Sense Codon Reassignment Enables Virus-Resistant Production Strains and Encoded Non-Natural Polymer Synthesis

Published in Science in 2021, this paper demonstrated two major consequences of Syn61's recoded genome: inherent resistance to viral infection, and the ability to genetically encode new classes of polymers using reassigned sense codons.

The viral resistance result is a direct consequence of genome recoding. Bacteriophages, the viruses that infect bacteria, rely on the host cell's translation machinery to produce their own proteins. When a phage injects its DNA into a Syn61-derived cell, the phage genome still contains the codons that have been removed from the host. With no tRNAs left to decode these codons, the cell is unable to translate phage proteins. The virus is effectively locked out at the translational level, providing a genetically encoded defence that requires no antibiotics, clean-room containment, or process intervention.

For biomanufacturing, this phage resistance has a practical benefit: production strains based on Syn61 are intrinsically protected against the bacteriophage contamination events that can destroy conventional E. coli fermentation batches, reducing bioprocessing risk.

The second advance was demonstrating that freed codons could be reassigned to direct the ribosomal incorporation of non-canonical monomers into sequence-defined polymers. The team showed that reassigned sense codons, paired with engineered aminoacyl-tRNA synthetase/tRNA systems, could direct the cell's ribosome to build polymers containing monomers that are not found in natural biology, opening the door to genetically encoded materials with new chemical properties.

This paper established the proof of principle that genome recoding simultaneously solves a practical manufacturing problem (phage contamination) and creates a new capability (programmable incorporation of non-natural building blocks). Both outcomes are central to Constructive Bio's BioForge platform and its therapeutic pipeline.