Savan Patel, a junior studying Bioengineering and Finance in the Jerome Fisher Management and Technology dual degree program, was selected as the recipient of the 2022 C. William Hall Scholarship from the Society for Biomaterials. The C. William Hall Scholarship is named in honor of the Society for Biomaterials’ first president and is awarded annually “to a junior or senior undergraduate pursuing a bachelor’s degree in bioengineering or a related discipline focusing on biomaterials.” As this year’s recipient, Savan will receive complimentary membership to the Society and will have expenses paid to the Society’s annual meeting being held April 27-30, 2022 in Baltimore, Maryland.
Savan is currently a member of the lab of Michael J. Mitchell, Skirkanich Assistant Professor of Innovation in Bioengineering. Savan’s research interests lie in the interface of drug delivery and immunoengineering with a particular focus on T cell delivery. His current project involves the use of modified cholesterol molecules to improve the delivery of nucleic acids (i.e., mRNA) to cell populations using lipid nanoparticles.
Lipid nanoparticles (LNPs) are a clinically proven delivery platform for nucleic acid therapeutics. One drawback of these particles is their high cellular recycling rate. Savan and the members of the Mitchell lab are working to reduce this recycling by leveraging cellular processes and incorporating modified molecules into our lipid nanoparticle formulations. The focus of Savan’s project is on modifying cholesterol, a molecule that is important to both our LNP formulations and cell membranes. The goal is to generate a more potent delivery platform to improve current therapeutics.
Following graduation, Savan intends to pursue a Ph.D. in Bioengineering.
Penn Engineering secured a multi-million-dollar contract with Wellcome Leap under the organization’s $60 million RNA Readiness + Response (R3) program, which is jointly funded with the Coalition for Epidemic Preparedness Innovations (CEPI). Penn Engineers aim to create “on-demand” manufacturing technology that can produce a range of RNA-based vaccines.
The Penn Engineering team features Daeyeon Lee, Evan C Thompson Term Chair for Excellence in Teaching and Professor in Chemical and Biomolecular Engineering, Michael Mitchell, Skirkanich Assistant Professor of Innovation in Bioengineering, David Issadore, Associate Professor in Bioengineering and Electrical and Systems Engineering, and Sagar Yadavali, a former postdoctoral researcher in the Issadore and Lee labs and now the CEO of InfiniFluidics, a spinoff company based on their research. Drew Weissman of the Perelman School of Medicine, whose foundational research directly continued to the development of mRNA-based COVID-19 vaccines, is also a part of this interdisciplinary team.
The success of these COVID-19 vaccines has inspired a fresh perspective and wave of research funding for RNA therapeutics across a wide range of difficult diseases and health issues. These therapeutics now need to be equitably and efficiently distributed, something currently limited by the inefficient mRNA vaccine manufacturing processes which would rapidly translate technologies from the lab to the clinic.
From COVID vaccines to cancer immunotherapies to the potential for correcting developmental disorders in utero, mRNA-based approaches are a promising tool in the fight against a wide range of diseases. These treatments all depend on providing a patient’s cells with genetic instructions for custom proteins and other small molecules, meaning that getting those instructions inside the target cells is of critical importance.
The current delivery method of choice uses lipid nanoparticles (LNPs). Thanks to surfaces customized with binding and signaling molecules, they encapsulate mRNA sequences and smuggle them through the cell membrane. But with a practically unlimited number of variables in the makeup of those surfaces and molecules, figuring out how to design the most effective LNP is a fundamental challenge.
Now, in a study featured on the cover of the journal Nano Letters, researchers from the University of Pennsylvania’s School of Engineering and Applied Science and Perelman School of Medicine have now shown how to computationally optimize the design of these delivery vehicles.
Using an established methodology for comparing a wide range of variables known as “orthogonal design of experiments,” the researchers simultaneously tested 256 candidate LNPs. They found the frontrunner was three times better at delivering mRNA sequences into T cells than the current standard LNP formulation for mRNA delivery.
The study was led by Michael Mitchell, Skirkanich Assistant Professor of Innovation in the Department of Bioengineering in Penn’s School of Engineering and Applied Science, and Margaret Billingsley, a graduate student in his lab.
The Society for Biomaterials is a multidisciplinary society of academic, healthcare, governmental and business professionals dedicated to promoting advancements in all aspects of biomaterial science, education and professional standards to enhance human health and quality of life.
Mitchell, whose research lies at the interface of biomaterials science, drug delivery, and cellular and molecular bioengineering to fundamentally understand and therapeutically target biological barriers, is specifically being recognized for his development of the first nanoparticle RNAi therapy to treat multiple myeloma, an incurable hematologic cancer that colonizes in bone marrow.
“Before this, no one in the drug delivery field has developed an effective gene delivery system to target bone marrow,” said United States National Medal of Science recipient Robert S. Langer in Mitchell’s award citation. “Mike is a standout young investigator and leader that intimately understands the importance of research and collaboration at the interface of nanotechnology and medicine.”
Academic recipients of the SFB Young Investigator Award should not exceed the rank of Assistant Professor and must not be tenured at the time of nomination. The award includes a $1,000 endowment.
The Center will conduct interdisciplinary, fundamental, and translational research in the synthesis of novel biomolecules and new polymers to develop innovative approaches to design complex three dimensional structures from these new materials to sense, understand, and direct biological function.
“Biomaterials represent the ‘stealth technology’ which will create breakthroughs in improving health care and saving lives,” says Penn President Amy Gutmann. “Innovation that combines precision engineering and design with a fundamental understanding of cell behavior has the potential to have an extraordinary impact in medicine and on society. Penn is already well established as an international leader in innovative health care and engineering, and this new Center will generate even more progress to benefit people worldwide.”
Penn Engineering will hire five new President’s Penn Compact Distinguished Professors, as well as five additional junior faculty with fully funded faculty positions that are central to the Center’s mission. New state-of-the-art labs will provide the infrastructure for the research. The Center will seed grants for early-stage projects to foster advances in interdisciplinary research across engineering and medicine that can then be parlayed into competitive grant proposals.
“Engineering solutions to problems within human health is one of the grand challenges of the discipline,” says Vijay Kumar, Nemirovsky Family Dean of Penn Engineering. “Our faculty are already leading the charge against these challenges, and the Center will take them to new heights.”
This investment represents a turning point in Penn’s ability to bring creative, bio-inspired approaches to engineer novel behaviors at the molecular, cellular, and tissue levels, using biotic and abiotic matter to improve the understanding of the human body and to develop new therapeutics and clinical breakthroughs. It will catalyze integrated approaches to the modeling and computational design of building blocks of peptides, proteins, and polymers; the synthesis, processing, and fabrication of novel materials; and the experimental characterizations that are needed to refine approaches to design, processing, and synthesis.
“This exciting new initiative,” says Interim Provost Beth Winkelstein, “brings together the essential work of Penn Engineering with fields across our campus, especially in the Perelman School of Medicine. It positions Penn for global leadership at the convergence of materials science and biomedical engineering with innovative new techniques of simulation, synthesis, assembly, and experimentation.”
Examples of the types of work being done in this field include new nanoparticle technologies to improve storage and distribution of vaccines, such as the COVID-19 mRNA vaccines; the development of protocells, which are synthetic cells that can be engineered to do a variety of tasks, including adhering to surfaces or releasing drugs; and vesicle based liquid biopsy for diagnosing cancer.
COVID-19 vaccines are just the beginning for mRNA-based therapies; enabling a patient’s body to make almost any given protein could revolutionize care for other viruses, like HIV, as well as various cancers and genetic disorders. However, because mRNA molecules are very fragile, they require extremely low temperatures for storage and transportation. The logistical challenges and expense of maintaining these temperatures must be overcome before mRNA therapies can become truly widespread.
With these challenges in mind, Penn Engineering researchers are developing a new manufacturing technique that would be able to produce mRNA sequences on demand and on-site, isolating them in a way that removes the need for cryogenic temperatures. With more labs able to make and store mRNA-based therapeutics on their own, the “cold chain” between manufacturer and patient can be made shorter, faster and less expensive.
The National Science Foundation (NSF) is supporting this project, known as Distributed Ribonucleic Acid Manufacturing, or DReAM, through a four-year, $2 million grant from its Emerging Frontiers in Research and Innovation (EFRI) program.
The project will be led by Daeyeon Lee, Evan C Thompson Term Chair for Excellence in Teaching and Professor in the Department of Chemical and Biomolecular Engineering (CBE), along with Kathleen Stebe, Richer and Elizabeth Goodwin Professor in CBE and in the Department of Mechanical Engineering and Applied Mechanics. They will collaborate with Michael Mitchell, Skirkanich Assistant Professor of Innovation in the Department of Bioengineering, Drexel University’s Masoud Soroush and Michael Grady, the University of Oklahoma’s Dimitrios Papavassiliou and the University of Colorado Boulder’s Joel Kaar.
The COVID vaccines currently being deployed were developed with unprecedented speed, but the mRNA technology at work in some of them is an equally impressive success story. Because any desired mRNA sequence can be synthesized in massive quantities, one of the biggest hurdles in a variety of mRNA therapies is the ability to package those sequences into the lipid nanoparticles that deliver them into cells.
Now, thanks to manufacturing technology developed by bioengineers and medical researchers at the University of Pennsylvania, a hundred-fold increase in current microfluidic production rates may soon be possible.
The researchers’ advance stems from their design of a proof-of-concept microfluidic device containing 128 mixing channels working in parallel. The channels mix a precise amount of lipid and mRNA, essentially crafting individual lipid nanoparticles on a miniaturized assembly line.
This increased speed may not be the only benefit; more precisely controlling the nanoparticles’ size could make treatments more effective. The researchers tested the lipid nanoparticles produced by their device in a mouse study, showing they could deliver therapeutic RNA sequences with four-to-five times greater activity than those made by conventional methods.
The study was led by Michael Mitchell, Skirkanich Assistant Professor of Innovation in Penn Engineering’s Department of Bioengineering, and David Issadore, Associate Professor in Penn Engineering’s Department of Bioengineering, along with Sarah Shepherd, a doctoral student in both of their labs. Rakan El-Mayta, a research engineer in Mitchell’s lab, and Sagar Yadavali, a postdoctoral researcher in Issadore’s lab, also contributed to the study.
They collaborated with several researchers at Penn’s Perelman School of Medicine: postdoctoral researcher Mohamad-Gabriel Alameh, Lili Wang, Research Associate Professor of Medicine, James M. Wilson, Rose H. Weiss Orphan Disease Center Director’s Professor in the Department of Medicine, Claude Warzecha, a senior research investigator in Wilson’s lab, and Drew Weissman, Professor of Medicine and one of the original developers of the technology behind mRNA vaccines.
“We believe that this microfluidic technology has the potential to not only play a key role in the formulation of current COVID vaccines,” says Mitchell, “but also to potentially address the immense need ahead of us as mRNA technology expands into additional classes of therapeutics.”
We are very pleased to announce that ten current and future graduate students in the Department of Bioengineering have received 2021 National Science Foundation Graduate Research Fellowship Program (NSF GRFP) fellowships. The prestigious NSF GRFP program recognizes and supports outstanding graduate students in NSF-supported fields. Further information about the program can be found on the NSF website. BE is thrilled to congratulate our excellent students on these well-deserved accolades! Continue reading below for a list of 2021 recipients and descriptions of their research.
Puneeth Guruprasad is a Ph.D. student in the lab of Marco Ruella, Assistant Professor of Medicine in the Division of Hematology/Oncology and the Center for Cellular Immunotherapies at the Perelman School of Medicine. His work applies next generation sequencing methods to characterize tumors and study the genetic basis of resistance to cancer immunotherapy, namely chimeric antigen receptor (CAR) T cell therapy.
Gabrielle (Gabby) Ho is a Ph.D. student in the lab of Brian Chow, Associate Professor in Bioengineering. She works on design strategies for engineering near-infrared fluorescent proteins and tools.
Abbas Idris is a Master’s student in the lab of Lukasz Bugaj, Assistant Professor in Bioengineering. His work focuses on using optogenetic tools to develop controllable protein assemblies for the study of cell signaling behaviors.
Additionally, seven NSF GRFP honorees from other institutions will be joining our department as Ph.D. students in the fall of 2021. We congratulate them as well and look forward to welcoming them to Penn:
As the technology behind two of the COVID-19 vaccines, Messenger RNA (mRNA) is having a moment. A single-stranded counterpart to DNA, mRNA translates its genetic code into proteins; by injecting mRNA engineered to produce proteins found on the exterior of the virus, the vaccine can train a person’s immune system to recognize the real thing without making them sick.
However, because mRNA is a relatively unstable molecule, distributing these vaccines involves extra logistical challenges. Doses must be transported and stored at ultra-cold temperatures to make sure the mRNA inside doesn’t degrade and lose the genetic information it carries.
As mRNA vaccines and other therapies take off, researchers are looking for other ways to forestall this degradation. One of them is Michael J. Mitchell, Skirkanich Assistant Professor of Innovation in the Department of Bioengineering, who is studying the use of lipid nanoparticles to encapsulate and protect mRNA on its way into the cell. That sort of packaging would be particularly beneficial in proposed mRNA therapies for certain genetic disorders, which aim to deliver the correct protein-making instructions to specific organs, or even a fetus in utero.
But for stabilizing mRNA for vaccine distribution, many other strategies are being explored. In “Keeping covid vaccines cold isn’t easy. These ideas could help,” Wudan Yan of MIT Technology Review reached out to Mitchell for insight on LIONs, or lipid inorganic nanoparticles. These nanoparticles work the opposite way of Mitchell’s organic ones, with the mRNA stabilized by binding to their exteriors.
As COVID-19 vaccines roll out, the concept of using mRNA to fend off viruses has become a part of the public dialogue. However, scientists have been researching how mRNA can be used to in life-saving medical treatments well before the pandemic.
The “m” in “mRNA” is for “messenger.” A single-stranded counterpart to DNA, it translates the genetic code into the production of proteins, the building blocks of life. The Moderna and Pfizer COVID-19 vaccines work by introducing mRNA sequences that act as a set of instructions for the body to produce proteins that mimic parts of the virus itself. This prepares the body’s immune response to recognize the real virus and fight it off.
Because it can spur the production of proteins that the body can’t make on its own, mRNA therapies also have the potential to slow or prevent genetic diseases that develop before birth, such as cystic fibrosis and sickle-cell anemia.
However, because mRNA is a relatively unstable molecule that degrades quickly, it needs to be packaged in a way that maintains its integrity as its delivered to the cells of a developing fetus.
To solve this challenge, Michael J. Mitchell, Skirkanich Assistant Professor of Innovation in the Department of Bioengineering, is researching the use of lipid nanoparticles as packages that transport mRNA into the cell. He and William H. Peranteau, an attending surgeon in the Division of General, Thoracic and Fetal Surgery and the Adzick-McCausland Distinguished Chair in Fetal and Pediatric Surgery at Children’s Hospital of Philadelphia, recently co-authored a “proof-of-concept” paper investigating this technique.
In this study, published in Science Advances, Mitchel examined which nanoparticles were optimal in the transport of mRNA to fetal mice. Although no disease or organ was targeted in this study, the ability to administer mRNA to a mouse while still in the womb was demonstrated, and the results are promising for the next stages of targeted disease prevention in humans.
Penn bioengineering professor Michael J. Mitchell, the other senior author of the mouse study, tested various combinations of lipids to see which would work best.
The appeal of the fatty substances is that they are biocompatible. In the vaccines, for example, two of the four lipids used to make the delivery spheres are identical to lipids found in the membranes of human cells — including plain old cholesterol.
When injected, the spheres, called nanoparticles, are engulfed by the person’s cells and then deposit their cargo, the RNA molecules, inside. The cells respond by making the proteins, just as they make proteins by following the instructions in the person’s own RNA. (Important reminder: The RNA in the vaccines cannot become part of your DNA.)
Among the different lipid combinations that Mitchell and his lab members tested, some were better at delivering their cargo to specific organs, such as the liver and lungs, meaning they could be a good vehicle for treating disease in those tissues.