Four University of Pennsylvania undergraduates have received 2024 Goldwater Scholarships, awarded to second- or third-year students planning research careers in mathematics, the natural sciences, or engineering.
They are among the 438 students named 2024 Goldwater Scholars from 1,353 undergraduates students nominated by 446 academic institutions in the United States, according to the Barry Goldwater Scholarship & Excellence in Education Foundation. Each scholarship provides as much as $7,500 each year for as many as two years of undergraduate study.
Mrksich, from Hinsdale, Illinois, is majoring in bioengineering. She is interested in developing drug delivery systems that can serve as novel therapeutics for a variety of diseases. Mrksich works in the lab of Michael J. Mitchell where she investigates the ionizable lipid component of lipid nanoparticles for mRNA delivery. At Penn, Mrksich is the president of the Biomedical Engineering Society, where she plans community building and professional development events for bioengineering majors. She is a member of the Kite and Key Society, where she organizes virtual programming to introduce prospective students to Penn. She is a member of Tau Beta Pi engineering honor society, and the Sigma Kappa sorority. She also teaches chemistry to high schoolers as a volunteer in the West Philadelphia Tutoring Project through the Civic House. After graduating, Mrksich plans to pursue an M.D./Ph.D. in bioengineering.
Mrksich was awarded a Student Award for Outstanding Research (Undergraduate) by the Society for Biomaterials earlier this year. Read the story in the BE Blog.
Like space shuttles using booster rockets to breach the atmosphere, lipid nanoparticles (LNPs) equipped with the new molecule more successfully deliver medicinal payloads. (Love Employee via Getty Images)
Inspired by the design of space shuttles, Penn Engineering researchers have invented a new way to synthesize a key component of lipid nanoparticles (LNPs), the revolutionary delivery vehicle for mRNA treatments including the Pfizer-BioNTech and Moderna COVID-19 vaccines, simplifying the manufacture of LNPs while boosting their efficacy at delivering mRNA to cells for medicinal purposes.
In a paper in Nature Communications, Michael J. Mitchell, Associate Professor in the Department of Bioengineering, describes a new way to synthesize ionizable lipidoids, key chemical components of LNPs that help protect and deliver medicinal payloads. For this paper, Mitchell and his co-authors tested delivery of an mRNA drug for treating obesity and gene-editing tools for treating genetic disease.
Previous experiments have shown that lipidoids with branched tails perform better at delivering mRNA to cells, but the methods for creating these molecules are time- and cost-intensive. “We offer a novel construction strategy for rapid and cost-efficient synthesis of these lipidoids,” says Xuexiang Han, a postdoctoral student in the Mitchell Lab and the paper’s co-first author.
Bispecific T cell engagers are emerging as a powerful class of immunotherapy to treat cancer but are sometimes hindered by unwanted outcomes, such as on-target, off-tumor toxicity; cytokine release syndrome; and neurotoxicity. Now, researchers Penn researchers have developed a novel “switchable” bispecific T cell engager that mitigates these negative effects by co-opting a drug already approved by the FDA. (Image: iStock / CIPhotos)
In the ever-evolving battle against cancer, immunotherapy presents a turning point. It began with harnessing the body’s immune system to fight cancer, a concept rooted more than a century ago but only gaining significant momentum in recent years. Pioneering this shift were therapies like CAR T cell therapy, which reprograms a patient’s T cells to attack cancer cells. Within this domain, bispecific T cell engagers, or bispecific antibodies, have emerged as effective treatments for many blood-borne cancers in the clinic and are being evaluated for solid tumor therapy.
These antibodies simultaneously latch onto both a cancer cell and a T cell, effectively bridging the gap between the two. This proximity triggers the T cells to unleash their lethal arsenal, thereby killing the cancer cells. However, bispecific T cell engagers, like many cancer therapies, face hurdles such as cell-specific targeting limitations, known as on-target off-tumor toxicity, which means the tumor is correctly targeted but so are other healthy cells in the body, leading to healthy tissue damage. Moreover, bispecific antibodies may also lead to immune system overactivation, a precursor for cytokine release syndrome (CRS), and neurotoxicity.
Now, researchers led by Michael Mitchell of the University of Pennsylvania have found a way to circumvent many of these deleterious effects by developing a bispecific T cell nanoengager that is equipped with an “off switch.” Their findings are published in Nature Biomedical Engineering.
“We’re excited to show that bispecific antibodies can be tweaked in a way that allows us to tap into their powerful cancer-killing potential without inducing toxicity to healthy tissues,” says Mitchell, associate professor of bioengineering at Penn’s School of Engineering and Applied Science. “This new controllable drug-delivery mechanism, which we call switchable bispecific T cell nanoengagers, or SiTEs, adds this switchable component to the antibody via administering an FDA-approved small-molecule drug, amantadine.”
(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.
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.
Joshua C. Doloff, Assistant Professor of Biomedical Engineering and Materials Science & Engineering at Johns Hopkins University, featured in The Jewish News Syndicate for his work on “Hope,” a new technology which offers pain- and injection-free treatment to people with Type 1 or “juvenile” diabetes. Doloff is an alumnus of Penn Bioengineering, Class of 2004:
“Doloff received his bachelor’s degree from the University of Pennsylvania and his graduate degrees from Boston University. In addition to his post in Johns Hopkins’ Department of Biomedical Engineering, he is a member of the Translational Tissue Engineering Center at Johns Hopkins University School of Medicine. His lab is interested in systems biology with an emphasis on engineering improved therapies in the fields of cancer, autoimmunity, transplantation medicine, including Type 1 diabetes and ophthalmology.”
The research team from left to right includes Kelsey Swingle, Hannah Safford, Alex Hamilton, Ajay Thatte, Hannah Geisler, and Mike Mitchell.
New research on reproductive health demonstrates the first successful delivery of mRNA to placental cells to treat pre-eclampsia at its root.
Pre-eclampsia is a leading cause of stillbirths and prematurity worldwide, occurring in 3 – 8 % of pregnancies. A disorder characterized by high maternal blood pressure, it results from insufficient vasodilation in the placenta, restricting blood flow from the mother to the fetus.
Currently, a health-care plan for someone with pre-eclampsia involves diet and movement changes, frequent monitoring, blood pressure management, and sometimes early delivery of the baby. These standards of care address symptoms of the condition, not the root cause, and further perpetuate health inequity.
Now, Penn engineers are addressing this longstanding gap in reproductive health care with targeted RNA therapy.
The COVID vaccines demonstrated how lipid nanoparticles (LNPs) efficiently deliver mRNA to target cells. The success of LNPs is opening doors for a variety of RNA therapies aiming to treat the root causes of illness and disease. However, drug development and health care have consistently neglected a portion of the population in need of targeted care the most – pregnant people and their babies.
In one of the first studies of its kind, published in the Journal of the American Chemical Society,Michael Mitchell, J. Peter and Geri Skirkanich Assistant Professor of Innovation in Bioengineering, and Kelsey Swingle, Ph.D. student in the Mitchell Lab and lead author, describe their development of an LNP with the ability to target and deliver mRNA to trophoblasts, endothelial cells, and immune cells in the placenta.
Once these cells receive the mRNA, they create vascular endothelial growth factor (VEGF), a protein that helps expand the blood vessels in the placenta to reduce the mother’s blood pressure and restore adequate circulation to the fetus. The researchers’ successful trials in mice may lead to promising treatments for pre-eclampsia in humans.
Savan Patel, a fourth year Penn Bioengineering student, is one of 42 finalists competing for a 2023 Hertz Fellowship in applied science, mathematics, and engineering, one of the most prestigious Ph.D. fellowships in the United States. Chosen annually, the Hertz Fellowship is awarded to the nation’s most promising graduate students in science and technology.
“Since 1963, the Hertz Foundation has granted fellowships empowering the nation’s most promising young minds in science and technology. Hertz Fellows receive five years of funding valued at up to $250,000, which offers flexibility from the traditional constraints of graduate training and the independence needed to pursue research that best advances our security and economic vitality […]
Over the foundation’s 60-year history of awarding fellowships, more than 1200 Hertz Fellows have established a remarkable track record of accomplishments. Their ranks include two Nobel laureates; recipients of 10 Breakthrough Prizes and three MacArthur Foundation “genius awards”; and winners of the Turing Award, the Fields Medal, the National Medal of Technology, and the National Medal of Science. In addition, 50 are members of the National Academies of Sciences, Engineering and Medicine, and 34 are fellows of the American Association for the Advancement of Science. Hertz Fellows hold over 3,000 patents, have founded more than 375 companies and have created hundreds of thousands of science and technology jobs.”
Patel is studying Bioengineering and Finance in the Jerome Fisher Program in Management and Technology (M&T), an interdisciplinary dual degree program coordinated by Penn Engineering and the Wharton School of Business. He is currently a member of the lab of Michael J. Mitchell, J. Peter and Geri Skirkanich Assistant Professor of Innovation in Bioengineering. Patel’s research interests lie at the interface of drug delivery and immunoengineering. His current project involves the use of modified cholesterol molecules to induce shifts in the biodistribution of ionizable lipid nanoparticles (LNPs). Following graduation, he intends to pursue a Ph.D. in bioengineering in which hopes to develop translatable immunotherapies and drug delivery platforms.
If chosen, the Hertz Fellowship will fund Patel’s graduate studies. Selected from over 750 applicants, Patel is one of fifteen undergraduates and one of two bioengineering students to make the final round of interviews. After a culminating round of interviews, the 2023 Class of Hertz Fellows will be announced in May.
Learn more about the Hertz Fellowship and read the full list of finalists here.
Engineers in the Center for Precision Engineering for Health (CPE4H) are focusing on innovations in diagnostics and delivery, cellular and tissue engineering, and the development of new devices that integrate novel materials with human tissues. Below is an excerpt from “Going Small to Win Big: Engineering Personalized Medicine,” featuring the research from the laboratory of Michael Mitchell, J. Peter and Geri Skirkanich Assistant Professor of Innovation in Bioengineering.
The Challenge
Solid tumors evade the immune system’s ability to attack them in part due to the tumors’ tough, fibrous biological barriers that circulating immune cells can’t cross. Researchers need to identify ways to deliver individualized treatments that can better target these tumors without causing damage to healthy tissues or affecting overall quality of life.
The Status Quo
Current cancer treatments typically involve surgery, radiation or chemo- therapy to eliminate solid tumors. These treatments are invasive and can cause numerous negative downstream effects. Newer treatments involve engineering a patient’s immune system to recognize and fight cancerous cells, but are so far only effective against certain “liquid” cancers, where the mutated cells circulate freely in the blood and bone marrow and are small enough to be picked off by the patient’s upgraded T cells. Additionally, existing methods can also require that the cell engineering take place in a lab rather than directly inside the body.
The Mitchell Lab’s Fix
Members of the lab of Michael Mitchell, J. Peter and Geri Skirkanich Assistant Professor of Innovation in Bioengineering, are looking to utilize nanoparticle delivery technology developed by their lab to engineer a different type of immune cell, the macrophage, in order to fight solid- tumor cancers from the inside.
The Mitchell lab is using lipid nanoparticles (LNPs) to carry mRNA and DNA sequences inside of macrophages, a type of immune cell that can consume tumor cells if engineered correctly. In theory, a patient would receive an injection carrying the LNP payload, and the macrophages, whose name literally means “big eaters,” would take up the genetic sequence, alter their function and be able to recognize a patient’s own unique tumor cells in the body.
Because of the way macrophages operate, they could cross the tumor’s biological barrier and attack the cells, destroying the tumor from the inside. An added benefit of the Mitchell Lab’s technology is that the destroyed tumor cells would then also allow other immune cells to present their antigens to circulating T cells, which could then learn to fight those same cancer cells in the future.
“One of the longstanding challenges that we face in the context of cancer and immunotherapies is that every tumor has unique antigens that are specific to patients,” says Mitchell. “This is why we’ve had a lot of trouble developing targeted therapies. Personalizing an approach by harnessing an individual’s immune system gives each patient a greater chance of a positive outcome.”
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.
In 
