Penn Pioneers a ‘One-Pot Platform’ to Promptly Produce mRNA Delivery Particles

by Nathi Magubane

Lipid nanoparticles present one of the most advanced drug delivery platforms to shuttle promising therapeutics such as mRNA but are limited by the time it takes to synthesize cationic lipids, a key component. Now, Michael Mitchell and his team at the School of Engineering and Applied Science have developed a faster way to make cationic lipids that are also more versatile, able to carry different kinds of treatments to target specific organs. (Image: iStock / Dr_Microbe)

Imagine a scenario where a skilled hacker must upload critical software to update a central server and thwart a potentially lethal virus from wreaking havoc across a vast computer network. The programmer, armed with the lifesaving code, must navigate through treacherous territory teeming with adversaries, and success hinges on promptly getting a safe, stealthy delivery vehicle that can place the hacker exactly where they need to be.

In the context of modern medicine, messenger RNA (mRNA) serves as the hacker, carrying genetic instructions to produce specific proteins within cells that can induce desired immune responses or sequester maladaptive cellular elements. Lipid nanoparticles (LNPs) are the stealthy delivery vehicles that transport these fragile mRNA molecules through the bloodstream to their target cells, overcoming the body’s defenses to deliver their payload safely and efficiently.

However, much like building an advanced stealth vehicle, the synthesis of cationic lipids—a type of lipid molecule that’s positively charged and a key component of LNPs—is often a time-consuming process, involving multiple steps of chemical synthesis and purification.

Now, Michael Mitchell and a team at the University of Pennsylvania have addressed this challenge with a novel approach that leverages a compound library fabrication technique known as “click-like chemistry” to create LNPs in a single, simple step. Their findings, published in the journal Nature Chemistry, show that this method not only speeds up the synthesis process but also presents a way to equip these delivery vehicles with a “GPS” to better target specific organs such as the liver, lungs, and spleen, potentially opening new avenues for treating a range of diseases that arise in these organs.

“We’ve developed what we call an amidine-incorporated degradable (AID) lipid, a uniquely structured biodegradable molecule,” Mitchell says. “Think of it as an easy-to-build custom mRNA vehicle with a body kit that informs its navigation system. By adjusting its shape and degradability, we can enhance mRNA delivery into cells in a safe manner. By adjusting the amount of the AID lipid that we incorporate into the LNP, we can also guide it to different organs in the body, much like programming different destinations into a GPS.”

First author Xuexiang Han, a former postdoctoral researcher in the Mitchell Lab, explains that their new approach allows the rapid creation of diverse lipid structures in just an hour, compared to the weekslong process traditionally required.

Read more in Penn Today.

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

Alison Pouch Wins 2024 Cardiac Center Innovation Award

Alison Pouch

Congratulations to Alison Pouch, Assistant Professor in Bioengineering in the School of Engineering and Applied Science, and in Radiology in the Perelman School of Medicine, on winning a 2024 Cardiac Center Innovation Award for scientific research from the Children’s Hospital of Philadelphia (CHOP)’s Philly Spin-In. Pouch’s study, titled “Systemic Semilunar Valve Mechanics and Simulated Repair in Congenital Heart Disease,” is a collaboration with Matthew Jolley, Assistant Professor of Anesthesiology and Critical Care at CHOP:

“Through biomechanical assessment, Drs. Matthew Jolley and Alison Pouch are leading an interdisciplinary CHOP-Penn team that plans to determine why current approaches to systemic semilunar valve (SSV) repair fail. They will also investigate methods to design improved repairs before going to the operating room by using computational simulation to iteratively optimize repair.

‘We believe that understanding biomechanics of abnormal SSVs and explorations of simulated repair will markedly improve our ability to characterize, risk stratify, and surgically treat SSV dysfunction, thereby improving long-term outcomes and quality of life in patients with SSV dysfunction,’ Dr. Jolley said.”

Pouch’s lab focuses on 3D/4D segmentation and modeling of heart valves in echocardiographic images with applications to surgical treatment of valvular regurgitation as part of the Penn Image Computing and Science Laboratory.

Read the full awards announcement in the CHOP Cornerstone Blog.

How to Learn About a World-class Double Bass? Give it a CT

by Darcy Lewis  

The instrument imaging team, from left: Philadelphia Orchestra bassist Duane Rosengard; Peter Noël, PhD, director of CT Research at the Perelman School of Medicine; luthier Zachary S. Martin; Leening Liu, a PhD student in Noël’s Laboratory of Advanced Computed Tomography Imaging; and Mark Kindig.

When you’re an expert in medical CT imaging, two things are bound to happen, says Peter Noël, PhD, associate professor of Radiology and director of CT Research at the Perelman School of Medicine. One: You develop an insatiable curiosity about the inner workings of all kinds of objects, including those unrelated to your research. And two: Both colleagues and complete strangers will ask for your help in imaging a wide variety of unexpected items.

Over the course of his career, in between managing his own research projects, Noël has imaged diverse objects ranging from animal skulls to tree samples from a German forest, all in the name of furthering scientific knowledge. But none has intrigued him as much as his current extracurricular project: the first known attempt to perform CT imaging of some of the world’s finest string basses. 

The goal is to crack the code on what makes a world-class instrument. This knowledge could both increase the ability to better care for masterworks built between the 17th and 19th centuries, as well as providing insights into refining the building of new ones, including possibly shifting from older, scarcer European wood to the use of sustainably harvested U.S. wood.

That’s why Noël and Leening Liu, a PhD student in Noël’s Laboratory of Advanced Computed Tomography Imaging, have found themselves volunteering to run the basses through a Penn CT scanner occasionally, when they’re not developing next-generation CT technology. 

“We always learn something out of projects like this … the more appealing part is that medical research can also be applied to non-medical things,” Noël said. “We have the opportunity to take what we learn in medicine and use it for something else—in this case, moving the arts forward.”

Read the full story in Penn Medicine News.

Peter Noël is Assistant Professor of Radiology in the Perelman School of Medicine and member of the Penn Bioengineering Graduate Group.

Leening Liu is a Ph.D. student in Bioengineering. She is a member of the Laboratory for Advanced Tomography Imaging (LACTI) with research interests including clinical applications of spectral CT and spectral CT thermometry.

Who, What, Why: Lasya Sreepada on Decoding Alzheimer’s Disease

by Nathi Magubane

Lasya Sreepada, Ph.D. student in Bioengineering

Lasya Sreepada has always been fascinated by the brain and the underlying biology that shapes how people develop and age. “My curiosity traces back to observing differences between myself and my sister,” says Sreepada, a Ph.D. candidate in Bioengineering whose research unites efforts across Penn Medicine and Penn Engineering. “We grew up in the same environment but had remarkably different personalities, which led me to question what drove these differences and which brought me to the brain.”

Her academic journey began by applying medical imaging to understand how brain injuries sustained by professional athletes or military veterans impact their brain structure and chemistry over time. She became curious about how neurotrauma impacts aging and degeneration in the long term. Now, she leverages large, multimodal datasets to investigate neurodegenerative disease, with a particular focus on Alzheimer’s.

Read the full story in Penn Today.

Lasya Sreepada is a Bioengineering Ph.D. student at the Bioinformatics in Neurodegenerative Disease (BiND) Lab at Penn, advised by Corey McMillan and Dave Wolk, both Associate Professors in Neurology and members of the Bioengineering Graduate Group.

The Penn Forum on Quantum Systems (FoQuS), QUIEST’s First Inaugural Symposium, Hosts International Experts in Quantum Research

by Melissa Pappas

Dawn Bonnell gave the opening remarks of FoQuS.

Sometimes, nature’s smallest objects have the biggest impact. Take the quantum realm, which involves the building blocks of matter itself. 

Quantum science aims to understand the behavior of matter and energy at the scale of atoms and subatomic particles. Because particles frequently defy human intuition at this scale, the field likely offers great, untapped potential to solve some of our most complex issues.

“Bringing ‘quantum superstars’ from academia and industry to a space where scientists of all levels could interact, exchange ideas and gain inspiration is just one way we can foster collaboration in advancing the field and exploring new possibilities,” says Lee Bassett, Associate Professor in Electrical and Systems Engineering (ESE) and Director of the Center for Quantum Information, Engineering, Science and Technology (QUIEST).

Established in June 2023, QUIEST hosted its first symposium, The Penn Forum on Quantum Systems (FoQuS), last month, which reached over 150 attendees and included keynote speakers from across the country and globe. 

“The event was a wonderful success,” says Bassett. “External speakers appreciated being part of these discussions and seeing the exciting things happening at Penn. Penn faculty and students were thrilled to learn more about the state-of-the-art quantum research happening around the world in industry and in national labs.”

The forum’s goals were to connect researchers, raise awareness about regional, national and international efforts in quantum engineering and help guide research and education priorities for the QUIEST Center. 

Touching on all four research domains of the Center (Materials for QUIEST, Quantum Devices, Quantum Systems and QUIEST Impact), the forum left attendees, including faculty as well as graduate, undergraduate and high school students, with new inspiration for future research. 

Read the full story in Penn Engineering Today.

Dawn Bonnell, Henry Robinson Towne Professor in Materials Science and Engineering, Senior Vice Provost for Research, and member of the Penn Bioengineering Graduate Group, delivered opening remarks of FoQuS.

2024 Graduate Awards for Bioengineering Students

Congratulations to the 2024 Bioengineering student recipients of the annual Penn Engineering Graduate Student Awards! The awardees were honored in a ceremony on May 15, 2024, hosted by Dean Vijay Kumar and graduate program faculty leadership.

Master’s Student Awards:
Elizabeth Brown – Outstanding Service
Tianyu Cai – Outstanding Research
Ekta Singh – Outstanding Service

PhD Student Awards:
Dimitris Boufidis – Outstanding Service
Katherine Mossburg – Outstanding Service
Kelsey Swingle – Outstanding Teaching

Looking to AI to Solve Antibiotic Resistance

by Nathi Magubane

Cesar de la Fuente (left), Fangping Wan (center), and Marcelo der Torossian Torres (right). Fangping holds a 3D model of a unique ATP synthase fragment, identified by their lab’s deep learning model, APEX, as having potent antibiotic properties.

“Make sure you finish your antibiotics course, even if you start feeling better’ is a medical mantra many hear but ignore,” says Cesar de la Fuente of the University of Pennsylvania.

He explains that this phrase is, however, crucial as noncompliance could hamper the efficacy of a key 20th century discovery, antibiotics. “And in recent decades, this has led to the rise of drug-resistant bacteria, a growing global health crisis causing approximately 4.95 million deaths per year and threatens to make even common infections deadly,” he says.

De la Fuente, a Presidential Assistant Professor, and a team of interdisciplinary researchers have been working on biomedical innovations tackling this looming threat. In a new study, published in Nature Biomedical Engineering, they developed an artificial intelligence tool to mine the vast and largely unexplored biological data—more than 10 million molecules of both modern and extinct organisms— to discover new candidates for antibiotics.

“With traditional methods, it takes around six years to develop new preclinical drug candidates to treat infections and the process is incredibly painstaking and expensive,” de la Fuente says. “Our deep learning approach can dramatically reduce that time, driving down costs as we identified thousands of candidates in just a few hours, and many of them have preclinical potential, as tested in our animal models, signaling a new era in antibiotic discovery.” César de la Fuente holds a 3D model of a unique ATP synthase fragment, identified by his lab’s deep learning model, APEX, as having potent antibiotic properties. This molecular structure, resurrected from ancient genetic data, represents a promising lead in the fight against antibiotic-resistant bacteria.

These latest findings build on methods de la Fuente has been working on since his arrival at Penn in 2019. The team asked a fundamental question: Can machines be used to accelerate antibiotic discovery by mining the world’s biological information? He explains that this idea is based on the notion that biology, at its most basic level, is an information source, which could theoretically be explored with AI to find new useful molecules.

Read the full story in Penn Today.

Largest-Ever Antibiotic Discovery Effort Uses AI to Uncover Potential Cures in Microbial Dark Matter

by Eric Horvath

Credit: Georgina Joyce

Almost a century ago, the discovery of antibiotics like penicillin revolutionized medicine by harnessing the natural bacteria-killing abilities of microbes. Today, a new study co-led by researchers at the Perelman School of Medicine at the University of Pennsylvania suggests that natural-product antibiotic discovery is about to accelerate into a new era, powered by artificial intelligence (AI).

The study, published in Cell, the researchers used a form of AI called machine learning to search for antibiotics in a vast dataset containing the recorded genomes of tens of thousands of bacteria and other primitive organisms. This unprecedented effort yielded nearly one million potential antibiotic compounds, with dozens showing promising activity in initial tests against disease-causing bacteria.

“AI in antibiotic discovery is now a reality and has significantly accelerated our ability to discover new candidate drugs. What once took years can now be achieved in hours using computers” said study co-senior author César de la Fuente, PhD, a Presidential Assistant Professor in Psychiatry, Microbiology, Chemistry, Chemical and Biomolecular Engineering, and Bioengineering.

Nature has always been a good place to look for new medicines, especially antibiotics. Bacteria, ubiquitous on our planet, have evolved numerous antibacterial defenses, often in the form of short proteins (“peptides”) that can disrupt bacterial cell membranes and other critical structures. While the discovery of penicillin and other natural-product-derived antibiotics revolutionized medicine, the growing threat of antibiotic resistance has underscored the urgent need for new antimicrobial compounds.

In recent years, de la Fuente and colleagues have pioneered AI-powered searches for antimicrobials. They have identified preclinical candidates in the genomes of contemporary humans, extinct Neanderthals and Denisovans, woolly mammoths, and hundreds of other organisms. One of the lab’s primary goals is to mine the world’s biological information for useful molecules, including antibiotics.

Read the full story in Penn Medicine News.

How “Invitations” from Penn Medicine Restored Mammogram Completion Rates

by Frank Otto

The first few waves of COVID-19 slowed life across the United States, affecting everything from attending school to eating out for dinner and going on vacation. Segments of health care were also affected: Services that were not considered immediately crucial to fighting the virus were slowed or stopped during the pandemic’s first wave.  

But once Penn Medicine invited patients back to resume normal health care—including preventive care, like screenings for disease—there was some lag in numbers. 

“As we opened up to routine outpatient care, screening rates for situations when patients didn’t have symptoms were not returning back to normal,” said Mitchell Schnall, MD, PhD, FACR, a professor of Radiology, now the senior vice president for Data and Technology Solutions at Penn Medicine, and then the head of a team focused on the “resurgence” efforts to ease patients back into outpatient care. “Although a short delay in health screening is likely not going to cause long-term health problems, we were concerned whether screening rates would stay lower and lead to a long-term impact.”  

Read the full story in Penn Medicine News.

Mitchell Schnall is a member of the Penn Bioengineering Graduate Group.