In Breakthrough, Scientists Resurrect Prehistoric Molecules in Search of Modern Medicine

In a major breakthrough, scientists have resurrected natural molecules that existed as early as 100,000 years ago by stitching together DNA from prehistoric microbes, reports a new study. 

Researchers taught living microbes to interpret genetic information from their ancient relatives, allowing them to synthesize compounds dubbed “paleofurans” that last existed in the Pleistocene era, when mammoths, saber-toothed cats, and Neanderthals still roamed our planet. 

The first-of-its-kind discovery offers an entirely new view of the past and could lead to the development of novel biomedical products, such as antibiotics, derived from organisms that may be extinct or otherwise unknown to modern science.

A multidisciplinary team of scientists co-led by Pierre Stallforth, a bioorganic chemist at Friedrich Schiller University Jena and head of paleobiotechnology at the Leibniz-HKI, meticulously pieced together the genetic fragments of microbes that lived in the dental plaque of ancient humans and our close relatives Neanderthals, a group that went extinct 40,000 years ago.

The results “chart a path for the discovery of ancient natural products to gain evolutionary insights on their formation and origins, as well as inform their potential future applications,” according to a study published on Thursday in Science.

“We knew it would be really cool to see if we can extract information from ancient DNA and translate it into a tangible and natural product,” Stallforth told Motherboard in a call. “We knew it'd be really challenging, but if you could do it, it would be a major advancement in how we can go back in the past and revive ancient functions that existed 100,000 years ago.”

Scientists have sequenced DNA from animals and ecosystems that are well over a million years old, but recovering genetic material from ancient microbes poses unique problems. Prehistoric microbes have left behind genetic odds and ends that are all mixed together with hundreds of species, making it difficult to untangle all the pieces and reassemble them in any clear order.

“Quite often, when you look at ancient DNA—the genetic information of the past—it's highly fragmented,” Stallforth explained “In order to get information out of it, we need to piece those fragments back together and that was a major hurdle. The older it is, the more difficult it gets. For instance, the samples that we work with are not a single bacterium, but a huge number of different bacteria.” 

“You try to piece it together, and to figure out which piece belongs to which organism, so it's almost like a multidimensional jigsaw to try and try and solve that,” he added.

Despite these head-spinning obstacles, the team was inspired to keep trying to decipher ancient genetic information using advances in computational biotechnology and genome reconstruction.

The researchers extracted microbial DNA from the teeth of 12 Neanderthals that lived between 40,000 and 102,000 years ago, as well as 34 humans that lived between 150 and 30,000 years ago. They also sequenced microbial DNA found in the dental plaque of 18 present-day people, which helped them to figure out the missing links in the genetic codes of their ancient counterparts. 

With this approach, Stallforth and his colleagues were able to successfully rebuild the genomes of ancient microbes, including the Chlorobium family of bacteria, which was particularly well-preserved on the teeth of a woman who lived 19,000 years ago in Spain who is known as Red Lady of El Mirón. 

The researchers then introduced the prehistoric DNA to living microbes, which were able to produce the same natural molecules and products as their ancient counterparts. Scientists have used modern microbes to synthesize a whole range of useful products, but the new research has now pushed the timeline on this technique back by tens of thousands of years, thereby “effectively adding a time dimension to natural product discovery,” according to the study.

“We may find some compounds that might be useful,” Stallforth said. “More than 70 percent of all commercially used antibiotics are microbial-produced natural products and are derived from those compounds.”

“It would be great to see if we can maybe tap into a new source of structurally diverse compounds that we could maybe use in biomedical applications,” he continued. “It would be a dream if we could show that they're actually useful for certain applications.”

While much more research will be needed to explore these potential applications, the new study could help shed light on a multitude of unanswered questions. For instance, scientists could use this technique to probe the diversity of microbes over long periods of time, and to assess their relationships to their hosts, including humans.

Future work “could tell us stories about [whether] a human being was suffering from certain diseases or maybe bacteria produced something that was beneficial to human beings, or to other bacteria,” Stallforth said. “Maybe it allows us to infer something about the specific habits of a human being at that time.”

“I think it's really a window into the past, from a different angle,” he concluded. “Archeology tries to reconstruct something based on ancient remains, and I think here we just add a new layer to that.”