focuswinter 2011
Destination: Wistar A Bold Vision for the Future of The Wistar Institute Cancer Center
vaccines in answering the the 21st century questions of melanoma from the president The Focus is on the Future
he term “frontier of science” prob- Among our newest colleagues is ably gets used a bit too much, but Dario Altieri, my successor as director T at Wistar we can take it literally. of The Wistar Institute Cancer Center. contents The stories in this issue of Focus represent, As you may know, I stepped down in many cases, the very frontier; beyond from my role as Cancer Center director our science lies the unknown, and Wistar this past summer to focus on ensuring Beyond our science is the unknown, researchers are among its first explorers. a strong future for the Institute in and the scientists of The Wistar The story about our new Wistar my role as president and chief executive Institute are among its first explorers. Institute Melanoma Research Center, for officer. In the years I served as director, p2 p6 p8 example, tells how the decades Meenhard we successfully renewed our National Herlyn has spent getting to know the Cancer Institute Cancer Center biology of melanoma will transform the Support Grant twice, with our score way doctors treat and prevent the disease. improving each time. Destination: Vaccines Answering Not “may” transform, will. In fact, they This is a testament to the excellence already have, with ongoing clinical trials of our Cancer Center and the many Wistar in the the Questions of BRAF inhibitors, which owe their scientists and staff members who 21st Century of Melanoma very existence to the Herlyn laboratory’s comprise it. The time is right for new work in categorizing mutations in scientific leadership of the Cancer melanoma cells. Center, and I am confident we have Of course, our scientists do not work found it in Dr. Altieri. He is a true in a vacuum, each pushing forward an visionary with the talents Wistar needs individual agenda. Part of Wistar’s evolu- to carry forth our strategic research tion has been toward new collaborative vision. He is also a tremendously kind, 13 The Shape of 23 In Memorium models, where our scientists leverage personable man, and I am sure you one another’s expertise to accelerate the will enjoy getting to know him. Things to Come Gerd G. Maul, Ph.D. pace of progress. We continue to recruit Welcome to the Winter 2011 issue Ken-ichi Noma, Ph.D., talented men and women to flesh out of Focus. Join us as we stride into on the path to 24 Wistarchives our complementary skill sets, to broaden the future, because we cannot hope discovering the structure Wistar’s ability to take the science we to get there without you. Wistar treasures know and translate it to the medicine of our genome join new Pennsylvania patients need. Academy of Fine Arts 14 Progress exhibit Russel E. Kaufman, M.D. The latest advances President and CEO from Wistar labs
18 Grant Highlights
19 People Making progress Focus is published two times per year for donors, Greg Lester The Wistar Institute is an equal opportunity/ friends, faculty and staff of The Wistar Institute Editor affirmative action employer. It is the policy of possible by the Office of Communications. To contact The Wistar Institute to provide equal employment Lee Christine Florida the editor, phone (215) 898-3943 or email opportunities to all individuals regardless of race, Communications Associate [email protected]. For general inquiries, contact color, creed, religion, national origin, ancestry, The Wistar Institute at (215) 898-3700. Send Staci Vernick Goldberg sex, age, veteran status, disability, sexual orientation, address changes to: Office of Development, The Director of Communications gender identity, or on the basis of genetic infor- Wistar Institute, 3601 Spruce Street, Philadelphia, mation, or any other characteristic protected by Contributing Writer: Christine M. Wilson PA 19104-4265, or email [email protected]. federal, state, or local law, with respect to all terms Design: GHI Design and conditions of employment. Principal Photography: Tommy Leonardi Additional Photography: 3601 Spruce Street James Hayden, Fred Keeney Philadelphia, PA 19104-4265 Stock Photography: iStock Photo 215.898.3700 The Wistar Institute is a National Cancer www.wistar.org Institute-designated Cancer Center
2 focus: summer 2010 1 Destination:
How The Framed by a set of well-earned laugh lines, the eyes of Dario Altieri, M.D., are the first thing you notice about the man. Institute’s New When he is excited, his eyes dance. When he is about to Cancer Center joke, his eyes laugh in anticipation. When he discusses the challenges of cancer medicine, they narrow with concern. Director (and And when he talks of the future, they gaze into an undefined First Chief distance, marveling at a vision he sees, challenging you Scientific Officer) to see it as well. Sees Wistar in If you could see The Wistar Institute through Altieri’s eyes, you would marvel too. In less than a decade, Altieri says, Wistar will be recognized as a “destination institution.” the 21st Century It is a vision that builds upon Wistar’s current reputation for excellence and its strengths in team science — where researchers from different disciplines come together to tackle difficult and emerging problems in biomedicine. “Wistar is known for the current strength of its science, for cancer biology and immunology, for vaccines and the basic understanding of processes that drive biology,” Altieri said. “We will augment all those strengths while keeping Wistar the flexible, nimble institution it is. It will be amazing.” Moreover, a destination institution, in Altieri’s eyes, provides a platform from which its researchers have the clout to drive collaborations with other institutions, accelerating the pace at which basic science feeds clinical research. “A lot of places have good scientists and build new buildings, but they are not destinations,” Altieri said. “They do not have that unmistakable aura that says ‘I can spend 10 to 15 years of my career here.’ Wistar has that; you can feel it in the bones of the place when you walk through the front door.” Altieri joined the Institute in the summer of 2010 as the fourth scientist to be named director of The Wistar Institute Cancer Center and the first to hold the title of chief scientific officer. He is also the first Robert and Penny Fox Distinguished Professor (see sidebar next page). Altieri’s first order of business is to implement Wistar’s Strategic Plan, in particular through faculty recruitment. The Wistar of the near future will expand from 30 to about 40 investigators. As director of the Cancer Center, Altieri follows Russel E. Kaufman, M.D., who will remain in his capacity as Wistar’s president and chief executive officer. Kaufman began the search for his own replacement after successfully leading Wistar through two renewal cycles of its National Cancer Institute Cancer Center Support Grant. “Dario Altieri has the experience and intellect we desired to further our progress …a few ideas will make history. in both basic cancer science and our ongoing efforts in translating scientific discovery * into practical therapies to prevent and cure cancer,” Kaufman said. “Throughout his career, he has shown excellent leadership and a remarkable ability to recruit top-notch scientific talent, capabilities that we plan to utilize in earnest as we expand our research faculty.”
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2 3 The Evolution of Dario Altieri Critical Mass. Transparency. Courage. Medicine came first for Altieri. Born in Milan to a mechanical engineer father and chemist In nuclear physics, it is called critical mass: the amount of material needed to sustain mother, Altieri was not particularly drawn to science. His academic aptitude guided a chain reaction. Around the halls of Wistar, Altieri has made “critical mass” the phrase him toward clinical medicine, however, and he graduated from the University of Milan of the day. Critical mass represents the strategic recruitment of new faculty who will with honors in 1982. mesh with Wistar’s current team of scientists. Together, with a broad array of skills His first taste of research came while working in an immunology laboratory as a and scientific approaches, Wistar faculty will be able to sustain the laborious process medical student, and continued as he began his secondary training in hematology. of translating laboratory insights into medical practices. However, it was not until Altieri joined the Scripps Research Institute in La Jolla, According to Altieri, the “era of the lone discoverer” has long since passed. In the California, in 1987 that he committed to a career in research. decade since the human genome was first published, scientists have shown that, more Altieri planned to stay for two years, but remained there for six. “It was a sobering, than anything, human biology is far more complicated than most could imagine. exhilarating experience. I learned not just simply how to think like an experimental “The way forward now is to build teams of investigators with widely different sets scientist, but how to plan and prioritize,” Altieri said. of knowledge and expertise,” Altieri said. “We want our scientists to feel the complete In 1994, he took a position as associate professor at the Yale University School of freedom of discovery and to pursue their ideas, of course, but the challenge is that Medicine in the Department of Pathology. It was purely a research position and, in we must work together.” 1997, it was where he made what he calls the most important discovery of his career: The second challenge for Wistar, Altieri says, is transparency. For Wistar, the team survivin, a gene later found to be over-active in nearly every human cancer. The role science approach cannot stop at the sidewalk of Spruce Street. Altieri points to how of surviving in allowing cancer cells to evade therapy is a topic his laboratory — the advocacy community, particularly in breast cancer and melanoma, has signifi- and many others around the world — is still studying. cantly influenced both cancer awareness and the flow of research dollars. Advocacy The Fantastic “Yale was a great setting and a great environment, but I grew concerned about groups, government, and the pharmaceutical industry need to work with academic Mr. & Mrs. Fox the need for a unified, integrated cancer program,” Altieri said. “I grew interested “Wistar is biomedical research on a very intimate level, Altieri says. in coming up with a new model in a new setting. As a destination institution, Altieri says, Wistar is uniquely poised to lead transparently. One of the ways Wistar will become a ideally poised Its faculty, not beholden to profit margins or patient volumes, is free to create links “destination institution” is by recruiting and He started with an entirely clean slate and no faculty, but within five years built a between otherwise competing entities in both industry and medicine. “Philadelphia retaining top-notch faculty, an effort Wistar’s program recognized as third in the nation for faculty productivity. has this remarkable concentration of academic institutions, yet it retains a culture benefactors support directly by endowing to fill that professorships. In fact, The Robert and of respect that underlies collaboration. It is a culture we need to tap into and build, Penny Fox Distinguished Professorship Altieri got his chance at the University of Massachusetts, where he was recruited in not just here, but internationally,” he said. made it possible to recruit Dario Altieri. 2002 to build and chair its first Department of Cancer Biology and direct the school’s gap between A third — and perhaps most difficult — concept is that of courage. In particular, The professorship is only one sign of Robert cancer center. The department would bring together molecular biologists with clinical as Altieri sees it, the courage to take on new challenges, for scientists to go where A. Fox’s long-term support of The Wistar oncologists, uniting two different worlds with few traditional points of contact. “The discovery the science leads them and not be afraid to push the boundaries of knowledge, even Institute and its scientific aims. Fox, a distin- program was based on the premise that cancer biology was truly different from cell in defiance of the status quo. The Institute itself requires courage to support its guished Philadelphia businessman and biology, and that cancer biology could be a point of aggregation for researchers across scientists, Altieri says. philanthropist, has made substantial gifts an entire institution,” Altieri said. and making “We don’t know the answer, but we know the answer is out there. We need the in recent years to support the critical goals He started with an entirely clean slate and no faculty, but within five years built resilience to stay the course,” Altieri said. described in Wistar’s Strategic Plan. He and his wife Penny endowed the professorship a program recognized as third in the nation for faculty productivity — a measure a difference In his vision, “Destination Wistar” will be a bigger place. It will be an institution with to specifically recruit an outstanding of success that includes quality of papers published by and awards granted to faculty a larger faculty and a larger portfolio of scientific interests. The Wistar of tomorrow will researcher in the field of cancer research. members — by the Chronicle of Higher Education. in medicine.” be poised to tackle complex biomedical processes by integrating emerging disciplines. Mission accomplished. Altieri’s path to Wistar represents his own evolution as a researcher and an appreciation “Genomics, proteomics, chemistry, immunology…these fields will all combine at for the role of basic research as an engine for clinical innovation. With the rise of Wistar in ways we cannot even foresee,” Altieri said. personalized medicine — profiling tumor genetics to determine how best to treat “Scientists know that the nuts and bolts of every biological discovery won’t necessarily a patient’s unique disease — basic science will drive medicine from “blockbuster” be relevant to medicine. Even in the best possible scenario, not everything will anticancer drugs to more individualized therapeutics, Altieri says. Institutions like work. In fact, most will work just a little,” Altieri said, and here his eyes gaze into that Wistar, are needed to cross scientific disciplines and create the building blocks undefined distance and his head nods. for future drugs. “But a few ideas will make history.” “My own journey leads me to believe that, more than ever, research equals oncology,” Altieri said. “Wistar is ideally poised to fill that gap between discovery and making a difference in medicine.”
4 focus: winter 2011 5 the rest of the virus, to stimulate the immune system. While some laboratories retract the original paper and lead the immune system. In 2009, Wistar patented have promoted the use of an attenuated British Medical Association to strip its the technology for a universal vaccine for adenovirus derived from humans — lead author, Andrew Wakefield, of his influenza that incorporates second-gener- which commonly causes respiratory medical license. ation principals. Such a vaccine would tract infections — Ertl has pioneered the Of course, a great deal of harm has allow people to forgo annual flu shots use of a simian (chimpanzee) adenovi- already been done, as 2010 has also seen Vaccines in in favor of one shot that will provide rus, a virus to which most humans have the first major outbreaks of rubella in the immunity against most strains of influenza, no prior exposures. United States in years. As vaccination rates including emerging or pandemic If you have ever had a common drop among isolated groups of people, strains like 2010’s H1N1 virus. cold, your immune system may have Plotkin says, so-called “herd immunity,” In 2010, Scott Hensley, Ph.D., joined memory of the human adenovirus. the protective effect of immunizing the the 21st Century The Wistar Institute as an assistant Unfortunately, this likely means that majority of people against a particular professor in Immunology and a member your immune system would take out a disease, also drops. Herd immunity protects Hildegund C. J. Ertl, M.D. of the Vaccine Center. His specialty is vector made from human adenoviruses both those who cannot be vaccinated, in how seasonal influenza changes from before it could enter your cells. Few due to their particular conditions, year to year, as proteins on the surface humans have been exposed to simian and those for whom the vaccine may of the virus accumulate mutations, a adenoviruses, however. In a 2010 paper not have been effective. ew public health advances have In 2007, Wistar formalized its vaccine tumors or prevent the buildup of phenomenon known as antigenic drift. in the Journal of Virology, Ertl provided This herd immunity is what protects saved more lives in the last century program with the creation of The Wistar brain-damaging protein plaques in evidence that these simian adenoviruses newborns from whooping cough, or F than clean water, antibiotics, and Institute Vaccine Center, a multidisci- Alzheimer’s patients. can produce a significant immune pertussis, a disease that can be deadly the widespread use of vaccines. That is plinary initiative designed to create the “The use of vaccines in treating and “The use of vaccines in treating and preventing cancer, in particular, is a response, paving the way for the use in infants. The first six months of 2010 according to Stanley Plotkin, M.D., a next generation of vaccines by pioneering preventing cancer, in particular, is a of the vector in future vaccine trials. saw a 418 percent increase in pertussis fascinating field of great public health Wistar emeritus professor, who recently new and emerging technologies. fascinating field of great public health “Both human and chimpanzee cases in California, according to the discussed the impact of vaccines in the “Our mission is to create new vaccines importance in which we are highly importance in which we are highly adenoviruses function in similar ways, U.S. Centers for Disease Control. At 20th century at an event marking the and expand the use of existing vaccines involved,” Ertl said. “The current vaccine involved,” Ertl said. but the simple benefit is that humans are least ten Californian children died of launch of an online exhibit on the in places, such as Asia and Africa, that against the human papillomavirus can rarely exposed to adenoviruses of the disease in 2010. history of vaccines by the College of are underserved by vaccination,” said prevent cancers that arise from HPV His laboratory is expected to contribute chimpanzee origin,” Ertl said. “HIV, According to Plotkin, there has always Scott Hensley, Ph.D. Physicians of Philadelphia. Hildegund C. J. Ertl, M.D., Wistar profes- infection, but our approach is somewhat to the development of a universal vaccine malaria, and other infectious diseases been an undercurrent of resistance to And Plotkin should know. In the 1960s sor and director of the Vaccine Center. different. We are investigating the by identifying segments of the viral coat take a tremendous toll in the developing vaccination along the fringes of society. he and his Wistar colleagues developed a “In the coming decade, I predict that we possibility of using a vaccine to help that are not subject to antigenic drift, world, especially in Sub-Saharan Africa, “There has always been a small, vocal vaccine against German measles (caused will see clinical trials for new vaccines shrink tumors that have resulted from namely the protein that the virus uses to and a vaccine platform that could minority against vaccination, and they by the rubella virus), which virtually against malaria, HIV, and cancer.” HPV infection. Moreover, we are gain entry into human cells. An immune be used in those regions could save will never go away entirely, “ said eliminated the disease in the United States. exploring the potential of an Epstein- response that generates antibodies the lives of millions.” Plotkin. “What is important is that the Few single places can boast as much New Technologies Barr virus vaccine as latent infections against this protein, therefore, may block public has seen that vaccines are safe and history and expertise in vaccinology for a New Century from EBV are also associated with cancer.” influenza viruses from infecting cells. Vaccines under Fire that not getting vaccinated has conse- as Wistar. The rubella vaccine was part The first generation of vaccines was All vaccines work through the same While researchers still use these earlier While the future of vaccinology seems quences. Right now we live in a time of a string of Wistar advancements that created from either dead or live general principal, namely by convincing approaches to create new vaccines, the bright, particularly at Wistar, 2010 without many of the major childhood included the invention of two rabies pathogens. The rabies vaccine, for the immune system that it is being third age of vaccines is at hand. The Ertl may go down in history as the beginning diseases we once had, and you will see vaccines — one the standard of care for example, was made from previously exposed to a foreign pathogen — that is, lab, for example, is currently working of the end of a very rocky period for vaccination rates rise tremendously if treating humans who have been bitten virulent microorganisms that had been a disease-causing element, such as a on what is termed a “recombinant virus- both vaccine research and use. In 1998, they return.” by rabid animals and the other a killed. Attenuated vaccines, like the bacteria or virus — so that the immune vectored vaccine” that could be used a fervent anti-vaccination community preventative vaccine for animals in the rubella vaccine, are made from living system will later “remember” that against rabies, HIV/AIDS or malaria. arose when a paper in the British journal wild — and, more recently, the co-devel- microorganisms that have been pathogen if it is ever exposed to the real These viral vector vaccines deliver The Lancet linked childhood vaccines opment of a vaccine against rotavirus. weakened or otherwise rendered thing. Vaccines are used to prevent engineered viral genes directly into the to the growing rates of autism. Rotavirus causes severe diarrhea in infants relatively harmless. diseases, such as German measles, but body by way of other viruses used as Subsequent research failed to show and young children, leading to half a The second generation of vaccines, they are also used to treat diseases. delivery vehicles. Once inside cells, the such a link, and, in 2010, further million deaths through dehydration like those against hepatitis B or human Emerging research shows that vaccines vector begins to produce harmless investigations by British medical annually, worldwide. papillomavirus, use viral proteins, absent can direct the immune system to attack viral proteins, which would sensitize the authorities led The Lancet to formally
6 focus: winter 2011 7 expertise with the goal of developing melanoma cells to that of normal cells. effective new therapies to lessen the Over the past decade, scientists have enormous burden of suffering and become far more sophisticated in their death caused by this disease. understanding of the differences that Among Herlyn’s teammates are Ronen exist between normal and cancerous Marmorstein, Ph.D., whose structural cells — knowledge that is the basis for biology work complements the search the development of drugs that target for new therapeutics, and David specific genetic mutations in cancer cells. Speicher, Ph.D., whose expertise will “The biology of a cell is not just what guide the hunt for clinical indicators, the pathologist sees under the microscope,” known as biomarkers, that will allow Herlyn said. “We need a much more doctors to diagnose their patients. intimate understanding of what is The MRC joins the Wistar team with happening at the cellular level in order to investigators from other major cancer develop new treatments. Some abnor- (Left) Meenhard Herlyn, Answering the centers, the pharmaceutical industry, malities are common to most tumors, D.V.M., D.Sc. and patient advocates. while others are unique to an individual (Opposite) Living melanoma cells (green), To Herlyn, the MRC represents a patient’s cancer. The challenge for cancer grown in a 3-D “artificial “formalization of what we have had researchers today is to understand skin” cell culturing system appear to have Questions of Melanoma here for many years, coming at a very those differences and use them to their own questions for good time in the history of cancer develop a whole new class of therapies.” the Herlyn laboratory. and melanoma research. For the last Herlyn’s group has made another How The Wistar Institute Melanoma Research Center 30 years, the treatments and prognosis critical contribution to melanoma Tackling the for melanoma have remained largely research by developing “artificial skin,” Toughest Problems Will Finally Tip The Balance on this Deadly Disease unchanged, but right now, there are a three-dimensional model that provides Herlyn and his group are using these tools three promising new melanoma drugs a tool for studying how living tumors to tackle the most difficult problems facing in trials, and more in the pipeline.” behave, as well as a testing ground cancer researchers today, such as drug “The basic science is really driving for new treatments. resistance. One of these is drug resistance. today’s therapeutic approaches, and this “A melanoma cell in a dish is not Cancer cells are “smart”— they continu- is a vital collaboration for us,” said Lynn the same as one in a patient,” said Herlyn. ally evolve and change in ways that allow rom the perspective of Wistar expected. Some tumors responded The Wistar Institute Melanoma Research Schuchter, M.D., chief of hematology “Melanoma cells interact with, and in them to resist initially effective treatments. professor Meenhard Herlyn, D.V.M., for brief periods of time, but inevitably, Center is the culmination of Herlyn’s and oncology at the Abramson Cancer many ways depend on, the cells around The pattern seems to repeat. A patient F D.Sc., this story began almost 35 the cancer cells began to grow again. career-long effort to encourage research Center of the University of Pennsylvania, them. You can’t really understand their with a specific type of cancer may respond years ago with the development of what “We were electrified by the possibilities on malignant melanoma, an often deadly and a colleague of Herlyn’s. “Our new behavior without understanding the well to a drug or combination of drugs. then seemed an exciting new approach of monoclonal antibodies. We thought we form of skin cancer diagnosed in over understanding of molecular interactions environment in which they live and grow.” In some cases, the cancer will disappear to treating cancer. For years, researchers had found the answer to treating melanoma 68,000 Americans every year. While the involved in this disease is transforming Herlyn’s skin model gives him a entirely; in others, the response may be have sought a way to activate the body’s and many other kinds of cancer,” Herlyn incidence of many cancers has begun to our approach to developing targeted dynamic means of tracking the progression that the tumors shrink or stop growing. natural immune system against malignant remembered. “We called it the ‘magic decrease in the U.S., the opposite is true treatments for melanoma.” of normal skin cells into malignant ones. Then, just as with the early monoclonal cells. In the early 1970s, Herlyn’s lab was bullet,’ but after years of disappointing for melanoma. The numbers of new Researchers know, for example, that in antibodies, after a period of time the one of many that began experimenting results, we had to admit that the magic cases and deaths have been rising Developing The Tools many instances abnormal melanocytes treatment stops working, and the cancer with a novel approach to treating bullet was illusive, and that cancer was far sharply, doubling over the last 30 years, to Advance Research become ordinary, benign moles, while returns or grows again, often more melanomas and many other cancers. more complex than we had believed.” and are expected to continue to do so for While the MRC is a new entity, Herlyn in others, they are transformed into aggressively than before the therapy. Researchers used melanoma cell lines “Since then, for the last 25 years, I years to come. Melanoma currently kills has a long history of contributing to malignant melanomas, deadly cancers “The best drugs that we have leave to produce hybrids called monoclonal have become a student of the biology of 8,600 people in this country every year the field of melanoma research. He and with the ability to invade neighboring behind a small percentage of surviving antibodies, which were then injected back melanoma,” said Herlyn. “Everything that with 85 percent of patients dying within his co-workers have assembled what tissue, spread to distant cancer cells,” said Herlyn. “Even if it into patients with the goal of stimulating we do in the future will depend on our five years of diagnosis. he describes as the “world’s largest sites throughout the body, and evade the is only five percent or one percent, those a specific immune response to the tumor. understanding of what’s happening at The Melanoma Research Center (MRC) collection of melanoma cell lines.” signals to stop growing that govern cells will start growing again, so we The results, while intriguing, were far the cellular level in this disease.” brings together a critical mass of scientists These cells are vital because they allow normal cells. The 3-D skin model provides need to overcome this huge problem less positive than the researchers had Officially launched in May, 2010, the and clinicians to share tools, ideas and researchers to compare the biology of a means of studying these processes. of drug resistance. “ continued next page
8 focus: winter 2011 9 In 2010, Herlyn and his colleagues Melanoma Science redefined the concept of cancer stem cells, is a Team Effort at least in terms of melanoma. They Meenhard Herlyn would be the first published evidence that suggests that all to admit that these are ambitious melanoma cells harbor cancer stem cell scientific goals, but he believes that potential and are capable of inducing new the time is right for this large-scale, tumors. This “dynamic stemness,” as collaborative effort. Herlyn calls it, may explain the aggressive- “We have reached the point where ness of the disease and the need to develop we have the technical tools to make clinical strategies to eliminate melanoma, this possible,” he said. “What we need entirely, at the outset of treatment. is the infrastructure and the critical Of course, eliminating cancer through mass of researchers and clinicians to therapy will require new means for get the job done.” detecting and assessing melanoma in “I can’t imagine doing our clinical patients. For some cancers, biomarkers research without this collaboration,” provide important tools to detect cancer said Schuchter. “We have to take the and monitor the effectiveness of treatment. clinical data, the information we derive from actually treating patients, back Eliminating cancer through therapy will to the lab to deepen our understanding These melanoma “spheroids” are formed require new means for detecting and of how these cells behave, of what is using a 3-D cell culturing assessing melanoma in patients. happening at the biological level with technique pioneered in the Herlyn laboratory. treated tumor cells. The days when the sadness and loss. Her sister, Noreen, died John Lee, Ph.D., a Wistar staff scientist, The blue dots are lab and the clinic were two different of melanoma in 2000 at age 48. Noreen melanoma cells that PSA tests for prostate cancer are one takes supporters through have been killed off worlds that seldom met are over.” was the founder and driving force a tour of the MRC facility of the best examples of an accurate, easy on its opening day. through combinations The MRC provides the platform behind the Foundation, a person who in of therapeutics. way to detect cancer biomarkers. A major to make that possible. Herlyn serves as objective of the MRC is to identify her sister’s words, “just thought things the Center’s director, and is backed up biological markers that clinicians can use were possible. It never occurred to her by an external Scientific Advisory The genetics of cancer is complex. disease by identifying the specific genetic “We have made a dent in this problem to diagnose and characterize melanomas, that she couldn’t get something done.” Scientists now know that all cancers, mutations that drive them. but we really need a better understanding as well as to chart the course of treatments. Board composed of leaders in cancer After Noreen’s death, Kate admits that including melanomas, are the product “We have identified genetic mutations of the mechanisms that lead to resistance.” The MRC also looks to apply its research from around the world. Over 21 she was “too deep in grief” to maintain top cancer centers have signed on as of a series of genetic mutations. A change in about 70 percent of melanoma patients. Herlyn and his group are also studying understanding of the biology of the Foundation and that she resisted collaborators for the MRC, as have seven in a single gene can disrupt the cellular About 50 percent have a mutation in the role of cancer stem cells, another melanoma to prevention. Everyone becoming its president. “I would have partners from the pharmaceutical sector. chemical conversation, triggering a a gene called BRAF,” Herlyn said. “If emerging piece in the intricate cancer knows that exposure to the ultraviolet given up,” she said, “but my mother was Equally important in the MRC cascade of mutations that results in we know that a patient has a specific puzzle. In normal tissue, stem cells are rays of the sun can be a major contrib- just so excited about keeping it going equation is the involvement of the increasingly aberrant cells. Even cancers mutation, we can target it with a specific a kind of generic brand that has the uting factor to melanoma. Fair-skinned in Noreen’s memory. Then I met people who have experienced melanoma that begin in the same organ of the therapy. That is the basis for what we ability to give rise to different kinds of people, those with less of the melanin Meenhard, and I fell in love with Wistar. on a personal level, the patients and Meenhard was such a visionary, a big body can have individual genetic profiles, call ‘personalized medicine.’ We also cells: for example, a skin stem cell can pigment that protects humans from advocates, who form the lay advisory thinker. It would never occur to him while cancer cells that have spread understand that melanomas involve potentially give rise to a melanocyte or ultraviolet rays, are far more likely to board. One member, a long-time to ignore a good idea. From the first from the original site inevitably differ more than one genetic change — so a dermocyte. Cancer stem cells, however, develop melanoma than darker-skinned supporter of Wistar and melanoma time I met him, he had the concept of from those in the primary tumor. ultimately our successful therapies are have the capacity to generate new tumor people. Understanding exactly why that research is Kate O’Neill, president of the Melanoma Research Center.” Melanoma is a good example of going to be combinations of drugs cells even when treatments have is the case could be key to developing strategies for preventing the disease, the Philadelphia-based Noreen O’Neill O’Neill turned her belief in Herlyn this phenomenon. Melanoma is not a that hit multiple targets as well.” eradicated other cancer cells. Cancer Herlyn says. Foundation for Melanoma Research. and his program into tangible support, single disease, but rather a number “Eighty percent of melanoma patients stem cells are thought to be both a major O’Neill’s path to becoming an organizing the annual Running for of different tumors that arise from the with the BRAF mutation will respond contributor to drug resistance and an advocate for melanoma research is, like Cover 5K Run/Walk, which along with same source. One of the first goals of to targeted therapy — but 100 percent important target for future successful so many other people’s, paved with from the IMAJNZ Foundation’s annual the Melanoma Research Center will of them will eventually relapse and see cancer therapies. be to define the distinct types of this their disease progress,” said Schuchter. continued next page
10 focus: winter 2011 11 ken-ichi noma, ph.d.
The Shape of Things to Come
n retrospect, the career path of Ken-ichi itself can create inheritable changes in Noma, Ph.D., seems curiously unlikely. the way cells read their DNA. I How else would you describe the Epigenetics is what brought Noma to way a young computer engineer’s interest the United States as a postdoctoral fellow in building a better carrot may ultimately at Cold Spring Harbor Laboratory, change how science perceives the structure where he pioneered a technique to map of the human genome? epigenetic changes in fission yeast. This However, each step along Noma’s path work led to the discovery that changes represents a logical progression; one to DNA-associated proteins determine driven by both compassion and curiosity. what shape DNA strands take when Noma began his academic career bunched together, a finding for which he at age 15 as an engineering student at was awarded the American Association for Takuma National College of Technology in the Advancement of Science’s Newcomb his native Japan. While the mathematical Cleveland Prize in 2003. It was a seminal The difference between untreated living cells skills he acquired would serve him well moment in Noma’s early career. “My data The 3-D structure (green) and dead cells (blue) indicates success of formed by the three drug combinations in killing resistant melanoma. in later life, the tedium of programming actually triggered this important research,” chromosomes of the yeast genome (l) Visitors to the Melanoma Research Center never quite suited him. “I liked — and he recalled. “It gave me more confidence highlights how related get a first-hand look at 3-D cell cultures. still like — computers,” Noma recalled. about the quality of my science.” genes interact. “But I wanted to do something bigger, In 2004, as a staff scientist at the National something for humanity.” Cancer Institute, his work showed that the complicated tangled formation that “Applying this technique to the human DNA takes on in our cells actually genome may provide both scientists dictates how DNA interacts with the and physicians a whole new framework cell’s protein-making system. “People are familiar with the X-shapes “A Date with a Plate” event, has raised another in front of melanoma cells and now, we are at the point where we can from which to better understand our chromosomes form during cell His work is the first to combine nearly $400,000 for melanoma research. they have circumnavigated them all.” realistically start talking about cures, genes and disease.” “Ultimately, we are hoping for a “We need to use what we learn in the even for people with advanced disease, division, but what they may not realize is microscopy with advanced genomic cure to come from the MRC,” she said. lab as the basis for better therapies — but but we still have a long road ahead of that DNA only spends a relatively small sequencing techniques, enabling “This center is critically important to it’s a two-way process. The days when the us. The Melanoma Research Center will So after completing an associate degree amount of time in that conformation,” researchers to literally see gene interac- the research effort — and to all of cancer lab and the clinic were two different be at the hub of this progress.” in engineering, he enrolled in a bioengi- said Noma. “DNA spends most of its tions. According to Noma, the genome research. We see melanoma as an worlds that seldom met are over.” neering program where he learned to active lifetime in a tangled, non-random bunches together in such a way that coax mutations in plant cell cultures. His clump of chromosomes, the shape of related genes — even ones on different excellent model for many cancers. The Melanoma Research Center I believe that with what we The time is right. With bright, creative represents Meenhard Herlyn’s three goal: to ease world hunger by developing which appears to have a purpose.” chromosomes — can interact readily. know now, we are at the point people working together on this decades of knowledge and experience, a strain of carrot that could grow in the Noma joined Wistar in 2007 as an “When the chromosomes come together, problem, the promise is incredible.” of thinking about melanoma and its where we can realistically start salty soils of desert environments. assistant professor in Wistar’s Gene this positioning helps cells interact with Meenhard Herlyn shares O’Neill’s causes, of seeking better treatments, talking about cures. While the project was a success — he Expression and Regulation Program, multiple genes at once,” Noma said. optimism for the future of melanoma of promise and disappointment, did create a new carrot strain — Noma where he plans to discover the shape of the “I believe we are looking at a new research, but his vision is tempered successes and failures — but it is also became more interested in the genetics human genome. Experience has provided way to visualize both the genome itself by his hard-earned respect for the a testimony to the very real possibilities that made his efforts possible. In particular, Noma with an amazing toolbox of and the movements of all the various complexity of this disease. “For 30 years, of a brighter future for melanoma he was fascinated by the phenomena talents — computer science, mathematics, molecules that act on the genome,” melanoma has defied all our attempts at research and cancer treatment as a whole. of retrotransposons — portions of DNA statistics, molecular biology, biochemis- Noma said. “Applying this technique a rapid cure or a single strategy,” he said. “Our goal has to be to cure this disease,” that multiply and reinsert themselves try, and epigenetics — tools he applied to the human genome may provide “We have placed one roadblock after he said. “I believe that with what we know elsewhere in the genome. As a graduate this past autumn with the publication both scientists and physicians a whole student at the University of Tokyo, Noma of the shape of the fission yeast genome. new framework from which to better would discover new retrotransposons While the yeast genome is smaller than understand genes and disease.” and uncover their role in epigenetics, the our own, Noma believes his techniques study of how factors outside of DNA can apply to the human genome.
12 focus: winter 2011 13 the latest advances from wistar labs
Bringing Complex Structures Down to Size Flushing a Potential Killer Out of Hiding onsider for a moment, the matter of scale from the perspective of a small Epstein-Barr virus (EBV) is a master at Her research, funded by the National Deaminase Acting on RNA). Specifically, protein. Within a seemingly vast ecosystem, this small protein is a lone worker hiding. While most commonly known for Institutes of Health and The Ellison Nishikura and her colleagues found how C in an enormous molecular metropolis. When physicists and engineers operate causing the “kissing disease” mononucle- Medical Foundation, explores the role ADAR1 inhibits the creation of functional at this scale, they call it nanotechnology. But for protein chemists like Wistar’s David osis, EBV can lie dormant in the body for of microRNAs in gene regulation. Our BART6 microRNA and prevents BART6 Speicher, Ph.D., it is the scale of life; the scale at which all the processes of life occurs. decades before it re-emerges, triggering own cells routinely use microRNA to from suppressing “Dicer,” an essential Understanding the form and structure of this world is essential for understanding diseases such as Burkitt’s lymphoma and suppress gene activity by knocking out protein component of the microRNA- how it works — and how to fix it when disease or mutation causes it to malfunction. a form of sinus cancer called nasopharyn- messenger RNAs, molecules that serve mediated gene silencing machinery. Dicer Biologists have tools for finding the shape of individual small proteins or modest- geal carcinoma. EBV hides within the to convey genetic instructions to our is required for synthesis of microRNAs sized pieces of large proteins (protein domains). Unfortunately, proteins rarely exist as cells of up to 95 percent of Americans, cells’ protein-making machinery. EBV throughout the cell. isolated individuals. In fact, much of the work that goes on in a cell occurs through according to the U.S. Centers for Disease uses one of its microRNA molecules, “Our findings suggest that EBV and (relatively) enormous conglomerations of proteins, referred to as macromolecular Control, waiting for any opportune called BART6, to remain in a latent, or humans have been engaged in a complex complexes, which can be more than 100 times larger than individual proteins. weakness in the immune system that quiet, state by preventing the host cell microRNA arms race, where EBV evolved “There is a major ongoing project called the Structural Genomics Consortium, would allow it to awaken unchallenged. from creating its own microRNA. microRNA that specifically exploits which catalogs all the basic shapes of protein structures with medical relevance,” According to Kazuko Nishikura, Ph.D., BART6 works like a timer, suppressing the human host cell’s own microRNA said Speicher. “This is important knowledge, but to make real progress, we need a professor in Wistar’s Gene Expression the ability of cells to make any microRNA machinery,” Nishikura said. to know how these structures all fit together. Macromolecular complexes are difficult and Regulation Program, it may be time — itself included —which also silences When the researchers removed BART6 to model because they are just too big to visualize by conventional means.” to end this game of viral hide-and-seek. an EBV gene that helps the virus spread. from infected cells grown in the lab, Speicher is a professor and co-leader of Wistar’s Molecular and Cellular Recently, in the Journal of Biological Eventually, amounts of BART6 dwindle, they began to produce a number of viral Oncogenesis Program and director of The Wistar Institute Center for Systems Chemistry, Nishikura described how EBV which frees the cell to make more proteins. In humans, Nishikura says, and Computational Biology. His laboratory is looking for a means to “solve” uses microRNA — small segments of RNA microRNA, in turn. If BART6 is on the this would expose cells to the immune these enormously complex structures. that suppress the effects of gene activity downswing while the immune system is system, enabling the body to clear itself Their method of choice involves a technique called “chemical crosslinking,” which — to hide within cells. “One day, we might impaired —such as in people with HIV/ of EBV in healthy patients. “It seems uses small probing molecules to identify specific sites where proteins contact each be able to use EBV’s reliance on microRNAs AIDS — the virus can reassert itself. counter-intuitive, but forcing EBV could other in large complexes. against the virus,” Nishikura said, “perhaps As a countermeasure, human cells allow immune cells to remove infected “At this point it is a computational problem,” Speicher said. “Using high- to flush EBV out of hiding in healthy evolved a process called “RNA editing,” cells,” Nishikura said. throughput techniques we can generate a great deal of crosslinking data, but we patients to allow a strong immune system an ability to alter microRNA through a Clearly, the Nishikura laboratory takes do not yet possess the software to adequately interpret this data.” to rid the body of the virus.” family of proteins called ADAR (Adenosine hide-and-seek very seriously.
In 2010, Speicher applied crosslinking to study the origins of hemolytic anemia, The crystal structure of a problem he had been chasing since he was a postdoctoral fellow in the late 1970s. Red the red cell spectrin tetramer complex superimposed on blood cells are essentially little bags that carry hemoglobin through the blood. About one blood cells taken from a patient in 10,000 people suffer from hemolytic anemias often caused by a mutation inherited with hereditary anemia. from a parent that makes these red blood cell membranes vulnerable to breaking. Wistar Database Culls Useful Info from Glut of Data “If you think of the membrane skeleton as a fishnet, we are looking at the links The latest high-speed technologies to The database specializes in finding “gene and international organizations, and between the knots,” Speicher said. “Mutations cause weaknesses in these links that sequence DNA have proven to be a promoters”— regions along a DNA strand receives funding from the National allow the net to break and the fish to get out. The result is anemia, as hemoglobin double-edged sword for biomedical that tell a cell’s transcription machinery Institutes of Health, the American slips through these breaks in the red cell membrane.” research. While doctors already use human where to start reading in order to create Cancer Society, and the Philadelphia Although the red blood cell membrane skeleton is complex and incompletely understood, genomic information to tailor medical a particular protein. Healthcare Trust. The current database other protein complexes, such as the knots in the fishnet Speicher described, will be even treatments, scientists are practically “MPromDB pinpoints known contains almost 100,000 human or tougher to crack. The Speicher laboratory is currently involved in finding experimental drowning in data. Where a single terabyte promoters and predicts where new ones mouse gene promoter sequences from approaches and software necessary to solve more complicated macromolecules. of data is enough to fill all the books are likely to be found,” said Ramana V. a number of different cell types, with If successful, “it will be a tremendous boon for medical biology,” Speicher said. in an average library, laboratories around Davuluri, Ph.D., Philadelphia Healthcare more being added constantly. “We are on the edge of another revolution in biology, where we soon will be able to the world routinely publish multiple Trust Professor and associate director of “Scientists are so good at generating develop detailed models of very large complexes throughout cells and, ultimately, terabytes of genetics data. The Wistar Institute Center for Systems this sort of sequencing information entire cells at a very precise level.” Fortunately, Wistar researchers created and Computational Biology. “With this that they collect information far in an online card catalog for this unwieldy information, researchers can design excess of what they might need for library. The MPromDb (the Mammalian personalized diagnostics and therapeutics a given experiment or project,” Davuluri Promoter Database) integrates the genome or delve deeper into the study of gene regu- said. “This information all ends up sequencing data generated at Wistar lation than previously thought possible.” in massive databases, waiting to be with vast streams of publicly available MPromDb pulls information from discovered and interpreted by groups data on human and mouse genomics. huge databases maintained by national like ours.”
14 focus: winter 2011 15 the latest advances from wistar labs
Tying a Knot in the Thread of Life
n Greek mythology, the three Fates While the nature of Cdc13 (a yeast determined the longevity of each protein with a counterpart in humans) I mortal by spinning, measuring, and had previously eluded scientists, the cutting the thread of life, in turn. While Wistar researchers found that two modern science favors fact over metaphor, copies of the protein bind together to there does seem to be a place in molecular form what is called a “dimer” [pro- biology for Lachesis, the “allotter,” who nounced DYE-mer]. They also showed was in charge of measuring lifespans. that the dimer physically interacts Nearly every cell in our bodies has its with DNA, regulating how the enzyme own “thread of life” in the form of telomerase lengthens the telomeres. telomeres, stretches of DNA at the tips According to Skordalakes, this discovery of our chromosomes that set a limit on sheds light on how the protein recruits the number of times a cell can divide. telomerase (which is also a dimer) to the While men and gods alike feared the Fates (they carried bronze cudgels, after Wistar’s Emmanuel Skordalakes, Ph.D. Receive secure fixed annual payments for life all), cancer cells successfully challenge seeks to understand how cancer Lachesis to gain “immortality” by manipulates telomeres in order to beat disrupting the natural limit on cell the disease using its own trick. while supporting Wistar research. division placed by telomeres. Wistar’s Emmanuel Skordalakes, Ph.D., an assistant professor in the Gene telomeres. Within the Cdc13 dimer are Expression and Regulation Program, multiple sites that can bind to DNA with seeks to understand how cancer manipu- varying degrees of affinity. This allows lates telomeres in order to beat the Cdc13 to straddle the DNA so that REAP THE BENEFITS OF A CHARITABLE GIFT ANNUITY: disease using its own trick. His efforts one section grips tightly to DNA, while are supported by The Ellison Medical another section — with a more relaxed FIXED PAYMENTS A CHARITABLE GIFT ANNUITY Foundation, the Emerald Foundation, grip — can bind nearer the tail-end of the Receive lifetime payments based on Allows you to earn a lifetime income For more information: The V Foundation for Cancer Research, DNA strand where telomerase binds. your age — the older you are, the for yourself while supporting Contact Peter Corrado, Wistar’s Vice and the National Institute of General “You can think of Cdc13 as if it were higher the payment. Wistar scientists in the fight against President of Institutional Development, Medical Sciences of the National you hanging on to the edge of a cliff, deadly diseases. at 215.898.3930 or [email protected]. Institutes of Health. with one grip stronger than the other,” TAX-DEDUCTIBLE PORTION In 2008, Skordalakes was the first to Skordalakes said. “You’re going to keep Take a charitable income tax deduction ONE-LIFE GIFT ANNUITY RATES describe in the journal Nature the active that strong hand on the cliff’s edge while for part of your gift. 60...... 5.2% parts of telomerase, the enzyme respon- your weaker hand reaches into your pocket 70...... 5.8% sible for maintaining telomeres. This for your cell phone to call for help.” WORRY-FREE MANAGEMENT 80...... 7.2% summer, in the journal Molecular and Skordalakes speculates that if Cdc13 Reduce stress over investment 90+...... 9.5% Cellular Biology, he and his colleagues could be dislodged, telomerase might responsibilities. Diagram shows how the ‘weak hand’ (light blue) Minimum contribution is $10,000. published the first detailed structure be prevented from repairing the telomere. of Cdc13 attaches to the tail-end of the telomere, of Cdc13, a protein that clamps onto Fortunately, Skordalakes does not need swinging out of the way to allow telomerase (green) GENEROUS SUPPORT Cash, stock, or other assets may be used to to attach to and lengthen the telomeric DNA. Your contribution helps Wistar researchers fund the annuity. This program is currently DNA and guides telomerase into place. his own bronze cudgel to knock the develop new treatments for cancers available only to Pennsylvania, Delaware, “Cdc13 has a crucial support role in dimer off its perch. His laboratory including melanoma, lung cancer, and and New Jersey residents. maintaining and lengthening telomeres, is on an epic quest of its own: scanning brain tumors and create new vaccines which are reduced in length through libraries containing millions of small against flu and other diseases. every round of DNA replication,” said molecules to find the one that just may Skordalakes. “We know that disabling disable telomerase and its helper this protein in humans will most likely proteins, like Cdc13. lead to cell death, which is of particular interest in cancer, because telomere lengthening is one of the ways cancer cells obtain their immortality.”
16 focus: summer 2010 17 peoplemaking progress possible Grant Highlights
Ken-ichi Noma, Ph.D. Ken-ichi Noma, Ph.D., an assistant professor in Wistar’s Gene Expression and Regulation Program, received a V Scholar award from The V Foundation for Cancer Research. The two-year, $200,000 grant will support Noma’s research identifying a novel pathway that facilitates chromosome instability in cancer. The research will provide important mechanistic insight into the chromosome instability found in most solid tumors, and has the potential to identify novel therapeutic targets and prognostic biomarkers for many different types of cancer. At the opening of the Melanoma Research Panelists at the Science Journalism Award Wistar supporters including (l to r) Jane Potash, Center in June, (l to r) Meenhard Herlyn, symposium in October, (l to r) Aubrey Watkins, Marta Adelson, and Amy Fox gathered in Timothy Turnham, executive director of the Paul Lieberman, and Meenhard Herlyn. October to honor the contributions of Robert Melanoma Research Foundation, and Kate and Penny Fox. the wistar institute O’Neill, president of the Noreen O’Neill Foundation for Melanoma Research. The Wistar Institute received a 3-year, $1 million grant from The Pew Charitable Trusts to support the expansion of Wistar’s research programs by recruiting three new biomedical investigators and establishing their laboratories.
Grant Awards private grants government grants
Edward Mallinckrodt, Jr. Foundation National Cancer Institute The Wistar Institute Qihong Huang, M.D., Ph.D. Paul Lieberman, Ph.D. Cancer Research, $60,000 Telomere Research, Four-Year and 10-Month Grant, $1.8 million and its scientists Ken-ichi Noma, Ph.D. Cancer Research, $60,000 National Center continue to compete for Research Resources Samuel Waxman Luis Montaner, D.V.M., D.Phil. Cancer Research Foundation successfully for grants Flow Cytometry Equipment This October, Robert Adelson (l) and The Science Journalism Award honors outstanding reporters who cover biomedical science. Frank Rauscher, III, Ph.D. to Support Institute-Wide Research, $363,500 Dario Altieri, the Robert and Penny Fox This year, the award went to Helen Pearson, an editor at Nature magazine. At the award ceremony this to support research Cancer Research, $60,000 Distinguished Professor. October (l to r) Bijal Trivedi, the 2006 winner, Helen Pearson, Daniel Wheeler and Russel E. Kaufman National Institute of gathered to celebrate. The Dr. Miriam and Sheldon G. Adelson and programs. Below Dental and Craniofacial Research Medical Research Foundation Ellen Heber-Katz, Ph.D. Meenhard Herlyn, D.V.M., D.Sc. is a sampling of recent Regeneration Research Melanoma Research, Three-Year and 10-Month Grant, $1.3 million awards over $50,000. Two-Year Grant, $80,000 National Institute The Philadelphia Foundation of General Medical Sciences Luis Montaner, D.V.M., D.Phil. Susan Janicki, Ph.D. HIV/AIDS Research, Live Cell Imaging Research Two-Year Grant, $100,000 Five-Year Grant, $1.6 million W. W. Smith Charitable Trust Ramin Shiekhattar, Ph.D. Qihong Huang, M.D., Ph.D. Cancer Epigenetics Research Cancer Research, $100,000 Four-Year Grant, $1.6 million Ellen Puré, Ph.D. The Robert and Penny Fox Distinguished Cardiovascular Disease Research, $113,000 Professorship made it possible to recruit the new Wistar Cancer Center director (see Destination: Wistar on page 2). This October, friends of Wistar gathered to honor the Foxes, including (l to r) Michael Coslov, Winston Churchill, and Robert Blumenthal.
18 focus: winter 2011 19 making progress possible
Joseph Grusemeyer: José Conejo-Garcia Joseph Kissil A Friend of Wistar Comes “Home” to Wistar Promoted Attend almost any social event at The Wistar Institute and you will find Joseph José Conejo-Garcia, M.D., Ph.D., grew to Associate Grusemeyer, somewhere in the room, chatting with researchers. Sometimes you will up in a small town at the foot of the see him asking them about their work, but just as often he will simply be listening, Pyrenees in Northern Spain, but he says Professor nodding attentively over cheese and crackers. that his arrival at Wistar was like coming Joseph Kissil, Such a fixture that he is, it is surprising to note that Grusemeyer, although a home. Conejo-Garcia completed his Ph.D., recently life-long resident of the region, may never have known Wistar if it were not for the postdoctoral training at the University earned the rank day in 2002 that he heard Wistar CEO Russel E. Kaufman, M.D. on the radio. “That of Pennsylvania before establishing his of associate very moment I thought, you know, this place sounds important and I really ought to own laboratory at Dartmouth in 2005. professor at get to know it,” he recalled. He joined The Wistar Institute as an The Wistar Grusemeyer has always been a science enthusiast and, since that time in 2002, a associate professor in the Immunology Institute. Kissil, friend of the Institute. Moreover, Joseph Grusemeyer is a benefactor. This summer, he Program in September, 2010. who was profiled in the last issue made it known that he would be leaving a generous gift for Wistar in his will. “I was very excited to come to Wistar,” of Focus (Summer 2010), joined “I cannot overstate the importance of gifts of this nature to the Institute, which Conejo-Garcia said. “Here, I am able the Institute in 2004 as an will go to broaden our endowment,” said Kaufman. “With support from our friends to reconnect with my old mentors assistant professor. like Joe Grusemeyer, The Wistar Institute is able to recruit new faculty, upgrade its and collaborators. My research is also The Kissil laboratory studies facilities, and, ultimately, advance the progress of medicine.” becoming progressively more translational the network of signals that carry “I’ve been following medical science for years, and we have seen some great things in nature so I wanted to be close to the huge biomedical community in Philadelphia.” information between a cell and its “Giving to The Wistar Institute happen in medicine within my lifetime,” Grusemeyer said, “I’d like to see more Conejo-Garcia’s work focuses on several of the most important areas in cancer surrounding “microenvironment.” advances in cancer and I hope to contribute to that.” research today. He and his colleagues are exploring how certain white blood cells was an easy decision.The greatest In particular, Kissil studies the Born to farmers of modest means in southern New Jersey, Grusemeyer never called vascular leukocytes promote the growth of ovarian cancers. These cells play a investment you can make is to role of such signaling in neurofi- realized his own dream of attending medical school. He paid his own way through dual role in helping these tumors grow. Vascular leukocytes are essential to forming bet on the human mind’s ability bromatosis 2 (NF2), a hereditary Catholic high school in Camden — while he also played semiprofessional baseball — and maintaining new blood vessels that “feed” ovarian tumors — the process known to solve problems.” disease that can cause benign before heading off to Peirce College of Business in Philadelphia to study accounting. as angiogenesis. In addition, they suppress the body’s normal immune response, brain tumors and spinal and eye He returned to Camden as an accountant in a division of RCA catering to the which allows a tumor to survive. lesions. NF2 is caused by muta- Department of Defense, where he remained through buyouts to General Electric Conejo-Garcia’s laboratory has demonstrated that withdrawing these “vascular tions in the gene that encodes a and Lockheed Martin before retiring in 2004. leukocytes” results in the collapse of the blood system supporting ovarian cancers tumor-suppression protein called Now, he enjoys the fruits of his labors. He spends most of his time in his Berlin, in mice, and enhances the effects of standard chemotherapy. His goal for human merlin, which itself is regulated New Jersey home, but summers not too far away at his house in the historic Gardens patients with this disease, though, is not to remove the vascular lymphocytes, but through a network of interrelated district of Ocean City, where he is known to ply visitors with homegrown plants and to transform them. signaling molecules. As a model vegetables. He enjoys his membership at the Greate Bay Country Club, but prefers “For us, success would be developing ways of targeting the mechanisms in tumors for faulty signal regulation, NF2 deep-sea fishing to golf. that suppress immune response,” he said. “For ovarian cancers, this could mean turning demonstrates how a communication Grusemeyer always took a special interest in the scientific progress against disease, these vascular leukocytes from brakes to accelerators — eliminating their role as breakdown along the signaling particularly after losing a close friend to ovarian cancer. He never misses an opportu- immunosuppressants and stimulating the immune response. The novelty of our network can manifest as disease. nity to query Kaufman on progress in the field of ovarian cancer, and expressed great work is that we are approaching this problem from both directions.” Since joining Wistar, Kissil has satisfaction in the recent recruitment to Wistar of José Conejo-Garcia, M.D., Ph.D., To accomplish this goal, the Conejo-Garcia laboratory is using vascular leukocytes also begun studying how genes whose work has led to advances in the understanding of the disease. as “nanocarriers,” to carry genetic material to the cancer cells. These ingested genes related to embryonic development Ultimately, however, he made the decision to give to Wistar in much the same way can then be used to boost the immune system against established tumors and silence may play an important role in he decided to invest for his retirement — by asking what this investment may yield. the activity of leukocytes that are suppressing immune activity in the tumor. the growth and spread of cancer. Little did Wistar faculty members know that Grusemeyer was not just curious about Conejo-Garcia hopes to see his work translated into clinical trials with human Specifically, his work explores their work, he was doing a little research of his own — probing the depths of their ovarian cancer patients in the near future. how embryonic genes, which potential to advance cancer science. “These strategies have significant implications for the development of new therapies.” should otherwise be “turned off” “Giving to The Wistar Institute was an easy decision,” Grusemeyer said. “The greatest Conejo-Garcia says. “ We know that the tumor is using these normal cells to support its in adult cells, may contribute investment you can make is to bet on the human mind’s ability to solve problems.” growth and block the body’s defenses. If we can use that same mechanism to transform to pancreatic cancer. these cells so that we are utilizing the patient’s own immune system to protect them from the tumor, we could potentially prevent recurrences of ovarian cancer.”
20 focus: winter 2011 21 making progress possible
Foundation Support Bolsters Crucial Wistar Training Program Wistar Mourns the Loss of Gerd Maul
aurence Bell was not an average everyone, it seems, the program is a “We are fortunate that Wistar faculty erd G. Maul, Ph.D., a faculty member of The Wistar Institute since 1973, died student. By any measure, he was an winning proposition. and staff (some of whom are former this summer at the age of 70. He was an accomplished scientist, artist, and L exceptional one. At merely 16, he The program was conceived to solve the BTT students themselves) do all they G mentor. Maul lived life with the passion of an explorer. He crossed boundaries enrolled in the University of Pennsylva- traditional problem of turnover in laborato- can to see that BTT students get the in art, science, and, in one notable instance, geopolitics. nia’s bioengineering program. ries. Research technicians, like postdoctoral best training possible,” Wunner said. It was 1960 — the height of the Cold War — and Maul, along with his lifelong Unfortunately, Bell may have been too fellows and graduate students, are typically For its success, BTT has always relied friend Rolf Mannesmann, managed to procure travel papers for the Soviet Union young for such a challenging program. After considered transitional employees, on grants and foundation support to keep via Iran. As they rode the train to Moscow, Soviet missiles were about to intercept an two years, he dropped out of Penn, drifting preparing to move on to the next step of the program running at a high standard. American spy plane. It would set off an international incident, of course, and help from job to job before deciding to take classes their careers. The BTT program is designed In fact, the program was facing cutbacks land two young German backpackers in an interrogation room for eight hours. at the Community College of Philadelphia. to save time and research momentum by until this October, when the Connelly After their release, the pair toured Moscow before returning to their hotel room, Today, Bell is a valued member of the training a professional class of committed, Foundation, a regional philanthropy with which was bugged with listening devices out of a b-grade spy flick. With their transit laboratory of Susan Janicki, Ph.D., which long-term technicians. a mission to fund valuable non-profit visas set to expire, the pair conspired to lose their minders and catch a flight to brought him on as a research assistant even “The BTT Program creates a pool of educational programs, stepped in with a Leningrad. From there, they mingled with Norwegians bargain-shopping for cheap though he is still midway between his first qualified technicians that can provide 2-year grant of $40,000. Connelly vodka and slipped across the border, none the worse for the experience and just and second years in Wistar’s Biomedical stability in a laboratory,” said William Foundation joined BTT supporters such in time for Christmas. Technician Training (BTT) Program. Wunner, Ph.D., administrative coordinator as The Hassel Foundation, Morphotek, This thirst for experience and desire for adventure was a common theme at Wistar’s “It is very difficult to find good of the BTT Program. “Each class is filled Inc., Cephalon, Inc., The Barra Foundation, memorial service for Maul this past September. There his wife Ursula, son Julius, laboratory techs, and Laurence is one with highly-talented students from diverse, The Dolfinger McMahon Foundation, and daughter Monika, joined friends (including Mannesmann) and colleagues to of the best we have had here,” said Ilona often disadvantaged backgrounds, who are and the National Cancer Institute’s reminisce and reflect on all of his remarkable journeys. Rafalska-Metcalf, Ph.D., a postdoctoral looking for a step-up or a second chance.” Continuing Umbrella of Research Gerd Maul was born in Silesia, Germany, and spent his youth traveling Europe fellow in the Janicki lab and a BTT New classes of about 12 trainees begin Experiences (CURE) Program. Previous and Asia. He earned his doctorate in zoology at the University of Texas in Austin, and Program instructor. “He thinks of each summer, with the first-year students supporters have included the Brotherton later took a position at Temple University in Philadelphia. Maul was recruited to new angles to laboratory problems taking an extensive orientation and Foundation, The William Penn Founda- Wistar on the strength of both his research and his expertise in electron microscopy. and always asks terrific questions.” laboratory practicum session at Wistar to tion, and several State agencies. Without The electron microscope had become Maul’s research tool of choice. It allowed So passionate was he about Bell’s success seems par for the BTT learn laboratory techniques and the the joint effort of foundations, govern- him to probe cell structures in order to understand how they functioned in both electron microscopy that, Program’s history. Since 2000, the 2-year theories behind them. For second-year ment, and industry, people like Bell may health and disease. He was known to regard microscopy as yet another form of art when Wistar retired one of BTT Program, run jointly by Wistar and students, the program resumes with a not get a second chance at success. — as valid as his photography. So passionate was he about electron microscopy his favorite electron microscopes, the Community College of Philadelphia, 12-week immersion into a functioning “I have to admit that the program that, when Wistar retired one of his favorite electron microscopes, Maul installed Maul installed it ornamentally has provided 73 students with a solid laboratory, either at Wistar or one of a has boosted my self-confidence as well it in his backyard. in his backyard. foundation in laboratory research. For number of regional research centers. as provided some useful problem-solving In addition to his family, one of Maul’s great loves was art. He worked in multiple some it provides a leg up into a field According to Wunner, more than half of and technical skills,” Bell said. “After media, including photography and sculpture. His works routinely reflected his often inaccessible to the disadvantaged. those who complete the program find I finish my summer training, I hope appreciation of form and structure, common themes in his science, as well. For others, BTT represents the first steps jobs as biomedical research assistants to find a long-term place in a lab and In science, Maul is widely recognized for two fundamental advances. In 1971, he toward higher degrees in biomedicine within six months, even in the current maybe, one day, enroll again in bioengi- determined the structure of nuclear pores, ports in the membrane of the nucleus that and other life sciences. For nearly downturn economy. neering at Penn.” allow molecules to travel in and out. With his eye for natural forms, he discovered “nuclear dots,” which store proteins to defend the cell from environmental changes. Laurence Bell and Ilona These proteins help buffer the cell from rapid changes due to stress, such as chemo- Rafalska-Metcalf, Ph.D., at work in the laboratory therapy, a notion that may apply to strengthening the effectiveness of cancer treatments. of Susan Janicki, Ph.D. “Gerd’s death affects us all, but I don’t want people to feel sad that it occurred so close to his retirement,” said Louise Showe, Ph.D., a Wistar professor and longtime friend of the Maul family. “He had a rich, curiosity-filled life and was not waiting until retirement to do the things he loved.”
22 focus: winter 2011 23 medical artifacts
Putting the Art into Medical Artifacts
A dozen objects from The Wistar Institute archives, including the famed anatomical models created by the artist William Rush, join a unique exhibit at the Pennsylvania Academy of Fine Arts this winter: ANATOMY/ACADEMY. Among these objects is a simple wood and leather case…
At first, it seems just like an ordinary box. The exhibit will explore the Philadelphia It is old and handsome, certainly, but not region’s role in advancing medical especially distinctive. Open it, however, science, from the colonial era to the to view the work of a master, by whom present day. we mean both its maker and the man who “While medical research has moved made use of its contents. light years beyond those early days, It is the dissection kit of Dr. Caspar it’s significant to note that the Wistar Wistar, the famed physician and anatomist name has been associated with medical for whom the Institute is named. It dates achievements since the days Dr. Caspar from around 1808, the year when Wistar Wistar rode in his carriage to visit became chair of anatomy at the University patients in the city,” said Nina Long, of Pennsylvania. Wistar’s archivist, who worked with The kit itself is a marvel. Designed curators at PAFA for nearly a year in by Henry Schively, whose long hunting preparation for the exhibit. “Philadelphia knives would become the model for is particularly rich in both its medical the famous “Bowie knife,” the instru- and artistic history, and our collections ments within are both expertly honed reflect these unique collaborations and beautiful to examine. Among the which began in the earliest days of tools are scissors, a scalpel, forceps, medical education.” and picks, rendered in steel, ivory and Among the select items of the silver. Schively was noted for crafting Institute’s archives on display are the high-grade surgical instruments Rush models, Dr. Wistar’s 1814 book (and household cutlery, which may Lessons in Practical Anatomy, and a tell you something about the science wax-injected human heart, prepared of surgery at the time). by Dr. Wistar, himself. This winter, the kit will become part The exhibition runs from January 29 of ANATOMY/ACADEMY, a first-of-its- through April 27 at the Academy’s Fisher kind exhibition at the Pennsylvania Brooks Gallery in the Samuel M.V. Academy of the Fine Arts, pairing art Hamilton Building, 128 N. Broad Street, and science with Philadelphia history. Philadelphia.
24 focus: winter 2011 25 Non-Profit U.S. Postage Paid 3601 Spruce Street Philadelphia, PA Permit #3211 Philadelphia, PA 19104-4265
Step into a Smaller World
What do you see in this picture?
ome odd, somewhat grotesque fish? A newly discovered species S of frilled caterpillar? No, this is something far more mundane: a fern spore, magnified 20 times. This particular fern spore picture has been named an Image of Distinction in the 2010 Nikon Small World exhibition, and it is a product of the unique talents of Frederick Keeney, an employee in The Wistar Institute Microscopy Facility. Keeney joins photomicrographers from around the world in the exhibition, which strives to demonstrate the beauty and complexity of life as seen through the lens of microscopes. Wistar is the only place in Philadelphia where you can see the 2010 Nikon Small World exhibit, which runs through March 13, free and open to the public. The event is sponsored by The Wistar Institute Leadership Council.