADIATION ONCOLOGY University of Pittsburgh Medical Center Thomas, Holly Kaufman, Matthew Gan, Gregory Lee, Dahmi UCLA Medical Center, Calif. University of Pittsburgh Medical Center University of Colorado University of Michigan Hospitals and Health Centers Wong, Susan Piluek, Wachirapon McGarry, Patrick University of Washington Affi liate Hospitals Stanford Hospital and Clinics, Calif. RADIOLOGY—DIAGNOSTIC Los Angeles County + USC Medical Center Zemke, Anna ORTHOPAEDIC SURGERY Huang, May Negron, Deylin University of Pittsburgh Medical Center North Shore University Hospital/ University Hospital/UMDNJ–New Jersey Dahl, Jason INTERNAL MEDICINE—PEDIATRICS Strong Memorial Hospital/ Albert Einstein College of Medicine, N.Y. Medical School Narla, Vinod Snapinn, Elizabeth University of Rochester, N.Y. Novack, Jared University of Washington Affi liate Hospitals University of Pittsburgh Medical Center Graham, Kraig University of Chicago Medical Center, Ill. Paidisetty, Sanjay Sturgeon, Tiffany University of Pittsburgh Medical Center Nuttall, Kevin Medical College of Wisconsin Affi liated Hospitals University at Buffalo School of Medicine and Kowalchuk, Deborah Beth Israel Deaconess Medical Center/ Price, Melissa Harvard University, Mass. Biomedical Sciences, N.Y. University of Massachusetts McClure, Philip UCLA Medical Center, Calif. Raducha-Grace, Laura Tung, Ka-Wah University of Pittsburgh Medical Center INTERNAL MEDICINE— Rhode Island Hospital/Brown University PRELIMINARY Spina, Nicholas University of Pittsburgh Medical Center Schenfeld, Eric Wang, David Greytak, Ryan University of Pittsburgh Medical Center Carolinas Medical Center/University of North Carolina University of Pittsburgh Medical Center at Chapel Hill Allegheny General Hospital/Drexel University, Pa. Wang, William Stockwell, Carrie Kumar, Vikas Long Island Jewish Medical Center/ SURGERY—GENERAL University of Pittsburgh Medical Center University of Pittsburgh Medical Center Albert Einstein College of Medicine, N.Y. Alston, Jane Stoler, Genevieve Raphael, Anna Wright, Adam McGaw Medical Center/Northwestern University, Ill. University of Pittsburgh Medical Center Montefi ore Medical Center/ University of Pittsburgh Medical Center Caporaso, Jenna Albert Einstein College of Medicine, N.Y. Van Epps, J. Scott OTOLARYNGOLOGY Louisiana State University University of Michigan Hospitals and Health Centers Chaffi n, Phillip Carter, Sarah Worrall, Christine INTERNAL MEDICINE— University of Minnesota Guthrie/Robert Packer Hospital/Drexel University, Pa. Hennepin County Medical Center/University of Minn. WOMEN’S HEALTH Kundaria, Summit Castleberry, Anthony Soni, Amy Duke University Medical Center, N.C. FAMILY MEDICINE University of Pittsburgh Medical Center University of Pittsburgh Medical Center Toney, Lauren Kilic, Arman Cortes De Jorge, Vanessa Johns Hopkins Hospital, Md. Greater Lawrence Family Health Center/ MAXILLOFACIAL SURGERY University of Washington Affi liate Hospitals University of Massachusetts Bilodeau, Elizabeth Ward, Bryan SURGERY—PRELIMINARY D’Agata, Caitlin University of Pittsburgh Medical Center Johns Hopkins Hospital, Md. Chen, Jennifer Pavlick, Matthew University of Wisconsin School of Medicine & PATHOLOGY Allegheny General Hospital/Drexel University, Pa. Public Health University of Pittsburgh Medical Center Nguyen, Lananh Gilbert, Mark Davis, Cordula NEUROLOGICAL SURGERY University of Pittsburgh Medical Center University of Colorado Carolinas Medical Center/University of North Carolina Srinivas, Ravi at Chapel Hill UROLOGY University of Pittsburgh Medical Center PEDIATRICS Ejiasa, Otuodita Ambani, Sapan Williamson, Richard Batsuli, Glaivy Oregon Health & Science University Hospital University of Michigan Hospitals and Health Centers St. Joseph’s Hospital & Medical Center/ Emory University, Ga. Gibbs, Lawrence Bieniek, Jared University of Arizona Chan, Steven Belleville Family Medicine/Scott AFB/St. Louis Children’s Hospital of Pittsburgh of UPMC Geisinger Medical Center/Temple University, Pa. University, Belleville, Ill. Chang, Angela Dudley, Anne Itano, Scott UCLA Medical Center, Calif. University of Pittsburgh Medical Center Swedish Medical Center/University of Washington Dickman, Katherine Kaffenberger, Samuel Children’s Hospital Boston/Harvard University, Mass. Vanderbilt University Medical Center, Tenn.

SUMMER 2009 35 ALUMNI NEWS

been known to set a few fi res to make his points. Really. Ehrenworth gives talks at scientifi c meetings and else- where on fi res in the operating room—covering safety points, including prevention and what to do when some- thing starts burning. He notes that anesthesiologists and surgeons frequently bring together all the requirements for a blaze in the OR: fuel, oxygen, and an ignition source. A professor of anesthesiology in the Yale University School of Medicine, Ehrenworth combines clinical work and resident training in the operating room. One patient ended three years of self-imposed isola- tion to see Lester Gottesman (MD ’78). The woman had a sigmoid enterocele, a hernia of the sigmoid into the rectum, and every other doctor she’d seen had told her there was nothing wrong with her. “They told her she was crazy. The symptoms are pretty subtle, but they often occur in young women who are in the prime of their physiological and social lives,” Gottesman says. Painful constipation had kept her housebound, but after surgery everything changed. (AACAP) for her leadership on discussions of confl icts of “She got her life back,” Gottesman says. “I think she CLASS NOTES interest in medicine. DeAngelis is credited with enforc- got married soon afterward.” ing one of the most rigorous disclosure policies of any Gottesman, an associate professor of clinical sur- academic publication. She also consulted on AACAP’s gery at Columbia University College of Physicians and ’60s new Guidelines on Confl ict of Interest for Child and Surgeons, also serves as chief of colorectal surgery at The past year looks like a major Adolescent Psychiatrists. St. Luke’s–Roosevelt Hospital. He’s working on several chapter in the storybook ride of Bert O’Malley (MD DeAngelis, a pediatrician and Pitt trustee, said in studies exploring HPV susceptibility in an HIV-positive ’63). He received the National Medal of Science from response to the recognition, “I truly believe that we, as individual. President George W. Bush in September 2008. O’Malley, individuals and as countries, display who we really are the chair of molecular and cellular biology in Baylor by the way we treat our children.” College of Medicine in Houston, is known as one of the ’80s An otherwise normal, healthy boy, age leading experts in understanding how hormones turn 12, goes with his parents to see the pediatrician because genes on and off, particularly in breast cancer. In April ’70s Jan Ehrenworth (MD ’73) has of unexplained redness and swelling around his ankle. An 2009, as this issue went to press, O’Malley returned to Pitt’s campus as commencement speaker for 6,000- some new graduates and their families and to receive an honorary Doctor of Science degree. “Just as no two human beings are the same, no SHARON MAYNARD two cancers are the same,” says Mark Orringer (MD PROBING PREECLAMPSIA ’67), coauthor of a 2008 paper in Nature that geneti- cally characterized 188 individual lung tumors. The researchers identifi ed 26 genes that were mutated at high frequencies in these tumors and, therefore, were n about 5 percent of pregnancies, preeclampsia causes the mother’s body to falter likely involved in the genesis of the cancer. The fi ndings as if poisoned. Her kidneys strain. Her blood pressure rises dangerously high. In shed light on how cancer develops and may lead to new Isevere cases, preeclampsia can cause seizures, organ failure, and even death. targets for treatment or prevention. It’s long been clear that the source of this toxicity is the placenta, explains Orringer is a professor and head of the section nephrologist Sharon Maynard (MD ’97, Res ’00). The syndrome goes away quickly of thoracic surgery at the University of Michigan. In after delivery of the baby and the placenta. “And when you look at [a preeclamptic] 2001, he served as president of the Society of Thoracic

placenta, it’s extremely abnormal,” she says. “There’s evidence of damage from a FRANK HARRIS Surgeons. He says that he takes great pride in balancing lack of adequate blood supply.” professional and family obligations. To date, the only treatment for severe preeclampsia is delivery—a devastating “I have fi ve grandkids, and whenever one of the dogs gets hold of their little fl uffy toys and rips them ultimatum in the uncommon case where the fetus is very premature. (Preeclampsia is apart, they always run them to me to sew them up. more common toward the end of pregnancy.) That’s my job, to save them.” In 2001, Maynard began a research fellowship in nephrology at Beth Israel Catherine DeAngelis (MD ’69), editor of the Journal Deaconess Medical Center with Ananth Karumanchi. There, she compared gene of the American Medical Association, received the expression in the placentas of women who had preeclampsia to those who didn’t. 2009 Catcher in the Rye Humanitarian Award from the One stark difference between the two types of samples emerged early on: A protein American Academy of Child and Adolescent Psychiatry called sFlt1, which stunts the growth of new blood vessels, is much more abundant in the placentas of preeclamptic women. Maynard then tested the effects of sFlt1 on

36 PITTMED echocardiogram rules out rheumatic fever neuroscience. When a volun- Theodore Roosevelt from 2001 to 2002 as a surgeon in but reveals a shocker: a half-inch hole teer failed to show one day, support of American soldiers in Afghanistan. She returns between the upper chambers of the boy’s Servan-Schreiber slid into to Pittsburgh in June to take a teaching position with the heart. Mark Hoyer (Pediatric Cardiology the tight confi nes of the MRI, general surgery staff at Allegheny General Hospital. Fellow ’85), the director of interventional which proceeded to clank When Michael Scheel (MD ’98) was entering medi- Bradley (right) during the Steelers cardiology at Riley Hospital for Children and hum as his colleagues cal school, the health professional military scholarship 2009 championship season. in Indianapolis, has performed hundreds took anatomical images of seemed like a safe, prudent option. That’s not how he of minimally invasive catheter-based heart repairs of his brain. Suddenly, everything stopped, and his friends would describe his experience today. defects like this, in which open heart surgery might said with concern, “We can’t do the experiment. There’s Scheel completed an orthopaedics residency then otherwise be indicated. He has published case studies something in your brain.” served four years of active military duty, including and descriptions of new techniques. In the case of the That was the day he learned about his brain tumor, one tour in Iraq. He was the only orthopaedist for a 12-year-old boy, Hoyer made a 1.5-inch incision—a partial as described in his book, Anti-Cancer: A New Way of base of 40,000 troops, so he saw a lot of recreational sternotomy—and threaded a catheter into the boy’s heart Life, which was published in his native France in 2007 injuries. But he also saw “about six months of shock- to place a patch over the hole. and in this country in 2008. ingly graphic” battlefi eld injuries, including gunshot Pittsburgh Steelers wide receiver Hines Ward suffered Today, Servan-Schreiber is cancer-free. He divides wounds, blast injuries, lost limbs, and damaged- a knee injury in a playoff game two weeks before the his time between the University of Pittsburgh, where beyond-repair limbs. Unable to offer the defi nitive Super Bowl this year. In an attempt to speed his recovery, he is a clinical professor of psychiatry, and Lyon, treatment, Scheel would clean, wash, and stabilize, James Bradley (Orthopaedics Resident ’87), a Pittsburgh France, where he is on the medical faculty at the then ship the soldier out to a larger facility. Steelers orthopaedic surgeon and clinical professor of University of Lyon. Now in private practice not far from Pittsburgh, orthopaedics at the University of Pittsburgh, performed a Scheel, who had one child before new procedure making the rounds in sports medicine— being deployed to Iraq and one after, ’90s says, “It’s hard to get me rattled at autologous conditioned plasma injection. Bradley drew “It was scary,” says Sheri Mancini blood from an arm, concentrated the platelets via centri- (MD ’96), “We had to be immunized for smallpox and this point. I take a deep breath, and I fuge, and injected the platelet-rich plasma into the injured anthrax.” And her company had to carry injectors with say, ‘It could be a whole lot worse.’” knee. Although the procedure requires more study, doctors them in case they were hit with nerve gas, she adds. speculate that the treatment concentrates and accelerates Mancini was deployed to Iraq as part of a fi eld trau- the healing process. Ward wasn’t 100 percent healed for ma surgical company in 2003. She served six months the Super Bowl, but he did recover enough to play. And, in the country as part of her four-year obligation to the of course, the Steelers managed to bring home their NFL- navy, which paid her medical school tuition. There she record sixth Lombardi Trophy. treated American soldiers and Iraqis alike as the marines Alumni in surgery As a resident in Pittsburgh, David Servan-Schreiber she accompanied pushed further into the country and tents in Iraq: Mancini (Psychiatry Resident ’87) had NIH funding to pursue some ultimately into Baghdad. (left) in 2003. Scheel (above) in 2004. MRI research he’d begun as a part of his graduate work in Mancini also served on the aircraft carrier U.S.S. ’00s “When patients ask me why it is they have colon cancer, I think that most often they are not looking for an explanation of the molecular oncogenesis of the colonocyte,” says Daniel Hall pregnant rats and found that they developed the clas- (Surgery Resident ’07), who is an Episcopal priest, a staff surgeon in the Veterans Affairs Pittsburgh sic symptoms of preeclampsia. Healthcare System, and a researcher for its Center The reason for the extra sFlt1 is still unclear, but this for Health Equity Research and Promotion. “They are new insight could eventually lead to better diagnosis, asking questions of meaning and value … ‘Why me? management, and treatment if the protein could be Why do bad things happen to good people?’” measured, monitored for upticks, and blocked. The In 2006, Hall did an analysis of data, published initial study, which was published in The Journal of in the Journal of the American Board of Family Clinical Investigation in 2003, led to several subse- Medicine, which showed that people who attend reli- Maynard’s findings may one day help quent papers and created a buzz in nephrology and gious services on a weekly basis live 1.8 to 3.1 years women with preeclampsia. obstetrics circles. longer than those who do not. In 2005, Maynard won a three-year Charles E. Culpeper Scholarship in Medical He suggests that, over time, religious commu- Science to continue this work. She is now an assistant professor in the Division of nities may foster longer life by lowering levels of stress and anxiety. Renal Disease and Hypertension at George Washington University. In one project, — Eric Donato, Meaghan Dorff, Chuck Staresinic funded by the Washington, D.C., chapter of the National Kidney Foundation, she’s hoping to discover the threshold range of sFlt1 levels that separates women whose preeclampsia can be managed with blood-pressure medication and bed rest from women whose health will deteriorate more quickly. Maynard will present her latest fi ndings at the World Congress of Nephrology in Milan in May. —Elaine Vitone

SUMMER 2009 37 THE WAY WE ARE CLASS OF ’90 WILLIAM I. COHEN ALEXANDER MINNO obert Neumar (MD ’90), associate pro- fessor of emergency medicine in the FEB. 13, 1946–FEB. 6, 2009 APRIL 27, 1921–JAN. 21, 2009 RUniversity of Pennsylvania School of Medicine and associate director of Penn’s Center n July 1990, William Cohen (Res ’78, lexander Minno’s Pittsburgh roots for Resuscitation Science, has since 1997 directed Fel ’80) became the director of what was ran deep. Minno (MD ’47) was the a lab aimed at revealing the mechanisms of brain Ithen the new Down Syndrome Center Ason of a steelworker and a Slovakian injury caused by acute brain trauma. at Children’s Hospital immigrant. After receiving his under- “I think there’s tremendous potential for of Pittsburgh. The graduate degree from the University of reducing brain damage after acute injury, whether developmental-behav- Pittsburgh in 1943, he enlisted in the that’s cardiac arrest, stroke, or trauma,” he said. ioral pediatrician, navy and returned to Pitt for medical His lab focuses on identifying molecular a professor of both school while a reservist. events that occur naturally in the brain after pediatrics and psychia- At the Mayo Clinic in Minnesota, injury is sustained—events which eventually lead try at the University Minno trained in rheumatology to neuronal death. A greater understanding of of Pittsburgh, once Cohen under Pitt grad Philip Hench these events, he says, may yield ways to decrease recalled some nervous- (MD ’20), who was instrumental damage caused by acute brain injury. ness on starting the position. At that point, in the discovery of cortisone and its Judith Badner (Human Genetics PhD ’88, he had seen only a handful of patients ability to relieve pain and infl am- MD ’90) says it’s her job to help unravel the bio- with Down syndrome. By the time he mation. Hench won the Nobel logical mystery of what’s behind conditions like died unexpectedly in February, thousands Prize in 1950. In 1953, Minno left schizophrenia, bipolar disorder, and autism. An of children with Down syndrome had Minnesota to create the rheumatol- Minno associate professor of psychiatry at the University come to see “Dr. Bill,” and the National ogy department at Lahey Clinic in of Chicago, Badner does clinical work and sta- Down Syndrome Society described him as Boston, where he met and married Frances tistical genetics research focused on discovering a “national leader in the Down syndrome Fraher. When job offers came in from as genes that contribute to psychiatric disorders—a movement” and a “dear friend.” He coau- far away as San Francisco, says Frances, challenging task considering studies thored the seminal guidelines for care for Pittsburgh won out because of its proximity that show a large number of genes, each children and adolescents with the condition to friends and family. with its own small effects, contribute to and helped found the Down Syndrome Minno practiced rheumatology in psychiatric illness. Medical Interest Group. Pittsburgh and was a Pitt clinical associ- The research she conducts, she says, Cohen died Feb. 6 of a heart attack in ate professor until his retirement in the may in time lead to better understand- Miami Beach while pursuing one of his late 1990s. The Minnos were active and ing of the genetic underpinnings of passions—inline skating. On July 4 this generous supporters of the medical school, psychiatric disorders and, she hopes, year, he and his partner, Donald Arnheim, hosting reunion dinners and encouraging Neumar new treatments for those suffering were planning to exchange vows at a com- Minno’s classmates to donate to the School from them. mitment ceremony. of Medicine. Minno served for several years Keith Mandel (MD ’90), vice presi- Colleagues describe Cohen as a great on the board of Pitt’s Medical Alumni dent of medical affairs for the physi- listener, teacher, patient advocate, and a Association. —CS cian-hospital organization at Cincinnati man who gave hugs easily. A char- Children’s Hospital Medical Center, is a ter member of Pitt’s Academy of physician-executive focusing on “the Master Educators, he was known IN science behind improving care,” as he for his teaching interests in family Mandel puts it. counseling, hypnotherapy, adapting MEMORIAM Mandel is leading an initiative to improve families to chronic conditions, and outcomes for 12,000 children with asthma across doctor/patient communication. He 40 primary care practices in Greater Cincinnati. taught med students how to interview ’40s ’60s As part of the initiative, parents and physi- patients. GEORGE J. JACOBS MARCIA MEARS STAVRIDES cians complete an in-depth survey during the “He gave so much of himself. MD ’46 MD ’61 patient visit. Acquiring this real-time informa- He really loved our families and our MARCH 12, 2009 JAN. 20, 2009 kids,” says Sheila Cannon, program tion, Mandel says, engenders a more robust inter- ’50s ALAN RENTON coordinator for the center and one of MD ’65 action between physician, parent, and patient JOHN H. SCOTT its founding parents. JAN. 14, 2009 and a better understanding of how all parties MD ’54 can manage the disease. Children in the program She recalls that Cohen enjoyed MARCH 9, 2009 miss fewer school days and experience a marked entertaining children by talking like ’70s the gravelly voiced Sesame Street char- JOHN BRANDON VINCENT MACHAJ improvement in symptoms. –ED MD ’56 MD ’76 acter Grover. Cohen was buried with APRIL 4, 2009 JAN. 14, 2009 his stethoscope and a Grover doll that he wore with it. —Erica Lloyd FACULTY NANCY NIELAND-FISHER MARCH 28, 2009

38 PITTMED J. NADINE GRACIA IN SERVICE, IN THE WHITE HOUSE

BY ELAINE VITONE

he truck could only take them so far. When the trail steep- COURTESY J.N. GRACIA J.N. GRACIA COURTESY ened, they climbed on foot, T The White House Fellows program offers exceptional young men and women experience working at the bringing vaccines to families in the highest levels of government. Gracia’s year includes literacy work in Washington, D.C. remote countryside. They announced their arrival with a bullhorn. been more than a few “pinch me” moments. resident at Children’s Hospital of Pittsburgh “It was a life-altering experience,” says “The fi rst one was when I met President of UPMC, Gracia completed a two-year J. Nadine Gracia (MD ’02, Res ’05) of her Bush for the fi rst time,” she says. “Here I was, research fellowship at Children’s Hospital of 1996 medical mission to Haiti. a daughter of immigrants, sitting in the Oval Philadelphia. She examined community-level “It showed me just how diffi cult living con- Offi ce. At one point, I had to pause and ask risk factors for violence, studying the built ditions can be—not just in the lack of access myself if this was real. My family has worked physical environment and its association with to medical care, but also to opportunity.” so hard to get me to this point.” aggravated assault. Gracia, who grew up in Novato, Calif., in Gracia’s parents were both educators in Gracia says her mentors in Pittsburgh a Haitian family, still carries the lessons of that Haiti. Her mother was a math teacher, and her were instrumental to her success, working trip as she serves in the most prestigious leader- father was a school principal. “They fostered with her to design an academic program that ship and public service program in the United this yearning for learning in me. And they also would accommodate her travel-heavy schedule States, the White House Fellows program. She helped me to embrace diversity,” she says. throughout her SNMA presidential term— is one of two MDs in the current 14-fellow In 2000, Gracia had the opportunity to especially Paula Davis, assistant vice chancellor class, which began the yearlong program in bring both passions to the fore when she in the Offi ce of Health Sciences Diversity; September 2008. As part of her assignment became Pitt’s fi rst med student to serve as the Joan Harvey, associate dean for student affairs; in the Department of Health and Human president of SNMA, the Student National and Arthur S. Levine, senior vice chancellor Services, Gracia works on an interagency effort Medical Association. During her term, she for the health sciences and dean of the School to improve health care delivery systems in the spearheaded partnerships with more than 15 of Medicine. Steven Kanter, the school’s vice Outer Pacifi c Islands. national organizations and oversaw the devel- dean, told Gracia about the White House She has met with Presidents George W. opment of policy statements on gun violence, Fellows program when she started med school Bush and Barack Obama, as well as with mem- organ donation, and diversity in education. and continues to mentor her today. Gracia met bers of their respective cabinets. There have Following her position as chief pediatrics Henri Ford—a fellow Haitian and then a Pitt professor and chief of pediatric surgery—in her fi rst year of med school. MEDICAL ALUMNI ASSOCIATION OFFICERS “We bonded immediately,” says Gracia. “He’s been like an uncle to me.” Davis, who interviewed Gracia for admis- PATRICIA CANFIELD (MD ’89) ADAM GORDON (MD ’95) President BRIAN KLATT (MD ’97) sion to Pitt and was a reference for her security clearance, saw something exceptional in Gracia GRAHAM JOHNSTONE (MD ’70) JOHN KOKALES (MD ’73) from the start. President-elect JAN MADISON (MD ’85) DONALD MRVOS (MD ’55) “Nadine is a gatherer of people,” Davis says. MARGARET LARKINS-PETTIGREW (MD ’94) CHARISSA B. PACELLA (MD ’98) “She has a unique ability to bring disparate Secretary BRETT PERRICELLI (MD ’02) views together at the table and move them VAISHALI DIXIT SCHUCHERT (MD ’94) PETER FERSON (MD ’73) along.” DAVID STEED (MD ’73) Treasurer It is, perhaps, a quality of every great public Members at Large servant, from the hills of Northern Haiti to ROBERT E. LEE (MD ’56) ■ Historian M-200k Scaife Hall Capitol Hill. SUSAN DUNMIRE (MD ’85) University of Pittsburgh Executive Director Pittsburgh, PA 15261 tel 412-648-9090; fax 412-648-9500 [email protected] SUMMER 2009 39 LAST CALL

HEART IN HAND In making a documentary film about Children’s Hospital of Pittsburgh in 1951 (see p. 12), pediatrician Barbara McNulty (MD ’75) was moved by the images of her professional forebears laying caring, attentive hands on patients. And she was reminded of a child’s drawing she received more than a decade ago. The artist was 4 years old when she accompanied her mother and 2-week-old sister on a visit to the pediatrician. McNulty had noticed that the baby’s femoral pulses were absent. Through her stethoscope, she heard the galloping rhythm that indicated serious cardiac trouble. The mother rushed the baby to the hospital on McNulty’s urging. The next morning, the baby had surgery to repair a congenital coarctation (constriction) of the aorta. The big sister said that her drawing showed McNulty checking her blood pres- sure, adding, “I know you can’t really see my heart, but I thought it should be in the picture.” The mother said that she and her daughter had talked about things that doctors do to help people, and that the drawing had helped the girl with the emotions she’d been holding in since her baby sister’s emergency surgery.

COURTESY B. MCNULTY

40 PITTMED CALENDAR

OF SPECIAL INTEREST TO ALUMNI AND FRIENDS

For information on an event, ESTATE PLANNING SCOPE AND SCALPEL’S unless otherwise noted, contact FOR THE CONFLICTED SCUTDOC MILLIONERRS the Medical Alumni Association: PHILANTHROPIST MAY 14 1-877-MED-ALUM, 412-648-9090 or MAY 15 7 p.m. [email protected]. 1:30 p.m. MAY 16 & 17 You can also visit the Web site at Holiday Inn Pittsburgh 3 p.m. www.maa.pitt.edu. University Center Antonian Theatre, Carlow University For information: For information: DEPARTMENT OF SURGERY Norma Wilson www.scopeandscalpel.org RESEARCH DAY 412-647-4726 MAY 13 [email protected] CLASS OF 2009 7 a.m. – 1:30 p.m. COMMENCEMENT SIMMONS LECTURE ALUMNI WEEKEND MAY 18 8 a.m. OPENING RECEPTION 10 a.m. David Geller, MD, Speaker MAY 15 Carnegie Music Hall William Pitt Union, Ballroom and 5:30 p.m. Assembly Room Scaife Hall LEVY LECTURESHIP For information: OCTOBER 9 www.surgery.upmc.edu CLASS OF 1949 & 1954 Joanne Jordan, MD, MPH, Speaker REUNION DINNERS MEDICAL ALUMNI WEEKEND MAY 15 MUSGRAVE LECTURESHIP MAY 15–18 7 p.m. OCTOBER 30 Reunion Classes: Scaife Hall 5:30 p.m. 1949 1954 Magee-Womens Hospital Auditorium 1959 1964 CLASS OF 1959 Fu-Chan Wei, MD, FACS, Speaker 1969 1974 REUNION DINNER 1979 1984 MAY 15 HOMECOMING WEEKEND 1989 1994 7:30 p.m. OCTOBER 22–25 1999 Concordia Club Pitt v. South Florida Saturday, Oct. 24 SENIOR CLASS LUNCHEON ALUMNI CHAMPAGNE For information: MAY 15 BREAKFAST www.alumni.pitt.edu 11 a.m. MAY 16 Alumni Hall, Connolly Ballroom 9 a.m. AAMC PITT RECEPTION Herberman Conference Center NOVEMBER 8 5:30 p.m. REUNION GALA AAMC Annual Meeting MAY 16 Boston 7 p.m. For information: Carnegie Science Center Office of the Vice Dean 412-648-9000 [email protected]

TO FIND OUT WHAT ELSE IS HAPPENING AT THE MEDICAL SCHOOL, GO TO www.health.pitt.edu. UNIVERSITY OF PITTSBURGH CHANGE SERVICE REQUESTED NONPROFIT ORG. SCHOOL OF MEDICINE U.S. POSTAGE SUITE 401 SCAIFE HALL PITTSBURGH, PA 15261 PAID PITTSBURGH, PA PERMIT NO. 1715

COME TOGETHER! HIPPOCRATEAN

These aspiring physicians of the School of Medicine’s Class of 1955 had no idea how much future Pitt med students would pay for a ham- burger, not to mention textbooks and tuition. Nevertheless, the class has banded together with the goal of leaving a special legacy under the MD ’55 banner.

To contribute to the Class of ’55 Scholarship Fund, or to discuss a legacy scholarship for another graduating class, please contact: Clare Flanagan Forbes Tower, Suite 8084 3600 Forbes Ave. Pittsburgh, PA 15213 412-647-0515 [email protected]