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Michael Mitchell on Keeping mRNA Vaccines Viable

A National Institute of Allergy and Infectious Diseases lab freezer used for COVID-19 vaccine research. Both of the current mRNA-based COVID vaccines require ultra-cold freezers to prevent their mRNA from degrading, spurring research into other ways to stabilize the molecule.

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.

Michael Mitchell
Michael Mitchell

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.

Continue reading at MIT Technology Review.

Originally posted in Penn Engineering Today.

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David Meaney Receives 2021 Lindback Award

David F. Meaney, PhD

David F. Meaney is among the recipients of the 2021 Lindback Awards.

The Lindback Awards, announced annually, are the most prestigious teaching awards that full-time faculty members at the University can receive.

Meaney is the Solomon R. Pollack Professor in Bioengineering and Senior Associate Dean of Penn Engineering and his research areas span from traumatic brain injury to brain network theory. He received his M.S. and Ph.D. in Bioengineering and Biomedical Engineering from Penn Engineering.

The Lindback Awards were established in 1961 with the help of the Christian R. and Mary F. Lindback Foundation.

Congratulations to Dr. Meaney from everyone in Penn Bioengineering for this well-deserved honor!

Read more stories on the BE blog featuring Dr. Meaney.

Originally posted in Penn Engineering Today.

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Penn, CHOP and Yale Researchers’ Molecular Simulations Uncover How Kinase Mutations Lead to Cancer Progression

by Evan Lerner

A computer model of a mutated anaplastic lymphoma kinase (ALK), a known oncogenic driver in pediatric neuroblastoma.

Kinases are a class of enzymes that are responsible for transferring the main chemical energy source used by the body’s cells. As such, they play important roles in diverse cellular processes, including signaling, differentiation, proliferation and metabolism. But since they are so ubiquitous, mutated versions of kinases are frequently found in cancers. Many cancer treatments involve targeting these mutant kinases with specific inhibitors.

Understanding the exact genetic mutations that lead to these aberrant kinases can therefore be critical in predicting the progression of a given patient’s cancer and tailoring the appropriate response.

To achieve this understanding on a more fundamental level, a team of researchers from the University of Pennsylvania’s School of Engineering and Applied Science and Perelman School of Medicine, the Children’s Hospital of Philadelphia (CHOP) and researchers at the Yale School of Medicine’s Cancer Biology Institute, have constructed molecular simulations of a mutant kinase implicated in pediatric neuroblastoma, a childhood cancer impacting the central nervous system.

Using their computational model to study the relationship between single-point changes in the kinase’s underlying gene and the altered structure of the protein it ultimately produces, the researchers revealed useful commonalities in the mutations that result in tumor formation and growth. Their findings suggest that such computational approaches could outperform existing profiling methods for other cancers and lead to more personalized treatments.

The study, published in the Proceedings of the National Academy of Sciences, was led by Ravi Radhakrishnan, Professor and chair of Penn Engineering’s Department of Bioengineering and professor in its Department of Chemical and Biomolecular Engineering, and Mark A. Lemmon, Professor of Pharmacology at Yale and co-director of Yale’s Cancer Biology Institute. The study’s first authors were Keshav Patil, a graduate student in Penn Engineering’s Department of Chemical and Biomolecular Engineering, along with Earl Joseph Jordan and Jin H. Park, then members of the Graduate Group in Biochemistry and Molecular Biology in Penn’s Perelman School of Medicine. Krishna Suresh, an undergraduate student in Radhakrishnan’s lab, Courtney M. Smith, a graduate student in Lemmon’s lab, and Abigail A. Lemmon, an undergraduate in Lemmon’s lab, contributed to the study. They collaborated with Yaël P. Mossé, Associate Professor of Pediatrics at Penn Medicine and in the division of oncology at CHOP.

“Some cancers rely on the aberrant activation of a single gene product for tumor initiation and progression,” says Radhakrishnan. “This unique mutational signature may hold the key to understanding which patients suffer from aggressive forms of the disease or for whom a given therapeutic drug may yield short- or long-term benefits. Yet, outside of a few commonly occurring ‘hotspot’ mutations, experimental studies of clinically observed mutations are not commonly pursued.”

Read the full post in Penn Engineering Today.

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Manuela Raimondi Appointed Visiting Professor in Bioengineering

Manuela Raimondi, PhD

Manuela Teresa Raimondi was appointed Visiting Professor in Bioengineering in the Associated Faculty of the School of Engineering and Applied Science for the 2020-2021 academic year. Raimondi received her Ph.D. in Bioengineering in 2000 from Politecnico di Milano, Italy. She is currently a Full Professor of Bioengineering at Politecnico di Milano in the Department of Chemistry, Materials and Chemical Engineering “G. Natta”, where she teaches the course “Technologies for Regenerative Medicine” in the Biomedical Engineering graduate program.

Raimondi is the founder and Director of the Mechanobiology Lab and of the Interdepartmental Live Cell Imaging lab. She has pioneered the development of cutting edge tools for cell modelling, ranging from micro-engineered stem cell niches, to miniaturized windows for in vivo intravital imaging, to microfluidic culture systems to engineer tissue-equivalents and organoids for cell modelling and drug discovery. Her platforms are currently commercialized by her start-up, MOAB srl. Her research is funded by the European Research Council (ERC), by The National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), by the European Commission, and by the European Space Agency.

“Getting to Penn was quite the challenge with the various travel restrictions and the pandemic, but I am used to overcoming adverse odds and I am really excited to be here now,” says Dr. Raimondi. “In this challenging time, when many new barriers are coming up, I think building bridges and new scientific collaborations is even more important. I very much look forward to being part of the Penn research community.”

Dr. Raimondi with host Riccardo Gottardi, PhD on Smith Walk

During her sabbatical at Penn, Raimondi is investigating her hypothesis that stem cells pluripotency reprogramming can be guided by mechanical cues. Over the past five years, she has cultured many different stem cell types in the “Nichoids,” the synthetic stem cell niche she developed, and gathered robust evidence on how physical constraints at the microscale level upregulate pluripotency. Raimondi is hosted in the Bioengineering and Biomaterials Lab of Riccardo Gottardi, Assistant Professor in Bioengineering and in Pediatrics at the Perelman School of Medicine, where she is helping to refine human stem cell sources that could be minimally manipulated for translational tissue engineering for a safe and effective use in regenerative therapies, as a key issue for clinical translation is the maintenance or enhancement of multipotency during cell expansion without exogenous agents or genetic modification.

“Dr. Raimondi is a trailblazer in Italy in regenerative medicine who has introduced many new concepts in a sometimes musty academic environment and has shattered a number of glass ceilings,” says Dr. Gottardi. “I think her sabbatical at Penn is a great opportunity for her and for the Penn community to build new and exciting trans-Atlantic collaborations.”

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Kevin Johnson Appointed Penn Integrates Knowledge University Professor

Ron Ozio

Kevin Johnson, Penn’s 27th Penn Integrates Knowledge University Professor.

Kevin Johnson has been named the University of Pennsylvania’s 27th Penn Integrates Knowledge University Professor.

The announcement was made by Penn President Amy Gutmann and Provost Wendell Pritchett.

A pioneer of medical information technologies to improve patient safety, Johnson will hold joint appointments in the Department of Biostatistics, Epidemiology, and Informatics in the Perelman School of Medicine and the Department of Computer and Information Science in the School of Engineering and Applied Science, with secondary appointments in the Annenberg School for Communication and in the Department of Bioengineering. He will also serve as vice president for applied informatics in the University of Pennsylvania Health System and professor of pediatrics at the Children’s Hospital of Philadelphia.

“Kevin Johnson is a gifted physician-scientist,” Gutmann said, “who has harnessed and aligned the power of medicine, engineering, and technology to improve the health of individuals and communities. He has championed the development and implementation of clinical information systems and artificial intelligence to drive medical research, encouraged the effective use of technology at the bedside, and empowered patients to use new tools to better understand how medications and supplements may affect their health. He is a board-certified pediatrician, and his commitment to patient health and welfare knows no age limits. In so many different settings, Kevin’s work is driving progress in patient care and improving our health care system. He is a perfect fit for Penn, where our goal is to create a maximally inclusive and integrated academic community to spur unprecedented global impact.”

Johnson is currently the Cornelius Vanderbilt Professor and chair of the Department of Biomedical Informatics at the Vanderbilt University School of Medicine, where he has taught since 2002. He is a world-renowned innovator in developing clinical information systems that improve best practices in patient safety and compliance with medical practice guidelines, especially the use of computer-based documentation systems and other digital technologies. His research bridges biomedical informatics, bioengineering, and computer science. As senior vice president for health information technology at the Vanderbilt University Medical Center from 2014 to 2019, he led the development of clinical systems that enabled doctors to make better treatment and care decisions for individual patients, in part by alerting patients as to how medications or supplements might affect their body chemistry, as well as new systems to integrate artificial intelligence into patient care workflows and to unify and simplify all the Medical Center’s clinical and administrative systems.

The author of more than 150 publications, books, or book chapters, Johnson has held numerous leadership positions in the American Medical Informatics Association and the American Academy of Pediatrics, leads the American Board of Pediatrics Informatics Advisory Committee, directs the Board of Scientific Counselors of the National Library of Medicine, and is a member of the NIH Council of Councils. He has been elected to the National Academy of Medicine (Institute of Medicine), American College of Medical Informatics, and Academic Pediatric Society and has received awards from the Robert Wood Johnson Foundation and American Academy of Pediatrics, among many others.

“Kevin Johnson exemplifies our most profound Penn values,” Pritchett said. “He is a brilliant innovator committed to bringing together disciplines across traditional boundaries. Yet he always does so in the service of helping others, finding technological solutions that can make a tangible impact on improving people’s lives. He will be an extraordinary colleague, teacher and mentor across multiple areas of our campus in the years to come.”

Johnson earned an M.D. from the Johns Hopkins University School of Medicine, an M.S. in medical informatics from Stanford University, and a B.S. with honors in biology from Dickinson College. He became the first Black chief resident in pediatrics at Johns Hopkins in 1992, and was a faculty member in both pediatrics and biomedical information sciences at Johns Hopkins until 2002.

The Penn Integrates Knowledge program was launched by Gutmann in 2005 as a University-wide initiative to recruit exceptional faculty members whose research and teaching exemplify the integration of knowledge across disciplines and who are appointed in at least two Schools at Penn.

Originally posted in Penn Today.

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‘RNA worked for COVID-19 vaccines. Could it be used to treat cancer and rare childhood diseases?’

William H. Peranteau, Michael J. Mitchell, Margaret Billingsley, Meghana Kashyap, and Rachel Riley (Clockwise from top left)

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.

Mitchel spoke with Tom Avril at The Philadelphia Inquirer about the mouse study and its implications for treatment of rare infant diseases through the use of mRNA, ‘the messenger of life.’

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.

Continue reading Tom Avril’s ‘RNA worked for COVID-19 vaccines. Could it be used to treat cancer and rare childhood diseases?’ at The Philadelphia Inquirer.

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Hao Huang Named AIMBE Fellow

Hao Huang, Ph.D.

Hao Huang, Research Associate Professor of Radiology in the Perelman School of Medicine and member of the Penn Bioengineering Graduate Group, has been named an American Institute for Medical and Biological Engineering (AIMBE) Fellow.

Election to the AIMBE College of Fellows is among the highest professional distinctions accorded to a medical and biological engineer. “The College of Fellows is comprised of the top two percent of medical and biological engineers in the country. The most accomplished and distinguished engineering and medical school chairs, research directors, professors, innovators, and successful entrepreneurs comprise the College of Fellows. AIMBE Fellows are regularly recognized for their contributions in teaching, research, and innovation.”

Huang was “nominated, reviewed, and elected by peers and members of the College of Fellows for contributions to the development and applications of innovative MR methods to study the developing brain.”

A formal induction ceremony will be held during AIMBE’s virtual 2021 Annual Event on March 26. Huang will be inducted along with 174 colleagues who make up the AIMBE Fellow Class of 2021.

Read the full press release.

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Penn Engineers’ New Bioprinting Technique Allows for Complex Microtissues

by Evan Lerner

Jason Burdick, Andrew C. Daly and Matthew Davidson

Bioprinting is currently used to generate model tissues for research and has potential applications in regenerative medicine. Existing bioprinting techniques rely on printing cells embedded in hydrogels, which results in low-cell-density constructs that are well below what is required to grow functional tissues. Maneuvering different kinds of cells into position to replicate the complex makeup of an organ, particularly at organlike cell densities, is still beyond their capabilities.

Now, researchers at the School of Engineering and Applied Science have demonstrated a new bioprinting technique that enables the bioprinting of spatially complex, high-cell-density tissues.

Using a self-healing hydrogel that allows dense clusters of cells to be picked and placed in a three-dimensional suspension, the researchers constructed a model of heart tissue that featured a mix of cells that mimic the results of a heart attack.

The study was led by Jason Burdick, Robert D. Bent Professor in the Department of Bioengineering, and Andrew C. Daly, a postdoctoral researcher in his lab. Fellow Burdick lab postdoc Matthew Davidson also contributed to the study, which has been published in the journal Nature Communications.

Even without a bioprinter, groups of cells can be made to clump into larger aggregates, known as spheroids. For Burdick and colleagues, these spheroids represented a potential building block for a better approach to bioprinting.

“Spheroids are often useful for studying biological questions that rely on the cells’ 3D microenvironments or in the construction of new tissues,” says Burdick. “However, we’d like to produce even higher levels of organization by ‘printing’ different kinds of spheroids in specific arrangements and have them fuse together into structurally complex microtissues.”

Read more at Penn Engineering Today.

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Penn Dental, Penn Engineering Unite to Form Center for Innovation & Precision Dentistry

by Beth Adams

With the shared vision to transform the future of oral health care, Penn Dental Medicine and Penn’s School of Engineering and Applied Sciences have united to form the Center for Innovation & Precision Dentistry (CiPD). The new Center marked its official launch on January 22 with a virtual program celebrating the goals and plans of this unique partnership. Along with the Deans from both schools, the event gathered partners from throughout the University of Pennsylvania and invited guests, including the National Institute of Dental and Craniofacial Research Director (NIDCR) Dr. Rena D’Souza and IADR Executive Director Chris Fox.

Conceived and brought to fruition by co-directors Dr. Michel Koo of Penn Dental Medicine and Dr. Kathleen Stebe of Penn Engineering, the CiPD is bridging the two schools through cutting-edge research and technologies to accelerate the development of new solutions and devices to address unmet needs in oral health, particularly in the areas of dental caries, periodontal disease, and head and neck cancer. The CiPD will also place a high priority on programs to train the next generation of leaders in oral health care innovation.

“We have a tremendous global health challenge. Oral diseases and craniofacial disorders affect 3.5 billion people, disproportionately affecting the poor and the medically and physically compromised,” says Dr. Koo, Professor in the Department of Orthodontics and Divisions of Community Oral Health and Pediatric Dentistry, in describing their motivation to form the Center. “There is an urgent need to find better ways to diagnose, prevent, and treat these conditions, particularly in ways that are affordable and accessible for the most susceptible populations. That is our driving force for putting this Center together.”

“We have united our schools around this mission,” adds Dr. Stebe, Richer & Elizabeth Goodwin Professor in the Department of Chemical and Biomolecular Engineering. “We have formed a community of scholars to develop and harness new engineering paradigms, to generate new knowledge, and to seek new approaches that are more effective, precise, and affordable to address oral health. More importantly, we will train a new community of scholars to impact this space.”

Born through Interdisciplinary Research

A serendipitous connection born through Penn’s interdisciplinary research environment itself brought Drs. Koo and Stebe together more than five years ago, an introduction that would eventually lead to creating the CiPD.

Dr. Tagbo Niepa, now assistant professor at the University of Pittsburgh, came to Penn Engineering in 2014 as part of Penn’s Postdoctoral Fellowship for Academic Diversity, an initiative from the office of the Vice Provost for Research. His studies on the microbiome led him to reach out to Dr. Stebe and Dr. Daeyeon Lee (also at Penn Engineering), and to connect them to Dr. Koo, initiating collaboration between their labs.

“Tagbo embodies what we are trying to do with the CiPD,” recalls Dr. Stebe. “He had initiative, he identified new tools and important context, and he did good science that may help us understand how to interrupt the disease process and identify new underlying mechanisms that can inspire new therapies.” Dr. Niepa worked on applying microfluidics and engineering to study the oral microbiome and better understand how the interactions between fungi and bacteria could impact dental caries.

“Upon meeting Michel, we became excited about the possibilities of bringing talent from the two schools together,” notes Dr. Stebe. A 2018 workshop organized by Drs. Koo and Stebe and funded by Penn’s Vice Provost of Research explored the potential for expanding cross-school research. “We invited researchers from dental medicine and engineering as well as relevant people from the arts and sciences to see if we could find a way to collaborate to advance oral and craniofacial health,” says Dr. Koo. “That was the catalyst for the Center; after the workshop, we put together a task force which would become the core members of the CiPD.”

In addition to Drs. Koo and Stebe, the CiPD Executive Committee includes Associate Directors Dr. Henry Daniell, Vice-Chair and W.D. Miller Professor, Department of Basic & Translational Sciences, Penn Dental Medicine, and Dr. Anh Le, Chair and Norman Vine Endowed Professor of Oral Rehabilitation, Department of Oral and Maxillofacial Surgery / Pharmacology, Penn Dental Medicine; as well as Dr. Andrew Tsourkas, Professor, Department of Bioengineering, Co-Director, Center for Targeted Therapeutics & Translational Nanomedicine (CT3N) and Chemical and Nanoparticle Synthesis Core, Penn Engineering; and Dr. Jason Moore, Edward Rose Professor of Informatics, Director of the Penn Institute for Biomedical Informatics. The core members of CiPD include 26 faculty from across both Penn Dental Medicine and Penn Engineering, and also from the Schools of Medicine and Arts & Sciences.

Read the full story in Penn Today.

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Penn Engineering and CHOP Researchers Identify Nanoparticles that Could Be Used in Therapeutic mRNA Delivery before Birth

by Evan Lerner

William H. Peranteau, Michael J. Mitchell, Margaret Billingsley, Meghana Kashyap, and Rachel Riley (Clockwise from top left)

Researchers at Children’s Hospital of Philadelphia and the School of Engineering and Applied Science at the University of Pennsylvania have identified ionizable lipid nanoparticles that could be used to deliver mRNA as part of fetal therapy. The proof-of-concept study, published today in Science Advances, engineered and screened a number of lipid nanoparticle formulations for targeting mouse fetal organs and has laid the groundwork for testing potential therapies to treat genetic diseases before birth.

“This is an important first step in identifying nonviral mediated approaches for delivering cutting-edge therapies before birth,” said co-senior author William H. Peranteau, MD, an attending surgeon in the Division of General, Thoracic and Fetal Surgery and the Adzick-McCausland Distinguished Chair in Fetal and Pediatric Surgery at CHOP. “These lipid nanoparticles may provide a platform for in utero mRNA delivery, which would be used in therapies like fetal protein replacement and gene editing.”

Michael J. Mitchell, Skirkanich Assistant Professor of Innovation in Penn Engineering’s Department of Bioengineering, is the other co-senior author of the study. The co-first authors are Mitchell Lab members Rachel Riley, a postdoctoral fellow, and Margaret Billingsley, a graduate student, and Peranteau Lab member Meghana Kashyap, a research fellow.

Recent advances in DNA sequencing technology and prenatal diagnostics have made it possible to diagnose many genetic diseases before birth. Some of these diseases are treated by protein or enzyme replacement therapies after birth, but by then, some of the damaging effects of the disease have taken hold. Thus, applying therapies while the patient is still in the womb has the potential to be more effective for some conditions. The small fetal size allows for maximal therapeutic dosing, and the immature fetal immune system may be more tolerant of replacement therapy.

Read the full story in Penn Engineering Today.

NB: Rachel Riley is now Assistant Professor in Biomedical Engineering at Rowan University.