Discovery, implications and initial use of semi-synthetic organisms with an expanded genetic alphabet/code

Area of Science:

• Chemical Biology
• Synthetic Biology
• Protein Engineering

Background:

• Natural proteins, composed of canonical amino acids, have limited functionalities, hindering the development of novel therapeutic agents.
• Recombinant protein expression incorporating non-canonical amino acids (ncAAs) offers a pathway to expand protein functions and discover new therapeutic properties.

Purpose of the Study:

• To review the development of synthetic nucleotides capable of forming unnatural base pairs for genetic code expansion.
• To highlight the application of these advancements in creating semi-synthetic organisms (SSOs) for next-generation protein therapeutics.

Main Methods:

• Summarizing over two decades of research focused on expanding the genetic alphabet with synthetic nucleotides.
• Describing the stable incorporation, transcription, and translation of unnatural base pairs in *Escherichia coli*.
• Discussing the conceptual implications and practical applications of engineered genetic systems.

Main Results:

• Discovery of synthetic nucleotides that form stable unnatural base pairs, enabling genetic code expansion.
• Successful incorporation and utilization of these unnatural base pairs for protein translation in *Escherichia coli*.
• Development of semi-synthetic organisms (SSOs) for advanced protein production.

Conclusions:

• Expansion of the genetic code through unnatural base pairs significantly broadens the scope of protein engineering.
• Semi-synthetic organisms represent a powerful platform for producing next-generation protein therapeutics with tailored functionalities.
• Ongoing efforts at Sanofi leverage these advancements for the development of innovative medical treatments.