Discovering the Genetic Secrets of Immunity – Scientists Bring Independent Molecules Back to Life

Marrying artificial intelligence with advanced experimental techniques, the Machine Biology Group has mined the past for the future of medical breakthroughs, bringing dead molecules back to life. Credit: Ella Marushchenko

Researchers have investigated molecular “de-tinction,” studying ancient genomes for antibiotics. Their work has produced antimicrobial molecules from Neanderthals and Denisovans, challenging traditional concepts of protein functions and raising bioethical questions.

“We need to think more about antibiotic research,” said Cesar de la Fuente. More than a million people die each 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 so few of us are dealing with this issue that we have to think beyond new drugs. We need new frameworks.”

De la Fuente is a Presidential Assistant Professor in the Department of Bioengineering and the Department of Chemical and Biomolecular Engineering at the University of Pennsylvania School of Engineering and Applied Sciences. He holds adjunct faculty positions in Psychiatry and Microbiology at the Perelman School of Medicine.

De la Fuente’s lab, the Machine Biology Group, developed these new guidelines using powerful collaborations in engineering and health sciences, drawing on “the power of machines to accelerate biological and medicinal discovery.”

Marrying artificial intelligence with sophisticated experimental methods, the team has mined the past for future medical breakthroughs. In a recent study published in A cell The Host and the Microbethis group pioneered the field of “molecular elimination.”

Our genomes – our genetic material – and the genomes of our ancient ancestors, express proteins with natural antimicrobial properties. “Molecular elimination” predicts that these molecules may be prime candidates for new, safer drugs. Naturally produced and evolutionarily selected, these molecules offer promising advantages over molecular discovery using AI alone.

In this paper, the team analyzed the proteomic profile of two extinct species – Neanderthals and Denisovans, the earliest precursors to humans. species – and discovered the sequence of small proteins with antibacterial properties. Their lab then worked to synthesize these molecules, restoring these long-lost chemistries.

“The computer gives us a sequence of amino acids,” de la Fuente said. “These are the building blocks of a peptide, a small protein. We can then make these molecules using a method called ‘solid-phase chemical synthesis.’ We translate the recipe of amino acids into a real molecule and build it.”

The team then applied these molecules to pathogens in a dish and in mice to test the validity and effectiveness of their computational predictions.

Ude la Fuente continues: “These work, they work very well. 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 that this first step will allow scientists to explore them with increasing efficiency and precision. “

This new research environment is particularly rich. In addition to providing an entirely new framework for drug discovery, their work has yielded unexpected insights into our immune system. Surprisingly, some of the peptide sequences in question had no previously known role in vaccination.

In fact, the team’s previous research has shown that some of the antimicrobial molecules they found are secreted, hidden within proteins related to different processes and functions in the body.

“One thing that surprised me,” said de la Fuente, “is that our lab found sequences in all the body’s systems – the cardiovascular, the nervous, the digestive, and so on. one system can contribute to overall safety. “

The traditional view in biology is that one gene codes for one protein, and each protein has one function. But what the team and their talented collaborators have discovered is that a single protein can have multiple functions.

De la Fuente says: “We are opening up a new way of studying how our bodies protect and fight disease.

With extinction based on these molecules, the Penn Engineering research team is now critically examining the effects of past awakenings.

Ude la Fuente says: “We are talking to bioethicists about what it means to bring genes back to life. “We make medicine for ourselves, but what if someone else wakes up something poisonous or harmful? We also work with patent attorneys. The current peptide sequence is not legally patentable. But what about the ones we create from extinct organisms?”

A simple molecule, thousands of years old, is alive – and it’s helping us ask questions we’ve never asked before.

Reference: “Molecular dissection of ancient antiviral peptides by machine learning” by Jacqueline RMA Maasch, Marcelo DT Torres, Marcelo CR Melo and Cesar de la Fuente-Nunez, 28 July 2023, Cell Host and Microbe.
DOI: 10.1016/j.chom.2023.07.001