The Central Dogma revisited: Insights from protein synthesis, CRISPR, and beyond

Abstract Francis Crick advanced two distinct but interrelated fundamental principles of molecular biology: (1) the Sequence Hypothesis and (2) the Central Dogma. The Sequence Hypothesis defines biological information transfer as the residue‐by‐residue transfer of sequence information between nucleic acids and to proteins. This is commonly summarized as DNA ➔ RNA ➔ protein and is colloquially referred to as the Central Dogma. More specifically, however, the Central Dogma expounded by Crick included a critical restriction, stipulating that “once sequential information has passed into protein it cannot get out again.” Under this definition, the Central Dogma has stood the test of time despite challenges. In principle, a violation of the Central Dogma could transpire through synthetic biology or by natural occurrence. To address these possibilities, we draw insights from existing modes of information transfer in protein synthesis and from synthetic C lustered R egularly‐ I nterspaced S hort P alindromic R epeats (CRISPR) gene‐editing. We introduce a three‐part evaluation scheme, which we apply to the CRISPR/Cas9 system and the more recent CRISPR prime editing system. Potential mechanisms by which engineered sequence editing systems might violate the Central Dogma are considered. We conclude that although information transfer in protein synthesis and CRISPR gene‐editing remain within the bounds of the Central Dogma, the underlying mechanisms point toward an avenue of synthetic biology that could directly violate the Central Dogma. Finally, we speculate on some of the theoretical and practical implications of a protein‐derived information transfer system. This article is categorized under: RNA Evolution and Genomics > Ribonomics RNA Interactions with Proteins and Other Molecules > Protein‐RNA Interactions: Functional Implications Translation > Mechanisms