Tag: Michael Mitchell

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Penn’s Siloxane-Enhanced Nanoparticles Chart a New Path in Precision mRNA MedicineBeyond Displays: Liquid Crystals in Motion Mimic Biological Systems

by Ian Scheffler

By adjusting the chemical structure of lipid nanoparticles (LNPs), Penn Engineers have discovered how to target specific organs, a major breakthrough in precision medicine. (Love Employee via Getty Images)

Penn Engineers have discovered a novel means of directing lipid nanoparticles (LNPs), the revolutionary molecules that delivered the COVID-19 vaccines, to target specific tissues, presaging a new era in personalized medicine and gene therapy.

While past research — including at Penn Engineering — has screened “libraries” of LNPs to find specific variants that target organs like the lungs, this approach is akin to trial and error. “We’ve never understood how the structure of one key component of the LNP, the ionizable lipid, determines the ultimate destination of LNPs to organs beyond the liver,” says Michael J. Mitchell, Associate Professor in Bioengineering.

In a new paper published in Nature Nanotechnology, Mitchell’s group describes how subtle adjustments to the chemical structure of the ionizable lipid, a key component of the LNP, allows for tissue-specific delivery, in particular to the liver, lungs and spleen.

Read the full story in Penn Engineering Today.

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Understanding the Cellular Mechanisms Driving Solid Tumors’ Robust Defense System

by Nathi Magubane

In a collaborative interdisciplinary study, Michael Mitchell of the School of Engineering and Applied Science, Wei Guo of the School of Arts & Sciences, and Drew Weissman of the Perelman School of Medicine show that solid tumors can block drug-delivery mechanisms with a “forcefield-like” effect but certain genetic elements that can effectively “shut down” the forcefield. Their findings hint at new targets for delivering cancer treatments that use the body’s immune system to fight tumors. (Image: iStock / CIPhotos)

The tumor microenvironment—an ad hoc, messy amalgamation of signaling molecules, immune cells, fibroblasts, blood vessels, and the extracellular matrix—acts like a “powerful security system that protects solid tumors from invaders seeking to destroy them,” says Michael Mitchell, a bioengineer at the University of Pennsylvania working on nanoscale therapeutics aimed at targeting cancers.

“A lot like the Death Star with its surrounding fleet of fighter ships and protective shields, solid tumors can use features like immune cells and vasculature to exert force, acting as a physical barrier to rebel forces (nanoparticles) coming in to deliver the payload that destroys it,” Mitchell says.

Now, researchers in the Mitchell lab have teamed up with Wei Guo’s group in the School of Arts & Sciences at Penn and Drew Weissman of the Perelman School of Medicine to figure out the molecular mechanisms that make tumor microenvironments seemingly impenetrable and found that small extracellular vesicles (sEVs) are secreted by tumor cells and act as a “forcefield,” blocking therapeutics. Their findings are published in Nature Materials.

“This discovery reveals how tumors create a robust defense system, making it challenging for nanoparticle-based therapies to reach and effectively target cancer cells,” Guo says. “By understanding the cellular mechanisms driving these responses, we can potentially develop strategies to disable this defense, allowing therapeutics to penetrate and attack the tumor more efficiently.”

The research builds on a prior collaboration between Guo and Mitchell’s labs, wherein the teams focused on how tumor-associated immune cells, known as macrophages, contribute to the suppression of anti-tumor immunity by secreting extracellular vesicles.

Read the full story in Penn Today.

Michael Mitchell is an associate professor in the Department of Bioengineering in the School of Engineering and Applied Science and director of the Lipid Nanoparticle Synthesis Core at the Penn Institute for RNA Innovation at the University of Pennsylvania.

Wei Guo is the Hirsch Family President’s Distinguished Professor in the Department of Biology in Penn’s School of Arts & Sciences.

Ningqiang Gong, a former postdoctoral researcher in the Mitchell lab at Penn Engineering, is an assistant professor at the University of Science and Technology of China.

Wenqun Zhong is a reseearch associate in the Guo Laboratory in Penn Arts & Sciences.

Other authors include: Alex G Hamilton, Dongyoon Kim, Junchao Xu, and Lulu Xue of Penn Engineering; Junhyong Kim, Zhiyuan Qin, and Fengyuan Xu of Penn Arts & Sciences; Mohamad-Gabriel Alameh and Drew Weissman of the Perelman School of Medicine; Andrew E. Vaughn and Gan Zhao of the Penn School of Veterinary Medicine; Jinghong Li and Xucong Teng of the University of Beijing; and Xing-Jie Liang of the Chinese Academy of Sciences.

This research received support from the U.S. National Institutes of Health (DP2 TR002776, R35 GM141832, and NCI P50 CA261608), Burroughs Wellcome Fund, U.S. National Science Foundation CAREER Award (CBET-2145491), and an American Cancer Society Research Scholar Grant (RGS-22-1122-01-ET.)

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Unlocking Nature’s Secrets: Sherry Gao Pushes the Boundaries of Genetic Engineering

by Ian Scheffler

Sherry (Xue) Gao, Presidental Penn Compact Associate Professor in Chemical and Biomolecular Engineering and in Bioengineering

Sherry (Xue) Gao, Presidential Penn Compact Associate Professor in Chemical and Biomolecular Engineering (CBE), always knew she had a future in the lab. “I grew up in China, and when I was little, maybe six or seven,” she recalls, “my teacher asked me, ‘What do you want to be when you grow up?’ I said, ‘I want to be a scientist!’”

Neither of her parents had studied beyond high school; when Gao finished her training as a chemical engineer, she became the first person in her family to graduate from college. “One of my greatest motivations is to help first-generation college students,” Gao says.

Now, as the newest faculty member in CBE, Gao is prepared to do just that: support the next generation of chemical engineers, while also conducting groundbreaking research in the development of small molecules to edit genes, pushing the boundaries of precision medicine.

The Presidential Penn Compact Professorships were created by former Penn President Amy Gutmann specifically to recruit and support faculty like Gao: transformative leaders working at the intersection of multiple fields with “a yen for collaboration,” as Gutmann told the Penn Gazette in 2021.

Gao joins Penn Engineering from Rice University, where she collected numerous accolades, including the 2024 BMES-CMBE Rising Star Award, a 2022 NSF CAREER Award, the 2022 Outstanding Young Faculty at Rice School of Engineering Award and the 2020 NIH MIRA R35 Award.

As a member of the Center for Precision Engineering for Health (CPE4H), Gao will partner with colleagues from across the School to develop technologies that bridge disciplines, all in the interest of advancing health care. “We are very excited to have Sherry as a new member of the Center,” says Daniel Hammer, Alfred G. and Meta A. Ennis Professor and inaugural Director of CPE4H. “Gene editing is an important new tool that can precisely alter cell behavior by deleting or redirecting cell pathways, as well as enhancing and suppressing gene expression. She will have significant interactions with other members of the Center, such as Mike Mitchell and myself, as well as the broader Penn community, especially with the CAR therapists.”

Read the full story in Penn Engineering Today.

Since this story was originally published in March 2024, Sherry Gao now holds a secondary appointment in Bioengineering, effective July 1, 2024.

Daniel Hammer and Michael Mitchell both hold primary appointments in Bioengineering.

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Showing Up for Penn in London

by Laura Bellet

Leaders and faculty from Penn Medicine, including Kevin Mahoney, Carl June, John Wherry, and Mike Mitchell (pictured left to right), speak on stage during the Penn London symposium.

Sharing the exciting work happening at Penn with alumni, parents, and friends throughout the world is a priority for Interim President J. Larry Jameson.

Shortly after challenging the graduating Class of 2024 to “keep reinventing, learning, and engaging” he brought that same spirit to the Penn community in London. He met with leadership volunteers from the region and welcomed approximately 200 attendees to an academic symposium titled “Frontiers of Knowledge and Discovery: Leading in a Changing World.”

Kevin Mahoney, CEO of the University of Pennsylvania Health System, moderated the first panel, on the genesis of breakthroughs. “When our faculty explain how landmark achievements like new fields of science or first-in-class cancer therapies come about, they never fail to emphasize how collaboration turns expertise into progress,” he said. “Hearing Mike Mitchell, John Wherry, and Carl June speak made plain how our brilliant, interconnected Penn faculty work together on one campus with results that are changing our world.”

Vijay Kumar, the Nemirovsky Family Dean of Penn Engineering, shared Mahoney’s perspective on collaboration—with a twist. “Non-engineers can be mystified, if not intimidated, by the complexities of the work we do,” he explained. “When a faculty member breaks down a project and talks it through, step by step, the engineering concepts become so much more understandable and relatable.” Kumar moderated a session with Dan Rader and Rene Vidal that focused on the increasing and powerful synergies among data science and AI, medical research, and clinical practice

Read the full story in the Penn Giving website.

Michael Mitchell is Associate Professor in Bioengineering. Read more stories featuring Mitchell in the BE Blog.

Carl June is Richard W. Vague Professor in Immunotherapy in the Perelman School of Medicine and is a member of the Penn Bioengineering Graduate Group. Read more stories featuring June in the BE Blog.

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2024 Graduate Research Fellowships for Penn Bioengineering Students

NSF Logo

Congratulations to the fifteen Bioengineering students to receive 2024 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. The recipients were selected from a highly-competitive, nationwide pool. Further information about the program can be found on the NSF website.

The following Ph.D. students in Bioengineering received awards:

Anushka Agrawal – Mitchell Lab

Amanda Bluem  – incoming student

Stephen Ching – incoming student, Research Staff in the Hast Lab

Ana Crysler – incoming student, de la Fuente Lab

Ellie Feng – incoming student

Stephen Lee – Alvarez lab

Jenlu Pagnotta – incoming student

Schyler Rowland – incoming student

Rayna L. Schoenberger – incoming student, Gottardi Lab

Eva Utke – incoming student

Delaney Wilde – Bugaj Lab

The following BE undergraduate students also received awards and will be pursuing graduate study:

Aditi Ghalsasi – Recent M&T program graduate (Bioengineering and Finance), Mitchell Lab

Ryan Lim – Recent B.S.E. graduate, incoming Ph.D. student at Harvard-MIT

Angela Song – Recent B.S.E. graduate, Wallace Lab

Dorix Xu – Recent B.S.E. graduate, Center for Neuroengineering and Therapeutics

The following students received honorable mention:

Ekta Singh – Recent Master’s in BE graduate, incoming Ph.D. student, Witschey Lab

Ksenija Tasich – incoming Ph.D. student

Emma Warrner – incoming Ph.D. student

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2024 Solomon R. Pollack Awards for Excellence in Graduate Bioengineering Research

The Solomon R. Pollack Award for Excellence in Graduate Bioengineering Research is given annually to the most deserving Bioengineering graduate students who have successfully completed research that is original and recognized as being at the forefront of their field. This year, the Department of Bioengineering at the University of Pennsylvania is proud to recognize the work of four outstanding graduates in Bioengineering: William Benman, Alex Chan, Rohan Palanki and Sunghee Estelle Park. 

Read more about the 2024 Solomon R. Pollack awardees and their doctoral research below.

William Benman

Dissertation: “Remote control of cell function using heat and light as inputs”

Will conducts research in the lab of Lukasz Bugaj, Assistant Professor in Bioengineering, focusing on reprogramming cells so that their basic functions can be regulated artificially using heat and/or light as inputs. The goal of this work ranges from clinical applications, such as localized activation of cell therapies within patients via application of heat, to biological manufacturing, using light to activate production of valuable biologics during key phases of a cell’s life cycle. He earned his undergraduate degree in biomedical engineering from Boston University, where he graduated summa cum laude. At BU, he worked in the lab of Wilson Wong, where he was introduced to synthetic biology. During that time, he worked to develop a genetic logic framework that would allow cells to integrate chemical signals, such that each combination of signals would lead to a different, user-defined combination of genes being expressed. Outside of the lab, Benman enjoys baking and sharing his treats with lab members. He mentored the 2021 Penn iGEM team, which recently published their work in Communications Biology. After graduation, he will start a postdoctoral fellowship in Mikhail Shapiro’s lab at Caltech, where he plans to explore electrogenetics, focusing on how to co-opt electrically active cell types to transmit biochemical information out of the body. He is interested in researching ways to get cells to talk to electronic devices and vice/versa for two way communication, especially in the context of patient monitoring and precision therapies. 

“Will’s Ph.D. work broke new ground across several fields, discovering how certain proteins sense temperature, engineering those proteins for on-demand control of human cells, and building devices to allow us to communicate with cells with precision,” says Bugaj. “He has managed these accomplishments while elevating those around him through mentorship, including of graduate students, scores of undergraduates, and even grade-school students in the community. I am immensely proud of Will and what he has accomplished and am gratified by the recognition from the Sol Pollack award.”

Alex Chan

Dissertation: “Engineering small protein based inhibitors and biodegraders for cytosolic delivery and targeting of the undruggable proteome”

Alex conducts research in the lab of Andrew Tsourkas, Professor in Bioengineering and Co-Director, Center for Targeted Therapeutics and Translational Nanomedicine (CT3N). His research focuses on developing novel cancer therapeutics by engineering protein scaffolds so that they can be efficiently delivered into cells using lipid nanocarriers. These proteins can either behave as oncogenic inhibitors or be imbued with E3 domains for targeted protein degradation. He graduated from The Pennsylvania State University in 2018 with a B.S in Biomedical Engineering. There, he conducted undergraduate research on photo-activated silver nanoparticle miRNA delivery systems and wrote his senior honors thesis on this topic. At Penn, Alex served as a wellness co-chair within GABE (the Graduate Association of Bioengineers) and was awarded a graduate research fellowship program award by the National Science Foundation (NSF GRFP). In his spare time, Chan loves to cook and explore the local restaurant scene (and he thinks Philly is one of the most vibrant food meccas in America). Post-graduation, he plans to explore Asia before starting as a Senior Scientist in the biopharma industry. He intends to continue working on novel biologics-based medicines for unmet medical needs.

“I cannot think of anyone more deserving of this award than Alex,” says Tsourkas. “He not only demonstrates all of the traits that we love to see in our most successful Ph.D. students — intelligence, hard work ethic, and perseverance — but Alex has also exhibited a level of scientific independence that is beyond his years. I cannot wait to see what Alex achieves in the future.”

Rohan Palanki

Dissertation: “Ionizable lipid nanoparticles for in utero gene editing of congenital disease”

Rohan completed his B.S. in Bioengineering from Rice University in 2019 and subsequently matriculated into the Medical Scientist Training Program (M.D./Ph.D.) at the University of Pennsylvania. He conducted his doctoral research as an NIH Ruth L. Kirschstein Pre-Doctoral Fellow in the laboratories of Michael J. Mitchell, Associate Professor in Bioengineering, and William H. Peranteau, Associate Professor of Surgery at CHOP. After defending his thesis in 2024, he returned to medical school to complete his clinical training. He plans to pursue a career as a physician-engineer, conducting translational research at the intersection of biomaterials and genomic medicine. Outside of the lab, Palanki enjoys exploring new restaurants in Philadelphia and cheering on Philadelphia sports teams.

“Rohan pioneered new lipid nanoparticle gene editing technology in the lab that can treat deadly childhood diseases before a child is ever born,” says Mitchell. “Rohan is extremely deserving of this award, and I cannot wait to see what he accomplishes as a physician scientist developing new biomaterial and drug delivery technologies for pediatric applications.”

Sunghee Estelle Park

Dissertation: “Engineering stem cells and organoids on a chip for the study of human health and disease”

Sunghee Estelle Park earned her BMSE and MSME from Korea University and her Ph.D. in Bioengineering at the University of Pennsylvania, graduating in July 2023. She conducted doctoral research in the BIOLines Lab of Dan Huh, Associate Professor in Bioengineering. Her Ph.D. research 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. Her doctoral dissertation presented engineering approaches to create stem cell derived three-dimensional (3D) miniature models of human organs on a chip that mimic the physiology and function of living human tissues. Park was appointed Assistant Professor of Biomedical Engineering in the Weldon School of Biomedical Engineering at Purdue University beginning January 2024. Her research lab focuses on using engineered tissues and organoid models to understand how biomechanical and biochemical cues direct stem cell differentiation, maturation, and function during development and disease progression, with a particular emphasis on the lung and intestine. 

“With her deep knowledge, extensive experience, and leadership, Estelle led the major undertaking of harnessing the power of microengineering technologies to create more in vivo-like culture environments in my group, and she played a central role in demonstrating the proof-of-concept of generating organoid-based in vitro models that enable new capabilities for studying complex human diseases and developing new therapeutics,” says Huh. “I am extremely proud of her tremendous accomplishments as a trailblazer in this emerging area and have every confidence that her work as an independent investigator will continue to make great contributions to advancing the field.”

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Accelerating CAR T Cell Therapy: Lipid Nanoparticles Speed Up Manufacturing

by Ian Scheffler

Visualization of a CAR T cell (in red) attacking a cancer cell (in blue) (Meletios Varras via Getty Images)

For patients with certain types of cancer, CAR T cell therapy has been nothing short of life changing. Developed in part by Carl June, Richard W. Vague Professor at Penn Medicine, and approved by the Food and Drug Administration (FDA) in 2017, CAR T cell therapy mobilizes patients’ own immune systems to fight lymphoma and leukemia, among other cancers.

However, the process for manufacturing CAR T cells themselves is time-consuming and costly, requiring multiple steps across days. The state of the art involves extracting patients’ T cells, then activating them with tiny magnetic beads, before giving the T cells genetic instructions to make chimeric antigen receptors (CARs), the specialized receptors that help T cells eliminate cancer cells.

Now, Penn Engineers have developed a novel method for manufacturing CAR T cells, one that takes just 24 hours and requires only one step, thanks to the use of lipid nanoparticles (LNPs), the potent delivery vehicles that played a critical role in the Moderna and Pfizer-BioNTech COVID-19 vaccines.

In a new paper in Advanced Materials, Michael J. Mitchell, Associate Professor in Bioengineering, describes the creation of “activating lipid nanoparticles” (aLNPs), which can activate T cells and deliver the genetic instructions for CARs in a single step, greatly simplifying  the CAR T cell manufacturing process. “We wanted to combine these two extremely promising areas of research,” says Ann Metzloff, a doctoral student in Bioengineering and NSF Graduate Research Fellow in the Mitchell lab and the paper’s lead author. “How could we apply lipid nanoparticles to CAR T cell therapy?”

Read the full story in Penn Engineering Today.

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Precision Pulmonary Medicine: Penn Engineers Target Lung Disease with Lipid Nanoparticles

by Ian Scheffler

Penn Engineers have developed a way to target lung diseases, including lung cancer, with lipid nanoparticles (LNPs). (wildpixel via Getty Images)

Penn Engineers have developed a new means of targeting the lungs with lipid nanoparticles (LNPs), the miniscule capsules used by the Moderna and Pfizer-BioNTech COVID-19 vaccines to deliver mRNA, opening the door to novel treatments for pulmonary diseases like cystic fibrosis. 

In a paper in Nature Communications, Michael J. Mitchell, Associate Professor in the Department of Bioengineering, demonstrates a new method for efficiently determining which LNPs are likely to bind to the lungs, rather than the liver. “The way the liver is designed,” says Mitchell, “LNPs tend to filter into hepatic cells, and struggle to arrive anywhere else. Being able to target the lungs is potentially life-changing for someone with lung cancer or cystic fibrosis.”

Previous studies have shown that cationic lipids — lipids that are positively charged — are more likely to successfully deliver their contents to lung tissue. “However, the commercial cationic lipids are usually highly positively charged and toxic,” says Lulu Xue, a postdoctoral fellow in the Mitchell Lab and the paper’s first author. Since cell membranes are negatively charged, lipids with too strong a positive charge can literally rip apart target cells.  

Typically, it would require hundreds of mice to individually test the members of a “library” of LNPs — chemical variants with different structures and properties — to find one with a low charge that has a higher likelihood of delivering a medicinal payload to the lungs.

Instead, Xue, Mitchell and their collaborators used what is known as “barcoded DNA” (b-DNA) to tag each LNP with a unique strand of genetic material, so that they could inject a pool of LNPs into just a handful of animal models. Then, once the LNPs had propagated to different organs, the b-DNA could be scanned, like an item at the supermarket, to determine which LNPs wound up in the lungs. 

Read the full story in Penn Engineering Today.

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Penn Bioengineering Student Kaitlin Mrksich Named 2024 Goldwater Scholar

by Louisa Shepard

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.

Penn’s 2024 Goldwater Scholars are third-years Hayle Kim, Eric Myzelev, and Eric Tao in the College of Arts and Sciences, and Kaitlin Mrksich in the School of Engineering and Applied Science.

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.

The students applied for the Goldwater Scholarship with assistance from Penn’s Center for Undergraduate Research and Fellowships. Penn has had 63 Goldwater Scholars named since Congress established the scholarship in 1986 to honor U.S. Senator Barry Goldwater.

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.

Read the full announcement in Penn Today.

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.

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A Moonshot for Obesity: New Molecules, Inspired by Space Shuttles, Advance Lipid Nanoparticle Delivery for Weight Control

by Ian Scheffler

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. 

Read the full story in Penn Engineering Today.