Michel Koo of the School of Dental Medicine and David Cormode of the Perelman School of Medicine and the School of Engineering and Applied Science led a team of researchers that uncovered a way to combine two FDA-approved treatments to treat tooth decay that taps into the blend’s bacteria-killing capabilities without disrupting the mouth’s microbiome. (Image: iStock / Alex Sholom)
The sting of a toothache or the discovery of a cavity is a universal dread. Dental caries, more commonly known as tooth decay, is an insidious adversary, taking a toll on millions of mouths worldwide. Caries can lead to pain, tooth loss, infection, and, in severe cases, even death.
While fluoride-based treatments have long been the gold standard in dentistry, this singular approach is now dated and has limited effect. Current treatments do not sufficiently control biofilm—the main culprit behind dental caries—and prevent enamel demineralization at the same time. This dual dilemma becomes particularly pronounced in high-risk populations where the onset of the disease can be both rapid and severe.
“Traditional treatments often come short in managing the complex biofilm environment in the mouth,” Koo, senior co-author on the study, says. “Our combined treatment not only amplifies the effectiveness of each agent but does so with a lower dosage, hinting at a potentially revolutionary method for caries prevention in high-risk individuals.”
David Cormode is an associate professor of radiology and bioengineering with appointments in Penn’s Perelman School of Medicine and School of Engineering and Applied Science.
Other authors are Yue Huang, Nil Kanatha Pandey, Shrey Shah, and Jessica C. Hsu of Penn’s Perelman School of Medicine; Yuan Liu, Aurea Simon-Soro, Zhi Ren, Zhenting Xiaang, Dongyeop Kim, Tatsuro Ito, Min Jun Oh, and Yong Li of Penn’s School of Dental Medicine; Paul. J Smeets, Sarah Boyer, Xingchen Zhao, and Derk Joester of Northwestern University; and Domenick T. Zero of Indiana University.
The work was supported by the National Institute of Health (grants R01-DE025848 and TL1TR001423 and awards S10OD026871 and R90DE031532) and the National Science Foundation (awards ECCS-2025633 and DMR-1720139).
Microwell device with a solution in the reservoir (Image: Courtesy of David E. Reynolds)
Akin to the packages sent from one person to another via an elaborate postal system, cells send tiny parcels that bear contents and packaging material that serve key purposes: To protect the contents from the outside world and to make sure it gets to the right place via a label with an address.
These packages are known as extracellular vesicles (EVs)—lipid-bound molecules that serve a variety of regulatory and maintenance functions throughout the body. They assist in the removal of unwanted materials within the cell, and they transport proteins, aid in DNA and RNA transfer, and promote tumorigeneses in cancerous cells.
Given their myriad roles, EVs have taken center stage for many researchers in the biomedical space as they have the potential to improve current methods of disease detection and treatment. The main challenge, however, is accurately identifying the molecular contents of EVs while also characterizing the EVs, which, unlike other cellular components that are more homogenous, have more heterogeneity.
Now, a team of researchers at the University of Pennsylvania has developed a novel platform, droplet-free double digital assay, for not only profiling individual EVs but also accurately discerning their molecular contents. The researchers took the digital assay, which quantifies the contents of a molecule via binary metric—a 1 corresponds to the presence of a molecule and a zero to the lack thereof—and applies it to the EV. The work is published in Advanced Science.
The team was led by Jina Ko, an assistant professor with appointments in the School of Engineering and Applied Science and Perelman School of Medicine. “Our method allows for highly accurate quantification of the individual molecules inside an EV,” Ko says . “This opens up many doors in the realm of early disease detection and treatment.”
The researchers first compartmentalized individual EVs utilizing a microwell approach to isolate the EVs. Next, they captured individual molecules within the EVs and amplified the signal for clarity. The team then was able to determine the expression levels of pivotal EV biomarkers with remarkable precision via fluorescence.
Jina Ko is an assistant professor in the Department of Pathology and Laboratory Medicine in the Perelman School of Medicine and an assistant professor in the Department of Bioengineering in the School of Engineering and Applied Science at the University of Pennsylvania.
David Reynolds is a Ph.D. candidate in the Department of Bioengineering in Penn Engineering.
Other authors include, Menghan Pan, George Galanis, Yoon Ho Roh, Renee-Tyler T. Morales, Shailesh Senthil Kumar, and Su-Jin Heo of the Department of Bioengineering at Penn Engineering; Jingbo Yang and Xiaowei Xu of the Department of Pathology and Laboratory Medicine at Penn Medicine; and Wei Guo of the Department of Biology in the School of Arts & Sciences at Penn.
The research was supported by the National Institutes of Health: grants R00CA256353, R35 GM141832, and CA174523 (SPORE).
Breaking the code of the immune system could provide a new fundamental way of understanding, treating, and preventing every type of disease. Penn Medicine is investing in key discoveries about immunity and immune system function, and building infrastructure, to make that bold idea a reality.
This grandfather lives with primary progressive multiple sclerosis (MS), an autoimmune disorder that he controls with a medicine that depletes his body of the type of immune cells that make antibodies. So while he has completed his COVID-19 vaccine course, his immune system function isn’t very strong—and the invitation has arrived at a time when COVID-19 is still spreading rapidly.
You can imagine the scene as an older gentleman lifts a thick, creamy envelope from his mailbox, seeing his own name written in richly scripted lettering. He beams with pride and gratitude at the sight of his granddaughter’s wedding invitation. Yet his next thought is a sober and serious one. Would he be taking his life in his hands by attending the ceremony?
“In the past, all we could do was [measure] the antibody response,” says Amit Bar-Or, the Melissa and Paul Anderson President’s Distinguished Professor in Neurology at the Perelman School of Medicine, and chief of the Multiple Sclerosis division. “If that person didn’t have a good antibody response, which is likely because of the treatment they’re on, we’d shrug our shoulders and say, ‘Maybe you shouldn’t go because we don’t know if you’re protected.’”
Today, though, Bar-Or can take a deeper dive into his patients’ individual immune systems to give them far more nuanced recommendations. A clinical test for immune cells produced in response to the COVID-19 vaccine or to the SARS-CoV-2 virus itself—not just antibodies—was one of the first applied clinical initiatives of a major new Immune Health® project at Penn Medicine. Doctors were able to order this test and receive actionable answers through the Penn Medicine electronic health record for patients like the grandfather with MS.
“With a simple test and an algorithm we can have a very different discussion,” Bar-Or says. A test result showing low T cells, for instance, would tell Bar-Or his patient may get a meaningful jolt in immunity from a vaccine booster, while low antibody levels would suggest passive antibody therapy is more helpful. Or, the test might show his body is already well primed to protect him, making it reasonably safe to attend the wedding.
This COVID-19 immunity test is only the beginning.
Physicians and scientists at Penn Medicine are imagining a future where patients can get a precise picture of their immune systems’ activity to guide treatment decisions. They are working to bring the idea of Immune Health to life as a new area of medicine. In labs, in complex data models, and in the clinic, they are beginning to make sense out of the depth and breadth of the immune system’s millions of as-yet-undeciphered signals to improve health and treat illnesses of all types.
Penn Medicine registered the trademark for the term “Immune Health” in recognition of the potential impact of this research area and its likelihood to draw non-academic partners as collaborators in its growth. Today, at the south end of Penn’s medical campus, seven stories of research space are being added atop an office building at 3600 Civic Center Blvd., including three floors dedicated to Immune Health, autoimmunity, and immunology research.
The concept behind the whole project, says E. John Wherry, director of Penn Medicine’s Institute for Immunology and Immune Health (I3H), “is to listen to the immune system, to profile the immune system, and use those individual patient immune fingerprints to diagnose and treat diseases as diverse as immune-related diseases, cancer, cardiovascular disease, Alzheimer’s, and many others.”
The challenge is vast. Each person’s immune system is far more complex than antibodies and T cells alone. The immune system is made of multiple interwoven layers of complex defenders—from our skin and mucous membranes to microscopic memory B cells that never forget a childhood infection—meant to fortify our bodies from germs and disease. It is a sophisticated system that learns and adapts over our lifetimes in numerous ways, and it also falters and fails in some ways we understand and others that remain mysterious. And each person’s intricate internal battlefield is in some way unique.
The immune system is not just a set of defensive barricades, either. It’s also a potential source of deep insight about a person’s physiological functioning and responses to medical treatments.
“The immune system is sensing and keeping track of basically all tissues and all cells in our body all the time,” Wherry says. “It is surveying the body trying to clean up any invaders and restore homeostasis by maintaining good health.”
“Our goal is to essentially break the code of the immune system,” says Jonathan Epstein, executive vice dean of the Perelman School of Medicine and chief scientific officer at Penn Medicine. “By doing so, we believe we will be able to determine your state of health and your response to therapies in essentially every human disease.”
(Left to right): Mike Mitchell, Noor Momin, and David Meaney recording the Innovation & Impact podcast.
In the most recent episode of the Penn Engineering podcast Innovation & Impact, titled “RNA: Past, Present and Future,” David F. Meaney, Senior Associate Dean of Penn Engineering and Solomon R. Pollack Professor in Bioengineering, is joined by Mike Mitchell, Associate Professor in Bioengineering, and Noor Momin, who will be joining Penn Engineering as an Assistant Professor in Bioengineering early next year, to discuss the impact that RNA has had on health care and biomedical engineering technologies.
Mitchell outlines his lab’s research that spans drug delivery, new technology in protecting RNA and its applications in treating cancer. Momin details her research, which is focused on optimizing the immune system to protect against illnesses such as cardiovascular diseases and cancer. With Meaney driving the discussion around larger questions, including the possibility of a cancer vaccine, the three discuss what they are excited about now and where the field is going in the future with these emerging, targeted treatments.
Jina Ko (left) and Kevin Johnson (right), both from the School of Engineering and the Perelman School of Medicine with appointments in Bioengineering, have received the National Institute of Health Director’s Award to support their “highly innovative and broadly impactful” research projects through the High-Risk, High-Reward program.
The National Institutes of Health (NIH) has awarded grants to three researchers from the University of Pennsylvania through the NIH Common Fund’s High-Risk, High-Reward Research program. The research of Kevin B. Johnson, Jina Ko, and Sheila Shanmugan will be supported through the program, which funds “highly innovative and broadly impactful” biomedical or behavioral research by exceptionally creative scientists.
The High-Risk, High-Reward Research program catalyzes scientific discovery by supporting highly innovative research proposals that, due to their inherent risk, may struggle in the traditional peer-review process despite their transformative potential. Program applicants are encouraged to think “outside the box” and pursue trail-blazing ideas in any area of research relevant to the NIH’s mission to advance knowledge and enhance health.
Two Penn Bioengineering faculty, Johnson and Ko, are among 85 recipients for 2023.
Johnson, the David L. Cohen University Professor of Pediatrics, is a Penn Integrates Knowledge University Professor who holds appointments in the Department of Computer and Information Science in the School of Engineering and Applied Science and the Department of Biostatistics, Epidemiology, and Informatics in the Perelman School of Medicine. He also holds secondary appointments in Bioengineering, Pediatrics, and in the Annenberg School for Communication. He is widely known for his work with e-prescribing and computer-based documentation and, more recently, work communicating science to lay audiences, which includes a documentary about health-information exchange. Johnson has authored more than 150 publications and was elected to the American College of Medical Informatics, Academic Pediatric Society, National Academy of Medicine, International Association of Health Science Informatics, and American Institute for Medical and Biological Engineering.
Ko is an assistant professor in the Department of Pathology and Laboratory Medicine in the Perelman School of Medicine and Department of Bioengineering in the School of Engineering and Applied Science. She focuses on developing single molecule detection from single extracellular vesicles and multiplexed molecular profiling to better diagnose diseases and monitor treatment efficacy. Ko earned her Ph.D. in bioengineering at Penn in 2018, during which time she developed machine learning-based microchip diagnostics that can detect blood-based biomarkers to diagnose pancreatic cancer and traumatic brain injury. For her postdoctoral training, she worked at the Massachusetts General Hospital and the Wyss Institute at Harvard University as a Schmidt Science Fellow and a NIH K99/R00 award recipient. Ko developed new methods to profile single cells and single extracellular vesicles with high throughput and multiplexing.
Let’s say you typically eat eggs for breakfast but were running late and ate cereal. As you crunched on a spoonful of Raisin Bran, other contextual similarities remained: You ate at the same table, at the same time, preparing to go to the same job. When someone asks later what you had for breakfast, you incorrectly remember eating eggs.
This would be a real-world example of a false memory. But what happens in your brain before recalling eggs, compared to what would happen if you correctly recalled cereal?
In a paper published in Proceedings of the National Academy of Sciences, University of Pennsylvania neuroscientists show for the first time that electrical signals in the human hippocampus differ immediately before recollection of true and false memories. They also found that low-frequency activity in the hippocampus decreases as a function of contextual similarity between a falsely recalled word and the target word.
“Whereas prior studies established the role of the hippocampus in event memory, we did not know that electrical signals generated in this region would distinguish the imminent recall of true from false memories,” says psychology professor Michael Jacob Kahana, director of the Computational Memory Lab and the study’s senior author. He says this shows that the hippocampus stores information about an item with the context in which it was presented.
Researchers also found that, relative to correct recalls, the brain exhibited lower theta and high-frequency oscillations and higher alpha/beta oscillations ahead of false memories. The findings came from recording neural activity in epilepsy patients who were already undergoing invasive monitoring to pinpoint the source of their seizures.
Noa Herz, lead author and a postdoctoral fellow in Kahana’s lab at the time of the research, explains that the monitoring was done through intracranial electrodes, the methodology researchers wanted to use for this study. She says that, compared to scalp electrodes, this method “allowed us to more precisely, and directly, measure the neural signals that were generated in deep brain structures, so the activity we are getting is much more localized.”
Michael Kahana is the Edmund J. and Louise W. Kahn Term Professor of Psychology in the School of Arts & Sciences and director of the Computational Memory Lab at the University of Pennsylvania. He is a member of the Penn Bioengineering Graduate Group.
In an era peppered by breathless discussions about artificial intelligence—pro and con—it makes sense to feel uncertain, or at least want to slow down and get a better grasp of where this is all headed. Trusting machines to do things typically reserved for humans is a little fantastical, historically reserved for science fiction rather than science.
Not so much for César de la Fuente, PhD, the Presidential Assistant Professor in Psychiatry, Microbiology, Chemical and Biomolecular Engineering, and Bioengineering in Penn’s Perelman School of Medicine and School of Engineering and Applied Science. Driven by his transdisciplinary background, de la Fuente leads the Machine Biology Group at Penn: aimed at harnessing machines to drive biological and medical advances.
“Biology is complexity, right? You need chemistry, you need mathematics, physics and computer science, and principles and concepts from all these different areas, to try to begin to understand the complexity of biology,” he said. “That’s how I became a scientist.”
Kathleen J. Stebe and Michel Koo urge “the academic community to adopt a coordinated approach uniting dental medicine and engineering to support research, training and entrepreneurship to address unmet needs and spur oral health care innovations.” (Image: Min Jun Oh and Seokyoung Yoon)
Penn’s Center for Innovation & Precision Dentistry (CiPD) is the first cross-disciplinary initiative in the nation to unite oral-craniofacial health sciences and engineering.
In just two years since CiPD was founded, the outcomes of this newly conceived research partnership have proven its value: microrobots that clean teeth for people with limited mobility, a completely new understanding of bacterial physics in tooth decay, enzymes from plant chloroplasts that degrade plaque, promising futures for lipid nanoparticles in oral cancer treatment and new techniques and materials to restore nerves in facial reconstructive surgery.
In addition, CiPD is training the next generation of dentists, scientists and engineers through an NIH/NIDCR-sponsored postdoctoral training program as well as fellowships from industry.
The center’s Founding Co-Directors, Kathleen J. Stebe, Richer & Elizabeth Goodwin Professor in Chemical and Biomolecular Engineering, and Michel Koo, Professor of Orthodontics in Penn Dental Medicine, published an editorial in the Journal of Dental Research, planting a flag for CiPD’s mission and encouraging others to mirror its method.
The two urge “the academic community to adopt a coordinated approach uniting dental medicine and engineering to support research, training and entrepreneurship to address unmet needs and spur oral health care innovations.”
On September 14, Wexford Science & Technology, LLC and the University of Pennsylvania announced that the University has signed a lease for new laboratory space that will usher in a wave of novel vaccine, therapeutics, and engineered diagnostics research to West Philadelphia. Research teams from Penn are poised to move into 115,000 square feet of space at One uCity Square, the 13-story, 400,000 square foot purpose-built lab and office building within the vibrant uCity Square Knowledge Community being developed by Wexford. This is the largest lease in the building, encompassing four floors, and bringing the building to over 90% leased. The building currently includes industry tenants Century Therapeutics (NASDAQ: IPSC), Integral Molecular, Exponent (NASDAQ: EXPO), and Charles River Laboratories (NYSE: CRL).
The new University space will house Penn Medicine’s Institute for RNA Innovation and Penn Engineering’s Center for Precision Engineering for Health, underscoring the University’s commitment to a multi-disciplinary and collaborative approach to research that will attract and retain the best talent and engage partners from across the region. Penn’s decision to locate at One uCity Square reinforces uCity Square’s evolution as a central cluster of academic, clinical, commercial, entrepreneurial, and amenity spaces for the area’s innovation ecosystem, and further cements Philadelphia’s position as a top life sciences market.
Jonathan Epstein, MD, Executive Vice Dean and Chief Scientific Officer of Penn Medicine, shared his anticipation for the opportunities that lie ahead: “Penn Medicine is proud to build on its existing clinical presence in uCity Square and establish an innovative and collaborative research presence at the heart of uCity Square’s multidisciplinary innovation ecosystem. This strategic move underscores our commitment to accelerating advancements in biomedical research, industry collaboration, and equipping our talented teams with the resources they need to shape the future of healthcare.”
Locating the Penn Institute for RNA Innovation in the heart of the uCity Square community brings together researchers across disciplines who are already pursuing new vaccines and treatments, and better ways to deliver them. Their shared work will help to power the next phase of vaccine discovery and development.
Likewise, anchoring the work of Penn Engineering’s Center in the One uCity Square space will allow the School’s multi-disciplinary researchers and their collaborators to advance new clinical and diagnostic methods that will focus on intelligent therapeutics, genome design, diagnostics for discovery of human biology, and engineering the human immune shield.
“Penn Engineering has made a substantial commitment to precision engineering for health, an area that is not only important and relevant to engineering, but also critical to the future of humanity,” said Vijay Kumar, Nemirovsky Family Dean of Penn Engineering. “The space in One uCity Square will add another 30,000 square feet of space for our engineers to develop technologies that will fight future pandemics, cure incurable diseases, and extend healthy life spans around the world.”
Spearheading the Penn Institute for RNA Innovation will be Drew Weissman, MD, PhD, the Roberts Family Professor for Vaccine Research, who along with Katalin Karikó, PhD, adjunct professor of Neurosurgery, discovered foundational mRNA technology that enabled the creation of vital vaccine technology, including the FDA-approved mRNA-based COVID-19 vaccines developed by Pfizer-BioNTech and Moderna.
In this new space at One uCity Square, Weissman and his research team and collaborators will further pursue their groundbreaking research efforts with a goal to develop new therapeutics and vaccines and initiate clinical trials for other devastating diseases.
In addition, two established researchers will join the Institute at One uCity Square: Harvey Friedman, MD, a professor of Infectious Diseases, who leads a team researching various vaccines. He will be joined by Vladimir Muzykantov, MD, PhD, Founders Professor in Nanoparticle Research, who focuses on several projects related to targeting the delivery of drugs, including mRNA, to create more effective, targeted pathways to deliver drugs to the vascular system, treating a wide range of diseases that impact the brain, lung, heart, and blood.
Dan Hammer, Alfred G. and Meta A. Ennis Professor in the Departments of Bioengineering and Chemical and Biomolecular Engineering in Penn Engineering and Director of the Center for Precision Engineering for Health, will oversee the Center’s innovations in diagnostics and delivery, cellular and tissue engineering, and the development of new devices that integrate novel materials with human tissues. The Center will bring together scholars from all departments within Penn Engineering and will help to foster increased collaboration with campus colleagues at Penn’s Perelman School of Medicine and with industry partners.
Joining the Center researchers in One uCity Square are Noor Momin, Sherry Gao, and Michael Mitchell. Noor Momin, who will join Penn Engineering in early 2024 as an assistant professor in Bioengineering, will leverage her lab’s expertise in cardiovascular immunology, protein engineering and pharmacokinetic modeling to develop next-generation treatments and diagnostics for cardiovascular diseases.
Penn Bioengineering is proud to congratulate Sunghee Estelle Park, Ph.D. on her appointment as Assistant Professor in the Weldon School of Biomedical Engineering at Purdue University. Park earned her Ph.D. at Penn Bioengineering, graduating in July 2023. She conducted doctoral research in the BIOLines Lab of Dan Huh, Associate Professor in Bioengineering. Her appointment at Purdue will begin January 2024.
During her Ph.D. research, Park forged a unique path that combined principles in developmental biology, stem cell biology, organoids, and organ-on-a-chip technology to develop innovative in vitro models that can faithfully replicate the pathophysiology of various human diseases. Using a microengineered model of the human retina, she discovered previously unknown roles of the MAPK, IL-17, PI3K-AKT, and TGF-β signaling pathways in the pathogenesis of age-related macular degeneration (AMD), presenting novel therapeutic targets that could be further investigated for the development of AMD treatments. More recently, she tackled a significant challenge in the organoid field, the limited tissue growth and maturity in conventional organoid cultures, by designing microengineered systems that enabled organoids to grow with unprecedented levels of maturity and human-relevance. By integrating these platforms with bioinformatics and computational analyses, she identified novel disease-specific biomarkers of inflammatory bowel disease (IBD) and intestinal fibrosis, including previously unknown link between the presence of lncRNA and the development of IBD.
“The unique interdisciplinary expertise I gained from these projects has shaped me into a scholar with a strong collaborative ethos, a quality I hold in high esteem as we work towards advancing our knowledge and management of health and disease,” says Park.
Her vision as an independent researcher is to become a leading faculty who makes impactful contributions to our fundamental understanding of the factors influencing the structural and functional changes of human organs in health and disease. To achieve this, she plans to lead a stem cell bioengineering laboratory with a primary focus on tissue engineering and regenerative medicine. This will involve developing human organoids-on-a-chip systems and establishing next-generation biomedical devices and therapies tailored for regenerative and personalized medicine.
“I am grateful to all my Ph.D. mentors and lab mates at the BIOLines lab and especially my advisor Dr. Dan Huh, for his exceptional guidance, unwavering support, and invaluable mentorship throughout my Ph.D. journey,” says Park. “Dan’s expertise, dedication, and commitment to excellence have been instrumental in shaping both my research and professional development, while also training me to become an independent scientist and mentor.”
Congratulations to Dr. Park from everyone at Penn Bioengineering!
