Tag: Penn Engineering

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“Switchable” Bispecific Antibodies Pave Way for Safer Cancer Treatment

by Nathi Magubane

Bispecific T cell engagers are emerging as a powerful class of immunotherapy to treat cancer but are sometimes hindered by unwanted outcomes, such as on-target, off-tumor toxicity; cytokine release syndrome; and neurotoxicity. Now, researchers Penn researchers have developed a novel “switchable” bispecific T cell engager that mitigates these negative effects by co-opting a drug already approved by the FDA. (Image: iStock / CIPhotos)

In the ever-evolving battle against cancer, immunotherapy presents a turning point. It began with harnessing the body’s immune system to fight cancer, a concept rooted more than a century ago but only gaining significant momentum in recent years. Pioneering this shift were therapies like CAR T cell therapy, which reprograms a patient’s T cells to attack cancer cells. Within this domain, bispecific T cell engagers, or bispecific antibodies, have emerged as effective treatments for many blood-borne cancers in the clinic and are being evaluated for solid tumor therapy.

These antibodies simultaneously latch onto both a cancer cell and a T cell, effectively bridging the gap between the two. This proximity triggers the T cells to unleash their lethal arsenal, thereby killing the cancer cells. However, bispecific T cell engagers, like many cancer therapies, face hurdles such as cell-specific targeting limitations, known as on-target off-tumor toxicity, which means the tumor is correctly targeted but so are other healthy cells in the body, leading to healthy tissue damage. Moreover, bispecific antibodies may also lead to immune system overactivation, a precursor for cytokine release syndrome (CRS), and neurotoxicity.

Now, researchers led by Michael Mitchell of the University of Pennsylvania have found a way to circumvent many of these deleterious effects by developing a bispecific T cell nanoengager that is equipped with an “off switch.” Their findings are published in Nature Biomedical Engineering.

“We’re excited to show that bispecific antibodies can be tweaked in a way that allows us to tap into their powerful cancer-killing potential without inducing toxicity to healthy tissues,” says Mitchell, associate professor of bioengineering at Penn’s School of Engineering and Applied Science. “This new controllable drug-delivery mechanism, which we call switchable bispecific T cell nanoengagers, or SiTEs, adds this switchable component to the antibody via administering an FDA-approved small-molecule drug, amantadine.”

Read the full story in Penn Today.

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Jenny Jiang Wins CZI Grant to Investigate the Potential Trigger for Neurodegenerative Diseases

Jenny Jiang, Ph.D.

TDP-43 may be one of the most dangerous proteins in the human body, implicated in neurodegenerative conditions like ALS and Alzheimer’s disease. But the protein remains mysterious: how TDP-43 interacts with the immune system, for instance, is still unclear. 

Now, Ning Jenny Jiang, J. Peter and Geri Skirkanich Associate Professor of Innovation in Bioengineering, has been selected for the Collaborative Pairs Pilot Project Awards, sponsored by the Chan Zuckerberg Initiative (CZI), to investigate the relationship between TDP-43 and the immune system. 

Launched in 2018, the Collaborative Pairs Pilot Project Awards support pairs of investigators to explore “innovative, interdisciplinary approaches to address critical challenges in the fields of neurodegenerative disease and fundamental neuroscience.” Professor Jiang will partner with Pietro Fratta, MRC Senior Clinical Fellow and MNDA Lady Edith Wolfson Fellow at the University College London Queen Square Institute of Neurology.

The TDP-43 protein is associated with neurodegenerative diseases affecting the central nervous system, including ALS and Alzehimer’s disease. While the loss of neurons and muscle degeneration cause the progressive symptoms, the diseases themselves may be a previously unidentified trigger for abnormal immune system activity. 

One possible link is the intracellular mislocalization of TDP-43 (known as TDP-43 proteinopathy), when the protein winds up in the wrong location, which the Jiang and Fratta Labs will investigate. Successfully proving this link could result in potentially game-changing new therapies for these neurodegenerative diseases. 

The Jiang Lab at Penn Engineering specializes in systems immunology, using high-throughput sequencing and single-cell and quantitative analysis to understand how the immune system develops and ages, as well as the molecular signatures of immune related diseases. Jiang joined Penn Bioengineering in 2021. 

Since arriving on campus, Jiang has teamed with the recently formed Penn Anti-Cancer Engineering Center (PACE), which seeks to understand the forces that determine how cancer grows and spreads, and Engineers in the Center for Precision Engineering (CPE4H), which focuses on innovations in diagnostics and delivery in the development of customizable biomaterials and implantable devices for individualized care. 

Jiang was elected a member of the American Institute for Medical and Biological Engineering (AIMBE) College of Fellows in 2021, and has previously won multiple prestigious awards including the NSF CAREER, a Cancer Research Institute Lloyd J. Old STAR Award, and a CZI Neurodegeneration Challenge Network Ben Barres Early Career Acceleration Award.

Jiang is a leader in high-throughput and high-dimensional analysis of T cells, a type of white blood cell crucial to the functioning of a healthy immune system. A recent study in Nature Immunology described the Jiang Lab’s TetTCR-SeqHD technology, the first approach to provide a multifaceted analysis of antigen-specific T cells in a high-throughput manner.

The CZI Collaborative Pairs Pilot Project Awards will provide $200,000 of funding over 18 months with a chance to advance to the second phase of $3.2 million in funding over a four-year period. 

Read the full list of grantees on the CZI’s Neurodegeneration Challenge Network (NDCN) Projects website here.

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Illuminating the Invisible: Bringing the Smallest Protein Clusters into Focus

by Ian Scheffler

The bright white spots represent tiny clusters of proteins detected by CluMPS. (Photo by: Thomas Mumford)

Penn Engineers have pioneered a new way to visualize the smallest protein clusters, skirting the physical limitations of light-powered microscopes and opening new avenues for detecting the proteins implicated in diseases like Alzheimer’s and testing new treatments.

In a paper in Cell Systems, Lukasz Bugaj, Assistant Professor in Bioengineering, describes the creation of CluMPS, or Clusters Magnified by Phase Separation, a molecular tool that activates by forming conspicuous blobs in the presence of target protein clusters as small as just a few nanometers. In essence, CluMPS functions like an on/off switch that responds to the presence of clusters of the protein it is programmed to detect.

Normally, says Bugaj, detecting such clusters requires laborious techniques. “With CluMPS, you don’t need anything beyond the standard lab microscope.” The tool fuses with the target protein to form condensates orders of magnitude larger than the protein clusters themselves that resemble the colorful blobs in a lava lamp. “We think the simplicity of the approach is one of its main benefits,” says Bugaj. “You don’t need specialized skills or equipment to quickly see whether there are small clusters in your cells.”

Read the full story in Penn Engineering Today.

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Researchers Breathe New Life into Lung Repair

by Nathi Magubane

Image: iStock/Mohammed Haneefa Nizamudeen

In the human body, the lungs and their vasculature can be likened to a building with an intricate plumbing system. The lungs’ blood vessels are the pipes essential for transporting blood and nutrients for oxygen delivery and carbon dioxide removal. Much like how pipes can get rusty or clogged, disrupting normal water flow, damage from respiratory viruses, like SARS-CoV-2 or influenza, can interfere with this “plumbing system.”

In a recent study, researchers looked at the critical role of vascular endothelial cells in lung repair. Their work, published in Science Translational Medicine, was led by Andrew Vaughan of the University of Pennsylvania’s School of Veterinary Medicine and shows that, by using techniques that deliver vascular endothelial growth factor alpha (VEGFA) via lipid nanoparticles (LNPs), that they were able to greatly enhance modes of repair for these damaged blood vessels, much like how plumbers patch sections of broken pipes and add new ones.

“While our lab and others have previously shown that endothelial cells are among the unsung heroes in repairing the lungs after viral infections like the flu, this tells us more about the story and sheds light on the molecular mechanisms at play,” says Vaughan, assistant professor of biomedical sciences at Penn Vet. “Here we’ve identified and isolated pathways involved in repairing this tissue, delivered mRNA to endothelial cells, and consequently observed enhanced recovery of the damaged tissue. These findings hint at a more efficient way to promote lung recovery after diseases like COVID-19.”

They found VEGFA’s involvement in this recovery, while building on work in which they used single cell RNA sequencing to identify transforming growth factor beta receptor 2 (TGFBR2) as a major signaling pathway. The researchers saw that when TGFBR2 was missing it stopped the activation of VEGFA. This lack of signal made the blood vessel cells less able to multiply and renew themselves, which is vital for the exchange of oxygen and carbon dioxide in the tiny air sacs of the lungs.

“We’d known there was a link between these two pathways, but this motivated us to see if delivering VEGFA mRNA into endothelial cells could improve lung recovery after disease-related injury,” says first author Gan Zhao, a postdoctoral researcher in the Vaughan Lab.

The Vaughan Lab then reached out to Michael Mitchell of the School of Engineering and Applied Science, whose lab specializes in LNPs, to see if delivery of this mRNA cargo would be feasible.

“LNPs have been great for vaccine delivery and have proven incredibly effective delivery vehicles for genetic information. But the challenge here was to get the LNPs into the bloodstream without them heading to the liver, which is where they tend to congregate as its porous structure lends favor to substances passing from the blood into hepatic cells for filtration,” says Mitchell, an associate professor of bioengineering at Penn Engineering and a coauthor of the paper. “So, we had to devise a way to specifically target the endothelial cells in the lungs.”

Lulu Xue, a postdoctoral researcher in the Mitchell Lab and a co-first author of the paper, explains that they engineered the LNP to have an affinity for lung endothelial cells, this is known as extra hepatic delivery, going beyond the liver.

Read the full story in Penn Today.

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Building Tiny Organs

by David Levin

Dan Huh, Ph.D. (Photo credit: Leslie Barbaro)

More than 34 million Americans suffer from pulmonary diseases like asthma, emphysema and chronic bronchitis. While medical treatments can keep these ailments in check, there are currently no cures. Part of the reason, notes Dan Huh, is that it’s incredibly hard to study how these diseases actually work. While researchers can grow cells taken from human lungs in a dish, they cannot expect them to act like they would in the body. In order to mimic the real deal, it’s necessary to recreate the complex, 3D environment of the lung — right down to its tiny air sacs and blood vessels — and to gently stretch and release the tissue to simulate breathing.

Huh, Associate Professor in Bioengineering, is the cofounder of Vivodyne, a Penn Engineering biotech spinoff that is creating tissues like these in the lab. Vivodyne uses a bioengineering technology that Huh has been developing for more than a decade. While a postdoctoral fellow at Harvard’s Wyss Institute, he played a central role in creating a novel device called an “organ on a chip,” which, as the name implies, assembles multiple cell types on a tiny piece of engineered plastic to create an approximation of an organ.

“While those chips represented a major innovation,” says Huh, “they still weren’t truly lifelike. They lacked many of the essential features of their counterparts in the human body, such as the network of blood vessels running between different kinds of tissue, which are essential for transporting oxygen, nutrients, waste products and various biochemical signals.”

Read the full article in the Fall 2023 issue of the Penn Engineering Magazine.

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The Heart and Soul of Innovation: Noor Momin Harnesses the Immune System to Treat Heart Disease

by Ian Scheffler

Noor Momin, Stephenson Foundation Term Assistant Professor of Innovation

While growing up, Noor Momin, who joined the Department of Bioengineering in January as the Stephenson Foundation Term Assistant Professor of Innovation, imagined becoming a physician. Becoming a doctor seemed like a tangible way for someone interested in science to make a difference. Not until college did she realize the impact she could have as a bioengineer instead.

“I was taping microscope slides together,” Momin recalls of her initial experience as an undergraduate researcher at the University of Texas at Austin. “I didn’t even know what a Ph.D. was.”

It wasn’t until co-authoring her first paper, which explores how lipids, the water-repelling molecules that make up cell membranes (and also fats and oils), can switch between more fluid and less fluid arrangements, that Momin understood the degree to which bioengineering can influence medicine. “Someone could potentially use that paper for drug design,” Momin says.

Today, Momin’s research applies her molecular expertise to heart disease, which despite numerous advances in treatment — from coronary artery bypass surgery to cholesterol-lowering statins — remains the primary cause of mortality worldwide.

As Momin sees it, the conventional wisdom of treating the heart like a mechanical pump, whose pipes can be replaced or whose throughput can be treated to prevent clogging in the first place, overshadows the immune system’s critical role in the development of heart disease.

Read the full story in Penn Engineering Today.

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Bioengineers on the Brink of Breaching Blood-brain Barrier

by Nathi Magubane

From left: Emily Han, Rohan Palanki, Jacqueline Li, Michael Mitchell, Dongyoon Kim, and Marshall Padilla of Penn Engineering.

Imagine the brain as an air traffic control tower, overseeing the crucial and complex operations of the body’s ‘airport.’ This tower, essential for coordinating the ceaseless flow of neurological signals, is guarded by a formidable layer that functions like the airport’s security team, diligently screening everything and everyone, ensuring no unwanted intruders disrupt the vital workings inside.

However, this security, while vital, comes with a significant drawback: sometimes, a ‘mechanic’—in the form of critical medication needed for treating neurological disorders—is needed inside the control tower to fix arising issues. But if the security is too stringent, denying even these essential agents entry, the very operations they’re meant to protect could be jeopardized.

Now, researchers led by Michael Mitchell of the University of Pennsylvania are broaching this long-standing boundary in biology, known as the blood-brain barrier, by developing a method akin to providing this mechanic with a special keycard to bypass security. Their findings, published in the journal Nano Letters, present a model that uses lipid nanoparticles (LNPs) to deliver mRNA, offering new hope for treating conditions like Alzheimer’s disease and seizures—not unlike fixing the control tower’s glitches without compromising its security.

“Our model performed better at crossing the blood-brain barrier than others and helped us identify organ-specific particles that we later validated in future models,” says Mitchell, associate professor of bioengineering at Penn’s School of Engineering and Applied Science, and senior author on the study. “It’s an exciting proof of concept that will no doubt inform novel approaches to treating conditions like traumatic brain injury, stroke, and Alzheimer’s.”

Read the full story in Penn Today.

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Little Bots That Could Put a Stop to Infectious Disease

Image: Courtesy of iStock / K_E_N

Biofilms—structured communities of microorganisms that create a protective matrix shielding them from external threats, including antibiotics—are responsible for about 80% of human infections and present a significant challenge in medical treatments, often resisting conventional methods.

In a Q&A with Penn Today, Hyun (Michel) Koo of the School of Dental Medicine and Edward Steager of the School of Engineering and Applied Science at Penn discuss an innovative approach they’ve partnered on: the use of small-scale robotics, microrobots, to offer a promising solution to tackle these persistent infections, bringing new capabilities and precision to the field of biomedical engineering.

Q: What is the motivation behind opting for tiny robots to tackle infections?

Koo: Treating biofilms is a broad yet unresolved biomedical problem, and conversely, the strategies for tackling biofilms are limited for a number of reasons. For instance, biofilms typically occur on surfaces that can be tricky to reach, like between the teeth in the oral cavity, the respiratory tract, or even within catheters and implants, so treatments for these are usually restricted to antibiotics (or antimicrobials) and other physical methods reliant on mechanical disruption. However, this touches on the problem of antimicrobial resistance: targeting specific microorganisms present in these structures is difficult, so antibiotics often fail to reach and penetrate the biofilm’s protective layers, leading to persistent infections and increased risk of antibiotic resistance.

We needed a way to circumvent these constraints, so Ed and I teamed up in 2017 to develop new, more precise and effective approaches that leverage the engineers’ ability to generate solutions that we, the clinicians and life science researchers, identify.

Read the full interview in Penn Today.

Hyun (Michel) Koo is a professor in the Department of Orthodontics and in the divisions of Pediatric Dentistry and Community Oral Health and the co-founder of the Center for Innovation & Precision Dentistry in the School of Dental Medicine at the University of Pennsylvania. He is a member of the Penn Bioengineering Graduate Group.

Edward Steager is a senior research investigator in Penn’s School of Engineering and Applied Science.

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Sydney Shaffer Wins Christopher J. Marshall Award for Melanoma Research

Sydney Shaffer, M.D., Ph.D.

Sydney Shaffer, Assistant Professor in Bioengineering in the School of Engineering and Applied Science and in Pathology and Laboratory Medicine in the Perelman School of Medicine, was named the 2023 Christopher J. Marshall Award winner by the Society for Melanoma Research (SMR). The award recognizes Shaffer’s contributions to melanoma research on oncogenic signalling and molecular pathogenesis of this disease, as well as her rapid development as a rising star and leader in the field, which have helped to further the SMR’s goal to eradicate melanoma. The award was presented at the SMR annual meeting in Philadelphia in November 2023. 

The Christopher J. Marshall Award was established in 2015 by the SMR in partnership with Melanoma Research Foundation Congress to recognize a student, postdoctoral fellow, or new independent PI who has published a substantial and original contribution to studies of signal transduction and melanoma.

Shaffer joined Penn as an Assistant Professor in 2019. She holds a M.D.-Ph.D. in Medicine and Bioengineering from the University of Pennsylvania and conducted postdoctoral research in cancer biology in the lab of Junwei Shi, Associate Professor in Penn Medicine. The Syd Shaffer Lab is an interdisciplinary team which focuses on “understanding how differences between single-cells generate phenotypes such as drug resistance, oncogenesis, differentiation, and invasion [using] a combination of imaging and sequencing technologies to investigate rare single-cell phenomena.” A recent paper in Nature Communications details the team’s method to quantify long-lived fluctuations in gene expression that are predictive of later resistance to targeted therapy for melanoma.

Read the award announcement and the full list of prior winners at the SMR website.

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Penn Scientists Reflect on One Year of ChatGPT

by Erica Moser

René Vidal, at the podium, introduces the event “ChatGPT turns one: How is generative AI reshaping science?” Bhuvnesh Jain, left at the table, moderated the discussion with Sudeep Bhatia, Konrad Kording, Andrew Zahrt, and Nick Pangakis.

As a neuroscientist surveying the landscape of generative AI—artificial intelligence capable of generating text, images, or other media—Konrad Kording cites two potential directions forward: One is the “weird future” of political use and manipulation, and the other is the “power tool direction,” where people use ChatGPT to get information as they would use a drill to build furniture.

“I’m not sure which of those two directions we’re going but I think a lot of the AI people are working to move us into the power tool direction,” says Kording, a Penn Integrates Knowledge (PIK) University professor with appointments in the Perelman School of Medicine and School of Engineering and Applied Science. Reflecting on how generative AI is shifting the paradigm of science as a discipline, Kording said he thinks “it will push science as a whole into a much more collaborative direction,” though he has concerns about ChatGPT’s blind spots.

Kording joined three University of Pennsylvania researchers from the chemistry, political science, and psychology departments sharing their perspectives in the recent panel “ChatGPT turns one: How is generative AI reshaping science?” PIK Professor René Vidal opened the event, which was hosted by the School of Arts & Sciences’ Data Driven Discovery Initiative (DDDI), and Bhuvnesh Jain, physics and astronomy professor and co-faculty director of DDDI, moderated the discussion.

“Generative AI is moving so rapidly that even if it’s a snapshot, it will be very interesting for all of us to get that snapshot from these wonderful experts,” Jain said. OpenAI launched ChatGPT, a large language model (LLM)-based chatbot, on Nov. 30, 2022, and it rapidly ascended to ubiquity in news reports, faculty discussions, and research papers. Colin Twomey, interim executive director of DDDI, told Penn Today that it’s an open question as to how it will change the landscape of scientific research, and the` idea of the event was to solicit colleagues’ opinions on interesting directions in their fields.

Read the full story in Penn Today.

Konrad Paul Kording is Nathan Francis Mossell University Professor in Bioengineering and Computer and Information Science in Penn Engineering and in Neuroscience in the Perelman School of Medicine.