Sense codon reassignment enables viral resistance and encoded polymer synthesis

Biological systems read all 64 triplet codons in DNA to encode the synthesis of proteins composed of 20 canonical amino acids. Robertson et al. created cells that do not read several codons and showed that this confers complete resistance to viruses, which normally rely on the host cell's ability to read all the codons in the viral genome to reproduce (see the Perspective by Jewel and Chatterjee). The authors reassigned each codon to several noncanonical amino acids (ncAAs). This advance enables the efficient synthesis of proteins containing three distinct ncAAs and the encoded synthesis of entirely noncanonical polymers and macrocycles. Science , abg3029, this issue p. 1057 ; see also abi9892, p. 1040 The genetic code of a synthetic Escherichia coli strain is reprogrammed to enable the encoded, programmable synthesis of noncanonical polymers. It is widely hypothesized that removing cellular transfer RNAs (tRNAs)—making their cognate codons unreadable—might create a genetic firewall to viral infection and enable sense codon reassignment. However, it has been impossible to test these hypotheses. In this work, following synonymous codon compression and laboratory evolution in Escherichia coli , we deleted the tRNAs and release factor 1, which normally decode two sense codons and a stop codon; the resulting cells could not read the canonical genetic code and were completely resistant to a cocktail of viruses. We reassigned these codons to enable the efficient synthesis of proteins containing three distinct noncanonical amino acids. Notably, we demonstrate the facile reprogramming of our cells for the encoded translation of diverse noncanonical heteropolymers and macrocycles.