The Spanish group Cesar de la Fuente at the University of Pennsylvania recreates extinct human biological material using artificial intelligence.

“In 10 to 20 years we will be dying from antibiotic-resistant bacterial infections,” says geneticist Edith Heard. The World Health Organization (WHO) has been warning for years about the plague of microorganisms that elude existing drugs and will kill 10 million people worldwide every year, more than those who die from cancer. In this battle of gigantic dimensions is Cesar de la Fuente, Princess of Girona award for scientific research and professor of bioengineering at the University of Pennsylvania (USA). His weapons are artificial intelligence and the experience of his research team, Machine Biology, capable of detecting thousands of molecules with antibacterial potential. They look for them in natural compounds, such as wasp venom, or in the general protein map of the body. And, now, in our Neanderthal and Denisovan ancestors, which have served to “resurrect” molecules lost by Homo sapiens in its evolution.

There are more bacterial cells in the body than human cells. Among the most relevant abilities of bacteria, the most abundant organisms on the planet and responsible from generating dental plaque to maintaining the fertility of the earth, is their ability to develop resistance to antibiotics. And in this way, become a threat to millions of people.

De la Fuente’s team searches for compounds to respond to this challenge. He has done it in the proteome, the complete set of proteins in the body, where he has discovered 2,603 peptides (molecules made up of amino acids) with biological functions unrelated to the immune system and which, however, have anti-infective activity.

Identified 2,603 molecules produced by the body naturally that have antibiotic capacities

De la Fuente, a 37-year-old from A Coruna, included in the list of the 50 most awarded Spaniards and distinguished among the best researchers by the American Chemical Society and the Massachusetts Institute of Technology, explains how they have noticed what he calls de-extinction, the recovery of compounds from the past that no longer exist. “We had developed an algorithm to explore the human proteome as a source of antibiotics and we found many of those sequences that we call encrypted peptides. This led us to think that these sequences had been produced throughout evolution and played a role in the immune system to defend us against invading or infectious agents such as bacteria”, explains the scientist. “So we decided to investigate the proteome of our closest ancestors, which are the Neanderthals and the Denisovans,” he adds.

The base proteome was made public thanks to research on ancestral DNA that culminated last year with the Nobel Prize to Svante baabo for revealing the genetics of extinct humans. “What we did”, details the Spanish researcher, “was to develop an algorithm to explore these data, those human proteomes to see if we could find antibiotics encoded in the proteins”.

De la Fuente explains that it is an idea inspired by Jurassic Park. “The concept of the film was to bring entire organisms back to life: dinosaurs. But that has many ethical, ecological and technical problems. Today we do not have enough genomic information to resurrect a dinosaur. We came up with the concept of molecular de-extinction: instead of an entire organism, trying to bring molecules from the past back to life to deal with problems of the present, such as antibiotic resistance.”

We came up with the concept of molecular de-extinction: instead of an entire organism, trying to bring molecules from the past back to life to deal with problems of the present.

Cesar de la Fuente, a biotechnologist at the University of Pennsylvania

The research, published in Cell Host & Microbe and reviewed by Nature, uses mitochondrial DNA genomic and proteomic information to find, with the help of the algorithm designed by the team and with the application of artificial intelligence, molecules that could be potential antibiotics.

“The most fascinating moment,” says De la Fuente, “was when we resurrected these molecules using a method called solid-phase chemical synthesis.” “From the code that the computer gives us about amino acids with antibiotic capacity, we make the machines chemically synthesize them,” he adds.

Experimental verification came when they exposed their resurrected molecules (four peptides from Homo sapiens, one from Homo neanderthalensis, and one from Denisovan) in petri dishes (laboratory vessels) and in mice affected by the bacterium Acinetobacter baumannii, a common cause of hospital infections. . All six showed positive effects to varying degrees, some with efficacy similar to that of current conventional antibiotics.

“The doses used were extremely high, but the idea is interesting,” Nathanael Gray, a chemical biologist at Stanford University in California and unrelated to the research, clarifies for Nature. Gray doubts an immediate effect on drug development from extinct compounds.

The Spanish researcher’s team has been diving for half a decade where they believe they can find a new fundamental weapon for human health: in the past and in the present, in humans or in other areas of nature. One example is the finding of potentially beneficial biological material in the venom of the Eumenes micado solitary wasp, research published in Cell Reports Physical Science.

“Poisons are a very little explored source of potential medicines or molecules with interesting functionalities. We have been looking at different poisons for a few years to reprogram them and remove or eliminate toxicity to take advantage of their antibiotic capacity”, explains De la Fuente.

The key is the combination of artificial intelligence tools with biotechnological robotics and the experience and knowledge of the Machine Biology Group. “Five years ago,” adds the scientist, “the average time to discover an antibiotic was three or six years. Now, in hours or days, we can discover thousands”.

However, De la Fuente believes that the objective of the research is not only to find new antibiotics, but “the new way of thinking about how to discover new molecules using information from extinct organisms.” “Molecular de-extinction can help us open up new spaces that we had not previously explored and this means that, perhaps, we can find a biology of our ancestors with which to learn more about ourselves and about the potential of some molecules,” he adds.

Euan Ashley, an expert in genomics and precision health at Stanford University in California, agrees: “Diving into the archaic human genome is an interesting and potentially useful approach.”