Reviving ancient bacteria: A breakthrough in discovering new therapeutic drugs

Scientists have made groundbreaking discoveries in the reconstruction of ancient genomes and biotechnology, revealing the molecular secrets of microorganisms from the Paleolithic era. Recently, a group of transdisciplinary researchers from the Leibniz Institute for Natural Product Research and Infection Biology, the Max Planck Institute for Evolutionary Anthropology, and Harvard University published a study in Science, detailing the reconstruction of bacterial genomes from previously unknown bacteria dating back to the Pleistocene era. By using these genetic blueprints, they were able to create a biotechnology platform that revived the ancient bacteria’s natural products.

Microbes are renowned for their chemical creations, including a large number of the world’s antibiotics and therapeutic drugs. However, creating these complex chemical natural products is not easy. Bacteria rely on specialized genes that encode enzymatic machinery capable of producing such chemicals.

Currently, the study of microbial natural products is primarily limited to living bacteria. However, considering bacteria have existed on Earth for more than three billion years, there is a vast range of past natural products with therapeutic potential yet to be discovered. This study has reached a significant milestone in uncovering the genetic and chemical diversity of our microbial past, according to co-senior author Christina Warinner. Warinner is an Associate Professor of Anthropology at Harvard University, a Group Leader at the Max Planck Institute for Evolutionary Anthropology (MPI-EVA), and an Affiliate Group Leader at the Leibniz Institute of Natural Product Research and Infection Biology (Leibniz-HKI).

Co-senior author Pierre Stallforth, who is a Professor of Bioorganic Chemistry and Paleobiotechnology at Friedrich Schiller University Jena and the Head of the Department of Paleobiotechnology at the Leibniz-HKI, adds that the study aims to pave the way for the discovery of ancient natural products and inform their potential future applications.

Dental calculus (tooth tartar) preserves DNA over millennia, providing unprecedented information about the biodiversity and functional capabilities of ancient microbes. Credit: Werner Siemens Foundation, Felix Wey

A billion-piece jigsaw puzzle

Scientists have faced a challenge in identifying ancient DNA fragments that cannot be matched to anything known today. This is because the DNA degrades and breaks into small pieces after an organism’s death. However, recent advances in computing have made it possible to piece together these fragments like a puzzle, reconstructing unknown genes and genomes. However, this approach has not worked well for highly degraded and extremely short ancient DNA from the Pleistocene. To overcome this, researchers had to rethink their approach and after three years of testing and optimization, they achieved a breakthrough. They were able to reconstruct stretches of DNA over 100,000 base pairs in length and recover various ancient genes and genomes, enabling them to reconstruct bacterial genomes from the Ice Age using billions of unknown ancient DNA fragments.

Entrance to the El Mirón cave, Spain, where 18,800-year-old “Red Lady” human remains were found. Credit: L.G. Straus

Exploring the microbial Paleolithic

To uncover the genetic secrets of ancient microbes, the researchers focused their attention on dental calculus, also known as tooth tartar, from 12 Neanderthals dating to 102,000-40,000 years ago, 34 archaeological humans dating to about 30,000-150 years ago, and 18 present-day humans. Tooth tartar is unique because it fossilizes during an individual’s lifetime and preserves living dental plaque as a mineralized graveyard of bacteria.

Using their innovative approach, the team reconstructed various oral bacterial species, as well as unfamiliar species with genomes that had never been described before. One such species was an unknown member of Chlorobium, whose highly damaged DNA showed the hallmarks of advanced age, and was found in the dental calculus of seven Paleolithic humans and Neanderthals. All seven Chlorobium genomes had a biosynthetic gene cluster of unknown function.

According to Anan Ibrahim, co-lead author of the study and postdoctoral researcher at the Leibniz-HKI, the Chlorobium genome from the dental calculus of the Red Lady of El Mirón in Spain, which is 19,000 years old, was particularly well-preserved. The team plans to investigate the functions of these mysterious ancient genes by bringing them into the lab.

The evaluation and reconstruction of degraded DNA is a huge bioinformatics challenge. Credit: Anna Schroll/Leibniz-HKI

Ice Age chemistry

Using synthetic molecular biotechnology, the team enabled living bacteria to synthesize chemicals from the ancient genes, which resulted in the discovery of a novel family of microbial natural products called “paleofurans.” This marks the first successful application of this approach to ancient bacteria and opens the door to uncovering the previously unknown chemical diversity of ancient microbes. “It’s an exciting breakthrough that adds a new time dimension to the exploration of natural products,” says Martin Klapper, co-lead author of the study and postdoctoral researcher at the Leibniz-HKI.

A novel collaboration to found a new field

The study’s achievement is a result of a collaborative effort among archaeologists, bioinformaticians, molecular biologists, and chemists, who worked together to overcome technical and disciplinary obstacles and push scientific boundaries.

“Our goal was to create connections between the humanities and natural sciences,” says Pierre Stallforth. “Through our collaborative work, we were able to develop the tools required to produce molecules that were made over 100,000 years ago,” adds Christina Warinner. Going forward, the team plans to utilize this method to discover novel antibiotics.

Leave a Comment