Expanded genetic alphabets for orthogonal encoding of genetic information

Objective

In OrthoScript, we aim to build a technology platform for the efficient synthesis, replication and evolution of DNA and RNA comprising alternative genetic alphabets that are either orthogonal to the natural alphabet or expand its combinatorial potential and information density. Our approach involves the leveraging of protein design and evolution approaches to generate bespoke DNA and RNA polymerase enzymes for the encoded synthesis and sequencing of expanded genetic alphabets with high efficiency and fidelity. If successful our approach unlocks the potential of these new alphabets for information storage and enables a systematic investigation of the relationship between complexity (informational density), evolvability and phenotypic diversity in informational biopolymers. The same polymerases are critical for the scalable integration of an expanded alphabet into an orthogonal replisome in a living cell. If realised, we provide a technology platform for the encoding of information in expanded, orthogonal genetic alphabets both in vitro and in bacteria with transformative potential in applications like molecular information storage and genetic code expansion.