Could 'reviving' 100,000-year-old bacteria be key to future antibiotics? Biotech says yes

They reconstructed the genomes of unknown bacteria from the time of the woolly mammoths, i.e., the Pleistocene Epoch (2.6 million to 11,700 years ago). And that's not all. They also introduced these genes into modern bacteria and produced 'novel' ancient natural products.

To gain a fuller picture of the significance of this latest work, Interesting Engineering (IE) connected with co-senior author Prof. Pierre Stallforth.

Microbes: Earth's ultimate chemists for antibiotics

"Microbial natural products are chemical compounds, which for instance, bacteria produce to fight different threats. We make use of some of these compounds, for example, as antibiotics," explained Stallforth.

"As a matter of fact, most commercially available antibiotics are natural products or derivatives thereof," he added. 

In other words, microbes are the ultimate chemists of nature, and they are responsible for many of the antibiotics and therapeutic drugs used worldwide. However, making these complex natural products is not easy, and bacteria need to be equipped with special genes to do so. 

While researchers have primarily focused on studying living bacteria, these organisms have been on Earth for over 3 billion years, which means there's a vast array of untapped natural products with healing properties waiting to be discovered – so what has been holding scientists back?

To understand this, first, it may be best to explain that when an organism dies, its DNA breaks apart into many small pieces that are difficult to identify. Even though some of these fragments can be matched to existing databases, most ancient DNA cannot be matched to anything currently known. 

Finally, scientists solve a billion-piece jigsaw puzzle

This has been a long-standing challenge for scientists. However, recent technological advancements allow researchers to piece together these DNA fragments, like solving a puzzle, to reconstruct unknown genes and genomes. 

The catch is that this process has not worked well with highly degraded and very short pieces of ancient DNA from the Pleistocene Epoch. Nonetheless, after three years of testing and optimizing, Stallforth's team has achieved a breakthrough in reconstructing DNA that is more than 100,000 base pairs long, as well as recovering a wide range of ancient genes and genomes. 

In a previous statement, co-author Alexander Hübner explained that scientists can now take billions of unidentified fragments of ancient DNA and organize them systematically to reconstruct bacterial genomes lost during the Ice Age.

"In these genomes, we identified genes which are needed for generating natural products," Stallforth told IE. 

A 19,000-year-old female yielded previously unknown species

The team's main focus was to reconstruct bacterial genomes trapped within dental calculus – also known as tooth tartar – from various time periods. Specifically, they analyzed dental calculus from 12 Neanderthals who lived between 102,000 and 40,000 years ago, 34 humans between 30,000 and 150 years ago, and 18 present-day humans.

Tooth tartar is the only part of the body that typically fossilizes while a person is still alive, preserving mineralized bacteria from dental plaque. Through their research, the team was able to reconstruct various bacterial species, including some that had never been previously described.

One of the species they discovered was a previously unknown member of Chlorobium, whose DNA was highly damaged and showed signs of being extremely old. This Chlorobium was found in the dental calculus of seven Paleolithic humans and Neanderthals. The team found that all seven Chlorobium genomes contained a gene cluster that had an unknown function.

"The dental calculus of the 19,000-year-old Red Lady of El Mirón, Spain yielded a particularly well-preserved Chlorobium genome," said co-author Prof. Anan Ibrahim in a previous statement. "Having discovered these enigmatic ancient genes, we wanted to take them to the lab to find out what they make."

For the first time, synthetic biotech is successfully applied to ancient bacteria 

The team used synthetic molecular biotechnology tools to enable modern bacteria to synthesize chemicals based on the instructions from ancient genes. "We used a combination of genome sequencing, genome assembly, and other bioinformatics tools to reconstruct the genomes," Stallforth explained to IE.

For the first time, the researchers effectively utilized this method on ancient bacteria, leading to the identification of a novel group of natural microbial products called "paleofurans."

The researchers highlighted that this is a significant breakthrough in exploring the untapped chemical variety of ancient microorganisms, which introduces an exciting time aspect to discovering natural products.

"It allows us to access the chemical structures that existed thousands of years ago. This will give us information on how bacteria interacted with each other or the human host," Stallforth said to IE. 

"In addition, we may find new compounds with interesting biological properties," he added. 

He also highlighted the limitations of the team's research, including the work needed to access more ancient compounds. "We would like to streamline our approach to increase the number of natural products we can discover. Hopefully, some of them will have antibacterial activities," he explained. 

Co-senior author Christina Warinner, from Harvard University, described this in a press release as charting "a path for the discovery of ancient natural products and to inform their potential future applications."

The study's achievement resulted from a bold partnership between archaeologists, bioinformaticians, molecular biologists, and chemists who worked together to overcome technological and disciplinary obstacles and make pioneering scientific progress.

"By working collaboratively, we were able to develop the technologies needed to recreate molecules produced a hundred thousand years ago," she added. Looking toward the future, the team hopes to use the technique to find new antibiotics.

While the idea of using ancient bacteria to develop new drugs is still in its early stages, the potential is encouraging, as demonstrated by the recent achievement of this study. Beyond antibiotics, who knows what other secrets these long-dormant organisms are hiding, just waiting to be unlocked by curious scientists?