The American Association for Cancer Research (AACR), the largest cancer research organization in the country and based in Philadelphia, will bestow its 2023 Award for Lifetime Achievement in Cancer Research to Carl June, Richard W. Vague Professor in Immunotherapy in the Department of Pathology and Laboratory Medicine at Penn Medicine. June is also Director of the Center for Cellular Immunotherapies, Director of the Parker Institute for Cancer Immunotherapy, and member of the Penn Bioengineering Graduate Group. He is recognized for his groundbreaking work in developing the first gene-editing cell therapy for cancer and for his pioneering work with CAR T cell therapy.
Throughout his career, Brian Litt has fabricated tools that support international collaboration, produced findings that have led to significant breakthroughs, and mentored the next generation of researchers tackling neurological disorders. (Image: iStock Photo/Alona Siniehina)
When Brian Litt of the Perelman School of Medicine and School of Engineering and Applied Science began treating patients as a neurologist, he found that the therapies and treatments for epilepsy were mostly reliant on traditional pharmacological interventions, which had limited success in changing the course of the disease.
People with epilepsy are often prescribed anti-seizure medications, and, while they are effective for many, about 30% of patients still continue to experience seizures. Litt sought new ways to offer patients better treatment options by investigating a class of devices that electronically stimulate cells in the brain to modulate activity known as neurostimulation devices.
Litt’s research on implantable neurostimulation devices has led to significant breakthroughs in the technology and has broadened scientists’ understanding of the brain. This work started not long after he came to Penn in 2002 with licensing algorithms to help drive a groundbreaking device by NeuroPace, the first closed-loop, responsive neurostimulator to treat epilepsy.
Building on this work, Litt noted in 2011 how the implantable neurostimulation devices being used at the time had rigid wires that didn’t conform to the brain’s surface, and he received support from CURE Epilepsy to accelerate the development of newer, flexible wires to monitor and stimulate the brain.
“CURE is one of the epilepsy community’s most influential funding organizations,” Litt says. “Their support for my lab has been incredibly helpful in enabling the cutting-edge research that we hope will change epilepsy care for our patients.”
Gregory Bowman, the Louis Heyman University Professor, has joint appointments in the Department of Biochemistry and Biophysics in the Perelman School of Medicine and the Department of Bioengineering in the School of Engineering and Applied Science. (Image: Courtesy of School of Engineering and Applied Sciences)
His research aims to combat global health threats such as COVID-19 and Alzheimer’s disease by better understanding how proteins function and malfunction, especially through new computational and experimental methods that map protein structures. This understanding of protein dynamics can lead to effective new treatments for even the most seemingly resistant diseases.
“Delivering the right treatment to the right person at the right time is vital to sustaining—and saving—lives,” Magill said. “Greg Bowman’s novel work holds enormous promise and potential to advance new forms of personalized medicine, an area of considerable strength for Penn. A gifted researcher and consummate collaborator, we are delighted to count him among our distinguished PIK University Professors.”
Bowman came to Penn from the Washington University School of Medicine’s Department of Biochemistry and Molecular Biophysics, where he served on the faculty since 2014. He previously completed a three-year postdoctoral fellowship at the University of California, Berkeley.
Bowman’s research utilizes high-performance supercomputers for simulations that can better explain how mutations and disease change a protein’s functions. These simulations are enabled in part through the innovative Folding@home project, which Bowman directs. Folding@home empowers anyone with a computer to run simulations alongside a consortium of universities, with more than 200,000 participants worldwide.
His research has been supported by the National Science Foundation, National Institutes of Health, National Institute on Aging, and Packard Foundation, among others, and he has received a CAREER Award from the NSF, Career Award at the Scientific Interface from the Burroughs Wellcome Fund, and Thomas Kuhn Paradigm Shift Award from the American Chemical Society. He received a Ph.D. in biophysics from Stanford University and a B.S. (summa cum laude) in computer science, with a minor in biomedical engineering, from Cornell University.
“Greg Bowman’s highly innovative work,” Winkelstein said, “exemplifies the power of our interdisciplinary mission at Penn. He brings together supercomputers, biophysics, and biochemistry to make a vital impact on public health. This brilliant fusion of methods—in the service of improving people’s lives around the world—will be a tremendous model for the research of our faculty, students, and postdocs in the years ahead.”
The Penn Integrates Knowledge program is a University-wide initiative to recruit exceptional faculty members whose research and teaching exemplify the integration of knowledge across disciplines and who are appointed in at least two schools at Penn.
The Louis Heyman University Professorship is a gift of Stephen J. Heyman, a 1959 graduate of the Wharton School, and his wife, Barbara Heyman, in honor of Stephen Heyman’s uncle. Stephen Heyman is a University Emeritus Trustee and member of the School of Nursing Board of Advisors. He is Managing Partner at Nadel and Gussman LLC in Tulsa, Oklahoma.
nucleus and membrane of pathogen micro organisms in blue background
Up to 50 percent of cancer-signaling proteins once believed to be immune to drug treatments due to a lack of targetable protein regions may actually be treatable, according to a new study from the Perelman School of Medicine at the University of Pennsylvania. The findings, published this month in Nature Communications, suggest there may be new opportunities to treat cancer with new or existing drugs.
Researchers, clinicians, and pharmacologists looking to identify new ways to treat medical conditions—from cancer to autoimmune diseases—often focus on protein pockets, areas within protein structures to which certain proteins or molecules can bind. While some pockets are easily identifiable within a protein structure, others are not. Those hidden pockets, referred to as cryptic pockets, can provide new opportunities for drugs to bind to. The more pockets scientists and clinicians have to target with drugs, the more opportunities they have to control disease.
The research team identified new pockets using a Penn-designed neural network, called PocketMiner, which is artificial intelligence that predicts where cryptic pockets are likely to form from a single protein structure and learns from itself. Using PocketMiner—which was trained on simulations run on the world’s largest super computer—researchers simulated single protein structures and successfully predicted the locations of cryptic pockets in 35 cancer-related protein structures in thousands of areas of the body. These once-hidden targets, now identified, open up new approaches for potentially treating existing cancer.
What’s more, while successfully predicting the cryptic pockets, the method scientists used in this study was much faster than previous simulation or machine-learning methods. The network allows researchers to nearly instantaneously decide if a protein is likely to have cryptic pockets before investing in more expensive simulations or experiments to pursue a predicted pocket further.
“More than half of human proteins are considered undruggable due to an apparent lack of binding proteins in the snapshots we have,” said Gregory R. Bowman, PhD, a professor of Biochemistry and Biophysics and Bioengineering at Penn and the lead author of the study. “This PocketMiner research and other research like it not only predict druggable pockets in critical protein structures related to cancer but suggest most human proteins likely have druggable pockets, too. It’s a finding that offers hope to those with currently untreatable diseases.”
William Danon and Luka Yancopoulos pose in front of College Hall in April 2022. They are co-founders of Grapevine and the winners of the 2022 President’s Innovation Prize. (Photo: Eric Sucar)
In April 2022, three President’s Prize-winning teams were selected from an applicant pool of 71 people to develop projects that promote engagement and innovation. Each project received $100,000, as well as a $50,000 living stipend per team member.
The President’s Innovation Prize and President’s Engagement Prize winners included Grapevine, which aims to better connect buyers and suppliers to stabilize the medical supply chain market; IF Ventures, with its mission to scale impact by supporting college students with early-stage startup ideas that have measurable social and environmental impact; and Cosmic Writers, which organizes writing workshops to cultivate K-12 students to be better writers and communicators — and, therefore, better citizens.
“In less than a year, these three PIP and PEP prize-winning teams have already proven their commitment to making a difference in the world,” says President Liz Magill. “Their projects are ambitious and inspiring, and I am proud the University has been able to provide financial and networking support for these determined changemakers.”
After graduating in May 2022, Luka Yancopoulos, an Environmental Studies major and a Bioengineering major in the School of Engineering and Applied Science and William Danon, a History major, relocated to an office space in Westchester, New York, and got to work on a research and validation process — first, by spending a day at a Penn Medicine facility, Lancaster General Health, then by committing hundreds of hours to interviewing distributor and procurement teams alike, along with potential client companies. The mission, as any researcher knows, was to understand key pain points. They also onboarded veterans in logistics, technology, and payment security and processing while devising an organizational structure in which Yancopoulous leads on technology and design solutions while Danon interfaces with customers to know what needs remain unmet.
Grapevine soft launched in fall 2022 and, they say, has interfaced with 30 companies through its digital platform to facilitate sales among 40 suppliers, amounting to more than $20,000 in transactions. The appeal of the platform, they say, remains the concept of the “digital supply chain network,” which Yancopoulos says partners can use to connect with resellers, hospitals, distributors, and others to reduce the risk of supply chain disruption that is not just a product of the pandemic, he adds, but “forever ongoing.”
“It’s driven by the principle that together we’re stronger, and I mean that in every aspect of my life,” he says. “That people are stronger, and with Grapevine we work to [bolster] supply chains and increase the accessibility of health care products — together.”
Since winning the President’s Innovation Prize, they’ve focused on working with small- to medium-sized businesses — whether local clinics or high-quality, specialized resellers — that struggle to compete with or pay for traditional, large-scale distributors that are better-resourced or too expensive. It’s allowed them to also find new users, like health care-adjacent businesses including funeral homes and tattoo parlors.
Their current tagline: “Grow with us,” Danon says.
Watch a video overview of Grapevine’s progress since receiving the PIP prize and read more about the other PIP/PEP prize winners at Penn Today.
A new Penn Medicine preclinical study demonstrates a simultaneous ‘knockout’ of two inflammatory regulators boosts T cell expansion to attack solid tumors.
by Meagan Raeke
Image: Courtesy of Penn Medicine News
A new approach that delivers a “one-two punch” to help T cells attack solid tumors is the focus of a preclinical study by researchers from the Perelman School of Medicine. The findings, published in the Proceedings of the National Academy of Sciences, show that targeting two regulators that control gene functions related to inflammation led to at least 10 times greater T cell expansion in models, resulting in increased anti-tumor immune activity and durability.
“We want to unlock CAR T cell therapy for patients with solid tumors, which include the most commonly diagnosed cancer types,” says June, the new study’s senior author. “Our study shows that immune inflammatory regulator targeting is worth additional investigation to enhance T cell potency.”
One of the challenges for CAR T cell therapy in solid tumors is a phenomenon known as T cell exhaustion, where the persistent antigen exposure from the solid mass of tumor cells wears out the T cells to the point that they aren’t able to mount an anti-tumor response. Engineering already exhausted T cells from patients for CAR T cell therapy results in a less effective product because the T cells don’t multiply enough or remember their task as well.
Previous observational studies hinted at the inflammatory regulator Regnase-1 as a potential target to indirectly overcome the effects of T cell exhaustion because it can cause hyperinflammation when disrupted in T cells—reviving them to produce an anti-tumor response. The research team, including lead author David Mai, a bioengineering graduate student in the School of Engineering and Applied Science, and co-corresponding author Neil Sheppard, head of the CCI T Cell Engineering Lab, hypothesized that targeting the related, but independent Roquin-1 regulator at the same time could boost responses further.
“Each of these two regulatory genes has been implicated in restricting T cell inflammatory responses, but we found that disrupting them together produced much greater anti-cancer effects than disrupting them individually,” Mai says. “By building on previous research, we are starting to get closer to strategies that seem to be promising in the solid tumor context.”
Perelman School of Medicine (PSOM) professors and Penn Bioengineering Graduate Group members Carl June and Avery Posey are leading the charge in T cell therapy and the fight against cancer.
Avery Posey, PhDCarl June, MD
Advances in genome editing through processes such as CRISPR, and the ability to rewire cells through synthetic biology, have led to increasingly elaborate approaches for modifying and supercharging T cells for therapy. Avery Posey, Assistant Professor of Pharmacology, and Carl June, the Richard W. Vague Professor in Immunotherapy, explain how new techniques are providing tools to counter some of the limitations of current CAR T cell therapies in a recent Nature feature.
The pair were also part of a team of researchers from PSOM, the Children’s Hospital of Philadelphia (CHOP), and the Corporal Michael J. Crescenz VA Medical Center to receive an inaugural $8 million Therapy ACceleration To Intercept CAncer Lethality (TACTICAL) Award from the Prostate Cancer Foundation. Their project will develop new clinic-ready CAR T cell therapies for Metastatic Castrate-Resistant Prostate Cancer (mCRPC).
Members of the research team include (from left to right) Xuexiang Han, Michael J. Mitchell, Ningqiang Gong, Lulu Xue, Sarah J. Shepherd, and Rakan El-Mayta.
Since the success of the COVID-19 vaccine, RNA therapies have been the object of increasing interest in the biotech world. These therapies work with your body to target the genetic root of diseases and infections, a promising alternative treatment method to that of traditional pharmaceutical drugs.
Lipid nanoparticles (LNPs) have been successfully used in drug delivery for decades. FDA-approved therapies use them as vehicles for delivering messenger RNA (mRNA), which prompts the cell to make new proteins, and small interfering RNA (siRNA), which instruct the cell to silence or inhibit the expression of certain proteins.
The biggest challenge in developing a successful RNA therapy is its targeted delivery. Research is now confronting the current limitations of LNPs, which have left many diseases without an effective RNA therapy.
Liver fibrosis occurs when the liver is repeatedly damaged and the healing process results in the accumulation of scar tissue, impeding healthy liver function. It is a chronic disease characterized by the buildup of excessive collagen-rich extracellular matrix (ECM). Liver fibrosis has remained challenging to treat using RNA therapies due to a lack of delivery systems for targeting activated liver-resident fibroblasts. Both the solid fibroblast structure and the lack of specificity or affinity to target these fibroblasts has impeded current LNPs from entering activated liver-resident fibroblasts, and thus they are unable to deliver RNA therapeutics.
To tackle this issue and help provide a treatment for the millions of people who suffer from this chronic disease, Michael Mitchell, J. Peter and Geri Skirkanich Assistant Professor of Innovation in the Department of Bioengineering, and postdoctoral fellows Xuexiang Han and Ningqiang Gong, found a new way to synthesize ligand-tethered LNPs, increasing their selectivity and allowing them to target liver fibroblasts.
Lulu Xue, Margaret Billingsley, Rakan El-Mayta, Sarah J. Shepherd, Mohamad-Gabriel Alameh and Drew Weissman, Roberts Family Professor in Vaccine Research and Director of the Penn Institute for RNA Innovation at the Perelman School of Medicine, also contributed to this work.
Penn Engineering’s newly established ASSET Center aims to make AI-enabled systems more “safe, explainable and trustworthy” by studying the fundamentals of the artificial neural networks that organize and interpret data to solve problems.
ASSET’s first funding collaboration is with Penn’s Perelman School of Medicine (PSOM) and the Penn Institute for Biomedical Informatics (IBI). Together, they have launched a series of seed grants that will fund research at the intersection of AI and healthcare.
Teams featuring faculty members from Penn Engineering, Penn Medicine and the Wharton School applied for these grants, to be funded annually at $100,000. A committee consisting of faculty from both Penn Engineering and PSOM evaluated 18 applications and judged the proposals based on clinical relevance, AI foundations and potential for impact.
Artificial intelligence and machine learning promise to revolutionize nearly every field, sifting through massive amounts of data to find insights that humans would miss, making faster and more accurate decisions and predictions as a result.
Applying those insights to healthcare could yield life-saving benefits. For example, AI-enabled systems could analyze medical imaging for hard-to-spot tumors, collate multiple streams of disparate patient information for faster diagnoses or more accurately predict the course of disease.
Given the stakes, however, understanding exactly how these technologies arrive at their conclusions is critical. Doctors, nurses and other healthcare providers won’t use such technologies if they don’t trust that their internal logic is sound.
“We are developing techniques that will allow AI-based decision systems to provide both quantifiable guarantees and explanations of their predictions,” says Rajeev Alur, Zisman Family Professor in Computer and Information Science and Director of the ASSET Center. “Transparency and accuracy are key.”
“Development of explainable and trustworthy AI is critical for adoption in the practice of medicine,” adds Marylyn Ritchie, Professor of Genetics and Director of the Penn Institute for Biomedical Informatics. “We are thrilled about this partnership between ASSET and IBI to fund these innovative and exciting projects.”
Seven projects were selected in the inaugural class, including projects from Dani S. Bassett, J. Peter Skirkanich Professor in the Departments of Bioengineering, Electrical and Systems Engineering, Physics & Astronomy, Neurology, and Psychiatry, and several members of the Penn Bioengineering Graduate Group: Despina Kontos, Matthew J. Wilson Professor of Research Radiology II, Department of Radiology, Penn Medicine and Lyle Ungar, Professor, Department of Computer and Information Science, Penn Engineering; Spyridon Bakas, Assistant Professor, Departments of Pathology and Laboratory Medicine and Radiology, Penn Medicine; and Walter R. Witschey, Associate Professor, Department of Radiology, Penn Medicine.
Optimizing clinical monitoring for delivery room resuscitation using novel interpretable AI
Elizabeth Foglia, Associate Professor, Department of Pediatrics, Penn Medicine and the Children’s Hospital of Philadelphia
Dani S. Bassett, J. Peter Skirkanich Professor, Departments of Bioengineering and Electrical and Systems Engineering, Penn Engineering
This project will apply a novel interpretable machine learning approach, known as the Distributed Information Bottleneck, to solve pressing problems in identifying and displaying critical information during time-sensitive clinical encounters. This project will develop a framework for the optimal integration of information from multiple physiologic measures that are continuously monitored during delivery room resuscitation. The team’s immediate goal is to detect and display key target respiratory parameters during delivery room resuscitation to prevent acute and chronic lung injury for preterm infants. Because this approach is generalizable to any setting in which complex relations between information-rich variables are predictive of health outcomes, the project will lay the groundwork for future applications to other clinical scenarios.
With OCTOPUS, Dan Huh’s team has significantly advanced the frontiers of organoid research, providing a platform superior to conventional gel droplets. OCTOPUS splits the soft hydrogel culture material into a tentacled geometry. The thin, radial culture chambers sit on a circular disk the size of a U.S. quarter, allowing organoids to advance to an unprecedented degree of maturity.
When it comes to human bodies, there is no such thing as typical. Variation is the rule. In recent years, the biological sciences have increased their focus on exploring the poignant lack of norms between individuals, and medical and pharmaceutical researchers are asking questions about translating insights concerning biological variation into more precise and compassionate care.
What if therapies could be tailored to each patient? What would happen if we could predict an individual body’s response to a drug before trial-and-error treatment? Is it possible to understand the way a person’s disease begins and develops so we can know exactly how to cure it?
Dan Huh, Associate Professor in the Department of Bioengineering at the University of Pennsylvania’s School of Engineering and Applied Science, seeks answers to these questions by replicating biological systems outside of the body. These external copies of internal systems promise to boost drug efficacy while providing new levels of knowledge about patient health.
An innovator of organ-on-a-chip technology, or miniature copies of bodily systems stored in plastic devices no larger than a thumb drive, Huh has broadened his attention to engineering mini-organs in a dish using a patient’s own cells.
