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.

The CiPD Partners with the Mack Institute for Innovation and Management to Develop Tooth-Brushing Robots

by Melissa Pappas

Left to right: Hong-Huy Tran, Chrissie Jaruchotiratanasakul, Manali Mahajan (Photo Courtesy of CiPD)

The Center for Innovation and Precision Dentistry (CiPD), a collaboration between Penn Engineering and Penn Dental Medicine, has partnered with Wharton’s Mack Institute for Innovation Management on a research project which brings robotics to healthcare. More specifically, this project will explore potential uses of nanorobot technology for oral health care. The interdisciplinary partnership brings together three students from different Penn programs to study the commercialization of a new technology that detects and removes harmful dental plaque.

“Our main goal is to bring together dental medicine and engineering for out-of-the-box solutions to address unresolved problems we face in oral health care,” says Hyun (Michel) Koo, Co-Founding Director of CiPD and Professor of Orthodontics. “We are focused on affordable solutions and truly disruptive technologies, which at the same time are feasible and translatable.”

Read the full story in Penn Engineering Today.

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

To learn more about this interdisciplinary research, please visit CiPD.

This press release has been adapted from the original published by the Mack Institute for Innovation Management.

Study Reveals Inequities in Access to Transformative CAR T Cell Therapy

Image: iStock/PeopleImages

Patients being treated for B-cell non-Hodgkin’s Lymphoma (NHL) who are part of minority populations may not have equal access to cutting-edge CAR T cell therapies, according to a new analysis led by researchers from the Perelman School of Medicine and published in NEJM Evidence.

CAR T cell therapy is a personalized form of cancer therapy that was pioneered at Penn Medicine and has brought hope to thousands of patients who had otherwise run out of treatment options. Six different CAR T cell therapies have been approved since 2017 for a variety of blood cancers, including B-cell NHL that has relapsed or stopped responding to treatment. Image: iStock/PeopleImages

“CAR T cell therapy represents a major leap forward for blood cancer treatment, with many patients living longer than ever before, but its true promise can only be realized if every patient in need has access to these therapies,” says lead author Guido Ghilardi, a postdoctoral fellow in the laboratory of senior author Marco Ruella, an assistant professor of hematology-oncology and scientific director of the Lymphoma Program. “From the scientific perspective, we’re constantly working in the laboratory to make CAR T cell therapy work better, but we also want to make sure that when a groundbreaking treatment like this becomes available, it reaches all patients who might be able to benefit.”

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.

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.

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.

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.

A Suit of Armor for Cancer-fighting Cells

by Nathi Magubane

Chimeric antigen receptor T cell (CAR T) therapy has delivered promising results, transforming the fight against various forms of cancer, but for many, the therapy comes with severe and potentially lethal side effects. Now, a research team led by Michael Mitchell of the School of Engineering and Applied Science has found a solution that could help CAR T therapies reach their full potential while minimizing severe side effects. (Image: iStock / Meletios Verras)

In recent years, cancer researchers have hailed the arrival of chimeric antigen receptor T cell (CAR T) therapy, which has delivered promising results, transforming the fight against various forms of cancer. The process involves modifying patients’ T-cells to target cancer cells, resulting in remarkable success rates for previously intractable forms of cancer.

Six CAR T cell therapies have secured FDA approval, and several more are in the pipeline. However, these therapies come with severe and potentially lethal side effects, namely cytokine release syndrome (CRS) and neurotoxicity. These drawbacks manifest as a range of symptoms—from high fever and vomiting to multiple organ failure and patient death—posing significant challenges to broader clinical application.

Now, a research team led by Michael Mitchell, associate professor in the School of Engineering and Applied Science at the University of Pennsylvania, has found a solution that could help CAR T therapies reach their full potential while minimizing severe side effects. Their findings are published in the journal Nature Materials.

“Addressing CRS and neurotoxicity without compromising the therapeutic effectiveness of CAR T cells has been a complex challenge,” says Mitchell.

He says that unwanted interactions between CAR T and immune cells called macrophages drive the overactivation of macrophages, which in turn result in the release of toxic cytokines that lead to CRS and neurotoxicity.

“Controlling CAR T-macrophage interactions in vivo is difficult,” Mitchell says. “So, our study introduces a materials engineering-based strategy that involves incorporating a sugar molecule onto the surface of CAR T cells. These sugars are then used as a reactive handle to create a biomaterial coating around these cells directly in the body, which acts as a ‘suit of armor,’ preventing dangerous interactions with macrophages.”

First author Ningqiang Gong, a postdoctoral researcher in the Mitchell Lab, elaborates on the technique, “We attached this sugar molecule to the CAR T cells using metabolic labeling. This modification enables the CAR T cells to attack cancer cells without any hindrance.”

“When symptoms of CRS begin to manifest, we introduce another molecule—polyethylene glycol (PEG)—to create the suit of armor, which effectively blocks dangerous interactions between these engineered T cells, macrophages, and the tumor cells themselves,” Gong says.

Read the full story in Penn Today.

An Improved Delivery System for mRNA Vaccines Provides More Powerful Protection

by Devorah Fischler

(From left to right) Xuexiang Han, Michael Mitchell and Mohamad-Gabriel Alameh

The COVID-19 vaccine swiftly undercut the worst of the pandemic for hundreds of millions around the world. Available sooner than almost anyone expected, these vaccines were a triumph of resourcefulness and skill.

Messenger RNA vaccines, like the ones manufactured by Moderna or Pfizer/BioNTech, owed their speed and success to decades of research reinforcing the safety and effectiveness of their unique immune-instructive technology.

Now, researchers from the University of Pennsylvania School of Engineering and Applied Science and the Perelman School of Medicine are refining the COVID-19 vaccine, creating an innovative delivery system for even more robust protection against the virus.

In addition to outlining a more flexible and effective COVID-19 vaccine, this work has potential to increase the scope of mRNA vaccines writ large, contributing to prevention and treatment for a range of different illnesses.

Michael Mitchell, associate professor in Penn Engineering’s Department of Bioengineering, Xuexiang Han, postdoctoral fellow in Mitchell’s lab, and Mohamad-Gabriel Alameh, postdoctoral fellow in Drew Weissman’s lab at Penn Medicine and incoming assistant professor in the Department of Pathology and Laboratory Medicine at the Perelman School of Medicine, recently published their findings in Nature Nanotechnology.

mRNA, or messenger ribonucleic acid, is the body’s natural go-between. mRNA contains the instructions our cells need to produce proteins that play important roles in our bodies’ health, including mounting immune responses.

The COVID-19 vaccines follow suit, sending a single strand of RNA to teach our cells how to recognize and fight the virus.

Read the full story in Penn Engineering Today.

Engineered White Blood Cells Eliminate Cancer

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“Macrophages killing cancer cell” photographed by Susan Arnold.

By silencing the molecular pathway that prevents macrophages from attacking our own cells, Penn Engineers have manipulated these white blood cells to eliminate solid tumors.

Cancer remains one of the leading causes of death in the U.S. at over 600,000 deaths per year. Cancers that form solid tumors such as in the breast, brain or skin are particularly hard to treat. Surgery is typically the first line of defense for patients fighting solid tumors. But surgery may not remove all cancerous cells, and leftover cells can mutate and spread throughout the body. A more targeted and wholistic treatment could replace the blunt approach of surgery with one that eliminates cancer from the inside using our own cells.

Dennis Discher, Robert D. Bent Professor in Chemical and Biomolecular Engineering, Bioengineering, and Mechanical Engineering and Applied Mechanics, and postdoctoral fellow, Larry Dooling, provide a new approach in targeted therapies for solid tumor cancers in their study, published in Nature Biomedical Engineering. Their therapy not only eliminates cancerous cells, but teaches the immune system to recognize and kill them in the future.

“Due to a solid tumor’s physical properties, it is challenging to design molecules that can enter these masses,” says Discher. “Instead of creating a new molecule to do the job, we propose using cells that ‘eat’ invaders – macrophages.”

Macrophages, a type of white blood cell, immediately engulf and destroy – phagocytize – invaders such as bacteria, viruses, and even implants to remove them from the body. A macrophage’s innate immune response teaches our bodies to remember and attack invading cells in the future. This learned immunity is essential to creating a kind of cancer vaccine.

But, a macrophage can’t attack what it can’t see.

“Macrophages recognize cancer cells as part of the body, not invaders,” says Dooling. “To allow these white blood cells to see and attack cancer cells, we had to investigate the molecular pathway that controls cell-to-cell communication. Turning off this pathway – a checkpoint interaction between a protein called SIRPa on the macrophage and the CD47 protein found on all ‘self’ cells – was the key to creating this therapy.”

Read the full story in Penn Engineering Today.

Multiple members in the biophysical engineering lab lead by Dennis Discher, including co-lead author and postdoctoral fellow and Penn Bioengineering alumnus Jason Andrechak and Bioengineering Ph.D. student Brandon Hayes, contributed to this study. The research was funded by grants from the National Heart, Lung, and Blood Institute and the National Cancer Institute, including the Physical Sciences Oncology Network, of the US National Institutes of Health.

CiPD Fellows Recognized with Research Awards

Members of the inaugural cohort of fellows in the Center for Innovation and Precision Dentistry (CiPD)’s NIDCR T90/R90 Postdoctoral Training Program have been recognized for their research activities with fellows receiving awards from the American Association for Dental, Oral, and Craniofacial Research (AADOCR), the Society for Biomaterials, and the Osteology Foundation. All four of the honored postdocs are affiliated with Penn Bioengineering.

Zhi Ren

Zhi Ren won first place in the Fives-Taylor Award at the AADOCR Mini Symposium for Young Investigators. A postdoctoral fellow in the labs of Dr. Hyun (Michel) Koo at Penn Dental Medicine (and member of the Penn Bioengineering Graduate Group) and Dr. Kathleen Stebe of Penn Engineering, Dr. Ren’s research focuses on understanding how bacterial and fungal pathogens interact in the oral cavity to form a sticky plaque biofilm on teeth, which gives rise to severe childhood tooth decay that affects millions of children worldwide. In his award-winning study, titled “Interkingdom Assemblages in Saliva Display Group-Level Migratory Surface Mobility”, Dr. Ren discovered that bacteria and fungi naturally present in the saliva of toddlers with severe decay can form superorganisms able to move and rapidly spread on tooth surfaces.

Justin Burrell

Justin Burrell won second place in the AADOCR Hatton Competition postdoctoral category for his research. Dr. Burrell has been working with Dr. Anh Le in Penn Dental Medicine’s Department of Oral Surgery/Pharmacology and Dr. D. Kacy Cullen of Penn Medicine and Penn Bioengineering. Together, their interdisciplinary team of clinician-scientists, biologists, and neuroengineers have been developing novel therapies to expedite facial nerve regeneration and increase meaningful functional recovery.

Marshall Padilla

Marshall Padilla earned third place at the Society for Biomaterials Postdoctoral Recognition Award Competition for a project titled, “Branched lipid architecture improves lipid-nanoparticle-based mRNA delivery to the liver via enhanced endosomal escape”. Padilla was also a finalist in the AADOCR Hatton Award Competition, presenting on a separate project titled, “Lipid Nanoparticle Optimization for mRNA-based Oral Cancer Therapy”. Both projects employ lipid nanoparticles, the same delivery vehicles used in the mRNA COVID-19 vaccine technology. A postdoctoral fellow in the lab of Dr. Michael J. Mitchell of Penn’s Department of Bioengineering, Dr. Padilla’s research focuses on developing new ways to enhance the efficacy and safety of lipid nanoparticle technology and its applications in dentistry and biomedicine. He has been working in collaboration with Dr. Shuying (Sheri) Yang and Dr. Anh Le in Penn Dental Medicine.

Dennis Sourvanos

Dennis Sourvanos (GD’23, DScD’23) was the recipient of the Trainee Travel Grant award through the Osteology Foundation (Lucerne Switzerland). Dr. Sourvanos will be presenting his research related to medical dosimetry and tissue regeneration at the International Osteology Symposium in Barcelona, Spain (April 27th – 29th 2023). He also presented at the 2023 AADOCR/CADR Annual Meeting for his project titled, “Validating Head-and-Neck Human-Tissue Optical Properties for Photobiomodulation and Photodynamic Therapies.” Dr. Sourvanos has been working with Dr. Joseph Fiorellini in Penn Dental Medicine’s Department of Periodontics and Dr. Timothy Zhu in the Hospital of the University of Pennsylvania’s Department of Radiation Oncology and the Smilow Center for Translational Research (and member of the Penn Bioengineering Graduate Group).

Read the full announcement in Penn Dental Medicine News.