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.”
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.
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.
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.”
Representing Bach’s pieces as networks reveals hidden structures in his music. (Credit: Suman Kulkarni)
Even today, centuries after he lived, Johann Sebastian Bach remains one of the world’s most popular composers. On Spotify, close to seven million people stream his music per month, and his listener count is higher than that of Mozart and even Beethoven. The Prélude to his Cello Suite No. 1 in G Major has been listened to hundreds of millions of times.
What makes Bach’s music so enduring? Music critics might point to his innovative harmonies, complex use of counterpoint and symmetrical compositions. Represent Bach’s music as a network, however, where each node stands for one musical note, and each edge the transition from one note to another, and a wholly different picture emerges.
In a recent paper in Physical Review Research, Dani S. Bassett, J. Peter Skirkanich Professor in Bioengineering and in Electrical and Systems Engineering within the School of Engineering and Applied Science, in Physics & Astronomy within the School of Arts & Sciences, and in Neurology and Psychiatry within the Perelman School of Medicine, and Suman Kulkarni, a doctoral student in Physics & Astronomy, applied network theory to Bach’s entire oeuvre.
The paper sheds new light on the unique qualities of Bach’s music and demonstrates the potential for analyzing music through the lens of networks. Such analysis could yield benefits for music therapists, musicians, composers and music producers, by giving them unprecedented quantitative insight into the structure of different musical compositions.
“This paper provides a starting point for how one can boil down these complexities in music and start with a simple representation to dig into how these pieces are structured,” says Kulkarni, the paper’s lead author. “We applied this framework to a dozen types of Bach’s compositions and were able to observe quantitative differences in how they were structured.”
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.
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.
The growing threat of antimicrobial resistance demands innovative solutions in drug discovery. Scientists are turning to artificial intelligence (AI) and machine learning (ML) to accelerate the discovery and development of antimicrobial peptides (AMPs). These short strings of amino acids are promising for combating bacterial infections, yet transitioning them into clinical use has been challenging. Leveraging novel AI-driven models, researchers aim to overcome these obstacles, heralding a new era in antimicrobial therapy.
A new article in Nature Reviews Bioengineering illuminates the promises and challenges of using AI for antibiotic discovery. Cesar de la Fuente, Presidential Assistant Professor in Microbiology and Psychiatry in the Perelman School of Medicine, in Bioengineering and Chemical and Biomolecular Engineering in the School of Engineering and Applied Science, and Adjunct Assistant Professor in Chemistry in the School of Arts and Sciences, collaborated with James J. Collins, Termeer Professor of Medical Engineering and Science at MIT, to provide an introduction to this emerging field, outlining both its current limitations and its massive potential.
In the past five years, groundbreaking work in the de la Fuente Lab has dramatically accelerated the discovery of new antibiotics, reducing the timeline from years to mere hours. AI-driven approaches employed in his laboratory have already yielded numerous preclinical candidates, showcasing the transformative potential of AI in antimicrobial research and offering new potential solutions against currently untreatable infections.
Recent advancements in AI and ML are revolutionizing drug discovery by enabling the precise prediction of biomolecular properties and structures. By training ML models on high-quality datasets, researchers can accurately forecast the efficacy, toxicity and other crucial attributes of novel peptides. This predictive power expedites the screening process, identifying promising candidates for further evaluation in a fraction of the time required by conventional methods.
Traditional approaches to AMP development have encountered hurdles such as toxicity and poor stability. AI models help overcome these challenges by designing peptides with enhanced properties, improving stability, efficacy and safety profiles, and fast-tracking the peptides’ clinical application.
While AI-driven drug discovery has made significant strides, challenges remain. The availability of high-quality data is a critical bottleneck, necessitating collaborative efforts to curate comprehensive datasets to train ML models. Furthermore, ensuring the interpretability and transparency of AI-generated results is essential for fostering trust and wider adoption in clinical settings. However, the future is promising, with AI set to revolutionize antimicrobial therapy development and address drug resistance.
Integrating AI and ML into antimicrobial peptide development marks a paradigm shift in drug discovery. By harnessing these cutting-edge technologies, researchers can address longstanding challenges and accelerate the discovery of novel antimicrobial therapies. Continuous innovation in AI-driven approaches is likely to spearhead a new era of precision medicine, augmenting our arsenal against infectious diseases.
The de la Fuente Lab uses use the power of machines to accelerate discoveries in biology and medicine. The lab’s current projects include using AI for antibiotic discovery, molecular de-extinction, reprogramming venom-derived peptides to discover new antibiotics, and developing low-cost diagnostics for bacterial and viral infections. Read more posts featuring de la Fuente’s work in the BE Blog.
Susan Davidson, Cesar de la Fuente, Surbhi Goel and Chris Callison-Burch speak on AI in Engineering in episode 4 of the Innovation & Impact podcast.
With AI technologies finding their way into every industry, important questions must be considered by the research community: How can deep learning help identify new drugs? How can large language models disseminate information? Where and how are researchers using AI in their own work? And, how are humans anticipating and defending against potential harmful consequences of this powerful technology?
In this episode of Innovation & Impact, host Susan Davidson, Weiss Professor in Computer and Information Science (CIS), speaks with three Penn Engineering experts about leveraging AI to advance scientific discovery and methods to protect its users. Panelists include:
Chris Callison-Burch, Associate Professor in CIS, who researches the applications of large language models and AI tools in current and future real-world problems with a keen eye towards safety and ethical use of AI;
Surbhi Goel, Magerman Term Assistant Professor in CIS, who works at the intersection of theoretical computer science and machine learning. Her focus on developing theoretical foundations for modern machine learning paradigms expands the possibilities of deep learning; and
Cesar de la Fuente, Presidential Assistant Professor in Bioengineering, Psychiatry and Microbiology with a secondary appointment in Chemical and Biomolecular Engineering, who leads research on technology in the medical field, using computers to find antibiotics in extinct organisms and identify pre-clinical candidates to advance drug discovery.
Each episode of Penn Engineering’s Innovation & Impact podcast shares insight from leading experts at Penn and Penn Engineering on science, technology and medicine.
NAM, founded in 1970, is an independent organization of professionals that advises the entire scientific community on critical health care issues. Each year, NAM chooses up to 10 new ELHM Scholars who are early-to-mid-career professionals from a wide range of health-related fields, including biomedical engineering, internal medicine, psychiatry, radiology and journalism to serve a three-year term.
“We are delighted that Dr. de la Fuente is receiving recognition from the National Academy of Medicine for his breakthrough contributions and exceptional leadership in the life sciences,” says Vijay Kumar, Nemirovsky Family Dean of Penn Engineering. “His pioneering work using computers to accelerate antibiotic discovery is extraordinary. We proudly celebrate his selection as part of this outstanding group of scholars.”
