Training Tomorrow’s Scientists Stem Cells and Cancer Wistar President’s Award

FocusSpr ing 2007

4 Scientists in Training Wistar is mentoring the next generationof researchers.

8 Sen. Arlen Specter Accepts 2006 President’s Award The Hodgkin’s lymphoma survivor was honored for his support of cancer research.

10 Getting to the Root of the ProblemStem cells are key to a new view of cancer.

13 A Focus on the Beauty of ScienceTeachers visited an exhibit of top photographs taken through themicroscope.

15 Wistar Hosts Prostate CancerSymposiumThe event raised awareness of risk, prevention, and treatment inAfrican-American men.

16 ProgressThe latest from Wistar labs.

20 BriefingsAwards, news, and notes.

22 Remembering David KritchevskyThe longtime Wistar professor was internationally recognized for researchon diet and disease.

On the Cover: Training the nextgeneration of scientific investi-gators has beenpart of Wistar’smission since theInstitute’s found-ing in 1892.Shown here aresome of the grad-uate students,postdoctoral fellows, and others currently training in Wistar labs, alongwith some of their scientific mentors.Full story on page 4. Photo by Tommy Leonardi.

D e c l i n e i n C a n c e r D e a t h s I s W e l c o m e N e w s

On January 17, the American Cancer Society announced thatthe number of deaths from cancer in the United States

dropped for the second year in a row. Worth noting, too, is that thedecline reported the year before was the first seen in more than 70years of data collecting. Time will tell, but researchers, clinicians,and patient advocates are hopeful that the new data represent atrend, a turning point at last in the long battle they have been wag-ing against cancer.

The news is being welcomed by everyone who has ever confronted cancer,whether in themselves, a friend, or a family member. But it also raises importantquestions about the decline in the government’s support for scientists’ efforts todefeat cancer. Why, when the return on the nation’s investment in cancer research ispaying such dividends, is federal funding falling for studies to better understandcancer and develop new diagnostic tests and treatments for the disease?

The American Cancer Society’s figures show that between 2003 and 2004, thenumber of cancer deaths in the nation fell by 3,014. Between 2002 and 2003, thedrop was 369. To be sure, the reported reductions in cancer deaths are relativelysmall when measured against the backdrop of total cancer deaths—553,888 peopledied of the disease in 2004, for example. The important point to keep in mind,however, is that the decline in cancer deaths, now seen in two consecutive years, hasno precedent.

Within the Wistar community, our response to the news that we are making realprogress against cancer while federal funding is falling has been to redouble ourefforts to ensure that we continue to have the resources we need to keep up the fight.

We’re forming new alliances with scientific colleagues and groups around theworld to advance our research. We’re partnering with other non-profit organizationsand with industry to pursue joint goals. Many members of Wistar’s Board and otherloyal supporters have chosen to step up their levels of commitment at this time.

Beyond financial support, crucial as it is, our friends can and do help us in othervital ways too. They serve as ambassadors-at-large for Wistar, for example, sharing withothers the importance of the Institute’s mission to improve human health throughleading-edge biomedical research, helping us expand our circle of support. For themany forms of assistance we receive in the pursuit of our goals, we are grateful.

Russel E. Kaufman, M.D.President and CEO

Focus is published two times per year for donors, friends, faculty, and staff of The Wistar Institute by the Office of

Public Relations, 3601 Spruce Street, Philadelphia, PA, 19104-4268. To contact the editor, phone (215) 898-3716, or e-mail hoke@wistar.org.For general inquiries, contact The Wistar Institute at (215) 898-3700. Send address changes to: Development Office, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104-4268.

FRANKLIN HOKEDirector of Public Relations

LEE CHRISTINE SHURTZPublic Relations Intern

KARLYN ROSEN AIRESDesigner

Fo c us

The Wistar Institute is a National Cancer Institute-designated Cancer Center.

The Wistar Institute is an equal opportunity/affirmative action employer. It is the policy of The Wistar Institute to provideequal employment opportunities to all individuals regardless of race, color, creed, religion, national origin, ancestry, sex,age, veteran status, disability, sexual orientation, or gender identity for all terms and conditions of employment.

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n the United States and West-ern Europe today, rubella andrabies infections are rare,thanks to vaccines that weredeveloped by scientists at The

Wistar Institute from the 1960sthrough the 1980s. In many otherparts of the world, however, includingChina, India, and Russia, theseinfections remain a serious threatto public health.

To help address this problem,Wistar has licensed its rubella andrabies viral seed stocks to compa-nies in each of these three coun-tries to permit them to developlow-cost vaccines for local use.

“The Institute will not receivesignificant royalties from thesetransactions,” says Meryle J. Mel-nicoff, Ph.D., Wistar’s director ofbusiness development. “Rather,the licensing agreements arestructured to ensure that thesevaccines developed at Wistar arewidely available in countrieswhere they can have a significantimpact on public health.”

Rubella is a virus that poses specialdangers to pregnant women and theirfetuses. When a pregnant woman isinfected with the rubella virus early inher pregnancy, there is a 90 percentchance that she will pass the virus onto her fetus, often resulting in eitherdeath or damage to the fetus. After arubella pandemic swept across Europeand the United States in 1963 and1964—leaving nearly 12,000 infantsborn deaf, or deaf and blind—StanleyPlotkin, M.D., began working on arubella vaccine at Wistar. In 1969, his

rubella vaccine became available. As use of the vaccine spread through

the industrialized world, rubella was allbut eliminated in these countries. InMarch 2005, the Centers for DiseaseControl announced that rubella hadbeen eradicated in the United Statesand gave Plotkin’s vaccine credit for the

achievement. In undeveloped countries,however, rubella still accounts forcountless birth defects and an estimated700,000 deaths each year. In China,which does not routinely vaccinateagainst rubella, estimates are that thenumber of children with birth defectscould double over the next severaldecades.

Likewise, rabies remains an impor-tant public health challenge in parts ofAsia, particularly China and India.According to the World Health Orga-nization, rabies is the tenth most com-mon cause of death from an infectiousagent worldwide. Asia accounts for

more than 90 percent of all rabies fatal-ities, with 30,000 deaths per yearreported in India alone. The rabies vac-cine developed at Wistar can prevent arabies infection in individuals who havebeen bitten by a rabid animal, providedit is given promptly after exposure.However, the vaccine is not always

readily at hand in the poor, oftenrural, regions where most ofrabies deaths occur. A locallyproduced, more widely availablevaccine could save many lives inthese areas.

In all, Wistar has completedseven licenses for either therubella or rabies vaccine from1999 to the present: four to com-panies in China between 1999and 2007; one in Russia in 2005;and two in India in 2006.

“We licensed the rubella andrabies vaccines to companies inChina, India, and Russia so theycan produce the vaccines for thelocal markets,” says Melnicoff.

In Russia, the agreement betweenWistar and the pharmaceutical companymaking the rubella vaccine was facili-tated by the Vishnevskaya-RostropovichFoundation, headed by renowned cellistMaestro Mstislav Rostropovich. In theprocess, Maestro Rostropovich andPlotkin became good friends.

“That must be a first,” says Plotkin.“The Maestro’s foundation has madeconsiderable headway, but in Russia the[availability of] rubella vaccination is farfrom complete. The major reason forthe licensing agreements is to produceenough vaccine for a very large popula-tion that has not had access to it.”

Rubella, Rabies Vaccines Finding New Purpose Overseas

W I S TA R W O R K I N G T O P R O T E C T G L O B A L P U B L I C H E A L T H

By Margaret O. Kirk

Stanley Plotkin, M.D., injecting Hilary Koprowski, M.D., with the then-experimental rabies vaccine in 1971, while TadeuszWiktor, D.V.M., playfully pretends to restrain Dr. Koprowski. The three developers of the vaccine were all inoculated with thevaccine that day, and none experienced any negative reactions.

I

ven though The Wistar Insti-tute is not a degree-grantinginstitution, the training ofyoung scientists has been oneof its highest priorities eversince its founding.

“The principal investigators whowork at Wistar take very seriously theeducational component of what theydo,” says Ronen Marmorstein, Ph.D.,the Institute’s director of training and aprofessor in the Gene Expression andRegulation Program.

About 100 graduate students, post-doctoral fellows, and visiting scientiststrain at Wistar each year. Most pre-doctoral trainees at the Institute arePh.D. or M.D.-Ph.D. candidates atthe University of Pennsylvania. Post-doctoral fellows come to Wistar afterobtaining Ph.D., M.D., or D.V.M.degrees from institutions around the

world. The Institute also offers a Bio-medical Technician Training Programfor students working toward theirAssociate in Arts degree at Commu-nity College of Philadelphia, as well asresearch opportunities for undergradu-ates and a Summer Research Fellow-ship Program for Philadelphia publichigh school students.

A number of former Institutetrainees have gone on to become highlyinfluential in the scientific community(see accompanying story, page 6).

“Science is one of the few profes-sions that still works through appren-ticeships,” notes Ellen Puré, Ph.D.,associate vice president for academicaffairs. Puré, who preceded Mar-morstein as director of training, is also aprofessor in the Molecular and CellularOncogenesis Program and theImmunology Program. “One of the

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greatest pleasures for most of us is train-ing the next generation of scientists.”

Wistar’s trainees “play a key role incarrying out the Institute’s research,”says Marmorstein. Troy Messick, Ph.D.,a postdoctoral fellow in Marmorstein’slab, notes that Wistar’s graduate stu-dents and postdocs are “down in thetrenches in the battle against cancer andimmune system diseases,” typicallyworking 50 to 80 hours per week.

“The principal investigators set thegeneral direction of research in thelabs,” Messick explains, “but it is thestudents and postdocs who are at thebench trying to sleuth out the underly-ing molecular mechanisms of the cell.”His own research focuses on a proteincalled Ovarian Tumor (OTU), which isin a complex with BRCA1, a tumorsuppressor involved in breast cancer.

Wistar’s trainees work closely withthe Institute’s scientists, conductinginvestigations at science’s cutting edge.“Trainees bring fresh, new ideas,” Purésays. “My students and postdocs havebeen absolutely critical to my research.”

The Institute’s size offers advantagesto trainees, according to Brandi Sanders,a third-year graduate student in Mar-morstein’s lab. Sanders is investigatingthe crystal structure of Sir2 (silent infor-mation regulator-2) proteins, whichhave been implicated in cancer, type IIdiabetes, and obesity and hold potentialfor structure-based drug design.

“At Wistar, we have a unique experi-ence,” she says. “It’s a great place towork because you have contact witheveryone. You know the other scien-tists, and it’s just so easy to walk over tothem if you need help. We have so

many venues where we share research.”One of those venues is the weekly

Research in Progress meeting (knownwithin the Institute as “RIP”), wherestudents and postdocs “have an oppor-tunity to present their research to acritical, but friendly, audience of theirpeers,” explains Messick. The informalRIP meetings are “not only an oppor-tunity for us to hang out with ourfriends and eat pizza, but also a chanceto share ideas and strike up collabora-tions,” he says.

The Institute’s size offers other ben-efits, as well. “We’re small enough toknow individuals’ contributions,” notesPuré. “We can credit people for theircooperative work.”

“The culture of Wistar is very inter-active and collaborative,” Marmorsteinsays, “more so than other places I’vebeen to or heard about.”

Currently, Wistar is receiving threeNational Institutes of Health-fundedtraining grants. One is a chemistry-biology interface training grant, led byMarmorstein, which provides fundingfor four predoctoral students on cam-pus. Another is an immunology train-ing grant, headed by professor andImmunology Program leader Hilde-gund C.J. Ertl, M.D., which supportsthree postdoctoral fellows. The third isa cancer-biology training grant, over-seen by professor and Gene Expressionand Regulation Program leader FrankJ. Rauscher III, Ph.D., which supportstwo predoctoral students and ten post-docs.

The Institute’s training program rec-ognizes excellence by bestowing severalawards and fellowships annually. TheChing Jer Chern Memorial Award,established in 1989 by June Chern inmemory of her husband, a member ofthe scientific staff from 1974-87, is

given to the postdoctoral fellow whohas written the most outstanding scien-tific paper in the previous year. TheChristopher M. Davis Memorial Fel-lowship, established in 1996 by TheWistar Institute in appreciation ofHarold and Eleanor Davis’ commit-ment to the Institute and in memoryof their son, is awarded to an outstand-ing postdoctoral fellow conductingbreast cancer research. The Dr. MonicaH.M. Shander Memorial Fellowship isgiven in memory of a former Wistarstudent by her parents and by Dr.Hilary Koprowski. It is presented to apredoctoral trainee who displaysnotable excellence in scholastic aptitudeand diligence in the laboratory.

Mentoring a trainee is “a big under-taking,” Puré says. “Each person is dif-ferent, and you have to learn to dealwith each individual to get them to liveup to their full potential. It takes a lotof thought and a lot of time. It’s a bigcommitment to do it right—support-ing the person, being their cheerleader,being constructively critical.”

The trainees who do well share sev-eral key characteristics, Wistar scientistssay. “They are motivated intellectually,”Marmorstein says. “They are lookingforward to what the next result is goingto be.”

“I look for people who are reallysmart, but that’s not enough,” Purésays. “I’m looking for someone who hasdrive, who has perseverance, who has agrasp of what science is all about—andthat it’s sometimes frustrating.”

Puré says it’s gratifying to watchyoung scientists progress through theirtraining.

Wistar’s undergraduate training, forexample, focuses on teaching studentsabout the culture of science to help

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S C I E N C E I S O N E O F T H E F E W P R O F E S S I O N ST H AT S T I L L W O R K S T H R O U G H A P P R E N T I C E S H I P S .

Ronen Marmorstein, Ph.D., discusses a molecular structure with postdoctoral fellowTroy Messick, Ph.D., and graduate studentBrandi Sanders.

prepare them for the world of graduateschool, according to Puré. Ten under-graduates are chosen from hundreds ofapplicants from around the country tospend ten weeks working in a labora-tory. While up to now a young studentmay have been focused on memorizinginformation for a test, as a researcher“no one can tell you whether you’vegot the right answer or not,” Puréexplains. “You learn to think differ-ently—it’s synthesizing information, asopposed to regurgitating it.”

At the next level, gradu-ate students are taking ontheir first independentresearch project, she notes.“They are learning how toask important questions, howto design an experiment,how to write it up for papers,and how to present the sci-ence. The grade of the learn-

ing curve gets less and less as they gofurther on; that’s one of the mostrewarding things. At the end of theirproject, they’re better experts on thatparticular project than the principalinvestigators are.”

The training of postdoctoral fellows,Puré explains, focuses on managementand human resources skills—how tomanage a budget, how to run a lab,and how to prioritize.

Graduate students and postdocs alsohelp mentor the undergraduates. “It’s avaluable teaching experience that wecan take with us to the next level,”Messick says.

Wistar’s Biomedical TechnicianTraining Program (BTT), jointly devel-oped by the Institute and CommunityCollege of Philadelphia (CCP), pre-pares CCP students for careers asresearch technicians. Students takecourses at CCP and train in researchlabs at Wistar and other institutions,including Temple University’s Fels Insti-tute and a number of area biotechnol-ogy companies. One of the program’sgoals is to bring minority students intothe Institute for a learning experiencethat might otherwise have been inacces-sible to them. The first BTT classbegan its studies in 2000.

The research component of theprogram is conducted over two sum-mers. “By the end of the first sum-mer, suddenly their eyes areopen—they’re contributing toresearch on diseases,” says William H.Wunner, Ph.D., administrative coor-dinator of the BTT program. “By theend of the second year, they’ve devel-oped a lot of confidence in addition

The Wistar Institute’s comprehensivetraining programs are highlyregarded in the scientific commu-

nity, so it’s not surprising that manyresearchers who trained at Wistar asgraduate students or postdoctoral fellowshave gone on to achieve internationalrecognition for their accomplishments.Here are two examples.

John C. Reed, M.D., Ph.D.,trained at Wistar from 1986 to 1988 asa postdoctoral fellow in the laboratoryof Carlo Croce, M.D., the Institute’s for-mer associate director who is nowdirector of the Human Cancer GeneticsProgram at Ohio State University.

Today, Reed is president and chiefexecutive officer of the Burnham Insti-

tute in La Jolla, CA. He also is one ofthe world’s most-cited scientists,according to the Institute for ScientificInformation. His research focuses onapoptosis, or programmed cell death,and he has written more than 550papers on the topic—more than anyother scientist, ISI reports. Even withhis administrative responsibilities atBurnham, his lab still produces 30 to50 papers a year, a recent profile in theSan Diego Union-Tribune noted.

Reed is also the inventor ofoblimersen sodium (Genasense), a DNA-based cancer drug. He was a scientificcofounder of the cancer diagnosticscompany GMP/Diagnostics and of IdunPharmaceuticals, a biotech companythat was acquired in 2005 by Pfizer. He

also serves on multiple corporate andnonprofit boards.

Reed joined the Burnham Institute

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John C. Reed, M.D., Ph.D. is now presidentand CEO of Burnham Institute.

F o r m e r W i s t a r T r a i n e e s a r e H i g h A c h i e v e r s

Trainees present their research to theirpeers at the weekly Research in Progressmeeting.

to competence; they become inde-pendent workers.”

Of 57 students who have beeninvited into the program, 38 havecompleted it. “We hire them asemployees-in-training,” he explains.“My goal is to have 50 percent of thememployed—either part-time or full-time—within six months of complet-ing the program.” To date, this goalhas been met, Wunner says.

Wunner says he and Michael Byler,his counterpart in CCP’s chemistrydepartment, visit the students at theirlabs and keep a “constant vigil on howthey’re doing.” BTT participants areasked to write a paper and give a pre-sentation “so they learn to speak thelanguage of the work.”

A number of BTT trainees havegone on to pursue B.S. degrees. One ofthose trainees is Jean Dorsey, who com-pleted the BTT program in 2001 and isnow studying at Drexel University whileworking in the lab of Shelley L. Berger,Ph.D., the Hilary Koprowski Professor

in the Gene Expression and RegulationProgram. Dorsey, a graduate of WestCatholic High School in Philadelphia,says Wunner’s encouragement standsout among her memories of the pro-gram. “Dr. Wunner was very enthusias-tic about the program,” she recalls. “Hemade you feel that you could do it.”

Laura Holderbaum, a recent gradu-ate of the BTT program, was recentlyhired as a research assistant in the labof Nadia Dahmane, Ph.D., an assistantprofessor in the Molecular and CellularOncogenesis Program. After earning adiploma from a computer school that“didn’t amount to much” and workingin a series of temporary jobs, Holder-baum entered the BTT program at age23. “I liked Wistar from the begin-

ning,” she recalls. “Everyone was sup-portive. It was constant learning, whichis what I love to do. It was a reallygood opportunity for me; it put me ina good direction.”

Dahmane says she knew Holder-baum would be a good hire during theprogram’s first summer. “She learnedvery quickly,” Dahmane says. “She’svery rigorous, she does things well,she’s very careful, and she gets alongwith the other people in the lab.”

Dahmane, who has worked withfour BTT trainees, says she also enjoysmentoring Ph.D. students. “I enjoytraining people and seeing theirprogress. You can see them develop as a scientist. I really like this part ofmy job.”

(then known as the La Jolla CancerResearch Institute) in 1992 as a programdirector and became the institute’sleader in 2002. Previously, he had beenan assistant professor at the Universityof Pennsylvania School of Medicine andassistant director of the Laboratory ofMolecular Diagnosis at the Hospital ofthe University of Pennsylvania.

Reed fondly remembers the “great col-leagues [and] highly supportive staff” atWistar. His Wistar training, he writes inan e-mail, “gave me an appreciation forthe highly efficient environment forresearch that private institutes are ableto create and which in my view is farsuperior to universities.”

James A. Thomson, D.V.M.,Ph.D., a developmental biologist andveterinarian, trained at Wistar from

1987 to 1989 as a graduate student inthe laboratory of Davor Solter, M.D.,Ph.D., who today is director of the MaxPlanck Institute for Immunobiology inFreiburg, Germany.

Thomson did postdoctoral researchat the Oregon National PrimateResearch Center and then joined thefaculty at the University of Wisconsin.Today, he is a professor of anatomy atWisconsin’s School of Medicine andPublic Health and the chief pathologistat the Wisconsin National PrimateResearch Center.

In 1995, Thomson’s research groupreported the first isolation of embry-onic stem cell lines from a non-humanprimate. In 1998, Thomson and col-leagues derived the first embryonicstem cell lines from frozen humanembryos. This pioneering work sparked

a wave of national attention—and con-troversy.

Thomson is also the scientific direc-tor at WiCell Research Institute Inc., a spinoff company of the WisconsinAlumni Research Foundation that dealswith licensing his patented stem cells.He is also a member of the GenomeCenter of Wisconsin at the University of Wisconsin, Madison.

In a 2002 interview with the Penn-sylvania Gazette, Solter said Thomsonwas “an ideal graduate student.” Soltertold the Gazette, “Every few months hewould ask if I had some time and thencome in with a piece of paper listingwhat he had done and what he wasgoing to do in the next three to sixmonths. We would discuss it a little,but not much was needed, and then hewould go and do it.”

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T R A I N E E S A R E L E A R N I N G H O W T O A S K I M P O R TA N T Q U E S T I O N S ,

H O W T O D E S I G N A N E X P E R I M E N T.

nited States SenatorArlen Specter (R-PA)accepted the third annualWistar Institute Presi-dent’s Award on Novem-ber 8 at the President’s

Luncheon, held at the National Con-stitution Center in Philadelphia.

The President’s Award honors apublic figure who has not only con-fronted cancer personally but alsoserved as an advocate for improve-ments in cancer education andincreases in research funding. The Pres-ident’s Luncheon recognizes Wistar’smost generous donors.

Sen. Specter, a stage IVB Hodgkin’slymphoma survivor, was recognized forhis steadfast national leadership overmany years for increasing support forbiomedical research. He was a majorforce behind the historic doubling of

federal funding between 1998 and2004 for the National Institutes ofHealth, the primary supporter of bio-medical research in the U.S., and hehas continued to be a strong propo-nent of investing in biomedicalresearch.

The award presentation took placethe day after national elections thatshifted the balance of power in the U.S.Congress from Republican to Democ-ratic control. Sen. Specter took theopportunity to comment on falling fed-

eral support for biomedical researchsince the budget doubling for the NIH.He spoke specifically about declines atthe National Cancer Institute, the mainsource of funding for Wistar’s research,and encouraged political advocacy toaddress to the problem.

“Last year, the National CancerInstitute had its funding cut by $50million, which I believe is intolerablein a nation which has a gross nationalproduct of $11 trillion and a federalbudget of $2.8 trillion,” Sen. Spectersaid. “There are 110 million people inAmerica who are affected directly orindirectly by these major maladies—cancer and heart disease and Parkin-son’s and Alzheimer’s—and that is anenormous political force which, ifmobilized, could direct adequate fund-ing for these very, very importantresearch projects.”

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SEN. ARLEN SPECTER ACCEPTS 2006 PRESIDENT’S AWARD

Sen. Arlen Specter and Jerry L. Johnson Sen. Specter with Paul Offit, M.D., and Hildegund C.J. Ertl, M.D.

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Wistar president and CEO RusselE. Kaufman, M.D., welcomed guestsand premiered a brief video overviewof Wistar research accomplishments,narrated by former football coach DickVermeil. (The video can also be viewedon Wistar’s web site: www.wistar.org).

He then introduced Brian Dovey,chair of Wistar’s Board of Trustees anda general partner of Domain Associ-ates, a venture capital firm with anexclusive focus on the life sciences, whopresented Sen. Specter with the 2006Wistar Institute President’s Award.

“Thank you very much for this ele-gant award,” Specter said. “But morefundamentally, thank you for the out-standing work you do at Wistar formedical research and curing diseases.”

Sen. Specter was elected to the U.S.Senate in 1980 and is currently servinghis fifth term. In 2005, he becamePennsylvania’s longest serving U.S.Senator. Among his committee assign-ments, he is ranking member of theSenate Judiciary Committee and rank-ing member of the Senate Appropria-tions Subcommittee on Labor, Healthand Human Services, and Education,which oversees federal funding for theNIH.

According to the American CancerSociety, more than 7,000 new cases ofHodgkin’s lymphoma, also calledHodgkin’s disease, are diagnosed in theU.S. each year, a number that has notchanged much in recent years. Men aresomewhat more prone to the diseasethan women. It is most common in 2age groups: early adulthood (age 15 to40) and late adulthood (after age 55).About 1,400 people will die ofHodgkin’s disease in the United Statesthis year. Because of advances inresearch, death rates have fallen morethan 60 percent since the early 1970s.By 2001, there were more than123,000 people who had survived thedisease.

Past recipients of the President’sAward include veteran ABC News correspondent and melanoma survivorSam Donaldson in the award’s firstyear, 2004, and prostate cancer survivor General H. NormanSchwarzkopf in 2005.

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Russel E. Kaufman, M.D., Joan Specter, Lew Klein, and Sen. Specter David Wachs and Sen. Specter

Sen. Specter with Fran and Sylvan Tobin

“Last year, the Nat ional

Cancer Inst i tute had i ts

funding cut by $50 million,

which is into lerable in

a nat ion with a GNP

of $11 t r i l l ion.”

or the past 30 years, Wistarprofessor Meenhard Herlyn,D.V.M., has been driven bya single question: Why aremelanoma tumors so hardto kill?

In the summer of 1978, two yearsafter his arrival at The Wistar Institute,he began collecting samples frommelanoma patients to study theirtumor cells more closely. When a newsample arrived, he meticulouslyrecorded information on the corre-sponding patient’s history and out-come, then “cleaned” the sample so itcould be cultured and frozen.

“When we got the samples frompatients, we saw some little round balls

of cells sitting on top of the tumorcells, just floating in the dish,” Herlynrecalls. “We didn’t know what to dowith them, so we washed them away.”

Six years ago, as scientific evidencebegan to mount that some types ofcancerous tumors were driven by asmall subpopulation of self-renewingcells, Herlyn decided to take a closerlook at those floating cells. In 2005, hemade a remarkable discovery: buriedwithin the balls are small caches ofspecialized cells—adult stem cells—that hold the potential to divide andgrow indefinitely.

Recent findings suggest that stemcell division gone awry can result incancer. The presence of stem cells in

tumors may also explain whymelanoma, and many other cancers,are resistant to treatment, says Herlyn.

“We know now from experimentalstudies in leukemia that if you don’teliminate the stem cell population in atumor, the cancer will come back,” saysHerlyn. “We think that’s what is hap-pening in melanoma and many othertypes of cancer.”

The idea that stem cells might causecancer is a hypothesis that has been dis-cussed in the scientific community fordecades. Stem cells and cancer cellsshare the ability to divide indefinitely,and some scientists have wondered ifthis overlap in capabilities was morethan coincidental.

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GETTING TO THE ROOT OF THE PROBLEM:

STEM CELLS ARE KEY TO A NEW VIEW OF CANCER

By Susan Gaidos

Stem cell photo courtesy of James A. Thomson/University of Wisconsin-Madison

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Then, in 1997, a group of scientistsat the University of Toronto foundsmall populations of stem cells in sometypes of leukemia, a finding thatdirectly linked stem cells to cancer.Though stem cells had not yet beentied to other types of cancer, the possi-bility was becoming hard to ignore.

In 2001, a group of Stanford scien-tists led by Irving Weissman, M.D.,published an article in the journalNature postulating that tumors in othertypes of cancer might also originatefrom the transformation of normalstem cells into cancer stem cells. Thearticle, co-authored by TannishthaReya, Ph.D., a University of Pennsylva-nia graduate who had studied at Wistarand is now at Duke University, madeHerlyn and others take notice.

“That’s when the cancer communitywoke up,” says Herlyn. “Cancer stemcells could explain many of the difficul-ties we have in treating solid tumors,

like melanoma, that are resistant totreatment.”

Since 2003, cancer stem cells havebeen found in breast, brain, bone, andlung tumors. In his 2005 paper pub-lished in the journal Cancer Research,Herlyn described a subpopulation ofcells derived from the melanoma-asso-ciated balls of cells that had several keystem-cell-like characteristics. The cellscould divide and renew themselves forlong periods of time. In addition, theycould differentiate to give rise to newcell types, including smooth muscle,neurons, fat, and bone cells. What’smore, the study showed that wheninjected into mice, these subpopula-tions of cells could trigger large, aggres-sive tumors.

The idea that not all cancer cells arethe same, and that only a select groupof cancer cells have replicating powers,lies in stark contrast to the concept ofcancer that developed in the 1970s and

early 1980s, says David Reisman,M.D., Ph.D., an oncologist studyingcancer stem cells at the University ofMichigan.

“For years, the philosophy was thatall malignant cells are equivalent,” hesays. “The idea behind treatment wasto apply chemotherapeutic agents towipe out as many cancer cells as possi-ble. We thought if we could get cancer

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CANCER STEM CELLS COULD EXPLAIN MANY OF THE DIFFICULTIESIN TREATING TUMORS LIKE MELANOMA.

Meenhard Herlyn, D.V.M.

Kazuhiro Noma, M.D., Ph.D., and Jennifer Marmion in the Herlyn laboratory.

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cells down to 100 cells or less, wecould eradicate the cancer.”

Scientists now recognize that cancercells are not a homogenous population,but that doesn’t mean that developingnew treatments will be easy, says Reis-man. Cancer stem cells can remaindormant for long periods of time,making them extremely resistant tochemotherapy agents.

“This explains why someone canhave a recurrence of cancer five to tenyears later,” says Reisman. “In thesecases, the cancer stem cells have beensitting in a quiescent state, and for rea-sons we don’t fully understand, they

suddenly spring back to life.”Herlyn says that all too often, that is

what happens in melanoma cases.“Melanoma is basically a drug-resistanttumor. The five-year survival rate, onceyou have a metastasis, is around 15percent, and that statistic hasn’tchanged in 30 years.”

Another problem in developing newtreatments is that cancer stem cellsmake up just a tiny fraction of the can-cer cells found in a tumor, making itdifficult to culture large quantities ofthe cells for study. Herlyn’s studies inmice show that, on average, only onein a thousand cells in a tumor is capa-ble of self-replicating and generatingnew tumors.

“This rare occurrence is the reasonwhy we didn’t find this subpopulationof cells much earlier,” he says.

His group is now vigorously investi-gating ways to target cancer stem cellswith directed therapies. The first step isto identify molecular properties thatcan define subpopulations that havethe ability to initiate a tumor.

Working with the cells frommelanoma patients and cancer stem cellsgrown in the laboratory, Herlyn and his

group recently identified three types ofmelanoma cells with stem cell-like char-acteristics. The first two cell types, calledCD20+ cells and side population cells,respectively, share a number of charac-teristics. CD20+ cells are named for aprotein found on the cell’s surface andare fairly rare. The side population cellswork as a pump to force foreign chemi-cals and toxins out of cells, and are seenin most drug resistant cancers.

The third group of cells, referred toas label-retaining cells, is the mostintriguing, Herlyn says, because thesecells simply don’t grow. They have atendency to reproduce very slowly, if atall, and can shut down their growthand other systems, making themselvesresistant to most currently used drugs.When stimulated under right condi-tions, however, these cells will burst

into activity and proliferate quickly. Herlyn says that by shutting down

their systems, these cells are able toremain dormant indefinitely.

“Our question now is, ‘Are these thecells we need to target in order to erad-icate melanoma?’”

Herlyn’s goal is to develop a two-stage strategy for melanoma therapy to

be tailored to individual patients. Thefirst step would involve removing thebulk of the cells—more than 90 per-cent—using currently available treat-ments. The second step would attackthe cancer stem cells using agents thatspecifically target that patient’s cells.

The Herlyn lab is now working toidentify the molecular factors that drivethese cancer stem cells. Together withcolleagues at the University of Pennsyl-vania, Herlyn is also developing waysto create genetic profiles of tumor cellsremoved from patients. As the patientsmove through their treatments, Herlynand his group will follow their progressto see what strategies work best on thedistinct subpopulations of cancer stemcells.

The scientists are also using mice toexperiment with new combinations ofdrugs to identify compounds that cantarget cancer stem cells. Though thestudies are in an early stage, Herlynsays he is optimistic about finding apermanent cure for melanoma.

“Our goal is no longer to suppressthe growth of the tumor, but to kill thetumor,” Herlyn says. “Once we get ahandle on the molecular properties ofthese cells, we will be able to targetcancer in a more effective, more ratio-nal way.”

ARE THESE THE CELLSWE NEED TO TARGETTO ERADICATE MELANOMA?

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n January 12, twenty win-ning images from Nikon’sannual Small World com-petition arrived at TheWistar Institute for a

seven-week stay in the Institute’satrium. In attendance at the openingnight reception were approximatelyforty science teachers from schoolsthroughout the Philadelphia regionwho joined Wistar researchers, scien-tists from neighboring institutions,Wistar supporters and friends, and asmattering of photographers and artiststo take in the exhibit.

The images from the competition,now in its 32nd year, combine original-ity, informational content, technicalproficiency, and visual impact to cele-brate the complexity and beauty of theworld as captured in photographstaken through the microscope.

“The hardest thing to rememberwhen examining the images in thisexhibit is that the subject matter isreal—not some fantasy artist’s interpre-tation of an unknown universe,” saidJames E. Hayden, manager of Wistar’sMicroscopy Facility and a previouswinner and judge for the Small Worldcompetition. Hayden was also coordi-nator of the exhibition at Wistar.“These amazing views of life and thephysical world have as much value tothe research scientist as they do to the3rd grade art student studying patternsand colors. It is this unique juxtaposi-

tion that the exhibit is ultimatelyabout; seeing rare beauty and art at thecutting edge of science.”

Wistar president and CEO RusselE. Kaufman, M.D., welcomed theguests at the reception and thankedSonia Siefert, president of OpticalApparatus Co. of Ardmore, PA, a localNikon Instruments dealer, for her sup-port of the event. Then, speaking par-ticularly to the educators in theaudience, Kaufman evoked Wistar’sown dedication to teaching.

“Since its founding in 1892, Wistarhas always had a dual mission, which isto do leading-edge biomedical researchto cure disease—and to train the scien-tists of tomorrow,” Kaufman said.“Today, we have training programs atevery level—for high school students,undergraduates, graduate students,postdoctoral fellows, and visiting scien-tists from around the world.”

A Focus on the Beauty of ScienceSC I ENC E TEACHER S V IS I T EXH IB I T O F TOP

PHOTOGRAPHS TAKEN THROUGH THE MICROS COP E

By Franklin Hoke

O

Photos, top to bottom:1st place winner, cellnuclei of the mouse colonby Dr. Paul L. Appleton;detail of 6th place winner,rat retina astrocytes andblood vessels by Thomas J. Deerinck; detail of 9thplace winner, wing scalesof urania ripheus (SunsetMoth) by Charles B. Krebs;and a reception guest viewing 11th placewinner, pupil of a Macrobrachium amazon-icum (freshwater shrimp) by Alex H. Griman.

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In a slide presentation, Eric Flem,Nikon communications manager andthe guiding force behind the annualcompetition, provided a brief historyof the three-decade-old contest andoffered a retrospective sampling of win-ning photographs from previous years.Through a judicious pairing of selectedimages, he was able to point out star-tling similarities in composition andcolor between certain photographs ofmicroscopic subjects and, for example,particular paintings by the Impression-ists. The pairings served to highlightthe artistry of the photographs in theexhibit.

Hayden also spoke, remind-ing reception guests that,although certainly beautiful,these micrographic imagesare primarily valued byscientists for the datathey capture. Heexplained the varioustechniques employed byresearchers working withadvanced microscopes andused still images and time-lapsemovies from the Wistarmicroscopy facility to illustrate someof the results. In one movie, twoadvancing “armies” of cells divide furi-ously to close an experimental wound.

In another, eerie movement shows thegrowth of an experimental melanoma.

During the run of the exhibit fromJanuary 15 through March 2,

Wistar offered guidedtours of the exhibition

to science teachers andtheir students by spe-cial arrangement.Groups from CityCenter Academy, PennAlexander School, andThe Baldwin School

were among those whovisited Wistar for tours.

Hayden led the tours,reprising his presentation at

the reception to provide anoverview of the role microscopes playin biological research today and explain

how selected photographs from theexhibit were made and the biologicalsignificance of their subjects. Nikon’sEric Flem returned to Wistar to speakto the Baldwin students with Hayden.

The Nikon Small World contestwas founded in 1974 to recognizeexcellence in photography through themicroscope. Each year, Nikon makesthe winning images accessible to thepublic through the Nikon Small World calendar, a national tour, and an electronic gallery featured atwww.nikonsmallworld.com.

Above: Katie Hayden looks through a demon-stration microscope at the opening reception. Left: 19th place winner, Condylostoma sp.(a protozoan) by Raul M. Gonzalez.

7th place winner, seed of a Clematis vitalba shrubby Viktar Sykora.

Detail of 20th place winner, thin nematic film (liquid crystals)by Dr. Oleg D. Lavrentovich.

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On February 21, The WistarInstitute hosted the DelbertW. Johnson Prostate CancerSymposium, an all-day sym-

posium for invited members of the pub-lic to raise awareness of prostate cancerrisk, prevention, and treatment inAfrican-American men. African-Ameri-can men are at substantially greater riskfor developing prostate cancer thanother population groups. They are alsomore likely to die from their disease.

“The prostate-cancer statistics forAfrican-American men are alarming,”said Jerry L. Johnson, chairman ofRadnor Trust Company, Radnor, PA,and chair of the organizing committeefor the symposium. “Knowledge ispower, however, and that’s what thissymposium is about. African-Americanmen and those who love them need toknow the facts about prostate cancer.”

“Recent years have seen a remark-able increase in our knowledge aboutcancer,” said Russel E. Kaufman,M.D., Wistar president and CEO.“More than ever before, we can speakwith confidence about the causes ofcancer, how to detect it, and how bestto treat it. With prostate cancer, whilewe now know that African-Americanmen are at increased risk for develop-ing the disease, we can also offer apowerful array of new tests and treat-ment options to help patients fighttheir cancer.”

Despite the fact that prostate canceris the second most common cancer inmen, research on the disease has beenrelatively neglected in the past, Kauf-man noted. The good news, however,is that it is now getting a more appro-priate level of attention, he said.

At the symposium, leadingresearchers and clinicians from across

the country shared the latest scientificand clinical information concerningprostate cancer in African-Americanmen. Among those presenting wasMatthew L. Freedman, M.D., a cancergenetics researcher at the Dana-FarberCancer Institute and Harvard MedicalSchool. His group last year identified aregion of the genome associated withelevated prostate cancer risk in African-American men.

Other speakers included Thomas A.Farrington, prostate cancer survivorand author of Battling the Killer Withinand Winning ; Gordon L. Grado,M.D., founder and medical director ofthe Southwest Oncology Center andthe Grado Radiation Center of Excel-lence in Scottsdale, AZ, a leader in

developing brachytherapy for prostatecancer, in which small radioactive“seeds” are implanted in the prostate toselectively kill the cancer cells; andDavid I. Lee, M.D., chief of urology atthe University of Pennsylvania Presby-terian Medical Center, a practitioner ofminimally invasive robotic surgery forprostate cancer.

David W. Speicher, Ph.D., professorand co-leader of the Molecular andCellular Oncogenesis Program at Wis-tar described his research to develop anearly detection blood test for prostatecancer. Such a test would look for mul-tiple biomarkers of early prostate cancerin the blood and would be a markedimprovement on the current PSA test.

Also speaking at the symposium wasArthur L. Stokes, M.D., a member ofWistar’s Board of Trustees and of theorganizing committee for the DelbertW. Johnson Prostate Cancer Sympo-sium, which honored the late DelbertW. Johnson, a prostate cancer survivorand supporter of cancer research, aswell as the brother of organizing com-mittee chair Jerry L. Johnson.

Left to right: Bernard W. Smalley, Jr.; Jerry L. Johnson; Fletcher H. Wiley; Yvette Franklin; andWillie Johnson, all members of the organizing committee, with Yolanda Turman; James Brown;and Lawrence Johnson. Committee members not pictured: Oliver St. Clair Franklin; Jeri LynneJohnson; Sam Jones; Michael Rashid; Arthur Stokes, M.D.; and Reggie Wilkes.

WISTAR HOSTS PROSTATE CANCER SYMPOSIUMFOR AFRICAN-AMERICAN MEN

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R I S K , P R E V E N T I O N ,A N D T R E AT M E N T

By Franklin Hoke

Real-T ime Moviesof the ImmuneSystem Target ingCancer

Wistar scientists havefor the first time cre-

ated three-dimensional,time-lapse movies showingimmune cells targeting can-cer cells in live tumor tis-sues. In recordedexperiments, immune cellscalled T cells can be seenactively migrating thoughtissues, making direct con-tact with tumor cells, andkilling them.

Insights from this newview of the body’s on-boarddefenses against cancer mayopen the way for improvedimmunotherapies to treatthe disease.

“We’ve taken the firstreal-time look at the finalphase of the immune sys-tem’s response to cancercells,” says WolfgangWeninger, M.D., an assistantprofessor in the ImmunologyProgram who led the newresearch. “This has enabledus to delineate the rules of T cell migration and engage-ment directly within theintricate microenvironmentof tumors.”

With a series of moviesmade under different experi-mental conditions, theresearchers resolved impor-tant questions about themechanisms by which Tcells act against cancer. Theirfindings were publishedNovember 27 in The Jour-nal of Experimental Medi-cine. Sixteen brief video clipsare available online at http://www.jem.org/cgi/content/full/jem.20060710/DC1.

The scientists used a lead-ing-edge instrument called atwo-photon microscope, ableto peer inside living tissues.The microscope tracked andrecorded the movements inthree dimensions over timeof T cells in a transgenicmouse developed byWeninger and Ulrich vonAndrian at Harvard MedicalSchool in which the cells flu-oresce green. In addition, forthis study, tumor cells in themice were engineered to flu-oresce blue.

The lead author on thestudy was Paulus Mrass,M.D., a postdoctoral fellowat Wistar. The other Wistar-based co-authors were LaiGuan Ng, Sachin Daxini,Marcio Lasaro, Amaya Ipar-raguirre, Lois L. Cavanagh,Ph.D., and immunologyprofessor Hildegund C.J.Ertl, M.D. The remainingco-authors were HajimeTakano and Philip G. Hay-don at the University ofPennsylvania and Ulrich H.von Andrian at the CBRInstitute for BiomedicalResearch, Harvard MedicalSchool.

Support for the researchcame from the National

Institutes of Health, theW.W. Smith CharitableTrust, the Max Kade Foun-dation, the Cancer ResearchInstitute, and the Com-monwealth UniversalResearch Enhancement Pro-gram of the PennsylvaniaDepartment of Health.Haydon has equity interestin the company PrairieTechnologies Corporation,which builds and marketsthe two-photon microscopeused in this project.

Insights into GenomeCompaction in Spores andSperm

In higher order animals,genetic information is

passed from parents to off-spring via sperm or eggs,also known as gametes. Insome single-celled organ-

isms, such as yeast, thegenes can be passed to thenext generation in spores. Inboth reproductive strategies,major physical changesoccur in the genetic materialafter it has been duplicatedand then halved on the wayto the production of maturegametes or spores. Near theend of the process, thematerial—called chromatin,the substructure of chromo-somes—becomes dramati-cally compacted, reduced involume to as little as fivepercent of its original vol-ume.

Wistar researchers, study-ing the mechanisms thatcontrol how the geneticmaterial is managed duringgamete production, havenow identified a single mol-ecule whose presence, ormark, is required forgenome compaction. Addi-tionally, after first noting

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the molecule’s activity dur-ing the production of yeastspores, the scientists saw thesame activity during the cre-ation of sperm in fruit fliesand mice, suggesting thatthe mechanisms governinggenome compaction areevolutionarily ancient,highly conserved in specieswhose lineages divergedlong ago. A report on thestudy appeared in the Sep-tember 15 issue of Genes &Development.

“This molecular mark isrequired at a critical timeleading up to genome com-paction in spores andsperm,” says Shelley L.Berger, Ph.D., the HilaryKoprowski Professor andsenior author on the study.“Also, there seems to be asimilarity in the way themark is used in organismsas different from each otheras yeast and mammals, sug-

gesting that compaction hasbeen important throughoutevolution.”

Thanuja Krishnamoorthy,Ph.D., at Wistar was thelead author on the study.With senior author Berger,the other Wistar-based co-author on the study wasJean A. Dorsey. The addi-tional co-authors were XinChen and Margaret Fullerwith the Stanford UniversitySchool of Medicine; JeromeGovin and Saadi Khochbinwith the Institut AlbertBonniot Faculté deMédecine in La Tronche,France; Wang L. Cheungand C. David Allis at theUniversity of Virginia,Charlottesville; KarenSchindler and Edward Win-ter at Thomas JeffersonUniversity; and VincentGuacci at the CarnegieInstitution, Baltimore.(Cheung is currently at the

Johns Hopkins Hospital,and Allis is with RockefellerUniversity.)

Support for the researchwas provided by theNational Institutes ofHealth and the NationalScience Foundation. Addi-tional support came fromLyon Rhône-Alpes Can-céropôle and the Regulomeconsortium, the Leukemiaand Lymphoma Society,and the CommonwealthUniversal ResearchEnhancement Program ofthe Pennsylvania Depart-ment of Health.

Promising NewAtherosc lerosisDrugs Linked toLeukemia

In recent years, scientistsstudying inflammation

and atherosclerosis haveseen their respective fieldsconverging. Inflammation isan aspect of the immuneresponse to injury and dis-ease. Atherosclerosis, withits characteristic lesions inthe blood vessel walls,underlies most cardiovascu-lar disease, including heartattacks and strokes.

Now, in a recent study,Wistar scientists pursuing apromising new immune-system target for anti-ather-osclerosis therapies havediscovered another conver-gence: An unwanted poten-tial side effect of any suchtherapies is a dangerousblood cancer called chronicmyelogenous leukemia, orCML. A silver lining, how-ever, is that the CML seenin the genetic strain of miceused in the study closely

mimics human CML, sothat the mice offer a newmodel for studying CML,opening the door forresearchers to better under-stand that disease. The Wistar team’s results werefeatured on the cover of theOctober 30 issue of TheJournal of ExperimentalMedicine.

The Wistar scientists ini-tiated their experiments tobuild on a series of findingsthat had suggested thatblocking certain enzymescalled lipoxygenases couldinhibit the kind of chronicinflammation in the bloodvessel walls that drives theatherosclerotic process. Evenbetter, blocking theseenzymes seemed only toaffect one type of immunecell, the macrophage, and tointerfere only with its rolein chronic inflammation.The acute response of themacrophages to infectiousagents like bacteria, criticalfor protection against dis-ease, remained unfettered.

“We and others hadhoped that blocking thisenzyme would safely slow orstop certain chronic inflam-matory responses that havebeen linked to atherosclero-sis,” says Ellen Puré, Ph.D.,a professor in the Molecularand Cellular Oncogenesisand Immunology programsand senior author on thestudy. “Now we know thatif we go that route, we mayalso unwittingly be promot-ing leukemia.”

The lead author on thestudy was Melissa KristineMiddleton at Wistar. AliciaMarie Zukas, Tanya Rubin-stein, Michele Jacob, Ph.D.,Ellen Puré, Ph.D.,

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and Liang Zhao, Ph.D., atWistar were co-authors, aswere Peijuan Zhu and IanBlair at the University ofPennsylvania. In addition toher Wistar affiliation, seniorauthor Puré also has associa-tions with Penn and withThe Ludwig Institute forCancer Research.

Funding for the researchwas provided by theNational Institutes ofHealth and the Common-wealth Universal ResearchEnhancement Program ofthe Pennsylvania Depart-ment of Health.

Genome-ManagementSystem ProtectsAgainst Cancer

A round the home, regu-larly used tools are

generally kept close at hand:a can opener in a kitchendrawer, a broom in the hallcloset. Less frequently usedtools are more likely to bestored in less accessible loca-tions, out of immediatereach, perhaps in the base-ment or garage. And haz-ardous tools might even bekept under lock and key.

Similarly, the humangenome has developed a setof sophisticated mechanismsfor keeping selected genesreadily available for usewhile other genes are keptsecurely stored away forlong periods of time, some-times forever. Candidategenes for such long-termstorage include thoserequired only for earlydevelopment and prolifera-tion, potentially dangerousgenes that could well trigger

cancers and other disordersshould they be reactivatedlater in life. Cancerresearchers and others havebeen eager to learn moreabout the molecules thatdirect this all-important sys-tem for managing thegenome.

In a study published inthe October issue of NatureStructural and MolecularBiology, researchers at TheWistar Institute and FoxChase Cancer Center suc-cessfully determined thethree-dimensional structureof a key molecular complexinvolved in long-term genestorage, primarily in cellsthat have ceased proliferat-ing, or growing.

“The two-molecule com-plex we studied is pivotalfor protecting certain genesfrom expression, genes that

could cause problems if theywere activated,” says RonenMarmorstein, Ph.D., a pro-fessor in the Gene Expres-sion and RegulationProgram and one of the twosenior authors on the study.Peter D. Adams, Ph.D., atFox Chase was the other.“This is the first time we’vebeen able to see the struc-ture of these moleculescommunicating and inter-acting with each other, andit provides importantinsights into their func-tion.”

The two lead authors onthe study were Yong Tang atWistar and Maxim V. Pous-tovoitov at Fox Chase.Kehao Zhao at Wistar was acoauthor, as were MeganGarfinkel, AdrianCanutescu, and RolandDunbrack at Fox Chase.

Funding for the researchwas provided by theNational Institutes ofHealth, the Leukemia andLymphoma Society, and theCommonwealth UniversalResearch Enhancement Pro-gram of the PennsylvaniaDepartment of Health.

StructureDetermined forEnzyme thatUnwinds GeneticStrands

The normal physicalconfiguration of the

human genome is a pair ofDNA strands linked bycross-bridging moleculesinto the now-familiar dou-ble helix. RNA, a kind ofmirror molecule derivedfrom DNA, is also com-monly double-stranded. Formany cellular purposes,however, these geneticstrands must be separated.Some of the vital tasks thatrely on unwinding thesedouble-stranded geneticmolecules are replication,repair, recombination, andtranscription.

The enzymes responsiblefor this critical unwinding ofdouble-stranded DNA,RNA, or, in some cases, aDNA/RNA hybrid, areknown as helicases. Heli-cases are molecularmachines some of whichassemble into rings of sixidentical subunits that encir-cle a single strand of theDNA or RNA and movealong it, separating it fromits sister strand as they go.Precisely how they do this,however, has been poorlyunderstood until now.

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In a study published inthe November 3 issue ofthe journal Cell,Emmanuel Skordalakes,Ph.D., an assistant profes-sor in the Gene Expressionand Regulation Program,determined the structure ofa helicase that has longbeen a textbook examplefor understanding thefunction of these molecularmachines. The structureanswered many outstand-ing questions about heli-case mechanism,including its activa-tion upon RNAencircling and how ittravels along a single-stranded RNA.Structural elementson the interior of thehelicase were seen tobe feeding the RNAthrough the ring in atightly orchestratedfashion.

“We wanted tounderstand the move-ment of the helicasealong the RNA,” saysSkordalakes. “Whatwe found is that a set ofsmall spring-like loops onthe inside of the ring act aslevers allowing the helicaseto move along the RNA in arotational fashion.”

The rotation allows forthe RNA to be passedaround the ring where itbriefly associates with eachone of the interfacesformed by adjacent sub-units. RNA binding atthese sites promotes thebreakdown of the energycurrency molecule of thecell, ATP, present in eachone of these pockets, aprocess that provides the

energy required for themovement of the helicase.

“Understanding howthese helicases work is notonly important from a bio-logical point of view, it’s alsopotentially valuable from ananotechnology view,” Sko-rdalakes says. “Maybe oneday we’ll be able to designsmall molecules like this,small machines to performcomplicated processes totreat disease or perhaps evendo microsurgery.”

Skordalakes conductedthe research as a postdoc-toral fellow in the labora-tory of James M. Berger,Ph.D., at the University ofCalifornia, Berkeley, beforejoining Wistar in Septem-ber. Skordalakes was leadauthor on the study; Bergerwas senior author. Thework was supported by theG. Harold and Leila Y.Mathers Charitable Foun-dation.

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P R I V A T E G R A N T STHE BARRA FOUNDATIONThe Wistar Institute, outreach, $1,500The Wistar Institute, President’sFund, $5,000

THE FRED J. BROTHERTONCHARITABLE FOUNDATIONWilliam H. Wunner, Ph.D., BiomedicalTechnician Training Program, $20,460

THE CHARLES WENTZ CARTERMEMORIAL FOUNDATIONNadia Dahmane, Ph.D., cancerresearch, $3,000The Wistar Institute, outreach, $2,000

CLAWS FOUNDATIONThe Wistar Institute, President’sFund, $100,000

GBH FOUNDATIONThe Wistar Institute, President’sFund, $5,000

THE HASSEL FOUNDATIONWilliam H. Wunner, Ph.D., 2007 HighSchool Program and Biomedical Tech-nician Training Program, $30,000

INNISFREE FOUNDATION OFBRYN MAWRThe Wistar Institute, Investing inLeadership Campaign, $20,000

KAPLAN POMERANTZ SCHAEFFERFOUNDATIONThe Wistar Institute, President’sFund, $10,000

LEROY E. KEAN FAMILYFOUNDATIONJoseph L. Kissil, Ph.D. and E. JohnWherry, Ph.D., lung cancer research,$140,000

LENORE AND HOWARD KLEINFOUNDATION, INC.Russel E. Kaufman, M.D., ovariancancer research, $7,000

LUPUS FOUNDATION OFSOUTHEASTERN PENNSYLVANIAAndrew J. Caton, Ph.D., Lupus Foun-dation Fellowship, $1,500

MERCK & CO., INC.Ethics of Vaccines Project SeminarSeries, $25,000Meenhard Herlyn, D.V.M., melanomaresearch, $75,000

THE NOREEN O’NEILLFOUNDATION FOR MELANOMA RESEARCHQihong Huang, M.D., Ph.D.,melanoma research, $30,000

THE WARREN V. MUSSERFOUNDATIONThe Wistar Institute, prostate cancerresearch, $3,000

PA EARLY STAGE PARTNERSThe Wistar Institute, President’sFund, $2,500

PHILADELPHIA HEALTH CARETRUSTThe Wistar Institute, Center for Computational and Systems Biology,$5,000,000

sanof i pasteur Ethics of Vaccines Project SeminarSeries, $50,000

FRANZ W. S ICHEL FOUNDATIONThe Wistar Institute, President’sFund, $1,000

V FOUNDATION FOR CANCERRESEARCHQihong Huang, M.D., Ph.D., cancerresearch, $100,000

W.W. SMITH CHARITABLE TRUSTRussel E. Kaufman, M.D., cancerresearch, $68,000

WAWA, INC.Nadia Dahmane, Ph.D., pediatricbrain tumor research, $10,000

G O V E R N M E N TG R A N T SNATIONAL CANCER INSTITUTE Paul M. Lieberman, Ph.D., Kaposi’ssarcoma associated herpes viruslatency, one-year grant of $100,000Ramin Shiekhattar, Ph.D., breast can-cer research, four-year, eleven-monthgrant of $1.5 millionLouise C. Showe, Ph.D., developmentof the Cancer Bioinformatics Grid(CaBIG), one-year grant of $33,366David W. Speicher, Ph.D., develop-ment of colon cancer blood test, four-year, ten-month grant of $1.8 million Chunling Yi, Ph.D., laboratory ofJoseph Kissil, Ph.D., tumor suppressorresearch, three-year grant of $145,000

NATIONAL INSTITUTE OF AGING Andrew J. Caton, Ph.D., changes inimmune system during aging research,four-year, eight-month grant of$184,445

NATIONAL INSTITUTE OFDIABETES & DIGESTIVE & KIDNEY DISEASESCarlo C. Maley, Ph.D., culturing ofpre-cancerous cells, one-year grant of$10,000

NATIONAL INSTITUTE OFGENERAL MEDICAL SCIENCESRamin Shiekhattar, Ph.D., biogenesisof microRNAs, four-year grant of $1.1 million

UNITED STATES DEPARTMENT OF AGRICULTURE James E. Hayden, development of atechnical workshop for microscopy(includes equipment donation), ten-month grant of $133,310

Information on Wistar technolo-gies available for licensing can befound at www.wistar.org under“Technology Transfer.”

N e w G r a n t A w a r d s

The Wistar Institute and its scientists continue to compete successfully for grantsto support research and programs. Below is a list of recent awards.

Emmanuel Skordalakes, Ph.D.

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Wistar PresidentTakes NewLeadership Roles

Russel E. Kaufman,M.D., president and

CEO of The Wistar Insti-tute, recently accepted twoimportant new leadershippositions.

Effective September 1,Kaufman became chair ofthe board of directors forBioAdvance, the Biotech-nology Greenhouse ofSoutheastern Pennsylvania.BioAdvance supports theadvancement of life sci-ences innovation and busi-ness development inSoutheastern Pennsylvania.On January 16, the Ameri-can Cancer Societyannounced his appoint-ment to chair its Councilfor Extramural Grants, acommittee of senior scien-tists that recommendsfunding levels for investiga-tor-initiated, peer-reviewedcancer research proposalssubmitted to the society.

“I’m pleased to welcomeDr. Kaufman as the newchair of BioAdvance,” saidBarbara S. Schilberg, man-aging director and CEO ofBioAdvance. “He is recog-nized nationally for his sci-entific innovation andshares our enthusiasm forthe region’s potential, aswell as the role entrepre-neurs play in bringingmedical advances topatients.”

Christopher C. Windell,Ph.D., scientific programdirector for extramuralgrants at the AmericanCancer Society, said, “Dr.Kaufman’s expertise will becrucial in insuring that the

society continues to makewhat will be an increasinglysignificant contribution tothe development of noveldirections in cancerresearch.”

11th AnnualJonathan LaxMemoria l Lectureon AIDS

The Wistar Instituteteamed with Philadel-

phia FIGHT to host the11th Annual Jonathan LaxMemorial Lecture onNovember 1. Two presen-ters focused on the impactof the AIDS epidemic in the U.S., where thenumber of cases diagnosedcontinues to rise whiletreatment resources arefalling. PhiladelphiaFIGHT offers education,treatment, and outreachprograms for HIV/AIDSpatients. The lecture hon-ors businessman JonathanLax, former president ofthe board of FIGHT, whodied of complications ofAIDS in 1996.

AIDS researcherMichael Saag, M.D, andMartin Delaney, founder ofProject Inform, were thespeakers. Saag is a professorof medicine at the Univer-sity of Alabama and direc-tor of the University ofAlabama at Birmingham’sCenter for AIDS Research.Delaney founded ProjectInform in San Francisco in1985 to provide reliableinformation about the dis-ease and its treatment at atime when such informa-tion was difficult to obtain.

Saag spoke in the after-noon at Wistar about

“Health Informatics: TheFuture of HIV Clinical andTranslational Research.”That evening, Saag andDelaney both spoke at TheRitz Carlton Hotel. Sagg’s

second talk, titled “TheEmerging Crisis in HIVTreatment,” precededDelaney’s, “The ChangingParadigm of HIV Treat-ment.”

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Funding Awarded for Melanoma Research

The Noreen O’Neill Foundation for MelanomaResearch presented a $30,000 check to The Wistar

Institute at an October 18 reception at the LoewsPhiladelphia Hotel. The funds, which were raised at thefoundation’s first annual “Running for Cover” 5Krun/walk on June 25, 2006, at the Wachovia Complex inSouth Philadelphia, will support research into metastaticmelanoma in the laboratory of Wistar assistant professorQihong Huang, M.D., Ph.D. Metastatic melanoma—melanoma that has spread beyond its original site—is oneof the leading causes of death from the disease.

Noreen O’Neill created the foundation after her owndiagnosis with melanoma in 1999. After the diseaseclaimed her life in 2000, her sister Kate O’Neill took overleadership of the organization. Today, the foundation con-tinues to promote melanoma awareness and research.

Teams are forming for the 2007 “Running for Cover”event, to be held on June 24, 2007. Visit www.founda-tionformelanomaresearch.org for more information.

Above: Wistar melanoma researcher Meenhard Herlyn, D.V.M.;Kate O’Neill, president of the Noreen O’Neill Foundation forMelanoma Research; Russel E. Kaufman, M.D., Wistar presidentand CEO; and foundation treasurer Maury J. Alsher.

Lung CancerInit iat iveReceives KeanFoundationSupport

The Leroy E. Kean Fam-ily Foundation has

awarded Wistar scientistsJoseph Kissil, Ph.D., and E.John Wherry, Ph.D.,$140,000 to launch an ini-tiative in lung cancerresearch. Lung cancer is thesecond most common can-cer and the deadliest formof cancer in men andwomen. One arm of theinitiative will focus on bet-ter understanding theimmune system’s responseto lung cancer with the goalof finding ways to enhanceits anti-cancer activity.Another aspect of the pro-ject will explore and fullydelineate the role of K-ras,one of the most commonlymutated genes in lung can-cer, again with an eyetoward development of newtherapies. The effort will beknown as the Lois S. KeanLung Cancer Research Ini-tiative, in honor of the lateMrs. Kean’s battle againstlung cancer. In addition toproviding insights into themechanisms underlying thedisease in search of poten-

tial treatments, an addi-tional goal of the projectwill be to create a researchnexus at Wistar that willattract other researchers tostudy lung cancer.

Wistar NamesEmeritus BoardMembers

The Wistar Institute hasnamed Nobel-prize win-

ner Peter C. Doherty,Ph.D., and businessmanVincent G. Bell, Jr., emeri-tus members of the Boardof Trustees.

“Wistar has benefitedtremendously from the steadyguidance and wisdom ofthese talented and dedicatedindividuals,” said Russel E.Kaufman, M.D., presidentand CEO of Wistar.

Doherty served as a Wis-tar investigator from 1975until 1982 and as a boardmember from 1997 to 2006.With colleague Rolf M.Zinkernagel, M.D., Ph.D.,he was awarded the NobelPrize in Physiology or Medi-cine in 1996 for research onhow immune system cellsrecognize targets. Bell, co-founder of Safeguard Busi-ness Systems, Inc., was aWistar board member from1995 until 2006.

Wistar-Aff i l iatedScientistsHonored forRotavi rus Vaccine

The Children's Hospitalof Philadelphia

(CHOP) awarded its GoldMedal to H. Fred Clark,D.V.M., Ph.D., Paul A.Offit, M.D., and Stanley A.Plotkin, M.D., on Septem-ber 12. The three scientists,all of whom have past andpresent ties to Wistar, werehonored for research con-ducted at Wistar andCHOP in the 1980s thatled to the development of anew vaccine againstrotavirus, approved for usein the U.S. in 2006.Rotavirus is the most com-mon cause of diarrhea ininfants and young childrenin the U.S. and the cause ofas many as 600,000 child-hood deaths worldwide eachyear. The medal was createdin 1963 to recognize indi-viduals who have made asignificant impact on chil-dren’s healthcare nationwideand throughout the world.

“By creating a vaccinethat will virtually eradicaterotavirus, Drs. Clark, Offit,and Plotkin have helped topromote the health and wel-fare of children, our nation'sgreatest resource,” saidRichard M. Armstrong, Jr.,chairman CHOP’s board oftrustees.

Author DavidQuammen Speaks

Author David Quam-men spoke at Wistar

on September 18 about hisrecent book The ReluctantMr. Darwin: An Intimate

Portrait of Charles Darwinand the Making of His Theory of Evolution.

After returning from hisfive-year voyage on theH.M.S. Beagle, Darwinnursed his ideas about theevolution of species in pri-vate for years, detailing hisobservations and experi-ments only in his note-books. Deeply conflicted,Darwin struggled for morethan two decades with thequestion of whether to pub-lish his work, aware of thecontroversy his findingswould cause. In his book,science journalist Quam-men tells the story of whatcaused Darwin to keep hisideas to himself for solong—and what finallypushed him to publish TheOrigin of Species in 1859.

Quammen, also theauthor of The Song of theDodo and Monster of God, isa three-time winner of theNational Magazine Award.He wrote a column called“Natural Acts” for Outsidemagazine for fifteen years.Quammen lives in Boze-man, MT. The Joseph FoxBookshop, an independentbookstore, provided booksfor sale at the event.

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David Quammen

Joseph Kissil, Ph.D., and E. John Wherry, Ph.D., will study lung cancerwith new support from the Kean Foundation.

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David Kritchevsky, Ph.D., alively contributor to theongoing national debate onnutrition and health for

almost six decades, died on November20, 2006, at the age of 86. Kritchevsky,an internationally recognized expert inthe role of dietary fats in heart diseaseand cancer, had been associated withThe Wistar Institute since 1957. At thetime of his death, he was Caspar WistarScholar at Wistar and a professor emer-itus at the University of Pennsylvania.

In addition to his distinguishedcareer in medical research, Kritchevskywas also noted for his humorous takeon life and the scientific enterprise,perhaps expressed best in a series ofsongs which he used to entertain whilealso teaching about science. Amongthese were the “Cholesterol Biosynthe-sis Song,” sung to the tune of “JingleBells” and “If I Had a Big Grant,” sungto the tune of “If I Was a Rich Man,”from Fiddler on the Roof.

Born in Kharkov, Russia, in 1920,Kritchevsky earned his B.A. in chem-istry and an M.S. degree in organicchemistry from the University ofChicago in 1939 and 1942 respectively.He was awarded a Ph.D. in organicchemistry from Northwestern Univer-sity in 1948. After a postdoctoral fellow-ship in Nobel-Prize winner LeopoldRuzicka’s laboratory at the FederalResearch Institute in Zurich, Switzer-land, in 1948 and 1949, he served as astaff member in the Bio-Organic Groupof the Radiation Laboratory withanother Nobel Prize winner, MelvinCalvin, at the University of California,

Berkeley, from 1950 to 1952. From1952 to 1957, he was a staff member inthe Virus and Rickettsial Research Sec-tion at Lederle Laboratories in PearlRiver, NY, where he met HilaryKoprowski., M.D. When Koprowskiwas named director of The Wistar Insti-tute in 1957, he invited Kritchevsky tojoin him at the Institute.

At Wistar, Kritchevsky was an asso-ciate member of the faculty from 1957to 1962 and member of the facultyfrom 1962 to 1975. In 1975, hebecame associate director of Wistar andserved in that position until 1991. Hewas named Caspar Wistar Scholar atthe Institute in 1995 and retained thattitle for the duration of his career.

Kritchevsky authored the first bookon cholesterol in 1958 and receivedmany national and international awardsduring his lifetime, including TheAuenbrugger Medal, University ofGraz; the Special Recognition Award,Council on Arteriosclerosis, AmericanHeart Association; and the ResearchAchievement Award, American Insti-tute of Cancer Research. In 2006, theAmerican Society for Nutritionannounced the establishment of theDavid Kritchevsky Career AchievementAward in Nutrition, to be awardedannually. He was one of the few scien-tists recognized for his research in boththe heart disease and cancer fields.

During the course of his career,Kritchevsky mentored many people indiverse fields of biochemistry, lipidmetabolism, nutrition, and cardiovas-cular disease. Many of his former stu-dents have gone on to illustriouscareers in academia, government, andindustry. He encouraged scientificcuriosity and independence in his stu-dents and was generous with his timeand ideas when any returned foradvice. His generosity extended to histechnicians, who were included asauthors on his many papers. As aresult, some Wistar technicians havelarger bibliographies than some facultymembers. Kritchevsky’s body of pub-lished work includes 421 research pub-lications, the most recent in September2006.

Kritchevsky is survived by his wifeof 58 years, Evelyn, their children Bar-bara, Janice, and Stephen, and sixgrandchildren.

David Kritchevsky, Ph.D.

R e m e m b e r i n g D a v i d K r i t c h e v s k yLongt ime Wis ta r P rofes sor Inte rnat iona l ly

Recognized fo r Research on D ie t and D i seaseBy Franklin Hoke

He encouraged curiosityand independence in his students.

Through a charitable gift annuity, you canjoin Wistar scientists in the fight against

disease while earning a lifetime income foryourself. Support Wistar’s researchers as theywork to develop new treatments for melanoma,lung cancer, and brain tumors and create newvaccines for flu and other diseases.

You can earn a return of up to 11.3 percent onyour gift, depending on your age. You willreceive an income tax deduction at the time ofthe gift, and a portion of your income will bedeductible in the future.The minimum contribu-tion is $10,000. Cash, stock, or other assetscan be used to fund the annuity.This program iscurrently offered to Pennsylvania residents only.

For more information, call Peter Corrado in Wistar Development at 215-898-3930.

CURRENT RATES FOR CHARITABLE GIFT ANNUITIES

AGE RATE

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JOIN US. BECOME A PARTNERIN THE SEARCH FOR CURES. Support Wistar’s innovative medical research—while earning a lifetime incomefor yourself—through a charitable gift annuity.

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PA I DPHILADELPHIA, PA

PERMIT NO. 3211

Sen. Arlen Specterreceives the 2006Wistar President’sAward from Russel E.

Kaufman, M.D. (left), Wistar's

president and CEO, and Brian

Dovey (center), chair of the

Board of Trustees. Specter, a

stage IVB Hodgkin's lymphoma

survivor was recognized for

his steadfast national

leadership over many years

for increasing support for

biomedical research.

Full story on page 8.