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.”
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.
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.
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.
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.
Students learn about bioengineering in the BE Labs at the inaugural BETA Day (credit: Felice Macera)
Last year marked not just the 50th anniversary of the Department of Bioengineering (BE) but the 10th anniversary of Bioengineer-Teach-Aspire (BETA) Day, one of the most beloved and impactful programs run by the Graduate Association of Bioengineers (GABE).
BETA Day, an annual event in which a diverse group of Philadelphia middle school students learns about bioengineering and a variety of science, technology, engineering and math (STEM) fields from BE graduate students, has grown into an institution, one whose impact no one could have foreseen.
GABE’s original goal was to provide social opportunities for BE graduate students. While this is still an important function of the group, in the mid-2010s, students and board members found themselves looking for opportunities to provide more formalized outreach and mentorship. They wanted to have an impact on Philadelphia and cultivate the next generation of bioengineers.
The Seeds of BETA Day
Benjamin Freedman, a principal investigator at Beth Israel Deaconess Medical Center, Assistant Professor of Orthopedic Surgery at Harvard Medical School, and founder of biotech startup Limax Biosciences, earned his doctorate in Bioengineering in the lab of Louis Soslowsky, Fairhill Professor in the Department of Orthopaedic Surgery within the Perelman School of Medicine (PSOM) and in Bioengineering within the School of Engineering and Applied Science (Penn Engineering). Freedman played a key role in BETA Day’s founding.
In 2009, Freedman, then an undergraduate at the University of Rochester, attended a talk at the City College of New York (CCNY), which sparked his interest in mentorship. Sheldon Weinbaum, a Distinguished Professor in Biomedical and Mechanical Engineering at CCNY and the Biomedical Engineering Society (BMES) inaugural diversity award winner, spoke about “fulfilling the dream” of mentorship and the struggle for inclusion in STEM fields, echoing the language of Martin Luther King Jr.
Inspired by this encounter, Freedman got involved with a mentorship program during his senior year. He later signed up for a lunch with Weinbaum to talk about mentorship. Freedman recalls that Weinbaum’s face “lit up” when he realized that this student didn’t just want to talk science but was genuinely interested in inclusion, diversity and mentorship.
Arriving at Penn Engineering and PSOM for graduate school in 2011, Freedman joined GABE, bringing this passion and experience with him and helping GABE to shape and clarify their outreach and mentorship programs.
From Campus to Community
Along with other GABE board members, such as Cori Riggin and Shauna Dorsey, Freedman worked over the course of a year and a half to identify the mentorship needs within BE and gauge student interest. David Meaney, Solomon R. Pollack Professor and then Chair of BE, and former BE faculty Susan Margulies, now Professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, were particularly involved in these discussions.
Benjamin Freedman (left) addresses the first BE mentoring cohort (credit: Felice Macera)
The GABE board reorganized to include mentorship and outreach chairs, and eventually started a formal mentorship program in partnership with the Penn undergraduate Biomedical Engineering Society (BMES). The mentorship program continues to this day, creating opportunities for BE graduate students to engage with undergraduate concerns through one-on-one meetings to discuss career or graduate school advice, summer BBQ’s, roundtable discussions and monthly meetups.
With an internal mentorship program established, the team turned their focus to Philadelphia. Initially, GABE established a partnership with iPraxis, a local STEM education non-profit, to do some outreach activities in middle schools. This partnership resulted in an Outstanding Outreach Award from the national Biomedical Engineering Society in 2014. But with the department’s 40th anniversary approaching, GABE’s members wanted to do something spectacular to celebrate and give back to the community.
Service Learning in Action
By then, Ocek Eke, Director of Graduate Students Programming at Penn Engineering, had been recently appointed Director of Global and Local Service Learning Programs. Eke provided Freedman and GABE advice on setting up effective outreach programs and to determine what resources the School could contribute. “We have a role to play to fulfill our mission,” Eke says, citing Penn’s motto, “Leges Sine Moribus Vanae,” which translates to “Laws without morals are useless.”
GABE’s efforts were part of a “wave” of interest in outreach and community service in both the department and the School, Eke remembers, including the undergraduate group Access Engineering and several service learning courses which took students to Asia, Africa and Central America. He was impressed by the lack of cynicism in the BE student body. “These are students who saw a need, who are passionate about what they want to achieve. They could have just been comfortable but were willing to go and stick their necks out. They used the resources we have here in Penn Engineering to address these needs.”
A (BETA) Day to Remember
The first BETA Day took place at the Singh Center for Nanotechnology, which had only just opened. Held with the enthusiastic participation of around 70 middle schoolers, and almost as many volunteers, the event included a full day of programming, with representation from every Penn Engineering department. There were science talks, workshops, and even a drone demo with Vijay Kumar, Nemirovsky Family Dean of Penn Engineering. The entire day was student-driven and staffed by volunteers, demonstrating the students’ commitment to making a difference.
The first annual BETA Day was held in the Singh Center for Nanotechnology (credit: Felice Macera)
GABE never imagined BETA Day as an annual event, but the first instance was so successful, it became hard to imagine not repeating it. Ten years later, the GABE board continues to introduce bioengineering to a diverse and ambitious group of middle schoolers every spring.
In 2021, during the COVID-19 lockdown, the industrious and creative GABE board even tailored BETA Day activities to be held in an entirely virtual environment. “These types of events are not as successful when they’re only initiated by faculty,” says Freedman. Generating and sustaining student involvement has been a cornerstone of BETA Day’s continued success.
The Legacy of BETA Day
GABE’s mentorship efforts have grown as well, changing to meet evolving student needs. The mentorship program now involves students being placed in “families” of around four undergraduates and two graduate students, spanning a range of class years and experience levels. A third student association, the Master’s Association in Bioengineers (MAB), was established to better foster community and facilitate opportunities for master’s students.
The department also launched an applicant support program in 2020, enhancing BE’s mission of increasing diversity, equity and inclusion by pairing Ph.D. applicants to current doctoral students, who serve as mentors to help navigate the admissions process, giving feedback on application materials and providing other support to prospective students.
Structures of support and outreach activities like BETA Day have become a key emphasis of the department’s graduate student recruitment, helping to attract students who value the department’s core mission and increasing opportunities for underserved or underrepresented communities.
The legacy of that original BETA Day also continues in Freedman’s Lab. After graduating in 2017, having served on the GABE board and as President from 2015-2016, Freedman continued to mentor over 20 students during his postdoctoral research at Harvard. He is now building his own independent lab where diversity, mentorship and outreach are foundational pillars.
A Nebula of Inspiration
Perhaps the most consequential impact of BETA Day is the impression it makes on the middle schoolers who participate each year. “To really get to know what happens on BETA Day and what it’s true impact is, you need to experience it,” says Ravi Radhakrishnan, Herman P. Schwan Chair of the Department of Bioengineering and Professor in Bioengineering and in Chemical and Biomolecular Engineering.
The legacy of BETA Day continues into its second decade. (credit: Afraah Shamim, BE Labs)
“I walked into the Stephenson Foundation Education Lab during BETA Day 2024,” recalls Radhakrishnan, “and what I saw was teams of teenagers tinkering with pipes that were clogged, strategizing on unclogging them without damaging them: an assignment that got them thinking in teams about how to prevent heart attacks.
“Expose these young minds to design thinking, versatile tools, and critical problems in biomedical engineering, and the elegant solutions they brainstorm are truly mind blowing. BETA Day is like the nebula where future biomedical stars are born.”
A multiracial Black and Asian self-described secular humanist, who was raised as one of Jehovah’s Witnesses and is now in an interracial, interfaith marriage, walked into a Passover seder.
It’s not the setup for a groaner of a joke, or an epic fail of an evening. Rather, as Roy H. Hamilton, MD, tells it, this was his experience this spring as his Jewish in-laws—the family he has loved as his own for over two decades—came together to commemorate the universal human themes of freedom and deliverance from oppression reflected in the Passover narrative. Though he does this every year, this year he had some trepidation. In a time marked by tragic conflict and with tensions both abroad and at home, it seemed like having a frank discussion of these themes might invite acrimony. But what emerged instead was a profound opportunity to listen, to appreciate each other’s perspective, and to “exercise empathy for trauma that’s happening to everyone.”
It was a bit of a revelation for Hamilton, Penn Medicine’s new vice dean for Inclusion, Diversity, and Equity. “In the moment that you would have thought would be the worst to open up certain topics, we all ended up having a great dialogue across differences,” he said. Why? “Because we all felt connected enough to give each other respect, compassion, and grace, even when our thoughts and opinions differed. It made me think about how we can further cultivate a culture of empathy at Penn too.”
Today, as Hamilton begins his third decade on the faculty at Penn’s Perelman School of Medicine, he is devoted to making academia a safe, supportive space for students and colleagues alike. He serves as a professor of Neurology, with secondary appointments in Psychiatry and Physical Medicine and Rehabilitation. Hamilton is also director of both the Laboratory for Cognition and Neural Stimulation; and the Penn Brain Science, Translation and Modulation (BrainSTIM) Center. Previously, he was the Perelman School of Medicine’s assistant dean for Cultural Affairs and Diversity for almost a decade, and launched similar efforts in his field, serving as Penn Neurology’s vice chair for Diversity and Inclusion from 2017 until his recent elevation to the role for Penn Medicine as a whole.
Given his own diverse background and personal life, Hamilton wants everyone—trainees, faculty, patients—to feel valued and included. “I touch enough spaces in my personal life that when groups are being clearly systematically disadvantaged, it often feels like it’s touching on some piece of my own identity,” he said, in discussing his background and hope for his new leadership position. “I bring a lot of myself to this role.”
In a recent discussion, Hamilton shared perspectives on why supporting inclusion, diversity, and equity matters—particularly for an institution training future doctors—and what Penn Medicine is doing in this sphere.
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.
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.)
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.
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.
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.”
