In an era peppered by breathless discussions about artificial intelligence—pro and con—it makes sense to feel uncertain, or at least want to slow down and get a better grasp of where this is all headed. Trusting machines to do things typically reserved for humans is a little fantastical, historically reserved for science fiction rather than science.
Not so much for César de la Fuente, PhD, the Presidential Assistant Professor in Psychiatry, Microbiology, Chemical and Biomolecular Engineering, and Bioengineering in Penn’s Perelman School of Medicine and School of Engineering and Applied Science. Driven by his transdisciplinary background, de la Fuente leads the Machine Biology Group at Penn: aimed at harnessing machines to drive biological and medical advances.
“Biology is complexity, right? You need chemistry, you need mathematics, physics and computer science, and principles and concepts from all these different areas, to try to begin to understand the complexity of biology,” he said. “That’s how I became a scientist.”
Marrying artificial intelligence with advanced experimental methods, the Machine Biology Group has mined the ancient past for future medical breakthroughs, bringing extinct molecules back to life. (Image credit: Ella Marushchenko)
“We need to think big in antibiotics research,” says Cesar de la Fuente. “Over one million people die every year from drug-resistant infections, and this is predicted to reach 10 million by 2050. There hasn’t been a truly new class of antibiotics in decades, and there are so few of us tackling this issue that we need to be thinking about more than just new drugs. We need new frameworks.”
Marrying artificial intelligence with advanced experimental methods, the group has mined the ancient past for future medical breakthroughs. In a recent study published in CellHost and Microbe, the team has launched the field of “molecular de-extinction.”
Our genomes – our genetic material – and the genomes of our ancient ancestors, express proteins with natural antimicrobial properties. “Molecular de-extinction” hypothesizes that these molecules could be prime candidates for safe new drugs. Naturally produced and selected through evolution, these molecules offer promising advantages over molecular discovery using AI alone.
In this paper, the team explored the proteomic expressions of two extinct organisms –Neanderthals and Denisovans, archaic precursors to the human species – and found dozens of small protein sequences with antibiotic qualities. Their lab then worked to synthesize these molecules, bringing these long-since-vanished chemistries back to life.
“The computer gives us a sequence of amino acids,” says de la Fuente. “These are the building blocks of a peptide, a small protein. Then we can make these molecules using a method called ‘solid-phase chemical synthesis.’ We translate the recipe of amino acids into an actual molecule and then build it.”
The team next applied these molecules to pathogens in a dish and in mice to test the veracity and efficacy of their computational predictions.
“The ones that worked, worked quite well,” continues de la Fuente. “In two cases, the peptides were comparable – if not better – than the standard of care. The ones that didn’t work helped us learn what needed to be improved in our AI tools. We think this research opens the door to new ways of thinking about antibiotics and drug discovery, and this first step will allow scientists to explore it with increasing creativity and precision.”
In a recent CNN feature, César de la Fuente, Presidential Assistant Professor in Bioengineering, Psychiatry, Microbiology, and in Chemical and Biomolecular Engineering commented on a study about a new type of antibiotic that was discovered with artificial intelligence:
“I think AI, as we’ve seen, can be applied successfully in many domains, and I think drug discovery is sort of the next frontier.”
The de la Fuente lab uses machine learning and biology to help prevent, detect, and treat infectious diseases, and is pioneering the research and discovery of new antibiotics.
César de la Fuente, Presidential Assistant Professor in Bioengineering, Microbiology, Psychiatry, and Chemical and Biomolecular Engineering, co-led a team of researchers who created autonomous particles covered with patches of protein “motors,” with the goal that these bots can eventually carry livesaving drugs through bodily fluids.
The antimicrobial peptides the researchers studied are “encrypted” in that they are contained within Apolipoprotein B, a blood plasma protein that is not directly involved in the immune response, but are not normally expressed on their own.
The rise of drug-resistant bacteria infections is one of the world’s most severe global health issues, estimated to cause 10 million deaths annually by the year 2050. Some of the most virulent and antibiotic-resistant bacterial pathogens are the leading cause of life-threatening, hospital-acquired infections, particularly dangerous for immunocompromised and critically ill patients. Traditional and continual synthesis of antibiotics will simply not be able to keep up with bacteria evolution.
To avoid the continual process of synthesizing new antibiotics to target bacteria as they evolve, Penn Engineers have looked at a new, natural resource for antibiotic molecules.
César de la Fuente, Ph.D.
A recent study on the search for encrypted peptides with antimicrobial properties in the human proteome has located naturally occurring antibiotics within our own bodies. By using an algorithm to pinpoint specific sequences in our protein code, a team of Penn researchers along with collaborators, led by César de la Fuente, Presidential Assistant Professor in Psychiatry, Bioengineering, Microbiology, and Chemical and Biomolecular Engineering, and Marcelo Torres, a post doc in de la Fuente’s lab, were able to locate novel peptides, or amino acid chains, that when cleaved, indicated their potential to fend off harmful bacteria.
Now, in a new study published in ACS Nano, the team along with Angela Cesaro, the lead author and post doc in de la Fuente’s lab, have identified three distinct antimicrobial peptides derived from a protein in human plasma and demonstrate their abilities in mouse models. Angela Cesaro performed a great part of the activities during her PhD under the supervision of corresponding author, Professor Angela Arciello, from the University of Naples Federico II. The collaborative study also includes Utrecht University in the Netherlands.
“We identified the cardiovascular system as a hot spot for potential antimicrobials using an algorithmic approach,” says de la Fuente. “Then we looked closer at a specific protein in the plasma.”
Dani S. Bassett, J. Peter Skirkanich Professor in Bioengineering and in Electrical and Systems Engineering
Bassett runs the Complex Systems lab which tackles problems at the intersection of science, engineering, and medicine using systems-level approaches, exploring fields such as curiosity, dynamic networks in neuroscience, and psychiatric disease. They are a pioneer in the emerging field of network science which combines mathematics, physics, biology and systems engineering to better understand how the overall shape of connections between individual neurons influences cognitive traits.
Jason Burdick, Ph.D.
Jason A. Burdick, Robert D. Bent Professor in Bioengineering
Burdick runs the Polymeric Biomaterials Laboratory which develops polymer networks for fundamental and applied studies with biomedical applications with a specific emphasis on tissue regeneration and drug delivery. The specific targets of his research include: scaffolding for cartilage regeneration, controlling stem cell differentiation through material signals, electrospinning and 3D printing for scaffold fabrication, and injectable hydrogels for therapies after a heart attack.
César de la Fuente, Ph.D.
César de la Fuente, Presidential Assistant Professor in Bioengineering and Chemical & Biomedical Engineering in Penn Engineering and in Microbiology and Psychiatry in the Perelman School of Medicine
De la Fuente runs the Machine Biology Group which combines the power of machines and biology to prevent, detect, and treat infectious diseases. He pioneered the development of the first antibiotic designed by a computer with efficacy in animals, designed algorithms for antibiotic discovery, and invented rapid low-cost diagnostics for COVID-19 and other infections.
Carl June, M.D.
Carl H. June, Richard W. Vague Professor in Immunotherapy in the Perelman School of Medicine and member of the Bioengineering Graduate Group
June is the Director for the Center for Cellular Immunotherapies and the Parker Institute for Cancer Therapy and runs the June Lab which develops new forms of T cell based therapies. June’s pioneering research in gene therapy led to the FDA approval for CAR T therapy for treating acute lymphoblastic leukemia (ALL), one of the most common childhood cancers.
Vivek Shenoy, Ph.D.
Vivek Shenoy, Eduardo D. Glandt President’s Distinguished Professor in Bioengineering, Mechanical Engineering and Applied Mechanics (MEAM), and in Materials Science and Engineering (MSE)
Shenoy runs the Theoretical Mechanobiology and Materials Lab which develops theoretical concepts and numerical principles for understanding engineering and biological systems. His analytical methods and multiscale modeling techniques gain insight into a myriad of problems in materials science and biomechanics.
The highly anticipated annual list identifies researchers who demonstrated significant influence in their chosen field or fields through the publication of multiple highly cited papers during the last decade. Their names are drawn from the publications that rank in the top 1% by citations for field and publication year in the Web of Science™ citation index.
Bassett and Burdick were both on the Highly Cited Researchers list in 2019 and 2020.
The methodology that determines the “who’s who” of influential researchers draws on the data and analysis performed by bibliometric experts and data scientists at the Institute for Scientific Information™ at Clarivate. It also uses the tallies to identify the countries and research institutions where these scientific elite are based.
David Pendlebury, Senior Citation Analyst at the Institute for Scientific Information at Clarivate, said: “In the race for knowledge, it is human capital that is fundamental and this list identifies and celebrates exceptional individual researchers who are having a great impact on the research community as measured by the rate at which their work is being cited by others.”
The full 2021 Highly Cited Researchers list and executive summary can be found online here.
The impending danger of bacterial resistance to antibiotics is well-documented within the scientific community. Bacteria are the most efficient evolvers, and their ability to develop tolerance to drugs, in addition to antibiotic overuse and misuse, means that researchers have had to get particularly resourceful to ensure the future of modern medicine.
WIRED’s Max G. Levy recently spoke with de la Fuente and postdoctoral researcher and study collaborator Marcelo Torres about the urgency of the team’s work, and why developing these solutions is critical to the survival of civilization as we know it. The team’s algorithm, based on pattern recognition software used to analyze images, makes an otherwise insurmountable feat tangible.
De la Fuente’s lab specializes in using AI to discover and design new drugs. Rather than making some all-new peptide molecules that fit the bill, they hypothesized that an algorithm could use machine learning to winnow down the huge repository of natural peptide sequences in the human proteome into a select few candidates.
“We know those patterns—the multiple patterns—that we’re looking for,” says de la Fuente. “So that allows us to use the algorithm as a search function.”
While biologists and chemists race to develop new antibiotics to combat constantly mutating bacteria, predicted to lead to 10 million deaths by 2050, engineers are approaching the problem through a different lens: finding naturally occurring antibiotics in the human genome.
The billions of base pairs in the genome are essentially one long string of code that contains the instructions for making all of the molecules the body needs. The most basic of these molecules are amino acids, the building blocks for peptides, which in turn combine to form proteins. However, there is still much to learn about how — and where — a particular set of instructions are encoded.
Now, bringing a computer science approach to a life science problem, an interdisciplinary team of Penn researchers have used a carefully designed algorithm to discover a new suite of antimicrobial peptides, hiding deep within this code.
The study, published in Nature Biomedical Engineering, was led by César de la Fuente, Presidential Assistant Professor in Bioengineering, Microbiology, Psychiatry, and Chemical and Biomolecular Engineering, spanning both Penn Engineering and Penn Medicine, and his postdocs Marcelo Torres and Marcelo Melo. Collaborators Orlando Crescenzi and Eugenio Notomista of the University of Naples Federico II also contributed to this work.
“The human body is a treasure trove of information, a biological dataset. By using the right tools, we can mine for answers to some of the most challenging questions,” says de la Fuente. “We use the word ‘encrypted’ to describe the antimicrobial peptides we found because they are hidden within larger proteins that seem to have no connection to the immune system, the area where we expect to find this function.”
César de la Fuente a Presidential Assistant Professor in the Perelman School of Medicine’s departments of Psychiatry and Microbiology and Engineering’s department of Bioengineering, has racked up accolades for his innovative, computational approach to discovering new antibiotics.
Now, in his most recent study, de la Fuente has shown how these vital drugs might be derived from wasp venom.
The study, published in The Proceedings of the National Academy of Sciences, involved altering a highly toxic small protein from a common Asian wasp species, Vespula lewisii, the Korean yellow-jacket wasp. The alterations enhanced the molecule’s ability to kill bacterial cells while greatly reducing its ability to harm human cells. In animal models, de la Fuente and his colleagues showed that this family of new antimicrobial molecules made with these alterations could protect mice from otherwise lethal bacterial infections.
There is an urgent need for new drug treatments for bacterial infections, as many circulating bacterial species have developed a resistance to older drugs. The U.S. Centers for Disease Control & Prevention has estimated that each year nearly three million Americans are infected with antibiotic-resistant microbes and more than 35,000 die of them. Globally the problem is even worse: Sepsis, an often-fatal inflammatory syndrome triggered by extensive bacterial infection, is thought to have accounted for about one in five deaths around the world as recently as 2017.
“New antibiotics are urgently needed to treat the ever-increasing number of drug-resistant infections, and venoms are an untapped source of novel potential drugs. We think that venom-derived molecules such as the ones we engineered in this study are going to be a valuable source of new antibiotics,” says de la Fuente.
De la Fuente and his team started with a small protein, or “peptide,” called mastoparan-L, a key ingredient in the venom of Vespula lewisii wasps. Mastoparan-L-containing venom is usually not dangerous to humans in the small doses delivered by wasp stings, but it is quite toxic. It destroys red blood cells, and triggers a type of allergic/inflammatory reaction that in susceptible individuals can lead to a fatal syndrome called anaphylaxis—in which blood pressure drops and breathing becomes difficult or impossible.
Mastoparan-L (mast-L) also is known for its moderate toxicity to bacterial species, making it a potential starting point for engineering new antibiotics. But there are still some unknowns, including how to enhance its anti-bacterial properties, and how to make it safe for humans.
“The AIChE 35 Under 35 Award was founded to recognize young chemical engineers who have achieved greatness in their fields,” reads the 2020 award announcement. “The winners are a group of driven, engaged, and socially active professionals, representing the breadth and diversity that chemical engineering exemplifies.”
De la Fuente was named in the list’s “Bioengineering” category for his his lab’s work in machine biology. Their goal is to develop computer-made tools and medicines that will combat antibiotic resistance. De la Fuente has already been featured on several other young innovators lists, including MIT Technology Review’s 35 under 35 and GEN’s Top 10 under 40, both in 2019. His research in antibiotic resistance has been profiled in Penn Today and Penn Engineering Today, and he was recently awarded Penn Health-Tech’s inaugural NEMO Prize for his proposal to develop paper-based COVID diagnostic system that could capture viral particles on a person’s breath.
In addition to being named on the 2020 list, the honorees will receive a $500 prize and will be celebrated at the 2020 AIChE Annual Meeting this November.
Learn more about de la Fuente’s pioneering research on his lab website.
