Life is made of the intimate interaction of metabolism and genetics, both built around the chemistry of the most common elements of the Universe (hydrogen, oxygen, nitrogen, and carbon). The transmissible interaction of metabolic and genetic cycles results in the hypercycles of organization and de-organization of chemical information, of living and non-living. The origin-of-life quest has long been split into several attitudes exemplified by the aphorisms “genetics-first” or “metabolism-first”. Recently, the opposition between these approaches has been solved by more unitary theoretical and experimental frames taking into account energetic, evolutionary, proto-metabolic and environmental aspects. Nevertheless, a unitary and simple chemical frame is still needed that could afford both the precursors of the synthetic pathways eventually leading to RNA and to the key components of the central metabolic cycles, possibly connected with the synthesis of fatty acids. In order to approach the problem of the origin of life it is therefore reasonable to start from the assumption that both metabolism and genetics had a common origin, shared a common chemical frame, and were embedded under physical–chemical conditions favourable for the onset of both. The singleness of such a prebiotically productive chemical process would partake of Darwinian advantages over more complex fragmentary chemical systems. The prebiotic chemistry of formamide affords in a single and simple physical–chemical frame nucleic bases, acyclonucleosides, nucleotides, biogenic carboxylic acids, sugars, amino sugars, amino acids and condensing agents. Thus, we suggest the possibility that formamide could have jointly provided the main components for the onset of both (pre)genetic and (pre)metabolic processes. As a note of caution, we discuss the fact that these observations only indicate possible solutions at the level of organic substrates, not at the systemic chemical level.

The simplest molecules grouping the four most common elements of the universe H,C,O and N (with the exception of the biologically inert He) are isocyanate HNCO and formamide H₂NCOH. Reasons for the availability of formamide on prebiotic Earth are presented. We review evidence showing that formamide in the presence of largely available catalysts and by moderate heating yields the complete set of nucleic bases necessary for the formation of nucleic acids. Formamide also favours the formation of acyclonucleosides and the phosphorylation and trans-phosphorylation of nucleosides, thus providing a plausible chemical frame for the passage from a simple one-carbon compound to nucleic polymers. Physico-chemical conditions exist in which formamide favours the stability of the phosphoester bonds in nucleic polymers relative to that of the same bonds in monomers. Starting from a formamide-laden environment subject only to the laws of chemistry, a hypothesis is outlined sketching the passage towards an aqueous world in which Darwinian rules apply.

Reactions of formamide (NH₂COH) in the presence of catalysts of both terrestrial and meteoritic origin yield, in plausible and variegated conditions, a large panel of precursors of (pre)genetic and (pre)metabolic interest. Formamide chemistry potentially satisfies all of the steps from the very initial precursors to RNA. Water chemistry enters the scene in RNA non-enzymatic synthesis and recombination.

3′,5′-Cyclic GMP spontaneously nonenzymatically polymerizes in a base-catalyzed reaction affording G oligonucleotides. When reacted with fully or partially sequence-complementary RNA (oligo C), the abiotically generated oligo G RNA displays a typical ribozyme activity consisting of terminal ligation accompanied by cleavage of an internal phosphate site of the donor oligonucleotide stem upon attack of the acceptor 3′ terminal OH. This reaction is dubbed Ligation following Intermolecular Cleavage (LIC). In a prebiotic perspective, the ability of oligo G polynucleotides to react with other sequences outlines a simple and possible evolutionary scenario based on the autocatalytic properties of RNA.

Molecular Darwinian evolution is an intrinsic property of reacting pools of molecules resulting in the adaptation of the system to changing conditions. It has no a priori aim. From the point of view of the origin of life, Darwinian selection behavior, when spontaneously emerging in the ensembles of molecules composing prebiotic pools, initiates subsequent evolution of increasingly complex and innovative chemical information. On the conservation side, it is a posteriori observed that numerous biological processes are based on prebiotically promptly made compounds, as proposed by the concept of Chemomimesis. Molecular Darwinian evolution and Chemomimesis are principles acting in balanced cooperation in the frame of Systems Chemistry. The one-pot synthesis of nucleosides in radical chemistry conditions is possibly a telling example of the operation of these principles. Other indications of similar cases of molecular evolution can be found among biogenic processes.