We started our research program with a closer look at the potential prebiotic origin of the canonical and non-canonical nucleosides. The first idea was to decipher a prebiotically plausible chemical pathway from very primitive molecules that were likely present on the early earth, to complex nucleosides and modified nucleosides including amino acid modified nucleosides. This involved the development of completely new early earth compatible synthetic pathways to nucleosides. These needed to be water-compatible (what classical synthetic routes to nucleosides are not!) and which are able to proceed without human intervention. We then continued to analyse the function of the non-canonical nucleosides that we find embedded in DNA and RNA in modern time. This forced us to develop new chemical synthesis pathways to the non-canonical nucleosides to give phosphoramidite derivatives that were needed to incorporate the non-canonical nucleosides into synthetic DNA and RNA strands. With these strands in hand, we started to investigate how these modified bases influence the physical properties of RNA. We wanted to learn whether these modified bases are able to form stable base pairs or if they induce alternative oligonucleotide structures, which are important for their function. With chemical synthesis of RNA containing modified bases available, we already started to perform biological studies in order to elucidate the function of these non-canonical bases during transcription and translation.
We indeed achieved development of a new prebiotic route to pyrimidine and purine nucleosides, based on simple molecules like formic acid, urea, hydroxylurea, sodium nitrite and isocyanate (Science 2016/2019). This allowed us to generate purine and pyrimidine bases under prebiotically plausible conditions. We could show that this chemistry generates not only the canonical uridine bases A, G, C and U but also a large number of modified nucleobases (Nat.Commun. 2018), which are those that are indeed found today in contemporary RNA. We could therefore formulate the theory that the modified RNA bases that are today found in human RNA are indeed likely relics of an early earth chemistry and that they must have been present as competitor and companion molecules of the canonical bases. The corresponding publication in Science 2019 has received tremendous attention in the international press. The article was highlighted not only in a large number of scientific journals but also in the daily news.
Our next milestone achievement was based on our ability to incorporate highly modified nucleosides into polymers, on which we developed a prebiotically plausible scenario of an RNA-peptide world and the transmission of chirality. Those high impact publications have earned us the participation in a television documentary ("Life from Outer Space", ARTE) , highlighting important aspects of our work. We were also invited to organize the Leopoldina conference on the "Origin of Life". A further highlight of our research was the synthesis of the highly modified non-canonical nucleosides glutamyl-, galactosyl- and mannosyl queuosine, which are hyper-modified nucleobases present in the anticodon loop of tRNA. Here we could show by total synthesis and direct comparison of the synthetic material with material isolated from various organs that the chemical structure of mannosyl queuosine reported in the literature was wrong. Our expertise in nucleic acids synthesis and analysis allowed us to successfully enter the world of immunology, to which we contributed novel STING agonists based on the second messenger cGAMP and the elucidation of the role of RNase T2 in innate immunity.
