Tag: research

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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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Melding AI and RNA: Penn’s $18 Million AIRFoundry to Revolutionize RNA Research

by Ian Scheffler

The NSF AIRFoundry will accelerate RNA research using the power of AI and educate the next generation of RNA researchers. (DesignCells via Getty Images)

In a typical foundry, raw materials like steel and copper are melted down and poured into molds to assume new shapes and functions. The U.S. National Science Foundation Artificial Intelligence-driven RNA Foundry (NSF AIRFoundry), led by the University of Pennsylvania and the University of Puerto Rico and supported by an $18-million, six-year grant, will serve much the same purpose, only instead of smithing metal, the “BioFoundry” will create molecules and nanoparticles.

NSF AIRFoundry is one of five newly created BioFoundries, each of which will have a different focus. Bringing together researchers from Penn Engineering, Penn Medicine’s Institute for RNA Innovation, the University of Puerto Rico–Mayagüez (UPR-M), Drexel University, the Children’s Hospital of Philadelphia (CHOP) and InfiniFluidics, the facility, which will be physically located in West Philadelphia and at UPR-M, will focus on ribonucleic acid (RNA), the tiny molecule essential to genetic expression and protein synthesis that played a key role in the COVID-19 vaccines and saved tens of millions of lives.

The facility will use AI to design, optimize and synthesize RNA and delivery vehicles by augmenting human expertise, enabling rapid iterative experimentation, and providing predictive models and automated workflows to accelerate discovery and innovation.

“With NSF AIRFoundry, we are creating a hub for innovation in RNA technology that will empower scientists to tackle some of the world’s biggest challenges, from health care to environmental sustainability,” says Daeyeon Lee, Russell Pearce and Elizabeth Crimian Heuer Professor in Chemical and Biomolecular Engineering in Penn Engineering and NSF AIRFoundry’s director.

“Our goal is to make cutting-edge RNA research accessible to a broad scientific community beyond the health care sector, accelerating basic research and discoveries that can lead to new treatments, improved crops and more resilient ecosystems,” adds Nobel laureate Drew Weissman, Roberts Family Professor in Vaccine Research in Penn Medicine, Director of the Penn Institute for RNA Innovation and NSF AIRFoundry’s senior associate director.

The facility will catalyze new innovations in the field by leveraging artificial intelligence (AI). AI has already shown great promise in drug discovery, poring over vast amounts of data to find hidden patterns. “By integrating artificial intelligence and advanced manufacturing techniques, the NSF AIRFoundry will revolutionize how we design and produce RNA-based solutions,” says David Issadore, Professor in Bioengineering and in Electrical and Systems Engineering at  Penn Engineering and the facility’s associate director of research coordination.

Read the full story on the Penn AI website.

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Student Builds on Zhiliang Chen’s Osteoarthritis Research

by Erica Moser

Rising second-year Sidney Wong, right, spent the summer working in the lab of Penn Vet professor Kyla Ortved, left, through the Penn Undergraduate Research Mentoring Program.

Roughly one in three Americans suffers from osteoarthritis, a progressive disease that causes joint cartilage to break down in a vicious cycle. The less cartilage, the more wear and tear on the joints, which further weakens the remaining connective tissue. In addition to joint pain, the condition can lead to loss of joint function, making it extremely hard to complete tasks of daily living.

At present, osteoarthritis has no cure. Zhiliang Cheng, Research Associate Professor in Bioengineering (BE), has studied the use of nanotechnology to treat the disease for years. In collaboration with Ling Qin, Professor in Orthopedic Surgery within the Perelman School of Medicine and member of the Penn Bioengineering Graduate Group, Cheng developed nanoparticles that activate the epidermal growth factor receptor (EGFR) pathway, increasing the expression of genes that promote healthy cartilage.

This summer, Sidney Wong, a rising second-year in the School of Arts and Sciences, built on Cheng and Qin’s research in the lab of Kyla Ortved, Jacques Jenny Endowed Term Chair of Orthopedic Surgery and Associate Professor in Large Animal Surgery at the School of Veterinary Medicine, studying the EGFR pathway in horses, whose joints resemble those of humans.

“What I’ve observed so far has been pretty promising,” says Wong, who found that equine cartilage treated with the nanoparticles appears healthier.

Read the full story in Penn Today.

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Mining the Microbiome: Uncovering New Antibiotics Inside the Human Gut

by Ian Scheffler

Penn Engineering and Stanford researchers leveraged AI to discover dozens of potential new antibiotics in the human gut microbiome. (ChrisChrisW via Getty Images)

The average human gut contains roughly 100 trillion microbes, many of which are constantly competing for limited resources. “It’s such a harsh environment,” says César de la Fuente, Presidential Assistant Professor in Bioengineering and in Chemical and Biomolecular Engineering within the School of Engineering and Applied Science, in Psychiatry and Microbiology within the Perelman School of Medicine, and in Chemistry within the School of Arts & Sciences. “You have all these bacteria coexisting, but also fighting each other. Such an environment may foster innovation.”

In that conflict, de la Fuente’s lab sees potential for new antibiotics, which may one day contribute to humanity’s own defensive stockpile against drug-resistant bacteria. After all, if the bacteria in the human gut have to develop new tools in the fight against one another to survive, why not use their own weapons against them?

In a new paper in Cell, the labs of de la Fuente and Ami S. Bhatt, Professor in Medicine (Hematology) and Genetics at Stanford, surveyed the gut microbiomes of nearly 2,000 people, discovering dozens of potential new antibiotics. “We think of biology as an information source,” says de la Fuente. “Everything is just code. And if we can come up with algorithms that can sort through that code, we can dramatically accelerate antibiotic discovery.”

Read the full story in Penn Engineering Today.

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Empowering Future Engineers: Lyle Brunhofer and the Impact of Senior Design

by Ian Scheffler

“Senior Design was such an incredible part of my senior year and Penn Engineering experience that when I joined the Board of the Engineering Alumni Society, I knew immediately that I would focus on helping the event continue,” says Lyle Brunhofer (EAS’14, GEng’14).

Today, Lyle Brunhofer (EAS’14, GEng’14) advises companies on digital transformations, applying the skills he learned at Penn Engineering to modernize firms’ understanding of customers in industries as diverse as pharmaceuticals and consumer products.

He also helps run Penn Engineering’s annual Senior Design Project Competition, which recruits dozens of alumni to evaluate seniors’ year-long capstone projects. As the Vice President and Senior Design Chair of the Engineering Alumni Society, Brunhofer works hand-in-hand with Bradley Richards (C’92, LPS’17), Director of Alumni Relations, to coordinate the year-long competition and multi-day concluding extravaganza — part Shark Tank, part science competition — in May.

While at Penn Engineering, Brunhofer’s own Senior Design team developed assistive technology to help those with physical disabilities interact with their environment using modular, 3D printed switches. Assist3D partnered with the HMS School for Children with Cerebral Palsy, located in West Philadelphia, to ensure that products met users’ needs. “We set out to create ability switches that would be affordable, customizable and simple, in contrast to the ability switches available on the market,” Brunhofer recalls. After graduation, the team provided the finished products to the HMS School.

As Brunhofer sees it, Senior Design instills skills far beyond the scope of typical engineering courses. “As a student, I felt that Senior Design was an extremely challenging, but rewarding experience,” he says. “It was also unlike any assignment we had been given previously.”

In a Q&A with Penn Engineering Today, Brunhofer discussed what motivates him to stay involved with Penn Engineering as an alumnus and the impact of participating in Senior Design.

How did you get involved as an alumni volunteer with Senior Design?

Senior Design was such an incredible part of my senior year and Penn Engineering experience that when I joined the Board of the Engineering Alumni Society, I knew immediately that I would focus on helping the event continue.

What do you feel makes Senior Design unique?

The mentorship. Students get to work with industry experts, faculty members, alumni and other professionals who help students hone their technical and soft skills, and foster networking opportunities for future careers.

Read the full story in Penn Engineering Today.

Lyle Brunhofer is Business Integration Manager at Accenture. He graduated with Bachelor’s and Master’s degrees in Bioengineering from the University of Pennsylvania in 2014.

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A 3D-printed Band-Aid for the Heart?

Biomaterials 3D-printed with the new method can be used inside the body and could even serve as bandages on a beating human heart. (Photo by Casey A. Cass/University of Colorado)

In the quest to develop life-like materials to replace and repair human body parts, scientists face a formidable challenge: Real tissues are often both strong and stretchable and vary in shape and size.

A CU Boulder-led team, in collaboration with researchers at the University of Pennsylvania, has taken a critical step toward cracking that code. They’ve developed a new way to 3D print material that is at once elastic enough to withstand a heart’s persistent beating, tough enough to endure the crushing load placed on joints, and easily shapeable to fit a patient’s unique defects.

Their breakthrough, described in the Aug. 2 edition of the journal Science, helps pave the way toward a new generation of biomaterials, from internal bandages that deliver drugs directly to the heart to cartilage patches and needle-free sutures.

“This is a simple 3D processing method that people could ultimately use in their own academic labs as well as in industry to improve the mechanical properties of materials for a wide variety of applications,” says first author Abhishek Dhand, a researcher in the Burdick Lab and doctoral candidate in the Department of Bioengineering at the University of Pennsylvania. “It solves a big problem for 3D printing.”

Read the full story by Lisa Marshall and Nicholas Goda on CU Boulder’s website

Jason Burdick is Bowman Endowed Professor in Chemical and Biological Engineering at the University of Colorado Boulder and Adjunct Professor in Bioengineering at Penn Engineering.

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The Structure of Sound: Network Insights into Bach’s Music

by Ian Scheffler

Representing Bach’s pieces as networks reveals hidden structures in his music. (Credit: Suman Kulkarni)

Even today, centuries after he lived, Johann Sebastian Bach remains one of the world’s most popular composers. On Spotify, close to seven million people stream his music per month, and his listener count is higher than that of Mozart and even Beethoven. The Prélude to his Cello Suite No. 1 in G Major has been listened to hundreds of millions of times.

What makes Bach’s music so enduring? Music critics might point to his innovative harmonies, complex use of counterpoint and symmetrical compositions. Represent Bach’s music as a network, however, where each node stands for one musical note, and each edge the transition from one note to another, and a wholly different picture emerges.

In a recent paper in Physical Review Research, Dani S. Bassett, J. Peter Skirkanich Professor in Bioengineering and in Electrical and Systems Engineering within the School of Engineering and Applied Science, in Physics & Astronomy within the School of Arts & Sciences, and in Neurology and Psychiatry within the Perelman School of Medicine, and Suman Kulkarni, a doctoral student in Physics & Astronomy, applied network theory to Bach’s entire oeuvre.

The paper sheds new light on the unique qualities of Bach’s music and demonstrates the potential for analyzing music through the lens of networks. Such analysis could yield benefits for music therapists, musicians, composers and music producers, by giving them unprecedented quantitative insight into the structure of different musical compositions.

“This paper provides a starting point for how one can boil down these complexities in music and start with a simple representation to dig into how these pieces are structured,” says Kulkarni, the paper’s lead author. “We applied this framework to a dozen types of Bach’s compositions and were able to observe quantitative differences in how they were structured.”

Read the full story in Penn Engineering Today.

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Knockout of CD5 on CAR T Cells Boosts Anti-Tumor Efficacy

by Meagan Raeke

The effectiveness of CAR T cell therapy against a variety of cancers, including solid tumors, could be boosted greatly by using CRISPR-Cas9 technology to knock out the gene for CD5, a protein found on the surface of T cells, according to a preclinical study from investigators at the University of Pennsylvania’s Perelman School of Medicine and Abramson Cancer Center.

CAR T cells are T cells that have been engineered to attack specific targets found on cancer cells. They have had remarkable results in some patients with blood cancers. But they have not performed well against other cancers including solid-tumor cancers, such as pancreatic cancer, prostate cancer, and melanoma. Researchers have been searching for techniques to boost the effectiveness of CAR T cell therapy.

The study, published today in Science Immunology, suggests that knocking out CD5 could be a prime technique. Illuminating the protein’s previously murky role, the researchers found that it works as a powerful immune checkpoint, reining in T cell effectiveness. Removing it, they showed, dramatically enhanced CAR T cell anticancer activity in a variety of preclinical cancer models.

“We’ve discovered in preclinical models that CD5 deletion greatly enhances the function of CAR T cells against multiple cancers,” said senior author Marco Ruella, MD, an assistant professor of Hematology-Oncology, researcher with the Center for Cellular Immunotherapies and the scientific director of Penn Medicine’s Lymphoma Program. “The striking effects we observed across preclinical models suggest that CD5 knockout could be a general strategy for enhancing CAR T cell function.”

The study’s first author is Ruchi Patel, PhD, a recent graduate student from the Ruella Laboratory.

Read the full story in Penn Medicine News.

Marco Ruella is a member of the Penn Bioengineering Graduate Group. Read more stories featuring Ruella in the BE Blog.

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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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Vijay Balasubramanian’s Academic Journey Explored

by Kristina García

Younger scientists often ask him about exploring multiple fields, Balasubramanian says. The advice he offers is to “have a central line where you have credibility, where you’ve established that you’re really, really good at what you do, and you can be trusted.” (Image: Eric Sucar)

Academia is a long journey of specialization and behind any professor’s CV are long hours of research and study. While the path can be direct for some, for others there’s a pivot, a moment or experience that changes the course of that journey.

Penn Today spoke with four professors whose academic paths diverged, to learn about the trajectory of their interdisciplinary work. Vijay Balasubramanian traverses the boundaries of physics and neuroscience. Tukufu Zuberi is a demographer-turned-curator. Brittany Watson integrates education, research, and veterinary medicine. Amy Hillier began her career studying historical mortgage redlining and moved into supporting trans youth.

Vijay Balasubramanian
The Cathy and Marc Lasry Professor of Physics in the School of Arts & Sciences

Wandering through Kolkata’s markets in India stimulates the mind. Hawkers’ cries pass through the inner ear as electrical signals; the pungent, earthy smell of turmeric enters the brain through olfactory sensory neurons. In 1976, a 7-year-old Vijay Balasubramanian had his own market revelation through a bookseller’s portico, where the cover of a slim volume showed a man peering through a microscope lens and a smattering of white paint scattered like stars across the firmament of man and machine.

“What is a scientist?” the book asked, running through a series of exciting adventure shots: archeologic discovery, venom extraction, missile control. In that moment, Balasubramanian knew he would be a scientist. It looked, he says, “amazingly cool.”

When he arrived at the Massachusetts Institute of Technology, Balasubramanian wanted to study the fundamental laws of nature. “So that’s physics,” he says. While earning his doctoral degree at Princeton University, a mentor suggested Balasubramanian read papers in the burgeoning field of neuroscience. It immediately resonated. “Oh my god, this stuff is so cool,” Balasubramanian thought. “But the final year of a Ph.D. is not the time to switch.”

He earned his degree and took a position as a junior fellow of the Harvard Society of Fellows. During the day, he worked on string theory and the information loss paradox for black holes. But in the evening, he would moonlight in a neuroscience lab.

As a young theoretical physicist at Penn, Balasubramanian met Peter Sterling. A former Freedom Rider and professor of neuroscience at the Perelman School of Medicine, Sterling was “a true intellectual,” Balasubramanian says. He knew everything, was interested in everything, and would talk with anybody.

The pair wrote a series of papers together regarding information processing and transmission. “He’s so quick and so much fun and so lively,” Sterling says of Balasubramanian. “He’s fearless; there’s nothing he won’t try.”

While in Cairo with wife Heather J. Sharkey, professor of modern Middle Eastern and North African history at Penn, Balasubramanian prepared a neuroscience grant and submitted it to the National Science Foundation, “sort of on a whim,” he says. “I put it in from an internet café on an island in the middle of the Nile.” He got the grant and started a research group.

After that, Balasubramanian says, “I was off and running.”

“I was certainly told,” Balasubramanian says of his work in neuroscience, “do not do this before tenure.” But, if he waited, “then I’d be too set my ways,” he says. “I just wouldn’t know enough; it would be too hard to learn; I wouldn’t have the time.”

Younger scientists often ask him about exploring multiple fields, Balasubramanian says. The advice he offers is to “have a central line where you have credibility, where you’ve established that you’re really, really good at what you do, and you can be trusted.” That gives you more latitude, he says.

After that, it’s just sheer discipline. “You’re going to have to wake up earlier than everybody else. You’re going to have to work longer days,” he says. “Otherwise, you know, everybody else is working hard too, and you’ll never be able to achieve the level of expertise and knowledge to be able to do things at that world-class level.”

Balasubramanian wants to see more interdisciplinary collaboration. “Each field trains its students with a certain body of techniques that has been found historically useful in that field,’ he says. “Very often, those techniques also have uses elsewhere, but they don’t know to apply it.”

Traversing borders can be helpful in producing new insights, Balasubramanian says. You can ask questions that people in the field won’t. You might experiment with new ideas or put two disjointed ideas together, he says. “If you’re coming from outside, you have the leeway to do all kinds of silly things. Sometimes, they’re not silly.”

Why not ask new questions and propose new answers? In the end, the data will tell you what’s true. “It gives me comfort to know how things tick.”

This post is adapted from a longer story in Penn Today. Read the full story here.

Balasubramanian is Cathy and Marc Lasry Professor in the Department of Physics and Astronomy in the Penn School of Arts and Sciences and is a member of the Penn Bioengineering Graduate Group. Read more stories featuring his research here.