Exploring the Genetic Secrets of Immunity – Reviving Extinct Molecules
Scientists have embarked on a journey into the realm of molecular "de-extinction," investigating ancient genomes to uncover potential sources of antibiotics. Their research has unearthed antimicrobial molecules from Neanderthals and Denisovans, challenging conventional understandings of protein functions and raising ethical questions.
Cesar de la Fuente, a Presidential Assistant Professor at the University of Pennsylvania School of Engineering and Applied Science, emphasizes the urgency of rethinking antibiotic research. He notes that over a million people die annually due to drug-resistant infections, a number projected to surge to 10 million by 2050. With a lack of genuinely new antibiotic classes for decades, the need for novel approaches and frameworks is critical.
De la Fuente's Machine Biology Group integrates engineering and health sciences to create innovative frameworks, leveraging the power of machines to expedite discoveries in biology and medicine. By combining artificial intelligence with advanced experimental techniques, the group has delved into the ancient past to pave the way for future medical advancements. In a recent study published in Cell Host and Microbe, the team introduced the concept of "molecular de-extinction."
The premise of molecular de-extinction is that our genomes, as well as those of our ancient ancestors like Neanderthals and Denisovans, encode proteins with inherent antimicrobial properties. These ancient molecules could serve as promising candidates for new drugs, offering advantages over AI-driven molecular discovery. In their research, the team investigated the proteomic expressions of these extinct species and identified numerous small protein sequences with antibiotic attributes. Subsequently, they synthesized these molecules, effectively resurrecting chemistries that had long vanished from the natural world.
"The computer provides us with a sequence of amino acids," explains de la Fuente. "These amino acids serve as the fundamental building blocks of a peptide, a small protein. Subsequently, we use a technique called 'solid-phase chemical synthesis' to create these molecules. We translate the amino acid recipe into an actual molecule and then proceed to construct it."
The team then subjected these molecules to pathogens both in a controlled environment and within mice, evaluating the accuracy and effectiveness of their computational predictions.
"For those that exhibited efficacy, the results were quite promising," de la Fuente continues. "In two instances, the peptides demonstrated comparable, if not superior, performance compared to the standard treatment. Even the peptides that didn't produce the desired outcome provided insights into enhancing our AI tools. This research, we believe, ushers in a new perspective on antibiotics and drug discovery, paving the way for scientists to explore it with increasing ingenuity and precision."
This novel realm of research holds profound significance. Beyond introducing an entirely fresh framework for drug discovery, their work has yielded unexpected revelations about our immune system. Surprisingly, certain peptide sequences identified had no previously known role in immunity.
Intriguingly, the group's prior research had already unveiled that some of the antimicrobial molecules they uncovered were concealed within proteins linked to entirely distinct systems and functions within the body.
One element that caught de la Fuente off guard was the presence of sequences across various body systems – cardiovascular, nervous, digestive, and more. What was previously unnoticed is that proteins or peptides engaged in specific system functions could also contribute to overall immunity.
The conventional biological notion is that one gene codes for one protein, each with a single function. However, the team's findings, along with the contributions of their accomplished collaborators, underscore that a single protein can possess multiple functions.
"We are venturing into an entirely new path for understanding how our bodies defend against and combat diseases," de la Fuente affirms.
With the de-extinction process established for these molecules, the Penn Engineering research team is now thoughtfully exploring the implications of resurrecting the past.
"We are engaging in discussions with bioethicists regarding the implications of resurrecting genetic material," de la Fuente states. "While our current focus is on medical applications, we must consider the possibility of others resurrecting substances that are toxic or harmful. Additionally, we are collaborating with patent lawyers. Under existing laws, current peptide sequences cannot be patented. However, what about those we recreate from extinct organisms?"
A seemingly simple, millennia-old molecule now holds the potential to raise unprecedented questions.
Reference: "Molecular de-extinction of ancient antimicrobial peptides enabled by machine learning" by Jacqueline R.M.A. Maasch, Marcelo D.T. Torres, Marcelo C.R. Melo and Cesar de la Fuente-Nunez, 28 July 2023, Cell Host & Microbe.
DOI: 10.1016/j.chom.2023.07.001
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