Abstract EANA2025-179

The "RNA first" model postulates that organic molecular systems first gained access to Darwinism through a spontaneous prebiotic formation of evolvable RNA molecules. 

Unfortunately, decades of research have shown that it is extremely difficult (if not impossible) to reproduce RNA species that should be central to the "RNA first" hypothesis, such as RNA replicases. This suggests that we might be missing something. Thus, many laboratories have sought alternative biopolymers that are both prebiotically accessible, and that also support Darwinism better than standard nucleic acids, managing the rather low intrinsic catalytic ability of RNA and DNA as it is today found in Earth biology.

Further, when we investigate how life might have originated on our planet, or look for alien life on other planets, we must recognize the possibility that before, or instead of, adding a second biopolymer to the informational molecules (such as proteins on Earth for extant life), primeval life might instead have taken a different route.

On Earth, starting with what was likely a RNA-like polymer, life decided to expand the catalytic activity of the polymer itself. We can see evidence that this path was at least one of the options on Earth in many contemporary examples that are regarded as relics of an “RNA Word”. Of special interest are functionalized RNA molecules involved in translation and other metabolisms, which are modified post-transcriptionally with various side-chains. From these examples the question arise of what kind of “RNA-like” polymer was really the first that started molecular evolution, and what kind of building blocks was it composed of. Can we experimentally evaluate what the basic information requirements might have been (in prebiotic Earth) or should be (on other planets) for this polymer to achieve optimal and effective evolution through the most possible straightforward, resource-saving pathway? 

This work reports on experimental results with such nucleic acid-like biopolymers made from six different building blocks (Artificially Expanded Genetic Alphabet, or AEGIS). These additional nucleotides carry functionality that chemical theory suggests might assist in binding and catalysis, perhaps even catalysis for the synthesis of RNA. 

The presentation will briefly describe molecular biology for this artificial genetic system, including procedures that place the expanded, richer, genetic system under Darwinian selection pressure.

These procedures have led to several discoveries. For example, additional building blocks appear to allow the system to access specific binding conformations. Moreover, the added functionality, depending on the chemical group, allows the system to get tighter and more specific interactions between evolvable biopolymers and a target as it serves both genetic and phenotypic roles. Further, results from parallel in-vitro selections of standard and AEGIS libraries indicate that added functionality does indeed allow for more efficient and faster evolvability of shorter biopolymers. Finally, specific chemical groups, such as nitro-, aminoxy, or phenyl-substitutions on the alien nucleobases, provide catalytic and binding properties unseen in standard nucleic acids. 

These results show not only that expanded nucleic acid libraries are better reservoirs of functional molecules than extant four-letters libraries, but also that specific alternative chemical groups, perhaps lost later in time as nucleic acids specialized for their informational roles, might have been present and pivotal for some steps of prebiotic evolution.