A transdisciplinary team of researchers reconstructed genomes of unknown bacteria dating from the Pleistocene.
With their genetic blueprints, they built a biotechnological platform to revive the natural products of ancient bacteria, as they publish in the journal Science.
Microbes are Nature’s best chemists, and among her creations are a large number of the antibiotics and other therapeutic drugs of the world. Producing these complicated natural chemicals is not easy, and to do this bacteria rely on specialized types of genes that code for enzymatic machinery capable of making such chemicals.
Currently, the scientific study of microbial natural products is largely limited to living bacteria, but since bacteria have inhabited the Earth for more than 3 billion years, there is an enormous diversity of natural products from the past with therapeutic potential which remain unknown to us up to now.
“With this study we have reached a important milestone in revealing the enormous genetic diversity and chemistry of our microbial past,” says Christina Warinner, co-senior author and Associate Professor of Anthropology at Harvard University, Group Leader at the Max Planck Institute for Evolutionary Anthropology (MPI-EVA) and affiliate Group Leader at the Leibniz Institute. Research Center for Natural Products and Biology of Infections (Leibniz-HKI).
“Our goal is to chart a path for the discovery of ancient natural products and inform about its possible future applications”, adds co-lead author Pierre Stallforth, Professor of Bioorganic Chemistry and Paleobiotechnology at the Friedrich Schiller University of Jena and director of the Department of Paleobiotechnology at Leibniz-HKI.
When an organism dies, its DNA quickly breaks down and breaks up into a multitude of tiny pieces. Scientists can identify some of these DNA fragments by checking them against databases, but for years microbial archaeologists have grappled with the fact that most ancient DNA cannot be matched to anything known nowadays.
This problem has been worrying scientists for a long time, but the latest computer advances now make it possible to recompose the DNA fragments to reconstruct unknown genes and genomes. The only problem is that it doesn’t work very well with ancient DNA from the Pleistocene, very degraded and extremely short.
“We had to completely rethink our approach,” recalls Alexander Hübner, a postdoctoral researcher at MPI-EVA and co-lead author of the study. Three years of testing and optimization later, Hübner says they have made a breakthrough, getting stretches of reconstructed DNA over 100,000 base pairs in length and the recovery of a wide range of genes and ancient genomes”.
“Now we can start from billions of unknown fragments of ancient DNA and systematically sort them into Ice Age bacterial genomes long lost,” he said in a statement.
The team focused on reconstructing the bacterial genomes encased in dental calculus, also known as dental tartar, from 12 Neanderthals from about 102,000-40 thousand years ago, 34 archaeological humans from about 30 thousand-150 years ago and 18 current humans. Dental tartar is the only part of the body that routinely fossilizes throughout life, turning living dental plaque into a graveyard of mineralized bacteria.
The researchers reconstructed numerous oral bacterial species, as well as other more exotic species whose genomes had not been described before. Among them was an unknown member of chlorobiumwhose badly damaged DNA showed the hallmarks of advanced age, and which was found in the dental calculus of seven Paleolithic and Neanderthal humans.
The seven Chlorobium genomes contained a group of biosynthetic genes of unknown function. “The dental calculus of the 19,000-year-old Red Lady from El Mirón (Spain) provided an especially well-conserved Chlorobium genome,” explains Anan Ibrahim, postdoctoral researcher at Leibniz-HKI and co-lead author of the study. After discovering these enigmatic ancient genes, we wanted to take them to the laboratory to find out what they make.”
The team used the tools of synthetic molecular biotechnology to make living bacteria produced the chemicals encoded by the ancient genes. It was the first time this method had been successfully applied to ancient bacteria, and the result was the discovery of a new family of microbial natural products that the researchers named paleofuranes.
“This is the first step towards access to the hidden chemical diversity of microbes of the past and adds an exciting new time dimension to the discovery of natural products,” says Martin Klapper, Leibniz-HKI postdoctoral researcher and co-lead author of the study.
The success of the study is the direct result of an ambitious collaboration between archaeologists, bioinformaticians, molecular biologists and chemicals to overcome technological and disciplinary barriers and open new scientific paths.
“With funding from the Werner Siemens Foundation, we set out to build bridges between humanities and natural sciences“, says Pierre Stallforth. “Working collaboratively, we were able to develop the technologies needed to recreate molecules produced a hundred thousand years ago,” adds Christina Warinner. The team now hopes to use the technique to find new antibiotics.