What Makes a Breakthrough? “Eight Steps Back” Before Making it to the Finish Lit

by Meagan Raeke

(From left to right) Breakthrough Prize recipients Drew Weissman, Virginia M-Y Lee, Katalin Karikó, and Carl June at a reception on Feb. 13. (Image: Courtesy of Penn Medicine News)

In popular culture, scientific discovery is often portrayed in “Eureka!” moments of sudden realization: a lightbulb moment, coming sometimes by accident. But in real life—and in Penn Medicine’s rich history as a scientific innovator for more than 250 years—scientific breakthroughs can never truly be distilled down to a single, “ah-ha” moment. They’re the result of years of hard work, perseverance, and determination to keep going, despite repeated, often discouraging, barriers and setbacks. 

“Research is [like taking], four, or six, or eight steps back, and then a little stumble forward,” said Drew Weissman, MD, PhD, the Roberts Family Professor of Vaccine Research. “You keep doing that over and over and somehow, rarely, you can get to the top of the step.” 

For Weissman and his research partner, Katalin Karikó, PhD, an adjunct professor of Neurosurgery, that persistence—documented in thousands of news stories across the globe—led to the mRNA technology that enabled two lifesaving COVID-19 vaccines, earning the duo numerous accolades, including the highest scientific honor, the 2023 Nobel Prize in Medicine

Weissman and Karikó were also the 2022 recipients of the Breakthrough Prize in Life Sciences, the world’s largest science awards, popularly known as the “Oscars of Science.” Founded in 2012 by a group of web and tech luminaries including Google co-founder Sergey Brin and Meta CEO Mark Zuckerberg, the Breakthrough Prizes recognize “the world’s top scientists working in the fundamental sciences—the disciplines that ask the biggest questions and find the deepest explanations.” With six total winners, including four from the Perelman School of Medicine (PSOM), Penn stands alongside Harvard and MIT as the institutions whose researchers have been honored with the most Breakthrough Prizes. 

Virginia M.Y. Lee, PhD, the John H. Ware 3rd Professor in Alzheimer’s Research, was awarded the Prize in 2020 for discovering how different forms of misfolded proteins can move from cell to cell and lead to neurodegenerative disease progression. Carl June, MD, the Richard W. Vague Professor in Immunotherapy, is the most recent recipient and will be recognized at a star-studded red-carpet event in April for pioneering the development of CAR T cell therapy, which programs patients’ own immune cells to fight their cancer.

The four PSOM Breakthrough Prize recipients were honored on Tuesday, Feb. 13, 2024, when a new large-scale installation was unveiled in the lobby of the Biomedical Research Building to celebrate each laurate and their life-changing discoveries. During a light-hearted panel discussion, the honorees shared how a clear purpose, dogged determination, and a good sense of humor enabled their momentum forward. 

Read the full story in Penn Medicine News.

Carl June and Jon Epstein are members of the Penn Bioengineering Graduate Group. Read more stories featuring them in the BE Blog here and here, respectively.

Weissman presented the Department of Bioengineering’s 2022 Herman P. Schwan Distinguished Lecture: “Nucleoside-modified mRNA-LNP therapeutics.” Read more stories featuring Weissman in the BE Blog here.

Secondary Cancers Following CAR T Cell Therapy Are Rare, Penn Medicine Analysis Shows

by Meagan Raeke

3d illustration of a damaged and disintegrating cancer cell. (Image: iStock/vitanovski)

The development of any type of second cancer following CAR T cell therapy is a rare occurrence, as found in an analysis of more than 400 patients treated at Penn Medicine, researchers from the Perelman School of Medicine at the University of Pennsylvania reported today in Nature Medicine. The team also described a single case of an incidental T cell lymphoma that did not express the CAR gene and was found in the lymph node of a patient who developed a secondary lung tumor following CAR T cell therapy.

CAR T cell therapy, a personalized form of immunotherapy in which each patient’s T cells are modified to target and kill their cancer cells, was pioneered at Penn. More than 30,000 patients with blood cancers in the United States—many of whom had few, if any, remaining treatment options available—have been treated with CAR T cell therapy since the first such therapy was approved in 2017. Some of the earliest patients treated in clinical trials have gone on to experience long-lasting remissions of a decade or more.

Secondary cancers, including T cell lymphomas, are a known, rare risk of several types of cancer treatment, including chemotherapy, radiation, and stem cell transplant. CAR T cell therapy is currently only approved to treat blood cancers that have relapsed or stopped responding to treatment, so patients who receive CAR T cell therapies have already received multiple other types of treatment and are facing dire prognoses.

In November 2023, the FDA announced an investigation into several reported cases of secondary T cell malignancies, including CAR-positive lymphoma, in patients who previously received CAR T cell therapy products. In January 2024, the FDA began requiring drugmakers to add a safety label warning to CAR T cell products. While the FDA review is still ongoing, it remains unclear whether the secondary T cell malignancies were caused by CAR T cell therapy.

As a leader in CAR T cell therapy, Penn has longstanding, clearly established protocols to monitor each patient both during and after treatment – including follow-up for 15 years after infusion – and participates in national reporting requirements and databases that track outcomes data from all cell therapy and bone marrow transplants.

Marco Ruella, M.D.

“When this case was identified, we did a detailed analysis and concluded the T cell lymphoma was not related to the CAR T cell therapy. As the news of other cases came to light, we knew we should go deeper, to comb through our own data to better understand and help define the risk of any type of secondary cancer in patients who have received CAR T cell products,” said senior author Marco Ruella, MD, an assistant professor of Hematology-Oncology and Scientific Director of the Lymphoma Program. “What we found was very encouraging and reinforces the overall safety profile for this type of personalized cell therapy.”

Read the full story in Penn Medicine News.

Marco Ruella is Assistant Professor of Medicine in the Perelman School of Medicine. He is a member of the Penn Bioengineering Graduate Group.

The Heart and Soul of Innovation: Noor Momin Harnesses the Immune System to Treat Heart Disease

by Ian Scheffler

Noor Momin, Stephenson Foundation Term Assistant Professor of Innovation

While growing up, Noor Momin, who joined the Department of Bioengineering in January as the Stephenson Foundation Term Assistant Professor of Innovation, imagined becoming a physician. Becoming a doctor seemed like a tangible way for someone interested in science to make a difference. Not until college did she realize the impact she could have as a bioengineer instead.

“I was taping microscope slides together,” Momin recalls of her initial experience as an undergraduate researcher at the University of Texas at Austin. “I didn’t even know what a Ph.D. was.”

It wasn’t until co-authoring her first paper, which explores how lipids, the water-repelling molecules that make up cell membranes (and also fats and oils), can switch between more fluid and less fluid arrangements, that Momin understood the degree to which bioengineering can influence medicine. “Someone could potentially use that paper for drug design,” Momin says.

Today, Momin’s research applies her molecular expertise to heart disease, which despite numerous advances in treatment — from coronary artery bypass surgery to cholesterol-lowering statins — remains the primary cause of mortality worldwide.

As Momin sees it, the conventional wisdom of treating the heart like a mechanical pump, whose pipes can be replaced or whose throughput can be treated to prevent clogging in the first place, overshadows the immune system’s critical role in the development of heart disease.

Read the full story in Penn Engineering Today.

Protein Partners Identified as Potential Key for Fetal Bone Development

Image: iStock/Christoph Burgstedt

A pair of proteins, YAP and TAZ, has been identified as conductors of bone development in the womb and could provide insight into genetic diseases such as osteogenesis imperfecta, known commonly as “brittle bone disease.” This research, published in Developmental Cell and led by members of the McKay Orthopaedic Research Laboratory of the Perelman School of Medicine, adds understanding to the field of mechanobiology, which studies how mechanical forces influence biology.

“Despite more than a century of study on the mechanobiology of bone development, the cellular and molecular basis largely has remained a mystery,” says the study’s senior author, Joel Boerckel, an associate professor of orthopaedic surgery. “Here, we identify a new population of cells that are key to turning the body’s early cartilage template into bone, guided by the force-activated gene regulating proteins, YAP and TAZ.”

Read the full story in Penn Medicine News.

Joel D. Boerckel is Associate Professor in Orthopaedic Surgery and in Bioengineering.

Riccardo Gottardi Receives BMES Rising Star Award

Riccardo Gottardi, Ph.D.

Riccardo Gottardi, Assistant Professor in Pediatrics and in Bioengineering and leader of the Bioengineering and Biomaterials Laboratory at the Children’s Hospital of Philadelphia (CHOP), received the Rising Star Award from the Biomedical Engineering Society-Cellular and Molecular Bioengineering (BMES-CMBE). The Rising Star Award recognizes a BMES-CMBE member who is at the early independent career stage and has made an outstanding impact on the field of cellular and molecular bioengineering. Awardees will give an oral presentation on their research at the BMES-CMBE conference in Puerto Rico in January and be recognized at the conference Gala dinner.

Dr. Gottardi’s research focuses on engineering solutions for pediatric health, primarily for airway disorders. He has previously received awards for work to create a biomaterial patch to repair the tympanic membrane and for work to develop cartilage implants to treat severe subglottic stenosis. He received grant support from the National Institutes of Health to further his work in subglottic stenosis.

This story originally appeared in the CHOP Cornerstone Blog.

Sydney Shaffer Wins Christopher J. Marshall Award for Melanoma Research

Sydney Shaffer, M.D., Ph.D.

Sydney Shaffer, Assistant Professor in Bioengineering in the School of Engineering and Applied Science and in Pathology and Laboratory Medicine in the Perelman School of Medicine, was named the 2023 Christopher J. Marshall Award winner by the Society for Melanoma Research (SMR). The award recognizes Shaffer’s contributions to melanoma research on oncogenic signalling and molecular pathogenesis of this disease, as well as her rapid development as a rising star and leader in the field, which have helped to further the SMR’s goal to eradicate melanoma. The award was presented at the SMR annual meeting in Philadelphia in November 2023. 

The Christopher J. Marshall Award was established in 2015 by the SMR in partnership with Melanoma Research Foundation Congress to recognize a student, postdoctoral fellow, or new independent PI who has published a substantial and original contribution to studies of signal transduction and melanoma.

Shaffer joined Penn as an Assistant Professor in 2019. She holds a M.D.-Ph.D. in Medicine and Bioengineering from the University of Pennsylvania and conducted postdoctoral research in cancer biology in the lab of Junwei Shi, Associate Professor in Penn Medicine. The Syd Shaffer Lab is an interdisciplinary team which focuses on “understanding how differences between single-cells generate phenotypes such as drug resistance, oncogenesis, differentiation, and invasion [using] a combination of imaging and sequencing technologies to investigate rare single-cell phenomena.” A recent paper in Nature Communications details the team’s method to quantify long-lived fluctuations in gene expression that are predictive of later resistance to targeted therapy for melanoma.

Read the award announcement and the full list of prior winners at the SMR website.

Penn Scientists Reflect on One Year of ChatGPT

by Erica Moser

René Vidal, at the podium, introduces the event “ChatGPT turns one: How is generative AI reshaping science?” Bhuvnesh Jain, left at the table, moderated the discussion with Sudeep Bhatia, Konrad Kording, Andrew Zahrt, and Nick Pangakis.

As a neuroscientist surveying the landscape of generative AI—artificial intelligence capable of generating text, images, or other media—Konrad Kording cites two potential directions forward: One is the “weird future” of political use and manipulation, and the other is the “power tool direction,” where people use ChatGPT to get information as they would use a drill to build furniture.

“I’m not sure which of those two directions we’re going but I think a lot of the AI people are working to move us into the power tool direction,” says Kording, a Penn Integrates Knowledge (PIK) University professor with appointments in the Perelman School of Medicine and School of Engineering and Applied Science. Reflecting on how generative AI is shifting the paradigm of science as a discipline, Kording said he thinks “it will push science as a whole into a much more collaborative direction,” though he has concerns about ChatGPT’s blind spots.

Kording joined three University of Pennsylvania researchers from the chemistry, political science, and psychology departments sharing their perspectives in the recent panel “ChatGPT turns one: How is generative AI reshaping science?” PIK Professor René Vidal opened the event, which was hosted by the School of Arts & Sciences’ Data Driven Discovery Initiative (DDDI), and Bhuvnesh Jain, physics and astronomy professor and co-faculty director of DDDI, moderated the discussion.

“Generative AI is moving so rapidly that even if it’s a snapshot, it will be very interesting for all of us to get that snapshot from these wonderful experts,” Jain said. OpenAI launched ChatGPT, a large language model (LLM)-based chatbot, on Nov. 30, 2022, and it rapidly ascended to ubiquity in news reports, faculty discussions, and research papers. Colin Twomey, interim executive director of DDDI, told Penn Today that it’s an open question as to how it will change the landscape of scientific research, and the` idea of the event was to solicit colleagues’ opinions on interesting directions in their fields.

Read the full story in Penn Today.

Konrad Paul Kording is Nathan Francis Mossell University Professor in Bioengineering and Computer and Information Science in Penn Engineering and in Neuroscience in the Perelman School of Medicine.

How Penn Medicine Is Changing the World with mRNA

by Rachel Ewing

Vaccines for COVID-19 were the first time that mRNA technology was used to address a worldwide health challenge. The Penn Medicine scientists behind that technology were awarded the 2023 Nobel Prize in Physiology or Medicine. Next come all the rest of the potential new treatments made possible by their discoveries.

Starting in the late 1990s, working together at Penn Medicine, Katalin Karikó, PhD, and Drew Weissman, MD, PhD, discovered how to safely use messenger RNA (mRNA) as a whole new type of vaccine or therapy for diseases. When the COVID-19 pandemic hit in 2020, these discoveries made Pfizer/BioNTech and Moderna’s new vaccines possible—saving millions of lives. 

But curbing the pandemic was only the beginning of the potential for this Nobel Prize-winning technology. 

These biomedical innovations from Penn Medicine in using mRNA represent a multi-use tool, not just a treatment for a single disease. The technology’s potential is virtually unlimited; if researchers know the sequence of a particular protein they want to create or replace, it should be possible to target a specific disease. Through the Penn Institute for RNA Innovation led by Weissman, who is the Roberts Family Professor of Vaccine Research in Penn’s Perelman School of Medicine, researchers are working to ensure this limitless potential meets the world’s most challenging and important needs.

Infectious Diseases and Beyond

Just consider some of the many projects Weissman’s lab is partnering in: “We’re working on malaria with people across the U.S. and in Africa,” Weissman said. “We’re working on leptospirosis with people in Southeast Asia. We’re working on vaccines for peanut allergies. We’re working on vaccines for autoimmunity. And all of this is through collaboration.”

Clinical trials are underway for the new malaria vaccine, as well as for a Penn-developed mRNA vaccine for genital herpes and one that aims to protect against all varieties of coronaviruses. Trials should begin soon for vaccines for norovirus and the bacterium C. difficile.

Single-Injection Gene Therapies for Sickle Cell and Heart Disease

Drew Weissman, MD, PhD, is a co-winner of the 2023 Nobel Prize in Physiology or Medicine for discoveries with mRNA.

The Weissman lab is working to deploy mRNA technology as an accessible gene therapy for sickle cell anemia, a devastating and painful genetic disease that affects about 20 million people around the world. About 300,000 babies are born each year with the condition, mainly in sub-Saharan Africa. Weissman’s team has developed technology to efficiently deliver modified mRNA to bone marrow stem cells, instructing red blood cells to produce normal hemoglobin instead of the malformed “sickle” version that causes the illness. Conventional gene therapies are complex and expensive treatments, but the mRNA gene therapy could be a simple, one-time intravenous injection to cure the disease. Such a treatment would have applications to many other congenital gene defects in blood and stem cells.

In another new program, Penn Medicine researchers have found a way to target the muscle cells of the heart. This gene therapy method developed by Weissman’s team, together with Vlad Muzykantov, MD, PhD, the Founders Professor in Nanoparticle Research could potentially repair the heart or increase blood flow to the heart, noninvasively, after a heart attack or to correct a genetic deficiency in the heart. “That is important because heart disease is the number one killer in the U.S. and in the world,” Weissman said. “Drugs for heart disease aren’t specific for the heart. And when you’re trying to treat a myocardial infarction or cardiomyopathy or other genetic deficiencies in the heart, it’s very difficult, because you can’t deliver to the heart.”

Weissman’s team also is partnering on programs for neurodevelopmental diseases and for neurodegenerative diseases, to replace genes or deliver therapeutic proteins that will treat and potentially cure these diseases.

“The potential is unbelievable,” Weissman said. “We haven’t thought of everything that can be done.”

Read the full story in Penn Medicine News.

Vladimir R. Muzykantov is Founders Professor in Nanoparticle Research in the Department of Systems Pharmacology and Translational Therapeutics in the Perelman School of Medicine. He is a member of the Penn Bioengineering Graduate Group.

The NEMO Prize Goes to Research Improving Soft-Tissue Transplant Surgeries

by Melissa Pappas

Daeyeon Lee (left), Oren Friedman (center) and Sergei Vinogradov (right)

Each year, the Nemirovsky Engineering and Medicine Opportunity (NEMO) Prize, funded by Penn Health-Tech, awards $80,000 to a collaborative team of researchers from the University of Pennsylvania’s Perelman School of Medicine and the School of Engineering and Applied Science for early-stage, interdisciplinary ideas.

This year, the NEMO Prize has been awarded to Penn Engineering’s Daeyeon Lee, Russel Pearce and Elizabeth Crimian Heuer Professor in Chemical and Biomolecular Engineering, Oren Friedman, Associate Professor of Clinical Otorhinolaryngology in the Perelman School of Medicine, and Sergei Vinogradov, Professor in the Department of Biochemistry and Biophysics in the Perelman School of Medicine and the Department of Chemistry in the School of Arts & Sciences. Together, they are developing a new therapy that improves the survival and success of soft-tissue grafts used in reconstructive surgery.

More than one million people receive soft-tissue reconstructive surgery for reasons such as tissue trauma, cancer or birth defects. Autologous tissue transplants are those where cells and tissue such as fat, skin or cartilage are moved from one part of a patient’s body to another. As the tissue comes from the patient, there is little risk of transplant rejection. However, nearly one in four autologous transplants fail due to tissue hypoxia, or lack of oxygen. When transplants fail the only corrective option is more surgery. Many techniques have been proposed and even carried out to help oxygenate soft tissue before it is transplanted to avoid failures, but current solutions are time consuming and expensive. Some even have negative side effects. A new therapy to help oxygenate tissue quickly, safely and cost-effectively would not only increase successful outcomes of reconstructive surgery, but could be widely applied to other medical challenges. 

The therapy proposed by this year’s NEMO Prize recipients is a conglomerate or polymer of microparticles that can encapsulate oxygen and disperse it in sustainable and controlled doses to specific locations over periods of time up to 72 hours. This gradual release of oxygen into the tissue from the time it is transplanted to the time it functionally reconnects to the body’s vascular system is essential to keeping the tissue alive. 

“The microparticle design consists of an oxygenated core encapsulated in a polymer shell that enables the sustained release of oxygen from the particle,” says Lee. “The polymer composition and thickness can be controlled to optimize the release rate, making it adaptable to the needs of the hypoxic tissue.” 

These life-saving particles are designed to be integrated into the tissue before transplantation. However, because they exist on the microscale, they can also be applied as a topical cream or injected into tissue after transplantation. 

“Because the microparticles are applied directly into tissues topically or by interstitial injection (rather than being administered intravenously), they surpass the need for vascular channels to reach the hypoxic tissue,” says Friedman. “Their micron-scale size combined with their interstitial administration, minimizes the probability of diffusion away from the injury site or uptake into the circulatory system. The polymers we plan to use are FDA approved for sustained-release drug delivery, biocompatible and biodegrade within weeks in the body, presenting minimal risk of side effects.”

The research team is currently testing their technology in fat cells. Fat is an ideal first application because it is minimally invasive as an injectable filler, making it versatile in remodeling scars and healing injury sites. It is also the soft tissue type most prone to hypoxia during transplant surgeries, increasing the urgency for oxygenation therapy in this particular tissue type.

Read the full story in Penn Engineering Today.

Daeyeon Lee and Sergei Vinogradov are members of the Penn Bioengineering Graduate Group.

Arjun Raj Receives 2023-24 Heilmeier Award

by Olivia J. McMahon

Arjun Raj, Ph.D.

Arjun Raj, Professor in Bioengineering in Penn Engineering, has been named the recipient of the 2023-24 George H. Heilmeier Faculty Award for Excellence in Research for “pioneering the development and application of single-cell, cancer-fighting technologies.”

The Heilmeier Award honors a Penn Engineering faculty member whose work is scientifically meritorious and has high technological impact and visibility. It is named for the late George H. Heilmeier, a Penn Engineering alumnus and member of the School’s Board of Advisors, whose technological contributions include the development of liquid crystal displays and whose honors include the National Medal of Science and Kyoto Prize.

Raj, who also holds an appointment in Genetics in the Perelman School of Medicine, is a pioneer in the burgeoning field of single-cell engineering and biology. Powered by innovative techniques he has developed for molecular profiling of single cells, his scientific discoveries range from the molecular underpinnings of cellular variability to the behavior of single cells across biology, including in diseases such as cancer.

Raj will deliver the 2023-24 Heilmeier Lecture at Penn Engineering during the spring 2024 semester.

This story originally appeared in Penn Engineering Today.

Read more stories featuring Dr. Raj here.