Tag: research

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Optogenetic Functional Profiling Indicates New Mechanisms of Drug Tolerance in Cancer Cells

While modern cancer treatments can have tremendous therapeutic impact, formidable obstacles remain. Foremost among these is drug resistance, the ability of cancers to withstand and ultimately progress despite the presence of an anti-cancer drug. However, ongoing research provides hope that these challenges can be overcome, including recent work performed by Penn Engineers.

The lab of Lukasz J. Bugaj, Assistant Professor in the Department of Bioengineering, recently published an article that uncovers new mechanisms of how oncogenes interact  with important pathways of cellular signaling that are associated with resistance. This work, titled “Oncogenic EML4-ALK Assemblies Suppress Growth Factor Perception and Modulate Drug Tolerance,” applied a new technique called ‘optogenetic functional profiling’ that allowed measurement of how important molecular signaling pathways respond to precise perturbations applied by the researchers.  By applying this technique to many different cell types, the group found important differences in resistance-associated signaling between cancer cells and healthy cells 

Specifically, the research showed that an oncogene called EML4-ALK, which activates oncogenic signaling, simultaneously inactivates adjacent pathways that can cause resistance.  As a consequence, once an oncogene-blocking drug is applied, the inactivation is relieved, thus boosting activity through these adjacent, resistance-associated pathways.  The study also showed that these pathways were not only de-repressed, but were actively stimulated by neighboring cancer cells, further enhancing cell survival in the presence of the drug. 

“Our work shows that oncogenes, while driving cell division in cancer cells, simultaneously suppress the cells’ regulation by their environment,” said Dr. Bugaj. “While the work reveals mechanisms of paradoxical responses to drug treatment related to resistance, they may also inspire new ideas for therapies that can more efficiently kill cancer cells while maintaining suppression of resistance signaling. This work was co-led by PhD student David Gonzalez-Martinez and by Lee Roth, PhD, a postdoctoral fellow, and was supported by a grant from the American Cancer Society. 

Dr. Bugaj’s article can be read here.

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New Class of Encrypted Peptides Offer Hope in Fight Against Antibiotic Resistance

by Eric Horvath

Cesar de la Fuente, Presidential Assistant Professor with appointments in the Perelman School of Medicine, School of Engineering and School of Arts & Sciences (Image: Eric Sucar)

In a significant advance against the growing threat of antibiotic-resistant bacteria, researchers have identified a novel class of antimicrobial agents known as encrypted peptides, which may expand the immune system’s arsenal of tools to fight infection. The findings, published in Trends in Biotechnology by Cell Press, reveal that many antimicrobial molecules originate from proteins not traditionally associated with immune responses.

Unlike conventional antibiotics that target specific bacterial processes, these newly discovered peptides disrupt the protective membranes surrounding bacterial cells. By inserting themselves into these membranes—much like breaching a fortress wall—the peptides destabilize and ultimately destroy the bacteria.

“Our findings suggest that these previously overlooked molecules could be key players in the immune system’s response to infection,” says César de la Fuente, presidential assistant professor in bioengineering and in chemical and biomolecular engineering in the School of Engineering and Applied Science, in psychiatry and microbiology in the Perelman School of Medicine, and in chemistry in the School of Arts & Sciences, who led the research team. “This may not only redefine how we understand immunity but also opens up new possibilities for treating drug-resistant infections.”

Read the full story in Penn Medicine News.

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Developing Kidneys from Scratch: Alex Hughes Tackles the Tremendous Burden of Kidney Disease

by Ian Scheffler

Alex Hughes, Assistant Professor in Bioengineering, holds a model of a developing kidney. (Credit: Bella Ciervo)

To Alex Hughes, Assistant Professor in Bioengineering within Penn Engineering and in Cell and Developmental Biology within Penn Medicine, the kidney is a work of art. “I find the development of the kidney to be a really beautiful process,” says Hughes.

Most people only ever see the organ in cross-section, through textbooks or by dissecting animal kidneys in high school biology class: a bean-shaped slice with lots of tiny tubes. “I think that really undersells how amazing the structure is,” says Hughes, who points out that kidneys grow in utero like forests of pipes, branching exponentially.

Densely packed with tubules clustered in units known as nephrons, kidneys cleanse the blood, maintaining the body’s fluid and electrolyte balance, while also regulating blood pressure. The organ played a crucial role in vertebrates emerging from the ocean: as one paper puts it, kidneys preserve the primordial ocean in all of us.

Unfortunately, kidneys struggle in the modern world. Excessively salty food, being overweight, not exercising enough, drinking too much and smoking can all raise blood pressure, which damages the kidney’s tiny blood vessels, as does diabetes.

In some cases, damage to the kidney’s nephrons can be slowed with lifestyle changes, but, unlike the liver, bones and skin, which can regrow damaged tissue, kidneys have a limited capacity to regenerate. At present, without a transplant, the nephrons we have at birth must last a lifetime.

Read the full story in Penn Engineering Today.

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Studying Wikipedia Browsing Habits to Learn How People Learn

by Nathi Magubane

A hyperlink network from English Wikipedia, with only 0.1% of articles (nodes) and their connections (edges) visualized. Seven different reader journeys through this network are highlighted in various colors. The network is organized by topic and displayed using a layout that groups related articles together. (Image: Dale Zhou)

At one point or another, you may have gone online looking for a specific bit of information and found yourself  “going down the Wiki rabbit hole” as you discover wholly new, ever-more fascinating related topics — some trivial, some relevant — and you may have gone so far down the hole it’s difficult to piece together what brought you there to begin with.

According to the University of Pennsylvania’s Dani Bassett, who recently worked with a collaborative team of researcher to examine the browsing habits of 482,760 Wikipedia readers from 50 different countries, this style of information acquisition is called the “busybody.” This is someone who goes from one idea or piece of information to another, and the two pieces may not relate to each other much.

“The busybody loves any and all kinds of newness, they’re happy to jump from here to there, with seemingly no rhyme or reason, and this is contrasted by the ‘hunter,’ which is a more goal-oriented, focused person who seeks to solve a problem, find a missing factor, or fill out a model of the world,” says Bassett.

In the research, published in the journal Science Advances, Bassett and colleagues discovered stark differences in browsing habits between countries with more education and gender equality versus less equality, raising key questions about the impact of culture on curiosity and learning.

Read the full story in Penn Today.

Dani S. Bassett is the J. Peter Skirkanich Professor at the University of Pennsylvania with a primary appointment in the School of Engineering and Applied Science’s Department of Bioengineering and secondary appointments in the School of Arts & Sciences’ Department of Physics & Astronomy, Penn Engineering’s Department of Electrical and Systems Engineering, and the Perelman School of Medicine’s Departments of Neurology and Psychiatry.

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

by Ian Scheffler

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

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

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

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

Read the full story in Penn Engineering Today.

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Penn Bioengineering Student Wins Gilliam Fellowship

Sam Preza (Image: Courtesy of Penn Medicine News)

Sam Preza, a doctoral student in Bioengineering, was named one of two Penn graduate students and one of 50 graduate students nationwide to receive a 2024 Howard Hughes Medical Institute (HHMI) Gilliam Fellowship.  The HHMI Gilliam Fellowship cohort is awarded annually to graduate students and their advisors for outstanding research and commitment to advancing equity and inclusion in science. The fellowship includes a one-year mentorship skills development course and support to promote healthy and inclusive graduate training environments at their home institution.

Preza is a member of lab of Juan Rene Alvarez Dominguez, Assistant Professor of Cell and Developmental Biology in the Perelman School of Medicine and member of the Bioengineering Graduate Group. He graduated from University of Maryland in 2019 with a degree in Chemical Engineering. After working for t three years at AstraZeneca in Bioprocess Development, he joined the J-RAD Lab where he researches technologies for unmet medical needs:

“[Preza’s] PhD program harnesses the power of stem cells and circadian rhythms to ultimately develop a cure for Type I diabetes, which he researches alongside his advisor, Juan Alvarez, PhD, an assistant professor in the Department of Cell and Developmental Biology. Their studies focus on beta cells, the type of cell found in the pancreas that helps regulate glucose. In the lab, they study how exposing cells to circadian rhythms could lead to functional beta cells that can be transplanted into diabetic patients to restore function. This work will be supported by their HHMI Fellowship grant.  

The fellowship not only supports their scientific research but also helps foster an inclusive research environment, ensuring various backgrounds and ideologies contribute to their research. Preza is starting a DEI ‘potluck’, where bioengineering students can gather to discuss new research or career ideas. The meetups are catered by whichever student is hosting the meeting and can either showcase their nationality’s food or a cuisine they are passionate about, highlighting the celebration of diversity of ideas through food.

‘I believe STEM fields should look more like a mosaic of all our backgrounds rather than a melting pot, to add to the richness that is the art of science,’ Preza said.”

Read “Inclusion meets innovation: Meet Penn’s new Gilliam Fellows” in Penn Medicine News.

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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 Cheng’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.