Doug and Peggy Briggs have laid the groundwork to bring emerging scientific stars to Wistar through the Institute’s newly founded Caspar Wistar Fellows Program.
It started with a meeting between former QVC president & CEO Doug Briggs, Wistar President & CEO Dario C. Altieri, M.D., and Institutional Advancement Vice President Anita Pepper, Ph.D., discussing how Doug could make the most impact with a philanthropic partnership, taking into consideration his vast experiences and unique background coupled with Wistar’s future goals and aims.
“Being a member of the Wistar Board of Trustees for a number of years, I became increasingly convinced that Wistar was doing exceptional research to advance biomedical science,” said Doug. “So, I thought, how can I help to create something totally new, potentially game-changing that will build Wistar’s brand for the long-term and take it to the next level of awareness with young aspiring scientists and potential new donors?”
From these discussions emerged the Caspar Wistar Fellows Program: a brand-new program and the only one of its kind in Philadelphia. It fast-tracks the most promising, early-career scientists to pursue creative, out-of-the box biomedical research for the benefit of humanity.
The Program is as ambitious as biomedical research is itself and taps the top echelon of early-career scientists to join Wistar under the mentorship of talented principal investigators committed to science and a culture of collaboration.
“If you follow the NFL, teams trade up in the draft to get the best new players coming out of college,” said Doug. “Everybody wants to draft number one, two, or three to get the top candidates. We tried to design this Program to allow Wistar to move up in the draft. Not by pecking order, but rather through a special fellowship that draws top candidates to Wistar because they’re going to get their own lab, more freedom, and the ability to work with top Wistar scientists.”
That new, emerging top talent is Dr. Rahul Shinde, Wistar’s first Caspar Wistar Fellow who comes to us from Canada.
Shinde has been making striking advances in cancer research focusing on the role of macrophages in shaping the tumor microenvironment—comprised of extracellular matrix, stroma, and immune cells—which is a key determinant of cancer initiation, progression and resistance to therapies. He is also interested in the gut microbiome and its connection in modulating the tumor microenvironment and tumor progression.
A second Caspar Wistar Fellow will be appointed soon, with a total of four new Caspar Wistar Fellows joining Wistar over the next four years.
“If you can identify high potential talented candidates, then what do you do?” said Doug. “You fuel their ambition by providing an opportunity that surpasses their expectations. That’s what this Program does. It recruits top emerging scientists from across the globe and supports the next phase of their research endeavors. Most peers will be working on someone else’s research project in a lab not their own. But not so for a Caspar Wistar Fellow. Wistar is giving them the freedom to independently embark on their creative endeavors.”
As early career scientists make a name for themselves so does Wistar.
“Wistar is doing exciting work that impacts medicine,” said Peggy Briggs. “We are proud to support these new scientists who can make a difference. We look forward to watching Dr. Shinde and future Caspar Wistar Fellows make an impact on human health.”
Monsoon season was just around the corner. A 26-year-old man living on the outskirts of a dense South Indian tropical forest became sick with flu-like symptoms. It was early May 2018 in the state of Kerala and the man’s symptoms quickly progressed to respiratory distress, mental confusion, disorientation, and ultimately death. A religious ritual burial followed where they bathed, shrouded him and prayed as they put him to rest. Two weeks later his brother died. A week after, his father. The aunt that visited him in the hospital died the following week.
Twelve people at the hospital to which the man, known as patient zero, came in chance contact with all died, except for two individuals of no relation.
Immediately, the Kerala state government and the Indian Consulate of Medical Research (the high authority in India similar to the U.S. Centers for Disease Control) became involved and contained the infection.
The cause: Nipah virus, a deadly disease.
Nipah is an RNA virus like Ebola, Zika, chikungunya (CHIKV), severe acute respiratory syndrome (SARS), measles, West Nile virus (WNV), and the common cold. RNA viruses tend to change and evolve faster than DNA viruses because their genetic material is prone to more mutations to adapt to new hosts. This allows the virus to jump from species to species, like how avian flu and swine flu jumped from birds and pigs to humans.
An Unknown Disease
Nipah was named after a town in Malaysia where it was first identified in 1998. There, an outbreak on a pig farm resulted in 257 people afflicted and 105 deaths. A zoonotic disease, the outbreak was caused by fruit bats and the overlap between bat habitats and pig farms. Fruit orchards in close proximity to pig farms created a point of contact between pig and bat habitats. From pigs it was spread to humans and infected pigs were transferred to other farms unknowingly. The virus was isolated in 1999 and one million pigs were culled.
Nipah is known to kill as quickly as it infects. Symptoms come on fast, appearing five to 14 days after exposure, and can progress within 24-48 hours into coma. Symptoms include fever, headache, aches, vomiting, drowsiness, shortness of breath, mental confusion, and disorientation. Complications include seizures and encephalitis (brain inflammation).
Luckily, to date, Nipah outbreaks have been small and contained. The virus appears each year in Bangladesh and has hit India three times, with previous outbreaks occurring in West Bengal in 2001 and 2007.
The 2018 outbreak in the Kerala State caught the attention of Kar Muthumani, Ph.D., director of the Laboratory of Emerging Infectious Diseases and assistant professor of the Vaccine & Immunotherapy Center, at The Wistar Institute. His hometown is near Kerala, and he specializes in the design and creation of synthetic enhanced DNA vaccines and antibody therapies against emerging infectious diseases that tend to land on the watch list of the World Health Organization (WHO).
Inspired by Curiosity
Muthumani is part of a global community of scientists, epidemiologists and health workers in government agencies, academia and the private sector, who monitor disease outbreaks and engineer vaccines for future pandemics. His lab — like others in Wistar’s Vaccine & Immunotherapy Center — is creating synthetic DNA vaccines and therapeutics against Nipah, Zika, Mayaro, CHIKV, Middle East respiratory syndrome coronavirus (MERS-CoV), human immunodeficiency virus (HIV), respiratory syncytial virus (RSV), Dengue (DV), Powassan (POWV), and others.
In May 2018, Muthumani was following international news related to his home-country and read an article about a Nipah virus outbreak in Kerala.
“Nipah is deadly, it’s transmitted easily and there is no effective treatment,” said Muthumani. “But there were some survivors. They were family members who cared for the infected and never had signs of the disease and people who contracted Nipah and lived.”
Muthumani needed to understand more and wanted to figure out what protective immune mechanisms allowed those family members who lived with infected patients to survive and how certain people were infected but their immune systems ultimately protected them from succumbing to the disease.
“Understanding what kind of protective immune mechanism is in place and what is different about the survivors will inform us on how to make better vaccines and therapeutics,” said Muthumani.
Four months after the Kerala outbreak, Muthumani personally visited the house where it all started. He needed to understand the timeline of events and how, from a single person, infection spread to two separate towns 50-60 miles apart, infecting 19 people and killing 17.
“Four people exposed to the virus did not die from Nipah: two contracted Nipah and survived and two had direct contact with a Nipah-exposed person and never caught it,” said Muthumani.
Patient zero became sick on May 3, 2018 and died just two days later. It was thought he had contracted the deadly disease from a traditional fermented drink consisting of raw date palm sap collected in open containers. As bats are endemic to the region, it is believed the open collection buckets high atop palm trees are the zoonotic link whereby infected bat urine and feces inadvertently become collected.
“The mother of patient zero lived,” said Muthumani. “She took care of all three sick family members and was never virus-positive. I still don’t know the details of her immunological response and need to understand more.”
Muthumani met the son whose mother contracted Nipah from patient zero and died. He took his mother and cousin (patient zero) to hospital and never contracted the disease. His pregnant sister was also not positive for Nipah. Muthumani wondered what was special about their immune system?
Connected by Events; a Continuing Investigation
He then learned a series of events that happened at the hospital and may be able to explain the spread of disease in another town, 50 miles away.
Another man, unrelated to the patient zero’s family took his friend to the hospital and was waiting for his friend’s x-ray in the same space where patient zero had also received an x-ray. The man became infected and went to his parents’ house to recover from what he thought was the flu. His parents took care of him for more than two weeks before he died. Before his death, he exhibited strange neurological behaviors including sleeplessness and hyper and manic behaviors. None of his family members contracted Nipah even though several resided in the house together.
Through working with local research scientists, Muthumani has puzzled together the Kerala outbreak story to understand how the virus spread. Government disease control teams have scoured the original outbreak area and the surrounding forest for bat samples and confirmed bats are, in fact, the source of the Nipah outbreak.
Muthumani is still driven by curiosity: why did certain people die yet others didn’t — even though they came in contact with same people. What protected them?
Now, as Muthumani works to better understand immune protection with his collaborators, these data will prove invaluable in fine-tuning a synthetic DNA Nipah vaccine and therapeutics he has been developing at Wistar.
“Our vaccine generated strong T-cell and antibody responses in mice and proves synthetic DNA can drive T and B cell activation, which are important for clearance of a viral infection,” said Muthumani. “Now we’re ready to conduct challenge studies and take the next testing steps, which will continue to test the response efficacy of our Nipah vaccine.”
Muthumani is working with labs in India to better understand these immunological puzzles.
“This is a valuable resource of national and international interest — every country will benefit from analysis of these samples,” said Muthumani. “Our studies will support an immune therapy approach for Nipah and ultimately lead to the application of our pioneering synthetic DNA monoclonal antibody therapy approach against Nipah and other emerging infectious diseases.”
Time will tell.
And time, conviction, curiosity, and scientific expertise are all on Muthumani’s side.
PHILADELPHIA — (July, 9, 2019) — Currently, no cure for HIV/AIDS exists, but more than 30 years of scientific advancements in treatment and care made possible because of basic research and clinical trials have improved the HIV therapy landscape. Now, once again, Philadelphia is on the map for its impact as a global center of HIV cure research.
In preparation for enrolling patients in two clinical trials in search of a cure, The Wistar Institute and partners at Philadelphia FIGHT Community Health Centers, the BEAT-HIV Community Advisory Board and University of Pennsylvania’s Center for AIDS Research (CFAR) have launched four first-in-class educational videos. The videos feature Philadelphians — HIV clinicians, researchers, patients and advocates — seeking an HIV research cure. These videos aim to demistify studies, and explain how scientific advances depend on the public participating in an HIV cure-directed clinical trials.
“This is our ‘Philadelphia story’ and Philadelphia has become the hub of HIV cure-directed research, especially since Wistar and partners received nearly $23 million in support from the Delaney Collaboratory grant in 2016,” said Luis Montaner, D.V.M., D. Phil, Herbert Kean, M.D., Family Professor and director of Wistar’s HIV-1 Immunopathogenesis Laboratory. “Because of this, we have been able to make remarkable progress in our understanding of how best to attack HIV beyond exisiting therapies. Our videos feature Philadelphia’s impact to advance HIV cure research by presenting this effort in a format that everyone can access — especially anyone looking to participate or understand this effort whether in Philadelphia or anywhere in the world where HIV cure research is underway.”
HIV Cure Research Educational Videos
The videos offer a unique opportunity for people living with HIV, community stakeholders and researchers to become educated about cure research perceptions, understandings and misunderstandings, and address important topics including what it takes to join an HIV cure study and the safety of interrupting anti-HIV medication while participating in the study.
“Our aim for these videos is to dispel any myths and make role models of the people involved in this effort who are participating in a clinical trial,” said Montaner. “With a very diverse cross-section of the people at the frontlines of this effort, the videos explain the experience and risks of participating in an HIV cure-directed study.”
“Game Changers” describes the roles and actions of the people behind an HIV cure-directed study. Experienced community members, medical care providers, case managers, and researchers come together to explain what to expect.
“The Top Ten” reviews the common areas that prospective participants should be aware of when they are considering particpating in a cure-directed study.
“The Art of A.T.I.” showcases what analytical treatment interruption (ATI) is and why it is included in cure-directed studies.
“Time. Commitment.” is a video that features people who have participated in recent studies and provides a platform for them to share their clinical trial journeys.
All of the Beat-HIV Delaney Collaboratory educational videos can be found on BEAT-HIV.org.
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About the BEAT-HIV Delaney Collaboratory Part of an international consortium of more than 80 top HIV researchers from academia, industry, government, and nonprofit sectors working toward an HIV cure, the BEAT-HIV Delaney Collaboratory is leading three advanced trials to define effective ways to combine immunotherapy regimes towards a cure.
About The Wistar Institute The Wistar Institute is an international leader in biomedical research with special expertise in cancer, immunology, infectious diseases and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.
PHILADELPHIA — (July 3, 2019) —The Wistar Institute, an international leader in biomedical research on cancer, immunology and infectious disease, has received more than $4.2 million in non-federal funding awarded by private foundations.
Rugang Zhang, Ph.D., deputy director of The Wistar Institute Cancer Center and professor & co-leader of the Gene Expression & Regulation Program, is the principal investigator on a three-year collaborative research development grant from the Ovarian Cancer Research Alliance. This grant totaling $900,000 will support in-depth research on the molecular mechanism of some key epigenetic regulators in ovarian cancer to identify potential targets for novel therapeutic strategies.
Alessandro Gardini, Ph.D., assistant professor in the Gene Expression & Regulation Program, was awarded a three-year, $825,000 grant from the G. Harold and Leila Y. Mathers Foundation in support of his research to identify new factors and mechanisms that regulate maturation of stem cells into blood and immune cells. Gardini also received an American Cancer Society Research Scholar Award for $792,000 over four years to study the role of the ARID1A protein in ovarian cancer.
Zachary Schug, Ph.D., assistant professor in the Molecular & Cellular Oncogenesis Program, received a Susan G. Komen Career Catalyst Award that will support his research for three years with $450,000. In addition, Schug was awarded a $110,000 grant from the W.W. Smith Charitable Trust. Both of these awards will support his work on tumor cell metabolism to expose new vulnerabilities that could be therapeutically targeted as more effective treatment options for patients with breast cancer, melanoma and acute myeloid leukemia.
David B. Weiner, Ph.D., Wistar executive vice president, director of the Vaccine & Immunotherapy Center, and the W.W. Smith Charitable Trust Professor in Cancer Research at The Wistar Institute, was the recipient of a subaward from a grant from the Bill & Melinda Gates Foundation awarded to Inovio Pharmaceuticals, Inc. This funding will provide support for a total of $414,000 to apply the DMAb technology developed at Wistar to develop an immunotherapeutic strategy against influenza.
Makan Khoshnejad, Ph.D., staff scientist in the Vaccine & Immunotherapy Center at Wistar, received a $231,000 grant over three years from the American Heart Association to fund research on a novel type of lipid-lowering therapeutics based on synthetic DNA technology developed at Wistar.
Qing Chen, M.D., Ph.D., assistant professor in the Immunology, Microenvironment & Metastasis Program, was granted a two-year award totaling $200,000 from the V Foundation for Cancer Research in support of a research project to develop methods for the visualization of interactions between tumor cells and brain cells during brain metastasis.
Mohamed Abdel-Mohsen, Ph.D., assistant professor in the Vaccine & Immunotherapy Center, was awarded a $130,000 grant over two years from amfAR, The Foundation for AIDS Research, to identify new biomarkers that can help predict the time in which HIV rebounds after treatment interruption.
Daniel Kulp, Ph.D., associate professor in the Vaccine & Immunotherapy Center, received a $110,000 grant from the W.W. Smith Charitable Trust to advance a structure-based HIV vaccine strategy.
Shuai Wu, Ph.D., postdoctoral fellow in the Zhang laboratory was awarded a $75,000 grant from the Ovarian Cancer Research Alliance to develop a new therapeutic strategy based on combination of two targeted inhibitors for ovarian cancer with mutations in the ARID1A gene.
The Institute received a $20,000 grant from the Fred J. Brotherton Charitable Foundation in support of Wistar’s Biomedical Technician Training Program that prepares college students to become research assistants in the biomedical field.
PHILADELPHIA — (July, 2, 2019) — The Wistar Institute, an international biomedical research leader in cancer, immunology, infectious disease and vaccine research, announces the appointment of Rahul Shinde, D.V.M., Ph.D., as the first Caspar Wistar Fellow.
Shinde’s research focuses on the role of specialized cells that act as a front-line defense system for our immune systems, called macrophages. He investigates how these cells alter the specialized milieu that surrounds a tumor, known as the the tumor microenvironment (TME), which is a key determinant of whether cancer is able to develop, progress and resist therapies.
The Caspar Wistar Fellows Program is a brand-new program and the only one of its kind in Philadelphia that fast-tracks the most promising, early-career scientists to pursue creative, out-of-the box biomedical research for the benefit of humanity. Shinde is the first to be selected into the Program, which cultivates accomplished, intellectually driven postdoctoral scientists from across the nation and beyond and provides Fellows both mentorship and freedom to pursue a strong, independent research program in their field.
Shinde’s laboratory at Wistar will study how alterations in the metabolism of macrophages contribute to their function in cancer progression. He is also interested in the gut microbiome and its connection in modulating the TME and tumor progression. Shinde aims to characterize the key factors that shift the balance between healthy and disease-modulating microbiome and identify new targets for therapies.
“Wistar is a leading research institute with a history of scientific excellence and a far-reaching vision of integrating basic, translational and disease-relevant cancer research for therapeutic benefits. I am thrilled to join the Institute through the Caspar Wistar Fellows Program and integrate my research into the Cancer Center’s innovative programs,” said Shinde. “I believe the state-of-the-art research facilities and the collaborative atmosphere at the Institute will provide excellent support, and I look forward to expanding my ongoing work and contributing to Wistar’s scientific mission.”
Shinde joins Wistar from Princess Margaret Cancer Center, Toronto, ON, Canada, where he was a postdoctoral fellow in the Tumor Immunotherapy Program. Shinde received a D.V.M. from Nagpur Veterinary College, Nagpur, India, and a Ph.D. in biomedical sciences from Augusta University, Augusta, GA.
“This new program was launched with the support of two remarkable donors, Doug and Peggy Briggs, to help recruit outstanding early-career scientists. I am pleased to name Rahul our first Caspar Wistar Fellow as he has distinguished himself with his outstanding postdoctoral work in tumor immunology and embodies the qualities we envisioned for this new position,” said Dario C. Altieri, M.D., president and CEO, director of the Cancer Center, and the Robert and Penny Fox Distinguished Professor at Wistar. “His research will further expand our program on myeloid cell biology and tumor immunology, and he brings a complementary body of knowledge through the critical understanding of the gut microbiome. I believe he will find the ideal support and freedom through this new program at Wistar to grow his scientific career and make important contributions to science.”
The Briggs have been Wistar supporters for more than a decade, and Mr. Briggs has served as a member of Wistar’s Board of Trustees for nine years. The Briggs are highly invested in the work of Wistar scientists and were interested in building a program that provided exceptional, early-career scientists with the autonomy and resources to take an accelerated path toward independence as principal investigators.
“We wanted to create something totally new and game-changing at Wistar by finding the best scientific talent and giving them all the tools and freedom they need to reach their potential — possibly more than they think they’re ready for — to attain that next level and succeed,” said Doug Briggs.
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The Wistar Institute is an international leader in biomedical research with special expertise in cancer, immunology, infectious diseases and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.
It is well established that some cancer risk factors are interconnected to genetics or other unchangeable factors, such as age or gender. We also know that external factors, such as sun exposure, increase one’s risk of developing melanoma. It’s now emerging how important other external aspects – related to our lifestyle – are for melanoma survival and response to therapy.
During the third annual Noreen O’Neill Melanoma Research Symposium at Wistar, speakers discussed inflammation, certain medications, vitamin D levels, obesity, and the bugs that populate our gut as potential modifiers of patients’ survival and outcome from targeted and immune therapies.
The Symposium, made possible through the Noreen O’Neill Melanoma Research Fund and supported by the Melanoma Research Alliance and the Melanoma Research Foundation, attracts a world class line up of speakers and has become a regular appointment for melanoma experts to come together and collectively discuss how melanoma research is advancing.
With its rates on the rise, it was estimated by the American Cancer Society that melanoma will strike 96,480 Americans in 2019. The research community has made giant leaps forward in the past decades with targeted and immune therapies that have brought tangible improvements in survival of patients for whom almost no hope was available before.
Yet, there is still a long way ahead to defeat the disease. And, as it often happens, when major advances hit the clinic, basic researchers are already working behind the scenes finetuning next steps, tackling drawbacks and figuring out the reasons for failure.
Melanoma is a highly-diverse disease. Within the same tumor, multiple cell populations exist that impact tumor growth and sensitivity to therapy differently. To further complicate the picture, melanoma cells change their characteristics over time or in response to therapy.
This complex aspect of the disease was the main theme of the Symposium.
Delving into the Science
Speaker Jean-Christophe Marine, Ph.D., professor and director of the VIB-KU Leuven Leuven Center for Cancer Biology, Belgium, discussed the adaptive ability of melanoma cells as the origin of therapy resistance.
Relapse after therapy is driven by a small number of cells that remain alive upon drug exposure while the bulk of the tumor is killed. This status is known as minimal residual disease. Drug tolerance is acquired by these cells through genetic mutations and, as recently discovered, non-genetic mechanisms that allow them to quickly adapt and survive.
Marine postulated that “single cell approaches” for tracking and isolating single residual cancer cells are the most effective way to tackle melanoma cell diversity. Such approaches allowed his laboratory to hunt for vulnerabilities of these cells that can be exploited to enhance therapy.
Martin McMahon, Ph.D., professor of cancer biology and senior director for preclinical translation at the University of Utah, discussed his most recent findings that explain why certain targeted therapies that were originally predicted to be the holy grail for melanoma failed to deliver clinical benefits.
According to McMahon’s results, one of these drugs called trametinib activates a particular process called autophagy, which allows the cells to recycle their building blocks and sustain survival.
Based on this discovery, a clinical trial is about to begin that combines trametinib with a drug that blocks the autophagy process. The researchers will evaluate if this drug combination can enhance the antitumor effects of trametinib in melanoma patients.
Research presented by Jennifer McQuade, M.D., assistant professor and physician scientist at MD Anderson Cancer Center, focuses on patient factors that contribute to shaping immunity and response to immunotherapy.
She discussed the obesity paradox in melanoma. This is the observation that obesity – well-established as a risk factor for several cancer types – predisposes to melanoma but is associated with better outcomes in response to immune and targeted therapies.
McQuade also spoke about the role of the microbiome (bacteria that populate our gut) in affecting therapy response. As less than 10% of the microbiome composition is determined by the host’s genetic makeup, and diet, environment and medications are major components, the microbiome is an external factor that can be modified with diet.
In fact, studies have shown that melanoma patients whose diet is high in fiber respond better to immunotherapy, while over-the-counter probiotics are associated with lower microbiome diversity.
To establish if diet intervention can influence outcomes in immunotherapy, McQuade’s team at MD Anderson is conducting rigorously controlled clinical trials in which melanoma patients undergoing immunotherapy also receive high-fiber diet.
On a similar theme, Julia Newton-Bishop, Ph.D., professor at the University of Leeds, U.K., reported evidence for a number of host factors and environmental exposures that modify the tumor microenvironment and influence melanoma survival, including systemic inflammation, which might be therapeutically controlled, smoking and vitamin D levels.
Wistar’s Meenhard Herlyn, D.V.M., D.Sc., director of the Melanoma Research Center and professor in the Molecular and Cellular Oncogenesis Program, took the audience on a historical journey through the different stages and accomplishments of melanoma research, from the era of monoclonal antibodies, believed to be “magic bullets” that would cure cancer, through the discovery of the genetic basis of melanoma and the causative effect of gene mutations, to immunology studies.
Despite those accomplishments, by the early 2000s, Herlyn said, it seemed like nothing worked. Then, the modern era of melanoma research began with the discovery of targeted therapies and, since then, giant leaps have been made.
A pioneer and witness to how the field has expanded, Herlyn has made important contributions to all those stages. He showed an overview of the many experimental models his laboratory has developed over the years, starting with melanoma cell lines, through 3-D skin reconstructs, to latest efforts in the creation of a patient-derived xenograft collection for preclinical drug testing, and “humanized mice”, in which the human immune system is rebuilt in a mouse. These powerful models have allowed the Herlyn lab and many other laboratories around the world to make important discoveries, and continue to be unique tools to advance melanoma research.
Closing the Symposium, Wistar’s Jessie Villanueva, Ph.D., associate professor in the Molecular and Cellular Oncogenesis Program, invited everyone back to Wistar in 2020 with their next breakthroughs in melanoma research.
“Hope is a state of mind, not a state of the world. Either we have hope within us or we don’t; it is a dimension of the soul not essentially dependent on some particular observation of the world or estimate of the situation. It is an orientation of the spirit, an orientation of the heart […] Hope is an ability to work for something because it is good, not just because it stands a chance to succeed. The more unpropitious the situation in which we demonstrate hope, the deeper the hope is.”
This quote by Czech statesman and writer Václav Havel was posted on the fridge in the home of Jonathan Lax, one of the most transformative AIDS activists in Philadelphia. Lax volunteered his time to provide medical care through drug access to treatments not available in the U.S., and helped many young, HIV-positive men connect with doctors to find medical help.
After his passing in 1996, The Wistar Institute, Philadelphia FIGHT and other scientific and community partners came together and established the Annual Jonathan Lax Memorial Lecture to honor his memory and create a direct channel of communication between the scientific process of studying HIV and the community it serves.
The Lecture has reached its 24th year, fittingly celebrated on Monday, June 24.
“Every year, this event carries forward our mission of making HIV science accessible to everyone, while researching better therapies for HIV,” said Luis J. Montaner, D.V.M., D.Phil., Herbert Kean, M.D., Family Professor and director of the HIV-1 Immunopathogenesis Laboratory at Wistar, and one of the founders of the Lax Memorial Lecture.
During the opening remarks, Jane Shull, executive director of Philadelphia FIGHT, commented that in the early days of the HIV epidemic, ordinary people had to stand up in the face of silence from government institutions and lack of resources to tackle AIDS. It was a growing public health emergency and people took it into their own hands to stop the epidemic.
“Although he was a rather extraordinary person, Jon was one of these ordinary people that made a difference,” said Shull. “Those activists won their battle and we are all the better for that.”
“We must remember the days when the barrier between science and the community came down,” added Shull. “This Lecture keeps that spirit going.”
Montaner remarked on how this event is meant to be an opportunity for the local community to be exposed to new trajectories of research and remain abreast of scientific advances in the HIV field.
The audience, including community members, HIV advocates and researchers, heard from Michel C. Nussenzweig, M.D., Ph.D., Zanvil A. Cohn and Ralph M. Steinman Professor at The Rockefeller University and Howard Hughes Medical Institute investigator, who studies the immune response to HIV infection with particular focus on antibodies and is advancing promising novel approaches.
Nussenzweig discussed the characteristics of HIV infection that make the immune response to this virus atypical compared with other infectious agents. In fact, only a small fraction of HIV-infected individuals develops effective antibodies, known as broadly neutralizing antibodies (bNAbs), able to neutralize the majority of circulating HIV virus variants. In addition, it takes their immune system a very long time — two to three years — to do so.
Only five of these antibodies were isolated between 1981 and 2009, and these were not very potent, reported Nussenzweig. This aspect, and the fact that HIV can shield itself with host-derived molecules to go undetected by the immune system, have made the process of developing an effective HIV vaccine extremely challenging.
His and other laboratories have recently developed more effective methods to isolate bNAbs from HIV-positive individuals.
“By looking to the people that develop bNAbs, we gain information that can assist us in designing future vaccines,” said Nussenzweig. “We also asked, what can we do with these potent antibodies for therapy and prevention?”
Therefore, they tested the possibility of passive immunization with bNAbs in animal models. These studies showed that bNAbs are able to suppress viremia, or presence of the virus in the blood, and preserve the host T cells, giving the immune system time to build a good response to the virus.
Based on these encouraging results, this approach has been moved to clinical testing. More than 200 people have been involved so far, confirming that bNAbs are very safe and can delay viremia rebounding in individuals that discontinue antiretroviral therapy (ART).
In particular, Nussenzweig and his collaborators tested in nine individuals a combination of two broadly neutralizing antibodies called 3BNC117 and 10-1074, which bind different portions of the HIV virus. All nine maintained long-term viral suppression in the absence of ART and none developed resistant viruses.
Nussenzweig said he is very optimistic that passive administration of potent bNAbs represents a potential alternative to ART therapy. “Not only can bNAbs neutralize the virus, they also engage the host immune system, something that ART cannot do.”
Answering a question from the audience regarding the cost of this approach, he said that it would be acceptable and believes that “bNAbs could be produced with acceptable costs and would be broadly available to the HIV community, including in developing countries.”
In this day and age in the fight against HIV, what we hope for and how far scientists have come are getting closer and closer.
PHILADELPHIA — (May 22, 2019) — New research from The Wistar Institute sheds light on the function of the ARID1A protein, encoded by a gene that is among the most frequently mutated across human cancers. According to the study, published online in Science Advances, ARID1A plays a role in the spatial organization of the genome; therefore, its loss has broad effects on global gene expression. This finding adds critical information towards deciphering the molecular alterations associated with several cancer types and especially with ovarian cancer.
“My lab has been studying the role of ARID1A in gene expression regulation as part of a complex known as SWI/SNF,” said principal investigator Rugang Zhang, Ph.D., deputy director of The Wistar Institute Cancer Center, and professor and co-program leader of the Gene Expression and Regulation Program. “In our search for new interacting proteins of this complex, we discovered one that offers new perspectives on the function of ARID1A as a genome-wide regulator of spatial chromosome organization.”
The three-dimensional organization of the genome dictates how several feet worth of DNA molecules are packed in a microscopic space while also allowing each gene to be accessible for transcription and expression at the appropriate time. The team found that ARID1A interacts with a component of the condensin II complex, which regulates gene expression through organizing chromosome structure.
“This is a finely regulated process and we revealed that ARID1A has a critical role in it,” added Zhang.
Results showed that ARID1A dictates the genome-wide positioning of condensin II on certain DNA regulatory elements called enhancers. Therefore, when ARID1A function is lost as a consequence of gene mutation, condensin II distribution is altered and so is expression of a large set of genes.
Zhang and colleagues also revealed that, through its interaction with condensin II, ARID1A controls how different parts of chromosomes are spatially organized together in regions known as chromosomal territories that facilitate the coordinated expression of certain sets of genes.
“Our findings add an important piece to the field of chromatin regulation in cancer,” said Shuai Wu, Ph.D., co-first author of the study and a postdoctoral researcher in the Zhang Lab. “By altering the special organization of chromosomes, ARID1A loss is expected to have much broader consequences on gene expression than we originally thought.”
Co-authors: Co-first author Nail Fatkhutdinov, Osamu Iwasaki, Hideki Tanizawa, Hsin-Yao Tang, Andrew V. Kossenkov, Alessandro Gardini, Ken-ichi Noma, and David W. Speicher from Wistar; Leah Rosin, Jennifer M. Luppino, and Eric F. Joyce from the University of Pennsylvania Perelman School of Medicine.
Work supported by: National Institutes of Health (NIH) grants R01CA160331, R01CA163377, R01CA202919, P01AG031862, R35GM128903, R50CA221838, and R50CA211199; U.S. Department of Defense grants OC140632P1 and OC150446. Core support for The Wistar Institute was provided by the Cancer Center Support Grant P30CA010815.
The Wistar Institute is an international leader in biomedical research with special expertise in cancer, immunology, infectious disease research, and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.
Wistar scientists advanced a novel anticancer treatment that targets the endoplasmic reticulum (a word you last heard in middle school cell biology) and discovered a new function for the ARID1 protein that is frequently mutated in ovarian cancer.
The endoplasmic reticulum (ER) is a cellular structure that oversees protein folding and assembly, and it activates stress response mechanisms in response to the accumulation of misfolded proteins or other stressful conditions.
In a study published online in the Journal of Medicinal Chemistry, the lab of Chih-Chi Andrew Hu, Ph.D., associate professor in Wistar’s Immunology, Microenvironment and Metastasis Program, and collaborators from the University of South Florida advanced a novel compound that specifically targets the ER stress response that is frequently hyperactivated in cancer.
“Certain cancers rely on the protective role of the ER stress response to sustain their growth in stressful environmental conditions,” said Hu.
The Hu lab has been developing compounds to block vital functions of the ER stress response as an effective way to attack various tumors.
In this study, Hu and collaborators created a molecule that is pharmacologically inactive and requires UV irradiation to be “turned on” into a very potent inhibitor. This strategy brings a double benefit: it finely controls the inhibitor activity at a precise time and location by UV irradiation and it provides a real-time therapy readout, since the activated molecule emits fluorescence that can be tracked in cells and potentially in vivo.
ARID1 is a tumor suppressor gene, which means it keeps cell proliferation at bay and prevents tumor formation. Mutations in this gene translate into a loss or reduction in its function and, in combination with other genetic changes, can lead to cancer.
New research by the lab of Rugang Zhang, Ph.D., deputy director of The Wistar Institute Cancer Center and co-program leader of the Gene Expression & Regulation Program, sheds light on the function of the ARID1A protein, among the most frequently mutated gene across human cancers, including ovarian cancer.
Published online in Science Advances, the study showed that ARID1A plays a role in the spatial organization of the genome, which dictates how several feet worth of DNA molecules are packed in a microscopic space while also allowing each gene to be accessible for transcription — how DNA is copied into a new molecule of messenger RNA — at the appropriate time.
“This is a finely regulated process and we revealed that ARID1A has a critical role in it,” said Zhang.
Results showed that ARID1A dictates the genome-wide positioning of condensin II, which regulates gene expression through organizing chromosome structure. Therefore, when ARID1A function is lost as a consequence of gene mutation, condensin II distribution is altered and so is expression of a large set of genes. Therefore, ARID1A loss has broad effects on global gene expression.
In the beautiful setting of the College of Physicians of Philadelphia, Wistar friends attended this year’s Wistar Party, a celebration of Wistar science that has carried on for decades, and an opportunity for the Institute to express its gratitude to our most committed supporters.
“Science is the answer,” said Dario Altieri, M.D., Wistar president and CEO, as he welcomed guests. “I cannot tell you how good it is to be with all of you tonight and how much your support means for our science and our mission to find new answers to fight cancer and infectious diseases.”
In the 1800s, the Institute’s namesake Caspar Wistar, M.D., hosted salon-style parties with local scientists, literati and distinguished guests to discuss the advancement of science. In line with this storied tradition, the 2019 Wistar Party hosted a very special guest.
Steffanie Strathdee, Ph.D., associate dean of Global Health Sciences, and Harold Simon Professor at the University of California San Diego (UCSD) Department of Medicine, told a fascinating scientific and personal story of how she resurrected an old therapy to save her husband’s life from a deadly, antibiotic resistant superbug.
Antibiotic resistance has emerged as a pressing public health issue as several infections that we used to be able to control and treat with antibiotics have stopped responding and are coming back as serious threats.
“It is an urgent matter that calls for urgent solutions,” said Farokh Dotiwala, M.B.B.S., Ph.D., assistant professor in Wistar’s Vaccine & Immunotherapy Center, who introduced Strathdee. Dotiwala said Strathdee’s story resonates with him because his research career is dedicated to finding novel approaches to defeat bacterial infections.
“Dr. Strathdee’s work is a powerful and innovative contribution that is already saving lives,” he added.
Strathdee, an infectious disease epidemiologist, shared the story of how she and her husband, Tom Patterson, Ph.D., a professor of psychiatry at UCSD, were vacationing in Egypt when he fell critically ill. While his health was rapidly deteriorating, he was transferred back home to San Diego and was diagnosed with an infection from multi-drug resistant Acinetobacter baumannii, one of the most dangerous bacteria in the world, which failed to respond to all the antibiotic treatments administered.
When all hope seemed lost, and no antibiotics were working, Strathdee went on a scientific quest to find a different approach to the problem and started combing through old and new research literature. That’s how she came across phage therapy.
Bacteriophages, also known as phages, are viruses that infect and kill bacteria. Their name, derived from a Greek word, literally means that they “eat” bacteria.
Research from the early 1900s on phages as an antibacterial treatment fell out of favor after antibiotic use went mainstream, but it might have a strong come back now that we face such a critical antibiotic resistant crisis. And especially after Strathdee opened the possibility of a path forward.
She turned to phage experts all over the world for help and they came together to find the right phage that could kill Patterson’s infection. Phages, in fact, have a high specificity for their bacterial prey. The researchers were eventually able to find the matching phages, which obtained expedited FDA approval and were given to Patterson, just when his organs were going into failure. Three days later, he opened his eyes and started recovering.
Strathdee’s and Patterson’s success story was a true medical breakthrough and helped jumpstart global research efforts on phage therapy. A few additional patients in the U.S. and abroad have been treated with success and no adverse effects. The UCSD School of Medicine created the interdisciplinary Center for Innovative Phage Applications and Therapeutics (IPATH) that is investigating bringing back phage therapy as an alternative tool to fight infections that cannot be treated with antibiotics. Strathdee co-directs the Center with Robert Schooley, M.D., infectious disease specialist and chief of the Division of Infectious Diseases at UCSD, who joined forces with her to make phage therapy a reality.
Strathdee and her husband wrote a book about their journey, The Perfect Predator, described by Scientific American as “fascinating and terrifying”, and in 2018, she was named one of TIME’s 50 Most Influential People in Health Care who “have changed the state of health care in America.”
Learn more about becoming a President’s Society member and being invited to events such as this.
Read a recent article in the New York Times about phage therapy that features Strathdee.
