The high potential of archaea

 “Archeas have long been under-studied. But the possibilities recently offered by sequencing and the advent of metagenomics (1) are rekindling the scientific community's interest in them”, says Hannu Myllykallio. This biologist, a researcher at the Optics and Biosciences Laboratory (LOB*), has been studying thermophilic and halophilic archaea, which tolerate high temperatures and high salt concentrations, for over 20 years. In summer 2024, he organized an international workshop (EMBO - European Molecular Biology Organisation) at École Polytechnique on the molecular biology of archaea.

New antibiotic leads 

In his lab, the researcher focuses on studying their genome. He found that a crucial reaction in the synthesis of one of DNA's nitrogenous bases was missing. “The conversion of uracil to thymine is not carried out by the same family of enzymes (thymidylate synthase) as in humans. The reaction mechanisms of this new thymidylate synthase are different”, stresses the researcher. The unexpected result was impactful enough to be published in the journal Science (2). At the same time, the biologist noticed that the pathogenic bacteria he was working on - Mycobacterium tuberculosis (responsible for tuberculosis) and Helicobacter pylori (responsible for stomach ulcers) - displayed these same enzymes and used them for their multiplication. This opened the door to a new antibiotic. Hannu Myllykallio's team has isolated an inhibitor of this new group of enzymes and is currently working with the Ecole Polytechnique Computer Science Laboratory (LIX*) on its modeling and optimization. 

Other work carried out in conjunction with a Japanese team has provided new insights into DNA repair mechanisms in archaea. When the molecule is duplicated, some of its nitrogenous bases, which have nothing to do with each other, pair up. This is the case with guanine and thymine. Enzymes not expected here correct this error. These enzymes are present in Mycobacterium tuberculosis and serve to repair its DNA. This was all it took to whet the curiosity of LOB researchers, particularly Rima Zein-Eddine, a post-doctoral student working alongside Hannu Myllykallio. The scientist analyzed over 60,000 genetic sequences of Mycobacterium tuberculosis and detected over a hundred mutations in these enzymes, potentially implicated in the bacterium's resistance to current antibiotics.

Molecular scale...and beyond

More than ever, archaea are a potential source of discovery in many fields. For example, these micro-organisms feature cell division mechanisms belonging to both prokaryotes and eukaryotes. This specificity has rekindled the interest of researchers in their quest for an ancestor common to all living cells. Scientists at Ecole Polytechnique's Structural Biology of the Cell Laboratory (BIOC*) have identified new DNA translation pathways in archaea, while virologists at Institut Pasteur have identified a wide range of viruses directed against them, in a variety of shapes and structures.

Looking beyond the cellular environment, the EMBO workshop highlighted the major role played by archaea in methanogenesis. “These microorganisms are certainly among the most important methane producers on Earth. Some scientists have even sought to direct a vaccine against them in order to reduce methane production by cattle”, says Hannu Myllykallio. Decidedly surprising, so-called autotrophic archaea find in the atmosphere's CO2 the carbon they need to produce their carbohydrates and other organic compounds. All these discoveries are more important given that archaea colonize most environments (land, water, microbiota, etc.) and not just extreme ones (hot springs, seabed black smokers, etc.). Their ecological impact is therefore not negligible.

Finally, archaea are of interest in the field of biotechnology. “Many of the enzymes marketed for in vitro DNA amplification (PCR kits and synthetic biology) are derived from these cells”, emphasizes Hannu Myllykallio. The pharmaceutical industry is also looking into the possibility of modifying their genome to produce medicinal molecules, while other teams are trying to get them to produce ethane, which has much less impact in terms of global warming than the methane or nitrous oxide (N2O) they emit naturally.

(1) Metagenomics combines sequencing and Big Data to analyze all or part of the genomes present in a sample without the need for laboratory culture.

(2) An alternative flavin-dependent mechanism for thymidylate synthesis, Hannu Myllykallio et al.2002, Science DOI : 10.1126/science.1072113

*LOB: a joint research unit CNRS, Inserm, École Polytechnique - Institut Polytechnique de Paris, 91120 Palaiseau, France

BIOC: a joint research unit CNRS, École Polytechnique - Institut Polytechnique de Paris, 91120 Palaiseau, France

LIX: a joint research unit CNRS, École Polytechnique - Institut Polytechnique de Paris, 91120 Palaiseau, France