Copyright The Philadelphia Inquirer
University of Pennsylvania professor E. John Wherry is good friends with Fred Ramsdell, who was recognized earlier this month with a Nobel Prize for his research in immunology. Wherry recalled sitting with Ramsdell, a scientific advisor for the California-based biotech company Sonoma Biotherapeutics, in a meeting two months ago and picking his brain about the future of autoimmunity research. “What are the opportunities? Where is the field going?” Wherry recalled asking. He said Ramsdell’s advice — to stay focused on supporting the foundational academic research — is helping to inform the scientific direction and programming at Penn’s Colton Center for Autoimmunity, which Wherry directs. The center opened in 2021 and is now the centerpiece of Penn’s recently launched $376 million research facility focused on immune health, autoimmunity, and infectious diseases. Wherry was happy to see Ramsdell awarded a 2025 Nobel Prize in Physiology or Medicine, shared among three scientists, for his research into peripheral immune tolerance, a process that prevents the immune system from attacking the body. “It could not have happened to a nicer guy,” he said. The Nobel-prize winning discovery is especially important for understanding autoimmunity, he emphasized, and could be leveraged to treat autoimmune diseases. “We now have the power to push the immune system in different directions, not only to treat those diseases, but also to tell us about where the diseases are going,” Wherry said. Penn’s new research facility, which will span seven floors of an office building at 3600 Civic Center Blvd. in University City, is focused on using immunology to diagnose, treat, and prevent diseases. Wherry’s lab is moving into the space this month. “We are in the most exciting time in my lifetime for immunology,” he said. The Inquirer spoke with Wherry to learn more about the future of immunology research at Penn in a conversation lightly edited for length and clarity. We have the Colton Center for Autoimmunity, with really wonderful philanthropic support from Judy and Stewart Colton. They’re giving us resources to make bets on high-risk, high-reward science, and to do that at a pretty good scale. We made some big bets on CAR-T cells and autoimmunity, on mRNA therapeutics, on high-throughput screening, and on AI drug discovery. We have this Immune Health Platform lab. The idea is that we should be capturing samples theoretically from every patient we treat, ideally around the time they get a new treatment or there’s some change in their disease. Once we’ve built a model using this data and understand the rules by which the immune system functions, we can separate the model from the primary data. You can fine-tune the model and make predictions about other diseases, clinical trials that a company might want to do, and other health systems data. Our large database contains about 3,000 patients’ worth of data. We hope to get to 10 or 20,000 patients’ worth. Who will be part of this new research facility? There are about 25 immunology labs moving in. They include disproportionately younger labs, people who have just arrived at Penn in the last two to three years. We have enough space for probably around 35 to 37 labs, so we would like to recruit and bring new ideas in. The way things happen in science is because people talk. We’ve created a physical workspace that’s going to force people to interact in new and different ways and just create more opportunities for serendipity. What are some of the new projects that have been funded? We have someone funded to work on the way the immune system recognizes our own DNA or RNA. lf the DNA in the nucleus of any cell in your body gets out of the nucleus, it’s a really bad thing, because that looks like a bacteria or a virus [to your immune system]. It triggers massive inflammation. The sensors for that can get miswired, and when they do, it can often lead to really devastating autoimmune disease, sometimes a fatal autoimmune disease within just a few years. We have a great researcher named Jonathan Miner who’s identified what happens when those proteins get mutated, and has also developed drugs that basically adapt the mutation to not be as pathogenic. We have some other really interesting studies on being able to regulate the way our bodies make antibodies, since that can be the pathogenic event in autoimmunity. If you make an antibody against proteins in your nerve ending, you can have diseases that end up causing muscle weakness. We’re starting to identify the way the immune system gets triggered to make antibodies against the wrong things. » READ MORE: A cold triggered an autoimmune disease in a Pa. man. Now he’s channeling his challenges into advocacy for people with rare diseases. And then we have some really cool projects on CAR-T cells and autoimmunity, where we’re using standard CAR-T cells from cancer to get rid of B cells, which are cells that make antibodies in autoimmune diseases. We also have people inventing new kinds of CAR-T cells to help address other challenges in autoimmunity. What is the focus of your lab’s research? In the late 1990s and early 2000s, I became very interested in how the immune system deals with chronic infections. When you can’t fully eradicate an infection, what does the immune system do? Why doesn’t the immune system clear things like HIV or hepatitis B, and what are the mechanisms behind that failure? During our studies, we identified a process called T cell exhaustion. T cells are the part of the immune system that fights viruses and also tumors. Our core is always to understand this idea of immune exhaustion. It plays a role in infectious disease, it plays a role in cancer, and it definitely plays a role in autoimmunity. What are some of your current projects? We’re trying to understand the heterogeneity in different autoimmune diseases. To give an example, one is a really challenging kind of blistering inflammatory skin disease called Hidradenitis suppurativa, where there’s just massive inflammation of immune cells in your skin, and it causes really hard-to-treat skin lesions. We now are profiling all of the immune cells in the tissue in the skin and identifying new targets for therapeutics. We’re also interested in this idea that the immune system sees everything that’s happening in your tissues, meaning it acts like a biosensor. If we understand the things the immune system is seeing, we can start to predict trajectories of disease. The inspiration for our study on infant health [not yet published] came from a neonatologist who came to the lab and said, ‘These really premature infants have this kind of lung inflammation that we don’t understand.’ We realized that somewhere around 10 or 20% of those really premature infants get infected while they’re in the ICU. And we were able to identify what those infections look like early in life. We think we can start to piece together ways that we might be able to use the immune system more effectively, or at least treat the damaging inflammation that might come from an early-life infection. What bets are you making on AI drug discovery? We’re very excited about an AI-based approach for drug discovery and drug repurposing that is being led by David Fajgenbaum, the physician who had Castleman disease and essentially cured himself. He has a big infrastructure to basically look at all FDA-approved drugs and identify ways to repurpose them for diseases they weren’t originally intended for. We can do AI predictions, take the top list of drugs from that, and then put that into a high throughput screening facility where Sara Cherry, who is brilliant and amazing, can now screen to identify which of those drugs might be able to provoke the effect we want from cells involved in autoimmunity.
