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Author: Steven Schneible

Wistar Institute Scientists Identify Important Factor in Neural Development

Written by Steven Schneible on . Posted in Press Releases.

PRESS RELEASE

PHILADELPHIA — (Nov. 26, 2024) — The Wistar Institute’s Alessandro Gardini, Ph.D., and lab have shed new light on how certain biological processes determine the development of neural cells. Their findings on a molecular “bridge” complex demonstrate a new level of detail in the understanding of early neural development — which is fundamental for the further understanding of neurodevelopmental syndromes. The new paper, “The enhancer module of integrator controls cell identity and early neural fate commitment” was published in the journal, Nature Cell Biology.

“By achieving a better understanding of how the nervous system develops at the earliest level, we are better positioned to assess the causes of and potential solutions to neurodevelopmental disorders. Our research provides valuable evidence that neural cell development is not solely driven by transcription factors” said Dr. Gardini.

Although every cell in our body carries the same genetic information, not every cell is identical. Cells get direction on what type of cell to become: muscle cells, blood cells, neurons, etc. In the early stages of biological development, stem cells transition from a state of “pluripotency,” which is the ability of an unspecialized cell to develop into any number of mature, specialized cell types based on the biological signals and inputs they receive along the way.

Dr. Alessandro Gardini was interested in the signals and inputs that cause pluripotent stem cells to commit to developing into neural cells during the process of “neurogenesis”: the formation of the human nervous system, including the brain. Human neurogenesis is not fully understood, but certain mutations within subunits of a protein complex called Integrator–which influences neurogenesis–have been associated with neurodevelopmental disorders.

Gardini and his team assessed the Integrator subunit INST10, which, across cells from both the central and peripheral nervous systems, was more abundant than other subunits of the same Integrator protein complex; this confirmed that neural cells had some essential need for INST10. Using a cell model that emulates early neural development, the researchers confirmed that cells with diminished INST10 not only exhibit very different gene-expression signatures — they also appeared to be drifting away from developing into neural cells and toward developing into mesenchymal cells, a confirmation that the presence of INST10 maintains the cellular identity of neurons.

At the single-cell level of analysis, the stem cell lines with decreased INST10 lost expression of “master neuronal genes” even as they gained gene expression signatures consistent with programming for becoming intestinal or smooth-tissue cells. These findings confirmed that INST10 is critical to maintaining the cellular identities of neural cells, both during initial development and throughout the cell’s life.

Co-authors: Yingjie Zhang1,4, Connor M Hill1,2,4, Kelsey Leach1,2, Luca Grillini1,3, Sandra Deliard1, Sarah R. Offley1,2, Martina Gatto1,3, Francis Picone1, Avery Zucco1, and Alessandro Gardini1.

1 The Wistar Institute

2 The Perelman School of Medicine at the University of Pennsylvania

3 The University of Bologna

Work supported by: National Institutes of Health grants R01HL141326, R01CA252223, T32CA09171, supplement HL141326-S1, and Ruth L. Kirschstein National Research Service Award F31 CA265257.  This study was funded by grants from the G. Harold and Leila Y. Mathers Charitable Foundation.

Publication information: “The enhancer module of integrator controls cell identity and early neural fate commitment” from Nature Cell Biology

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ABOUT THE WISTAR INSTITUTE:

The Wistar Institute is the nation’s first independent nonprofit institution devoted exclusively to foundational biomedical research and training. Since 1972, the Institute has held National Cancer Institute (NCI)-designated Cancer Center status. Through a culture and commitment to biomedical collaboration and innovation, Wistar science leads to breakthrough early-stage discoveries and life science sector start-ups. Wistar scientists are dedicated to solving some of the world’s most challenging problems in the field of cancer and immunology, advancing human health through early-stage discovery and training the next generation of biomedical researchers. wistar.org

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Dr. Jozef Madzo, Biomedical Science Interpreter at The Wistar Institute

Written by Steven Schneible on . Posted in Featured News.

In July 2024, Jozef Madzo, Ph.D., joined Wistar’s faculty as an assistant professor and new director of the Bioinformatics Core Facility, which provides investigators with critical data analysis support. We sat down with him to learn more about how bioinformatics plays a role in modern biomedical research.

At the highest level, what is bioinformatics, to you?

Bioinformatics, at its core, is the intersection between biology and computational science — that is, data analysis techniques that we develop using programming languages. The field exists to answer biological questions that are basically impossible to approach without computer assistance. Mostly, that means what people call Big Data: enormous datasets with multiple variables.

Bioinformaticians are similar to computational biologists, but where that field has specialized to split work between the lab and the keyboard, bioinformaticians are very much coders: we’re writing scripts to analyze big datasets for a variety of research areas. Technically, there is a Madzo lab at Wistar, but it’s all computer-based — I don’t use pipettes or live cells. For me, the science is the coding and the analysis.

I typically write in a programming language called R because it has well-integrated data visualization elements, and in my role of supporting different scientists’ need for data analysis, it’s important that I export critical findings to easy-to-read graphics.

Why has bioinformatics become so important to biomedical research?

The datasets are too big. To find anything significant or interpret any data properly, you need to run it through code. There have always been big datasets, but the technology that researchers use has improved — and for us, improved technology basically means even larger datasets. Advanced sequencing methods are better because they “see” more of what’s going on in cells’ genetics, but “seeing more” is another way of saying “producing more data.” Somebody has to sort through it.

Developing the code to analyze these datasets properly is a specialization in its own right. Students enrolled in Ph.D. programs right now learn a certain amount of coding through their training by necessity, but generally speaking, having a biology background does not guarantee that you’ll know how to interpret the results of your own experiment — that’s how complex biological datasets have become. Mainly we want to make sure that the best statistical methods are used so that the significance of results is clear and undistorted (which can be a pitfall of advanced statistics, especially with big data).

Large, complex datasets have better statistical powering, which means that we can have greater confidence in our results. We also have more opportunity for discovery, but the era of Big Biological Data does create a need for labor specialization between scientists. On the one hand, you have PIs in their labs running their experiments, and then on the other, you have people like me and Dr. Andrew Kossenkov in Wistar’s Bioinformatics Facility running the analysis on the data that the experiments produce.

How did you become interested in bioinformatics?

I didn’t start to specialize until I was a postdoctoral fellow. I’m from Slovakia, so I got my Ph.D. in Prague and had planned to complete a postdoc fellowship in the U.S. before returning — but that’s when I met my wife, so I stayed here.

I was working in a lab at the University of Chicago where we started to deal with a lot of epigenetic data, which involves very large quantities of information. We didn’t have much bioinformatics support, so I tried to work through it on my own, occasionally checking my work with UChicago’s bioinformatics core specialist.

My methods for that analysis eventually wound up in a paper we published, and I stuck with the coding from there because I found that I enjoyed it. I finished my postdoc and found out that there was a bioinformatics master’s program at Temple, so I worked in a cancer research lab at the Fels Institute while finishing up my specialization. 

What role do you see for artificial intelligence in bioinformatics?

I think we’ll continue to use and improve on machine learning, which is a subset of artificial intelligence. Whenever I hear “AI,” I tend to think of sentient robots and science fiction, but that’s distinct from the classical machine learning methods we use. 

A lot of what gets called AI now refers to neural networks or deep learning technology, which is really good at identifying undefined variables — for example, training a program to figure out whether an image contains a cat.

Sometimes, we do use neural networks — especially when there’s an image dimension to something, like in spatial transcriptomics, where subsets of data are associated with a physical region of a cell or tissue — but mostly, our data are already defined because we know what we’re measuring in advance. Classical machine learning allows us to optimize algorithms that can sort through the big data and test for patterns or associations with confidence.

Personally, I find repetitive elements very interesting, which used to be thought of as “junk DNA” — noncoding regions of genetic material that don’t produce proteins. The thinking went that those areas didn’t really do anything, so many scientists ignored them. But it turns out that, in the aggregate, patterns in repetitive elements can be very useful in analyzing cancer biology because they can predict — for example, how well people will respond to certain treatments, or even, potentially, the existence of cancer itself. But without good code and computing power, those discoveries are almost impossible to make.

What do you think the future looks like for bioinformatics?

I think it will keep improving; that’s what computers do. And as sequencing technologies get better and cheaper, that gives everybody more data — which means we’ll continue to have even more opportunities for discoveries. As a field, to make sure these improvements are their very best, we need to continue pushing in the direction of providing our methods and code with every publication so that our colleagues can properly replicate our data.

Ultimately, a big part of the appeal for me with bioinformatics is the opportunity for collaboration. Almost everyone requires our support, which means that I can work to solve a wide variety of important problems.

I get excited at the opportunity to work with really smart people; when you have that chance as a scientist, you’re pushed to do your best work. And Wistar — well, Wistar has dozens of geniuses. I’m excited about the work we’re going to do together.

The Wistar Institute Honors Nobel Laureate Dr. Katalin Karikó with 2024 Helen Dean King Award

Written by Steven Schneible on . Posted in Featured News.

In front of the 200-plus audience gathered in The Wistar Institute’s standing-room-only Sarah and Matthew Caplan Auditorium — as well as many more tuning in virtually — the 2023 Nobel Laureate in Physiology or Medicine, Katalin Karikó, Ph.D., received a scientific distinction, this prize a little closer to home: Wistar’s Helen Dean King Award, bestowed each year in the memory of prominent geneticist and the Institute’s first female scientist Dr. Helen Dean King.

Upon her introduction from Wistar’s Dr. Maureen Murphy, deputy director of the Ellen and Ronald Caplan Cancer Center and Ira Brind Professor, Dr. Karikó delivered her lecture: “My journey to develop mRNA for therapy.”

In her presentation, Dr. Karikó spoke of the road she followed on her way to the Nobel Prize. Starting in childhood competitions in local science fairs in her small Hungarian town, she learned to roll with the punches of the scientific method’s trial and error, channeling frustration into determination, which ultimately led her to Philadelphia — where her indefatigable enthusiasm for research (honed by daily 6-km pre-research jogging sessions) led her to pursue mRNA’s potential.

While at the University of Pennsylvania, Dr. Karikó (now famously) met her soon-to-be collaborator at the copy machine: Dr. Drew Weissman would go on to share the 2023 Nobel Prize with Dr. Karikó. Together, they refined mRNA immunization technology into an effective elicitor of immune response, with their findings on mRNA’s effectiveness against cancer and influenza published in the 90s.

As she details in her bestselling memoir, Breaking Through: My Life in Science, these results, however promising, struggled to attract attention and funding. Dr. Karikó persevered through years in a scientific wilderness at the periphery without grant funding but with a whole lot of scientific freedom. The global emergency of COVID-19 and the frantic search for an effective vaccine led to the emergence of her and Dr. Weissman’s technology as the basis for the world-famous mRNA vaccines for COVID-19 — which were essential to stemming the tide of disease around the world.

But this hard and often frustrating work did not discourage her, she said — because Nobel Prize or not, she loves the call of research, a message she made sure to emphasize to the scientists and scientists-in-training in the audience.

“This is what I find most important: you have to be happy,” she said. “You have to enjoy what you are doing. If you want to follow instructions, do not become a scientist. If you want to make a lot of money — well, then I don’t know where to go,” she quipped, to a big laugh.

“But if you want to solve problems — and if you enjoy solving problems — this work is for you. You will get better and better at it because you love it.”

Following her talk, Dr. Ami Patel, assistant professor in Wistar’s Vaccine & Immunotherapy Center, presented Dr. Karikó with this year’s Helen Dean King Award, to thunderous applause. But Dr. Karikó wasn’t done: she pulled out her phone to photograph her audience and capture the moment. A line of attendees clutching her book for signatures & selfies formed with the willing and amiable Nobel Laureate; it was a very long line.

Scientists at The Wistar Institute Discover Novel Series of SARS-CoV-2 Mpro Inhibitors for Potential New COVID-19 Treatments

Written by Steven Schneible on . Posted in Press Releases.

PRESS RELEASE

PHILADELPHIA — (Oct. 8, 2024) — New research from The Wistar Institute’s Salvino lab — led by professor Joseph Salvino, Ph.D. — has identified a novel series of SARS-CoV-2 Mpro inhibitors that may lead to potential new COVID-19 treatments that, according to preclinical testing, effectively inhibits COVID-19 and synergizes with existing anti-COVID therapies. Their new discovery is detailed in the paper, “Design of novel and highly selective SARS-CoV-2 main protease inhibitors,” published in the journal Antimicrobial Agents and Chemotherapy.

Despite effective vaccines approved for use worldwide, COVID-19 continues to contribute to mortality and morbidity — an issue compounded by the problems of vaccine & therapy access. However, the existing drug designs in use for COVID-19 therapy lend themselves to drug interactions and the risk of incomplete viral inhibition.

To address this problem, Salvino — a medicinal chemist at Wistar — led a drug discovery team with the goal of improving upon the existing Mpro inhibitor design, an approach to viral therapy that seeks to prevent both viral replication and mutation-based drug resistance by targeting a component of the virus that regulates its ability to spread. And because Mpro is not an easy-to-mutate biological feature like a spike protein, inhibiting Mpro can help retain antiviral effectiveness even between different variations.

The team used a drug discovery technique that applied an “acyloxymethyl ketone electrophilic warhead” — in essence, a molecule designed to identify the important binding regions that a drug candidate compound would interact with. Using their drug discovery process, Salvino and the team identified a novel series of Mpro inhibitors with greater selectivity — that is, more reliable at producing an inhibitory effect — than the existing Mpro inhibitor for COVID-19 on the market.

The group’s novel compounds successfully inhibited viral replication in vitro against three different COVID variants, including within lung tissue. The compound also synergized (i.e., achieved greater-than-the-sum-of-its-parts strength) with other existing antivirals in fighting the virus. In the preclinical testing, no apparent toxicities were observed — a positive indication of the compound’s safety.

“We’re very excited to have identified such a promising new pathway for developing future therapies,” said Salvino. “As we continue to refine the chemistry through further testing and optimization, we look forward to achieving improved potency in anti-coronaviral therapies.”

Co-authors: Adi N. R. Poli, Ian Tietjen, Nitesh K. Nandwana, Joel Cassel, Troy E. Messick, Emery T. Register, Frederick Keeney, Luis J. Montaner, and Joseph M. Salvino of The Wistar Institute; and Rajesh Rajaiah, Atul K. Verma, Kabita Pandey, Arpan Acharya, and Siddappa N. Byrareddy of The University of Nebraska Medical Center.

Work supported by: NIH grants S10OD030245 and P30CA010815; Canadian Institutes of Health Research grant CIHR PJT-153057; and Commonwealth of Pennsylvania Special Initiatives Grant – COVID-19 Funding, SAP #4100089371

Publication information: “Design of novel and highly selective SARS-CoV-2 main protease inhibitors,” from Antimicrobial Agents and Chemotherapy.

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ABOUT THE WISTAR INSTITUTE:

The Wistar Institute is the nation’s first independent nonprofit institution devoted exclusively to foundational biomedical research and training. Since 1972, the Institute has held National Cancer Institute (NCI)-designated Cancer Center status. Through a culture and commitment to biomedical collaboration and innovation, Wistar science leads to breakthrough early-stage discoveries and life science sector start-ups. Wistar scientists are dedicated to solving some of the world’s most challenging problems in the field of cancer and immunology, advancing human health through early-stage discovery and training the next generation of biomedical researchers. wistar.org

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The Wistar Institute and University of Pennsylvania Scientists Identify Potential Target Gene within Certain HIV Reservoir Cells

Written by Steven Schneible on . Posted in Press Releases.

PRESS RELEASE
Drs. Lieberman, Collman, and Co-Authors Link RSAD2/Viperin Gene with Certain
Chronically HIV-Infected Cells

PHILADELPHIA — (Oct. 3, 2024) —New findings could lead to different research tactics for scientists investigating a cure for HIV. Results from The Wistar Institute’s Lieberman lab, led by Hilary Koprowski, M.D., Endowed Professor Paul M. Lieberman, Ph.D., and researchers at the Perelman School of Medicine’s Center for AIDS Research and center director Ronald G. Collman, M.D. — have identified the RSAD2/Viperin gene as a potential HIV treatment target within certain HIV reservoir cells. Their results were published in the paper, “HIV-induced RSAD2/Viperin supports sustained infection of monocyte-derived macrophages,” in the Journal of Virology.

HIV does not have a cure because there is no known method — yet — for eliminating the virus from the body once infected. Although HIV can be managed with antiretroviral therapy (ART), the virus persists in infected cells throughout the body, called “HIV reservoirs.” Reservoirs not only serve as the main barrier in HIV cure research, which focuses in large part on strategies to destroy these HIV reservoirs, but also contribute to chronic inflammation and comorbidities in people living with HIV.

A certain type of immune cell — myeloid cells, including macrophages and microglia — often serves as an HIV reservoir because, unlike other cells infected with HIV, these cells tend not to be killed by HIV’s viral replication. Due to their comparative longevity as reservoirs and prevalence within the nervous system, HIV-infected macrophages often cause neurocognitive complications in people with HIV that develop even despite antiretroviral treatment (ART).

Lieberman and Collman, joined forces to research the genetics of macrophages that might play a role in maintaining the HIV reservoir status quo. Their investigation revealed a surprising candidate in the gene RSAD2/Viperin — which usually fights viruses. In HIV-infected macrophages, RSAD2/Viperin expression was quite high compared both with controls and HIV-infected CD4+ T cells (the other major type of cell that can become a viral reservoir of HIV).

RSAD2/Viperin is a gene associated with interferon response, and typically, both the gene itself and the interferons that trigger its activation have antiviral effects. However, certain interferons have been found to play paradoxical roles in chronic HIV by enabling the virus’ persistence, and upon finding RSAD2/Viperin’s elevated expression in reservoir macrophages, the researchers hypothesized that the gene must be abetting HIV’s continued presence within these cells.

To test this, the research team used the siRNA method to target and reduce RSAD2/Viperin’s expression in macrophages infected with HIV. Once they reduced the gene’s expression, several measures of HIV’s presence and activity fell, including viral transcripts, p24 protein production, and multinucleated giant cells (another indicator of active viral activity). Reduced RSAD2/Viperin also altered histone modification of HIV genomes — that is, the control of HIV’s latency by chromatin and epigenetic factors. These findings suggest a novel role for RSAD2/Viperin in regulating chromatin that otherwise might suppress HIV replication during latency.

“Looking closely at RSAD2/Viperin in these HIV-infected MDMs, we’ve identified yet another paradox of HIV infection,” said Lieberman, program leader, Genome Regulation and Cell Signaling Program, Ellen and Ronald Caplan Cancer. “Our data show that while, yes, this is an antiviral gene that can come to the body’s defense against the virus at first, it also seems to maintain HIV’s ability to persist as a chronic infection. That makes RSAD2/Viperin a compelling candidate for further research and possible targeting of HIV reservoirs — which is critical to future cure research.”

“We’ve come to understand yet another facet of chronic HIV infection’s complexity,” agreed Collman. “We’re hopeful that these findings will be helpful as the field continues to pursue possible therapeutic interventions that would eliminate the viral reservoir in the search for an HIV cure, or reduce negative consequences of infection that can persist even despite effective therapy, such as neurocognitive decline.”

Co-authors: Urvi Zankharia, Fang Lu, Olga Vladimirova, Bhanu Chandra Karisetty, Jayamanna Wikramasinghe, Andrew Kossenkov, and Paul M. Lieberman of The Wistar Institute; and Yanjie Yi and Ronald G. Collman of The Perelman School of Medicine at The University of Pennsylvania.

Work supported by: NIH grants R6133-133696, P30AI045008, and P30CA010815.

Publication information: “HIV-induced RSAD2/Viperin supports sustained infection of monocyte-derived macrophages,” from Journal of Virology.

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ABOUT THE WISTAR INSTITUTE:

The Wistar Institute is the nation’s first independent nonprofit institution devoted exclusively to foundational biomedical research and training. Since 1972, the Institute has held National Cancer Institute (NCI)-designated Cancer Center status. Through a culture and commitment to biomedical collaboration and innovation, Wistar science leads to breakthrough early-stage discoveries and life science sector start-ups. Wistar scientists are dedicated to solving some of the world’s most challenging problems in the field of cancer and immunology, advancing human health through early-stage discovery and training the next generation of biomedical researchers. wistar.org

ABOUT PENN MEDICINE:

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, excellence in patient care, and community service. The organization consists of the University of Pennsylvania Health System and Penn’s Raymond and Ruth Perelman School of Medicine, founded in 1765 as the nation’s first medical school.

The Perelman School of Medicine is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $550 million awarded in the 2022 fiscal year. Home to a proud history of “firsts” in medicine, Penn Medicine teams have pioneered discoveries and innovations that have shaped modern medicine, including recent breakthroughs such as CAR T cell therapy for cancer and the mRNA technology used in COVID-19 vaccines.

The University of Pennsylvania Health System’s patient care facilities stretch from the Susquehanna River in Pennsylvania to the New Jersey shore. These include the Hospital of the University of Pennsylvania, Penn Presbyterian Medical Center, Chester County Hospital, Lancaster General Health, Penn Medicine Princeton Health, and Pennsylvania Hospital—the nation’s first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

Penn Medicine is an $11.1 billion enterprise powered by more than 49,000 talented faculty and staff

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The Wistar Institute’s Gelvina Stevenson, JD, Named Latina Attorney of the Year

Written by Steven Schneible on . Posted in Press Releases.

PRESS RELEASE
Hispanic National Bar Association Honors Wistar’s General Counsel and Corporate Secretary

PHILADELPHIA — (September 18, 2024) —The Hispanic National Bar Association (HBNA) has named The Wistar Institute’s Gelvina Stevenson, JD, as the 2024 Latina Attorney of the Year. Ms. Stevenson — who has served as the Institute’s General Counsel and Corporate Secretary since 2022 — received the recognition for her “commitment to advancing diversity, equity and inclusion within the legal profession generally and the health law bar in particular.” She has been a longstanding member of the HNBA, where she serves as co-chair of the Health and Life Sciences Section.

As General Counsel, Ms. Stevenson has helped to guide Wistar through a pivotal period of growth and expansion while lending her expertise to the stewardship of the Institute’s intellectual property. In addition to her invaluable service to Wistar, she is a mentor to the next generation of life science professionals, whom she instructs in the sector’s legal matters in her role as an adjunct professor of law at the Drexel University School of Medicine. Ms. Stevenson also sits on the board of both the American Health Lawyers Association and the Child Center of New York.

“I feel deeply grateful to have received this recognition from my friends and colleagues at the Hispanic National Bar Association,” said Stevenson. “My career in the nonprofit biomedical research sector has honed my sense for the value of inclusion, and I am proud to have contributed to that mission both in my service to The Wistar Institute and the Hispanic National Bar Association.”

Ms. Stevenson received the award at a formal reception at the Gaylord National Harbor Resort as part of the HNBA’s annual convention.

ABOUT THE WISTAR INSTITUTE:

The Wistar Institute is the nation’s first independent nonprofit institution devoted exclusively to foundational biomedical research and training. Since 1972, the Institute has held National Cancer Institute (NCI)-designated Cancer Center status. Through a culture and commitment to biomedical collaboration and innovation, Wistar science leads to breakthrough early-stage discoveries and life science sector start-ups. Wistar scientists are dedicated to solving some of the world’s most challenging problems in the field of cancer and immunology, advancing human health through early-stage discovery and training the next generation of biomedical researchers. wistar.org

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Wistar Institute Researchers Identify Parkinson-related Protein’s Role in Cancer and T Cell Activation

Written by Steven Schneible on . Posted in Press Releases.

PRESS RELEASE
Wistar’s Altieri lab uncovered the protein’s powerful influence on immune response to tumors

PHILADELPHIA — (September 17th, 2024) — The Wistar Institute’s President and CEO, Dario C. Altieri, M.D., and team have demonstrated the role of Parkin — a protein implicated in Parkinson’s disease — in the body’s innate immune response to cancer. Parkin is not expressed in several cancers. Dr. Altieri and his team engineered cancer cells to re-express Parkin and found that Parkin contributes to the production of interferons, which activate and attract T cells to fight the tumor. The lab’s findings were published in The Journal of Clinical Investigation in the paper, “Parkin activates innate immunity and promotes anti-tumor immune responses.”

“Parkin has only recently been implicated for its role in cancer, so our study adds to the knowledge base being formed around that role. We are the first to demonstrate its dual role in suppressing tumor traits while activating innate immunity,” said Altieri, president and CEO, director of the Ellen and Ronald Caplan Cancer Center and the Robert & Penny Fox Distinguished Professor at The Wistar Institute.

Parkin is well known for its role in breaking down damaged and excess proteins, and the loss of Parkin expression due to genetic mutation in the PRKN gene is most commonly associated with Parkinson’s disease. However, Parkin can also be epigenetically silenced in cancer and has been implicated in several types, including lung, ovarian, and breast cancer.

Epigenetic silencing occurs when physical changes to the genome prevent certain genes from being turned into proteins or expressed. In the case of Parkin, cancers epigenetically silence the gene through DNA methylation, a process that attaches methyl molecules to DNA. To better understand the interplay between Parkin and cancer cells, Altieri, and an international team of collaborators began by reintroducing Parkin into tumor cells in vitro and in vivo.

They found that in the presence of Parkin, interferons — a group of cytokine proteins that aid in immune responses to threats — were produced as a result of Parkin activation. The team followed up with an in vivo experiment where they restored PRKN expression in mice by using the approved demethylating agent decitabine, which removes the gene-silencing methyl groups from DNA. The drug treatment worked to restore Parkin expression and slow down tumor growth.

By stimulating the production of interferons — a key element of immune response — the team found that Parkin’s interferon-signaling effects ultimately recruited anti-cancer T cells, which slowed tumor growth. To confirm this mechanism, the researchers expressed Parkin but cancelled interferon signaling, and then they expressed Parkin in immunocompromised mice. In both instances, the tumor-suppression effect was eliminated, even while Parkin was expressed — ultimately proving that the immune system’s anti-cancer response mediates the role Parkin plays in tumor reduction.

“We are excited to uncover a new mechanism of crosstalk between the immune system and tumor cells because we can only cure what we know,” said Michela Perego, Ph.D., the paper’s first author. “By reactivating Parkin, it may be possible to develop new treatment options and boost the immune system’s ability to fight cancer.”

Co-authors: Michela Perego, Minjeong Yeon, Ekta Agarwal, Andrew T. Milcarek, Irene Bertolini, Jagadish C. Ghosh1, Hsin-Yao Tang, Andrew V. Kossenkov, Sarah Preston-Alp, Italo Tempera, Noam Auslander, and Dario C. Altieri from The Wistar Institute; Chiara Camisaschi from IRCCS Humanitas Research Hospital; Nathalie Grandvaux from Centre de Recherche du Centre Hospitalier de l’Université de Montréal, and Marcus Ruscetti from University of Massachusetts Chan Medical School.

Work supported by: National Institutes of Health (NIH) grants R35 CA220446 and R01 CA286080 (D.C.A.), P01 CA269043 (I.T.), T32 CA009171 (S.P.-A.), R50 CA221838 (H.Y.T), and R50 CA211199 (A.V.K.). Wistar Shared Resources are supported by P30 CA010815. The Thermo Q-Exactive HF-X mass spectrometer was purchased with NIH grant S10 OD023586.

Publication information: “Parkin Activates Innate Immunity and Promotes Anti-tumor Immune Responses,” The Journal of Clinical Investigation.

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ABOUT THE WISTAR INSTITUTE:

The Wistar Institute is the nation’s first independent nonprofit institution devoted exclusively to foundational biomedical research and training. Since 1972, the Institute has held National Cancer Institute (NCI)-designated Cancer Center status. Through a culture and commitment to biomedical collaboration and innovation, Wistar science leads to breakthrough early-stage discoveries and life science sector start-ups. Wistar scientists are dedicated to solving some of the world’s most challenging problems in the field of cancer and immunology, advancing human health through early-stage discovery and training the next generation of biomedical researchers. wistar.org

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Scientists at The Wistar Institute Clone Several New Anti-Interferon Antibodies, Developing Future Therapeutic Candidates with Broad Application Potential

Written by Steven Schneible on . Posted in Press Releases.

PRESS RELEASE
Honored as the Top Read in the September 15 Issue of the Journal of Immunology

PHILADELPHIA — (September 16, 2024) — New research from The Wistar Institute’s Montaner lab — led by Wistar Executive Vice President, director of the HIV Cure and Viral Disease Center, and Herbert Kean, M.D., Family Professor, Luis Montaner, D.V.M., D.Phil. — has successfully isolated and cloned fully human antibodies that can block specific Type-I interferon molecules in vitro; their discovery has an array of potential clinical & research applications, enabling scientists with a new way to investigate the role of specific Type-I interferons in a variety of diseases. The work, published in the paper “Cloning and functional characterization of novel human neutralizing anti-interferon-alpha and anti-interferon-beta antibodies,” has been honored as the Top Read in the September 15 issue of the Journal of Immunology.

As an immunomodulating subtype of cytokine — an inflammatory molecule class that our bodies release in response to stress — Type I interferons, or IFNs, help the immune system combat disease, cancer, and viral diseases in particular. Type I IFNs include several specific IFNs that can aid in the modulation of how our immune systems respond to infection, but when they become dysregulated or over-expressed, they can also contribute to shutting down the immune system. In HIV infections, Type I IFNs have been observed to produce paradoxical effects, working for and against the virus simultaneously.

Due to the complexity and ambiguity of how best to therapeutically target IFNs’ broad effects on immune control, scientists in the Montaner lab sought to develop several antibodies to target and selectively block two major but distinct Type I IFNs: interferon alpha (IFN-α) and interferon beta (IFN-β). First author Emmanouil Papasavvas, Ph.D., and his collaborators sought to take advantage of the body’s natural immune response in persons receiving IFN-α or IFN-β treatment, as these persons can generate their own anti-IFN antibodies.

Using cryopreserved blood plasma samples from these same persons receiving IFN-α or IFN-β treatment, respectively, the team successfully isolated and cloned four selective anti-IFN antibodies, two against IFN-α and two against IFN-β. The success of the novel approach taken — which leveraged the pooling of complementary DNA from original samples to optimize cloned antibodies — circumvents more complex techniques to derive monoclonal antibodies. Having demonstrated their antibodies’ ability to selectively block IFN-α or IFN-β in vitro, the team predicts that future studies in vivo will yield similar promising results.

“These novel, effective human antibodies against specific Type I interferons have the potential to be an indispensable tool for understanding and ultimately serving as immunotherapy against cancer, autoimmune or infectious disease conditions,” said Dr. Montaner.

“We are very pleased with our methodological proof-of-concept report, and I believe it will lead to exciting future work,” agreed Dr. Papasavvas. “With the ability to selectively target and inhibit specific interferons, scientists will have a valuable tool for developing future therapies.”

Co-authors: Emmanouil Papasavvas, Lily Lu, Matthew Fair, Isabela Oliva, Joel Cassel, Sonali Majumdar, Kar Muthumani, and Luis J. Montaner of The Wistar Institute; Karam Mounzer of the Jonathan Lax Immune Disorders Treatment Center; Jay R. Kostman of the Jonathan Lax Immune Disorders Treatment Center and the John Bell Health Center; and Pablo Tebas and Amit Bar-Or of the Perelman Center for Advanced Medicine.

Work supported by: NIH grants UM1 AI164570 and P30 CA010815; Robert I. Jacobs Fund of the Philadelphia Foundation; and the Herbert Kean, M.D., Family Professorship.

Publication information: “Cloning and functional characterization of novel human neutralizing anti-interferon-alpha and anti-interferon-beta antibodies,” from Journal of Immunology

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ABOUT THE WISTAR INSTITUTE:

The Wistar Institute is the nation’s first independent nonprofit institution devoted exclusively to foundational biomedical research and training. Since 1972, the Institute has held National Cancer Institute (NCI)-designated Cancer Center status. Through a culture and commitment to biomedical collaboration and innovation, Wistar science leads to breakthrough early-stage discoveries and life science sector start-ups. Wistar scientists are dedicated to solving some of the world’s most challenging problems in the field of cancer and immunology, advancing human health through early-stage discovery and training the next generation of biomedical researchers. wistar.org

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The Wistar Institute Celebrates Ten Years of The Robert and Penny Fox Tower

Written by Steven Schneible on . Posted in Featured News.

On September 14th, 2014, The Robert and Penny Fox Tower at The Wistar Institute was opened, marking a monumental change in the look and biomedical research capacity of the Institute. This September, we celebrate 10 years of the Fox Tower made possible by Robert and Penny Fox — a reminder of philanthropy’s role in empowering foundational biomedical research.

As the nation’s first nonprofit biomedical research institute, The Wistar Institute has stood resolute at 36th and Spruce Streets since 1894 — but the building West Philadelphia sees today is a far cry from its historic brick-and-mortar origins. The modern, all-glass, seven-story structure that expanded Wistar’s place on the Philadelphia skyline has a name and a birthday: ten years ago today, the ribbon was cut, and the Robert and Penny Fox Tower was opened to advance Wistar biomedical research. In the decade since, The Wistar Institute has stretched the horizons of discovery, with the track record in biomedical research advances to prove it.

In 2011, Wistar began the $100 million Tower’s construction under the direction of the late Robert A. Fox, one of Institute’s most ardent and long-standing supporters. Fox led the building committee responsible for overseeing construction projects, and he also led the capital campaign responsible for raising a significant portion of the funds that made the expansion possible. Fox’s legacy at Wistar goes beyond the Tower that bears his name; Wistar president and CEO Dario Altieri, M.D., holds the Robert and Penny Fox Distinguished Professorship in the Genome Regulation and Cell Signaling Program.

Upon Fox’s passing in 2021, Dr. Altieri said, “It is [Robert’s] vision and commitment that brought Wistar to where it is today — to the pinnacle of research organizations worldwide. There is no greater honor and no greater distinction for me, personally and professionally, than to have my name indissolubly linked to Bob’s in the Robert and Penny Fox Professorship.”

As the chair of the “Building Wistar, Changing the World” committee, Fox helped Wistar raise $35 million, $25 million of which was contributed to the Tower’s construction. Standing at seven stories, the Tower includes 90,000 square feet in laboratory and office space and upon its completion, The Wistar Institute had added space for up to 15 additional labs — a 50% increase from the Institute’s previous biomedical research capacity.

The additional space also revitalized the main atrium, which brings together the old and the new as exposed brick from the original building’s walls joins with the open air, glass, and steel of the modern Tower’s edifice — creating one of the truly unique interiors in Philadelphia architecture. At the base of the Tower sits the 200-person-capacity Sarah and Matthew Caplan Auditorium, which has hosted countless scientific seminars & special events in the intervening decade.

As Robert Fox said, “There is no greater investment than saving lives through science.” The Robert and Penny Fox Tower made an indelible change on the Philadelphia landscape and biomedical research.

“In marking Wistar’s success, over the last ten years, accomplished in the labs & corridors of the Robert and Penny Fox Tower, I am optimistic on what the next ten years will bring,” said Dr. Altieri. “With our new HIV Cure and Viral Diseases Center & our soon-to-come Center for Advanced Therapeutics — Wistar science has an exciting path forward with many new fundamental biomedical research milestones to come.”