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Wistar Scientists Find Gut Microbe Byproduct Drives Antitumor Immunity

Written by The Wistar Institute on . Posted in Featured News.

The team identified the metabolite TMAO drives immune activation in the tumor microenvironment and boosts response to immune checkpoint blockade therapy in pancreatic cancer.

Rahul S. Shinde, D.V.M., Ph.D., Assistant Professor in the Immunology, Microenvironment, and Metastasis Program of Wistar’s Ellen and Ronald Caplan Cancer Center and the Institute’s inaugural Caspar Wistar Fellow published evidence in Science Immunology of a therapeutic target in the gut microbiome for pancreatic cancer.

Recently awarded the Pancreatic Cancer Action Network Career Development Award, Shinde focuses his research efforts on understanding the gut microbiome and identifying potential targets for cancer therapies. In this newly published paper, Shinde and his collaborators reveal that a metabolite derived from a gut microbe called trimethylamine N-oxide (abbreviated TMAO) boosts immunity against tumors by triggering immune activation in pancreatic cancer. Furthermore, the study provides evidence that targeting TMAO production in the gut microbiome could improve the efficacy of immune checkpoint blockade (ICB) therapy for the disease.

Pancreatic cancer is a particularly deadly disease with a tumor microenvironment that aggressively suppresses immune response. Immunotherapies can be improved by boosting immune activation in the tumor microenvironment – a function influenced by the gut microbiome. In the study, the researchers administered TMAO and observed effects on tumor growth and immune response in the tumor microenvironment. They found evidence that TMAO stimulated action from immune cells such as macrophages and T cells as well as increased pancreatic cancer’s responsiveness to ICB therapy, ultimately boosting the body’s ability to identify and attack cancer cells.

“With growing interest in selective targeting of the gut microbiome to improve cancer treatments, this study can create a new paradigm for discovering novel gut microbial metabolites influencing anti-tumor immunity and inform innovative treatment strategies for highly lethal and hard-to-treat pancreatic cancer,” says Shinde, corresponding author on the paper.

He elaborates that his findings raise a series of questions with clinical implications, including what sources of TMAO confer its anti-tumor effects and whether this beneficial TMAO can be achieved by altering these sources. Additionally, he emphasizes that potential future directions of this work could delve into understanding whether TMAO can promote anti-tumor immunity in other cancer types with treatment resistance.

Shinde collaborated with fellow Wistar principal investigators Chi Van Dang, M.D., Ph.D., Aaron Goldman Ph.D., Hsin-Yao Tang Ph.D., Noam Auslander, Ph.D., Mohamed Abdel-Mohsen, Ph.D., and Andrew Kossenkov, Ph.D. on this study.

This work was generously supported by the following: NIH, the W. W. Smith Charitable Trust, 2022 Pancreatic Cancer Action Network Career Development Award, Grant Number “22-20-SHIN,”, the Tobin-Kestenbaum families, as well as the Caspar Wistar Fellowship Program at The Wistar Institute.

Michele Schiavoni poses for the camera at the Wistar office

The Wistar Institute Welcomes Michele A. Schiavoni, New Vice President of Communications & Marketing

Written by The Wistar Institute on . Posted in Press Releases.

PHILADELPHIA—(September 8, 2022)—The Wistar Institute is pleased to announce the appointment of Michele A. Schiavoni, M.S., as Vice President of Communications & Marketing, in a central leadership role that will bolster the visibility of the Institute’s ambitious biomedical research science initiatives and programs advancing the organization’s newly launched Bold Science // Global Impact Capital Campaign.

“I am delighted to welcome Michele to Wistar,” said Dario C. Altieri, M.D., Wistar president & CEO, director of the Ellen and Ronald Caplan Cancer Center, and Robert and Penny Fox Distinguished Professor, “Michele’s leadership will be critical to implementing an integrated communications strategy fluidly aligning priorities as we grow and advance our science and the needs of the Institute. Her knowledge and strong communications experience will be a vital component to the ongoing success of Wistar’s strategic goals.”

A longtime communications executive, Schiavoni brings decades of expertise in building brands for health care systems, nonprofit social services entities, and economic development organizations. Collaborating closely with scientists and administrative leaders, she will oversee marketing and brand strategy across the Institute to coordinate internal and external messaging and reinforce Wistar’s growth trajectory supporting the Institute’s goals and mission. She will also provide strategic communications guidance to the president & CEO.

“It is a privilege to become a part of the Wistar team — Wistar science has a remarkable history of breakthrough research discoveries and developing innovative technologies that have a global impact saving lives,” said Schiavoni. “Wistar scientists continue creating transformative advances in cancer care and infectious disease research. Their latest Capital Campaign supports a bold growth strategy to recruit more scientists to advance international collaboration as well as play a leadership role training the next generation of scientists. I look forward to collaborating with the Wistar team during this exciting time in the organization’s growth.”

Schiavoni joins Wistar from the Delaware Prosperity Partnership, where she served as vice president for external relations and led marketing and communications for Delaware’s lead economic development organization. She previously held communication leadership positions at Elwyn Foundation and ChristianaCare Health System. Schiavoni received a B.A. in communications from the University of Delaware and a M.S. in management communications from Syracuse University, Newhouse School of Public Communication. She also serves as president of the Board of the Tilton Society of Delaware.

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The Wistar Institute is an international leader in biomedical research with special 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.

A cancer cell divides

The Wistar Institute and Jubilant Therapeutics Inc. Find PAD4 Inhibition in Neutrophils Halts Cancer Progression and Metastasis

Written by The Wistar Institute on . Posted in Press Releases.

PHILADELPHIA — (Sept. 7, 2022) — Researchers in the laboratory of Yulia Nefedova, M.D., Ph.D., at The Wistar Institute and collaborators at Jubilant Therapeutics Inc. have uncovered a novel mechanism by which protein arginine deiminase 4 (PAD4) in neutrophils promotes cancer progression. The paper also found that inhibition of this function of PAD4 reduces primary tumor growth and metastasis and enhances checkpoint inhibitor treatments. Jubilant Therapeutics Inc. is developing a novel small molecule PAD4 inhibitor that directly targets this mechanism. The findings appear in Cancer Research, a journal of the American Association for Cancer Research.

“Development of metastases remains a leading cause of death from cancer. Tumor-associated neutrophils have long been implicated in cancer progression. Understanding the mechanisms by which these cells promote tumor growth and metastatic spread is critically important for the development of new treatments,” shares Yulia Nefedova, M.D., Ph.D., associate professor, Immunology, Microenvironment & Metastasis Program, Ellen and Ronald Caplan Cancer Center of The Wistar Institute.

This research revealed the importance of PAD4 protein in the migration of neutrophils, specialized white blood cells that serve as the first line of immune defense in the body, directly impacting both primary tumor growth and secondary malignant tumor spread. Both genetic deletion of PAD4 and pharmacological inhibition of PAD4 using Jubilant Therapeutic Inc’s novel inhibitor dramatically down-regulated chemokine CXCR2, reduced immune suppressive polymorphonuclear myeloid derived suppressor cells (PMN-MDSCs) at tumor and metastatic sites, activated T cells, and synergized with immune checkpoint blockade.

All results point to a potent anti-tumor effect of PAD4 inhibition to target PMN-MDSCs in the tumor microenvironment. This finding is being further investigated in Wistar’s Nefedova laboratory.

“These results highlight the potential of PAD4 inhibition as a novel treatment approach for cancer in addition to the previously established role of this pathway in autoimmune diseases,” said Luca Rastelli, Ph.D., Chief Scientific Officer, Jubilant Therapeutics Inc. “We are developing several highly selective oral, small molecule PAD4 inhibitors, with the goal of bringing this novel mechanism to the clinic as potential therapeutics for tumor metastasis in colorectal and pancreatic cancers, patients with liver metastasis as well as for both acute and chronic autoimmune/inflammatory diseases.”

These findings were only made possible through the supportive collaboration between Wistar, a Philadelphia based nonprofit biomedical research institute, and Jubilant Therapeutics Inc., a clinical-stage precision therapy company developing new therapies to treat oncology and autoimmune disease.

“Only working together are we able to efficiently translate our fundamental research discoveries into clinical realities,” states Heather Steinman, Ph.D., MBA, The Wistar Institute vice president for Business Development & executive director of Technology Transfer.

Co-authors: Hui Deng, Cindy Lin, Laura Garcia-Gerique, Shuyu Fu, Zachary Cruz, Erin Bonner Matthew Rosenwasser, Sridharan Rajagopal, M. Naveen Sadhu, Chandru Gajendran, Mohd Zainuddin, Ramachandraiah Gosu, Dhanalakshmi Sivanandhan, Miriam A. Shelef, Brian Nam, Dan T. Vogl, and Dmitry I. Gabrilovich.

Publication Information: Regulation of tumor progression by PAD4-mediated neutrophil migration and its targeting with a novel selective inhibitor JBI-589. Cancer Research, 2022. Online publication.

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer 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’s Business Development Team is dedicated to advancing Wistar Science and Technology Development through creative partnerships. wistar.org.

Jubilant Therapeutics Inc. is a clinical stage precision therapeutics company advancing potent and selective small molecule modulators to address unmet medical needs in oncology and autoimmune diseases. Its advanced discovery engine integrates structure-based design and computational algorithms to discover and develop novel, precision therapeutics against both first-in-class and validated but intractable targets in genetically defined patient populations. The Company’s advanced pipeline consists of a first in class dual epigenetic modifier, JBI-802, currently in a Phase I/II clinical trial to treat solid tumors, a novel brain-penetrant modulator of PRMT5 for which an IND has been accepted, a brain penetrant PDL1 inhibitor, as well as PAD4 inhibitors for oncology and inflammatory indications. The Company is headquartered in Bedminster, New Jersey and guided by globally renowned key opinion leaders and scientific advisory board members. For more: https://www.jubilanttx.com/

Advancing Scientific Enterprise at Wistar’s Vaccine and Immunotherapy Center

Written by The Wistar Institute on . Posted in Featured News.

With just over a year at The Wistar Institute under their respective scientific belts, innovator-scientists Amelia Escolano, Ph.D., and Daniel Claiborne, Ph.D., have been pushing the scientific envelope in Wistar laboratories using mouse models to pursue basic research and potential therapies for one of the toughest problems in medicine: HIV.

In line with the priorities of Wistar’s Bold Science // Global Impact Strategic Plan to advance the scientific enterprise at the Institute, they are making their mark as the newest members of The Vaccine & Immunotherapy Center (VIC) at The Wistar Institute.

Escolano joined Wistar from Rockefeller University, where she was a postdoctoral fellow. With a background in inflammatory diseases, Escolano began her postdoctoral work focusing on vaccine design. There, she was one of the first researchers to use a mouse model called immunoglobulin knock-in mice for HIV vaccine research. Escolano’s expertise with this mouse model, along with her experience developing sequential immunization protocols, make her a valuable addition to the VIC team.

A knock-in mouse is a mouse that has a specific DNA fragment inserted into a particular position on the mouse’s genome. In the case of immunoglobulin knock-in mice, genes that make antibodies are inserted into the genome. Escolano and her lab then use the mice to test whether their immunogen designs — proteins that induce an immune response, like in vaccines — activate the mouse’s B cells to produce those antibodies that fight disease.

“These mice are used to see how we can activate those B cells and how we can make them evolve to become broadly neutralizing antibodies,” said Escolano.

“Making antibodies evolve” is Escolano’s area of research, specifically designing a sequential immunization protocol to induce neutralizing antibodies against HIV. Sequential immunization involves a first injection with one immunogen, then a subsequent injection with a slightly different immunogen, and so on. The purpose is to gradually introduce mutations on the antibodies which make them evolve to neutralize against HIV more effectively so that the result is a potent and broadly neutralizing antibody. This sophisticated form of antibody is necessary to combat HIV and other viruses that mutate quickly and form many different strains.

“Here at Wistar, I’m continuing my efforts to design these types of sequential immunization protocols and make them work in model systems and eventually in humans,” said Escolano. Ultimately, she and her lab hope to answer the question of why some vaccines induce protection for years, while others only offer protection for months. With this knowledge, scientists will be able to design vaccines that induce protection for a long time — potentially even a lifetime.

Claiborne came to the VIC as a Caspar Wistar Fellow. This fellowship is awarded to early-stage investigators with outstanding research records who, as Claiborne puts it, “have unique angles on things.” His distinct expertise is using humanized mouse models to research T-cell dysfunction, specifically in pursuit of therapies that could cure HIV. “At the same time Wistar was just starting a humanized mouse program, I came in with knowledge on how to use that model well,” Claiborne shares.

In the context of vaccinology and immunology research, a humanized mouse is a mouse that is engineered to have a human immune system. Claiborne is a proponent of this model because it can be more readily translated to clinical settings. “I’m a basic scientist, but it’s always important to think about how this is going to advance human health,” he said. “In humanized mice, you can use authentic strains of HIV, which facilitates the translatability of anything you’re doing that’s a therapeutic intervention.”

In his own research, Claiborne is using humanized mice to try to answer the question of how T cells, a type of white blood cell, become dysfunctional when they see their target over and over again, like in chronic HIV or cancer. “Functional exhaustion” turns off T cells and protects them from becoming overactivated — a state in which T cells could kill you. However, when it comes to certain therapies for HIV and cancer, such as CAR T-cell therapies, T cells that turn off ruin the efficacy of the treatment.

In CAR T-cell therapies, T cells are removed from a patient’s blood. Then, a specific receptor is added to the T cells that helps them find the target the patient’s body needs to fight. The T cells — now called “chimeric antigen receptor” or “CAR” T cells — are injected back into the patient. However, these cells are only effective as long as they continue to find and fight that target. Researchers found that when CAR T cells encounter the same antigen repeatedly and do not clear it, as with HIV, they self-regulate and turn off. Claiborne and his lab are investigating how this process begins.

“At the end of the day, we’re trying to figure out how T cells start to go down that path of functional exhaustion so we can stop that from happening,” said Claiborne. “That would have implications for all CAR T-cell therapies.”

Scientists Drive Innovation at Wistar’s Ellen and Ronald Caplan Cancer Center

Written by The Wistar Institute on . Posted in Featured News.

Wistar continues to be a dynamic environment prepared to tackle biomedical challenges in a collaborative, innovative, and inclusive culture. Read more about our Ellen and Ronald Caplan Cancer Center commitment to scientific career development, a diverse research community, and how previously introduced recruits are settling in and advancing impactful science.

ENHANCING CAREERS AND EXPANDING DIVERSITY

Italo Tempera, Ph.D., newly appointed Associate Director for Cancer Research Career Enhancement, was a postdoctoral fellow at Wistar and returned as an associate professor in the Gene Expression and Regulation Program in 2020. His research focuses on epigenetic mechanisms behind Epstein-Barr Virus (EBV). He was recently named associate director for Cancer Research Career Enhancement.

Tempera considers the time he spent at Wistar to be formative. With its very collaborative introductory environment, Wistar is an “… opportunity for our students not only to learn about our science but to get in contact with scientists.”

Furthermore, he outlines what he would like to accomplish in his new role. “We’re outstanding scientists and we have excellent mentors. The opportunities for our trainees to do an internship with different departments is something we want to push forward, and we want to expand the Cancer Biology Ph.D. program that we have now with Saint Joseph’s University.”

He shares that Wistar gave him the opportunity to grow as a scientist and advance in his research career. “When someone asks what was one of the most important aspects of a scientist’s pre- or post-doctoral training, my goal is for the trainee to think back and reply that being at Wistar has made all the difference.”

Jessie Villanueva, Ph.D., newly appointed Associate Director for Diversity, Equity, and Inclusion, joined Wistar first as a postdoctoral fellow and then was appointed assistant professor in the Molecular and Cellular Oncogenesis Program. Her work aims to identify targets for therapy to treat melanoma.

“Diversity leads to innovation and scientific excellence. New discoveries and scientific breakthroughs often rely on collaborations, and diverse teams are more creative and resourceful,” she shares.

For her new role, Villanueva aims to lead and inspire everyone at Wistar to integrate inclusion, diversity, and equity into all facets of the Institute. “Our goal is to continue fostering an inclusive community where everyone can develop to their full potential while contributing to Wistar’s mission of scientific discoveries.” To accomplish this, she plans to work with leaders and stakeholders across the Institute to identify challenges and areas for
improvement and propose strategies to address them.

“Diversity supports Wistar’s mission,” Villanueva asserts. She elaborates that many of the Institute’s scientific breakthroughs are largely impactful for biomedical sciences and human health, and these discoveries rely on “… outstanding scientists, trainees and staff with diverse backgrounds and skills who support Wistar’s goals wholeheartedly.”

ADVANCING IMPACTFUL SCIENCE

Nan Zhang, Ph.D., Assistant Professor, Immunology, Microenvironment & Metastasis Program, joined Wistar in September 2021 as an assistant professor and currently researches how immune cells play a role in tumor growth in abdominal cancers.

“Studying disease was always one of my passions,” Zhang shares as he describes both a personal and professional draw to cancer research. He began his career studying the immune system — particularly macrophages, a special population of white blood cells that removes unwanted materials in the body like harmful microorganisms or dead cells.

Upon completion of his postdoctoral position, Zhang felt that cancer in the peritoneal space — the area of the body encompassing the abdomen and the organs within it — would be a great direction to pursue for his future career because of its unique complexity and how it’s less understood relative to other focus areas for cancer research. This is what he works on now at Wistar.

Immersed in the Institute’s world class techniques, resources, and renowned scientists, Zhang continues to push forward his research to tackle how to use specialized cells called macrophages to combat tumors as a checkpoint therapy for cancer. He is also investigating immunological questions about the microenvironment of the peritoneal space and how this knowledge can help inform therapeutics and treatment development.

He shares, “Wistar is competitive, and the support in the Institute for junior faculty is great. We have meetings every week and this is an environment I really wanted for my career and research.”

Noam Auslander, Ph.D., Assistant Professor, Molecular & Cellular Oncogenesis Program, joined Wistar in June 2021 as an assistant professor and conducts her research at the intersection of computer science and biological science. She uses machine learning to investigate genetic factors underpinning cancer evolution to improve diagnostics and therapeutics.

“I work on cancer and viruses. Both are complex and have high mutation rates. As a computational scientist, it’s very interesting because there are a lot of computational challenges that can be investigated,” Auslander comments.

She joined The Wistar Institute because of its reputation and expertise, particularly in researching both cancer and viruses. She shares her experience during her first year, “It’s a small institute with a lot of opportunities to collaborate. It’s a very good environment and people are very helpful and supportive.”

Simultaneous to establishing and expanding her lab group, Auslander is currently looking into improving clinical prognosis to cancer and other diseases by uncovering unknown infectious agents and therapeutic biomarkers. To accomplish this, her lab applies the power of advanced computational platforms to very intricate and complex biomedical data to make these predictors of treatment responses more biologically interpretable. She says, “My main focus at the moment is to train my growing lab and develop frameworks to identify new viruses and eventually new microbiomes in cancer.”

A Wistar Journey Through the Past, Present, and Future of Immunization Work

Written by The Wistar Institute on . Posted in Featured News.

Vaccines are a crucial public health tool in its’ arsenal against diseases. Resurgences of diseases long thought eradicated are popping up decades later in sewage waters here and abroad, and we’ve witnessed what the impact of war has on countries whose health systems have crumbled under the ravages of war—we are not as far removed as we’d like to be from diseases once prevented by vaccines. With more than half a century of basic research for vaccine development, The Wistar Institute plays an integral role in immunization around the globe.

Rubella, rabies, and rotavirus. Wistar scientists developed vaccines for these diseases that are used in immunization programs worldwide. The rubella vaccine by Wistar scientists effectively ended the pandemic in the United States, as declared by the CDC in 2005. Two rabies vaccinations developed from the Institute addresses the disease in both animals and humans. In 2006, Wistar and collaborators created a rotavirus vaccine which became part of the regular immunization schedule for U.S. babies and is used or approved in over 45 countries. And we’re just getting started.

“Immunization is possibly one of the most impactful medical interventions ever developed. Millions of lives are saved each year by vaccination, and we live healthier and longer lives due to vaccines.” states David Weiner, Ph.D., Executive Vice President, Director of Wistar’s Vaccine & Immunotherapy Center, and W.W. Smith Charitable Trust Professor in Cancer Research, in the Immunology, Microenvironment & Metastasis Program at Wistar’s Ellen and Ronald Caplan Cancer Center.

This National Immunization Awareness Month, we have shared a few snapshots of current vaccine development projects at the Institute as well as what these researchers’ hopes are for the future of immunization.

Tackling Both Infectious Disease and Cancer with Immunization

Dr. Weiner’s research takes on both infectious disease and cancer. His work encompasses developing new ways to build and deliver synthetic nucleic acid vaccines – particularly advancing a new approach that drives self-assembly of an antigen into a more potent vaccine inside a vaccinated person. This approach gives the body the genetic information to become the factory to create the vaccine. Furthermore, his lab is developing new types of cancer therapeutic vaccines with the goals of creating strong anti-cancer immunity and eradicating cancer cells.

Weiner’s collaborations with public and private institutions is centered around novel immunization technology developed from his lab called DNA-encoded monoclonal antibodies (DMAbs) against diseases such as COVID-19, Zika, and Ebola.

Regarding the future, he shares, “Together with our collaborators, we hope to move new prototype HIV vaccines into human clinical trials later this year, and continue to advance vaccines for emerging pathogens, as well as cancer immunotherapies.”

Developing DNA Vaccines

Ami Patel, Ph.D., Caspar Wistar Fellow in the Vaccine and Immunotherapy Center, focuses her scientific efforts on DNA vaccines which have potential to be more stable and economical over traditional vaccine production. “We are trying to understand how different vaccines work in the body. How do vaccines generate different types of immune responses and can we use this to understand protection against infectious diseases. We are using this information to help develop the next generation of potential vaccines.” she says.

Patel emphasizes the importance of vaccines for young children and adults by calling back to various infectious diseases like polio that are no longer very common because of immunization. “Vaccines help protect us against serious disease. Some of us remember the discomfort of chicken pox as children. There is now a vaccine.”

While she calls the COVID-19 pandemic “devastating to global health”, Patel also recognizes the pandemic’s challenges proved fertile ground for an extraordinary collaborative time for biomedical scientists. “My hope is for vaccine researchers across different disciplines to continue to work together to help us understand different infectious diseases and develop better vaccines.”

Zooming in on a Nanoscale

In collaboration with Weiner, Daniel Kulp, Ph.D., associate professor in the Vaccine and Immunotherapy Center, has embraced nanotechnology in his vaccine research. “We are developing rationally engineered nanoparticle vaccines that can elicit extremely broad coronavirus immunity providing a proof-of-concept that a pan-coronavirus vaccine is possible,” Kulp elaborates.

While the Kulp laboratory is developing several promising vaccines, he emphasizes that his goal is to assess these candidates in humans. He says, “We are working to reduce barriers for launching small experimental medicine clinical trials allowing for broader evaluation of our best vaccine concepts. Through this type of work, I have high hopes that our generation can claim credit for the eradication of SARS-CoV-2.”

Kulp expresses that “Vaccines are one of the single most effective medical technologies humans have developed saving hundreds of millions of lives. Vaccines do not work without immunizations. This message is incredibly important.”

Looking Inside the Gut for Answers to Long-COVID

Written by The Wistar Institute on . Posted in Featured News.

This Q&A offers a behind the science peek into some of the long-term effects of COVID on the body influenced by the gut microbiome.

In a paper published in JCI Insight, Mohamed Abdel-Mohsen, Ph.D., associate professor in The Wistar Institute Vaccine & Immunotherapy Center, and collaborators from across the country and world, found that changes to the human microbiome can contribute to certain symptoms of long-COVID. Abdel-Mohsen has been dissecting the “gut-lung” axis for years, and these new findings build upon past research on this system and further identifies a specific phenomenon – the translocation of fungal microbes from the gut and/or the lung to the blood – that could possess clinical relevance in the development of treatments for persistent, long term effects of SARS-CoV-2 on the body.

We had a conversation with Abdel-Mohsen to learn more about the latest knowledge surrounding “leaky gut” and long COVID.

Q: What is the gut microbiome and why is it important in combatting disease?

A: In our gut and other surfaces like our lungs and mouth, there are many microbes that are very important for maintaining human health. In the last decade, it has become very clear that these microbes play a very important role in regulating health and disease. The gut microbiome is a combination of microbes such as bacteria and fungus that occupy a host’s gut. There is a rising number of papers linking the microbiome with diseases such as Alzheimer’s and Parkinson’s. There is a lot of interest in understanding this microbiome, what microbes do, and how to take advantage of this knowledge to design novel strategies to fight different diseases. For example, in addressing cancer, cancer immunotherapy has been associated with changes in composition of the gut microbiome. Another example is that it has now become clear that the microbes in the gut can impact the brain through the gut-brain axis. The microbiome has also been associated with cardiovascular diseases through the gut-heart axis. And the gut microbiome could be involved in a biological cycle with the lung, which itself has a microbiome, through what’s called the gut-lung axis.

Q: What makes long COVID an interesting and particularly complex topic to study?

A: Some people do not completely recover from COVID-19. Between 10 to 30 percent of COVID-19 patients experience either persistent, recurrent, or even new symptoms. If they have these symptoms at least three months after acute COVID-19 infection, it can be called long-COVID or post-acute sequelae of SARS-CoV-2 (PASC). A person’s quality of life is significantly compromised by this syndrome, and some of the symptoms continue for more than a year. This is why we and many others are interested in understanding what might be causing these persistent, recurrent, or new symptoms three to four months after infection.

However, there is no good definition of the phenomena yet. It’s not clear what should be considered long COVID and what is not. There is nothing that the physician can measure to diagnose long COVID. People cannot go and take a test for long COVID, so physicians and researchers rely on self-reporting symptoms from patients, making it very difficult to study because scientists need a very clear system and a very good database. Furthermore, because long COVID is diverse, there are a lot of potential mechanisms that might be contributing to it either in the same individual or within a group of individuals, which makes it complex. One of these potential mechanisms is microbial translocation – some disruption in the gut and/or the lung that leads microbes to translocate which causes inflammation.

Q: What is microbial translocation?

A: Microbial translocation is when microbes translocate through the epithelial barrier of an organ like the gut or lung and go from where they should be to where they should not be – such as the blood. With infection or injury in the lung, like from SARS-CoV-2, comes inflammation in the body and the release of molecules by the host called cytokines.

Cytokines can injure the gut by disrupting the gut’s barrier, allowing microbes such as fungus or bacteria and their byproducts to translocate from the gut to the blood. When the immune system in the blood sees these microbes that should not be there, it reacts by increasing inflammation. This can worsen the original lung disease, which leads to more inflammation and so on, leading to a vicious cycle. This could cause immune exhaustion where this phenomenon of higher inflammation and lower immune function can lead to many diseases.

Q: Can you briefly summarize the findings of your recent research paper?

A: In this scientific collaboration, blood samples were studied from two independent cohorts of long COVID patients from San Francisco and Chicago. We looked at markers of gut barrier permeability and microbial translocation. We found that individuals with long COVID have higher level of markers of gut barrier permeability and fungal translocation compared to individuals who are fully recovered. This level of fungal translocation is correlated with more inflammation and a higher number of symptoms where this individual suffers from lower quality of life.

Specifically, to measure fungus in the blood, we measured β-glucan – a polysaccharide sugar molecule that is on the surface of the fungi. In patients with long COVID, we found levels of β-glucan higher than the normal level in people who are fully recovered or who never got COVID-19. That was interesting for us because the polysaccharide β-glucan can directly cause inflammation. We also did mechanistic experiments and showed that the amount of β-glucan in the plasma of people suffering from long COVID is enough to directly cause inflammation.

Q: How translatable are these findings to understanding the disease and toward the development of COVID therapeutics?

A: Inflammation by fungal translocation may be targeted by drugs. You can block the signaling pathway activated when a fungal polysaccharide binds to the cell, which prompts it to produce inflammation. There are many steps of the signaling pathway in the cell that can be inhibited.

In this paper, we use one small molecule inhibitor to inhibit this inflammation signaling pathway and saw the pathway could be inhibited successfully. In summary, we identified one of the potential mechanisms of long COVID which might contribute to inflammation directly and this mechanism can be targeted with a small molecule inhibitor.

There are many different potential drugs that may be further developed for inhibition. These are potential therapeutic applications that could be tested as soon as preclinical animal models of long COVID are available.

Q: What are some related questions or future directions you would like to see your own lab or other scientists take the findings of this paper in?

A: One of the most common symptoms of long COVID is neurological impact. We are interested in exploring the potential link between the gut-lung and gut-brain axis.

Also, how much does the gut versus the lung contribute to fungal translocation? How can we use antagonists as therapeutic options in a preclinical animal model to treat long COVID as a step to move it to the clinic?

Additionally, we need to understand whether the gut resilience to common stimuli is compromised after acute SARS-CoV-2 infection and whether this contributes to this microbial translocation we observed. I think there are a lot of studies we need to do on the upstream mechanism of this disruption.

Finally, we don’t believe that long COVID is solely caused by microbial translocation. This is probably one out of several mechanisms that contribute to symptoms. It is likely that long COVID is multifactorial in nature and involves multiple processes to some degree, either in the same individuals or in different groups of individuals. For example, how is fungal translocation related to the B cell dysfunction, related to SARS-CoV-2 antibodies, or related to the persistent virus? We eventually need to connect all these mechanisms together to see the full picture.

Q: What would you like readers to take away from this research?

A: The gut microbiome is being recognized as a very important contributor to overall health and conversely in association with many diseases. Persistent and recurrent symptoms have also been reported for SARS-CoV-1, MERS, polio, and many other infections. Understanding mechanisms that contribute to this post-acute infection sequela will be a very important factor moving forward for SARS-CoV2 but also for a plethora of existing and emerging infections. For long-COVID, this is an opportunity for us to understand the disease and how gut microbial translocation is likely a major contributor of these symptoms.

This research was supported by The Campbell Foundation, Commonwealth of Pennsylvania COVID-19 funding, and NIH Cancer Center Support Grant.

Congratulations to the 2022 BTT Program and Fox BRT Apprenticeship Graduates!

Written by The Wistar Institute on . Posted in Featured News.

On August 4, The Wistar Institute hosted a ceremony celebrating the 2022 graduates of the Biomedical Technician Training (BTT) Program and Fox Biomedical Research Technician (BRT) Apprenticeship.

The hybrid event kicked off with a welcome by Dario Altieri, M.D., President and CEO of the Institute, and brief remarks from Kristy Shuda McGuire, Ph.D., Wistar dean of Biomedical Studies. Shuda McGuire expressed the Institute’s gratitude to all the supporters of both programs as well as her excitement for what the future holds for Wistar education and training program trainees. “It is a testament to The Wistar Institute’s support that education and life sciences represents one of three pillars in our BOLD Science // GLOBAL Impact strategic plan and capital campaign.”

Juan Esteban Perez Rodriguez, graduate from the BTT Program, and Jane Koshy, graduate from the Fox BRT Apprenticeship, each spoke, reflecting on their personal experiences as Wistar trainees and what they learned throughout their time. From what it means to work in a lab to the victories and mistakes made, the graduates felt they are now individuals capable of adapting and working independently in the life science workforce.

BTT speaker Juan Esteban Perez Rodriguez recounted one of his early days in the program where Shuda McGuire summed up what their time together could accomplish, “Kristy said ‘We are the BTT program. We are a family, and we are one,’ and that really set the tone for the year. Even though we students came from different community colleges, we were there to support and lean on each other.”

Keynote speaker Lois Tolvinski, M.S., a former BTT graduate and current manager of laboratory operations at life science company Chimeron Bio – the newest industry collaborator of the BTT program (thanks to Tolvinski’s connection) – shared her path to science and congratulated trainee graduates. She encouraged them to ask questions, take what they learned from Wistar with them throughout their academic and professional journeys, and carry that initial spark they had for science upon starting the Program with them throughout their careers. “My success story was built on the foundation of my BTT training,” Tolvinski shared. “It’s amazing to bring my professional experience full circle and connect my time at Wistar to my current role at Chimeron Bio.”

After the presentation of certificates to graduates by leaders from Community College of Philadelphia and Montgomery County Community College, a reception followed in the Tobin Family Atrium.

Aligning with strategic plan goals for the next five years to expand education in the Hubert J.P. Schoemaker Education and Training Center, Wistar is looking forward to the expansion of both the BTT and Fox BRT education and training programs with funding from the PA Department of Labor and Industry, National Science Foundation Advanced Technological Education Program, the Fox Family, and various philanthropic supporters.

Click here to watch the event recording and listen to the full speeches.

Completion Ceremony of the Biomedical Technician Training Program and the Biomedical Research Technician Apprenticeship: Class of 2020 and 2022

Rahul Shinde, D.V.M, Ph.D., Receives Pancreatic Cancer Action Network Career Development Award

Written by The Wistar Institute on . Posted in Featured News.

The Pancreatic Cancer Action Network announced that Rahul S. Shinde, D.V.M., Ph.D., Assistant Professor in the Immunology, Microenvironment & Metastasis Program of Wistar’s Ellen and Ronald Caplan Cancer Center, was bestowed the Pancreatic Cancer Action Network Career Development Award.

Shinde was the Institute’s first Caspar Wistar fellow and was promoted to assistant professor at the start of 2022. He describes his experience as a researcher as “wonderful” and “one in which I have developed personally and professionally” – crediting the collaborative atmosphere and scientific environment at Wistar as excellent support in helping to garner his lab funding. Currently, Shinde is working on characterizing the gut microbiome and host metabolism in the context of immune responses to cancer.

“Growing as a researcher at Wistar is an amazing feeling filled with learning, discovering, and sharing science,” he says, adding that receiving this award at this stage in his research career is an honor. “The PanCAN Career Development Award is a gratifying experience that reassures me that I’m conducting impactful research in my laboratory.”

The $250,000 in grant funding will help propel forward his scientific focus on characterizing how gut microbe-derived metabolites impact immune cell function and support foundational research into a potential supplementary therapy for pancreatic cancer. Shinde elaborates, “The successful outcome of this research may form the basis for gut bacteria-based therapies or diet-based therapies to improve the survival as well as the quality of life of pancreatic cancer patients.”

Research supported by the 2022 Pancreatic Cancer Action Network Career Development Award, Grant Number “22-20-SHIN.”

The Wistar Institute building

Wistar Receives Merit Extension from the National Cancer Institute

Written by The Wistar Institute on . Posted in Press Releases.

PHILADELPHIA — (August 2, 2022) — The National Cancer Institute (NCI) has granted a Merit Extension Award to The Wistar Institute’s Ellen and Ronald Caplan Cancer Center totaling more than $5 million. The Institute is the first NCI-designated Basic Cancer Center in the nation to receive this prestigious award, which extends its Cancer Center Support Grant (CCSG) for two additional years. Furthermore, Wistar’s Ellen and Ronald Caplan Cancer Center is among the first five NCI-designated Cancer Centers to earn the distinction countrywide.

“The Wistar Institute is the first basic NCI-designated cancer center to earn the prestigious Cancer Center Support Grant Merit Extension,” said Henry P. Ciolino, Ph.D., director of the Office of Cancer Centers at the NCI. “NCI extended the NCI-designation based on Wistar’s continued exceptional performance in uncovering the fundamental aspects of cancer, advancing these basic discoveries to impact patients through translation to clinical applications, and for conducting education and training of future cancer scientists. The seven-year term of the current NCI-designation will allow Wistar to increase its scientific impact through longer-range planning.”

Wistar’s Ellen and Ronald Caplan Cancer Center focuses on research for cancer prevention, diagnosis, and therapy, and the Cancer Center Support Grant (CCSG) facilitates the Institute’s ability to embrace an interdisciplinary approach that merges basic, translational, and disease-relevant research. Having received an “exceptional” rating – the highest possible – in its past two, consecutive CCSG renewal applications, and maintained exceptional research progress, institutional commitment, and leadership, the Merit Extension application was approved by the NCI. This award will enable the Ellen and Ronald Caplan Cancer Center to further advance the initiatives of its 2019 CCSG as well as expand on programmatic initiatives recently launched by the Institute’s Bold Science // Global Impact five-year strategic plan.

“The Wistar Institute is honored to receive this extension,” said Dario C. Altieri, M.D., president and chief executive officer, director of the Ellen and Ronald Caplan Cancer Center, and the Robert and Penny Fox Distinguished Professor at The Wistar Institute. “We are committed to scientific excellence in the face of diseases affecting people across the country, and we are grateful the NCI recognizes our determination and single-mission focus that has propelled forward a deeper understanding of cancer biology. We will continue to invest in promising scientific talent and training programs and pursue innovative solutions to cancer.”

Rugang Zhang, Ph.D., deputy director of the Ellen and Ronald Caplan Cancer Center, Christopher M. Davis Endowed Professor, and program leader of the Immunology, Microenvironment & Metastasis Program shares, “This merit extension not only reflects the NCI’s confidence in our Cancer Center’s remarkable momentum and exceptional trajectory, but also recognizes the excellent leadership of Dr. Altieri and the team at Wistar. This is truly a great achievement for our Cancer Center.”

In 1972, Wistar became the first NCI-designated Basic Cancer Center in the nation and has since been continuously recognized and supported by the NCI. Wistar’s Ellen and Ronald Caplan Cancer Center tackles cancer through multiple lenses, exemplified through the three scientific research programs at the Institute: the Gene Expression and Regulation Program; the Immunology, Microenvironment and Metastasis Program; and the Molecular and Cellular Oncogenesis Program. Recognized as a Basic Cancer Center, Wistar does not treat patients, grant degrees nor does it have an in-house health care system. This opens opportunities to collaborate with regional health care systems and public and private sectors on focused efforts into the science behind the treatments for cancer.