Rewriting bacteria’s genetic code

By re-engineering the cellular machinery used to translate DNA into proteins, researchers have engineered bacteria to resist viruses and to make synthetic polymers.

The language of protein translation contains synonyms. Each three-nucleotide sequence on a strand of messenger RNA is called a codon and corresponds to the instruction to add a particular amino acid to a protein chain or to end it. With four nucleotide options, there are 64 possible codons but only 20 typical amino acids, meaning multiple synonymous codons can encode the same amino acid. Jason W. Chin and coworkers at the MRC Laboratory of Molecular Biology and the University of Cambridge took advantage of this fact. They previously engineered an Escherichia coli strain from which they removed three codons—two of the six that encode serine and one of the three that stop translation—and replaced them at every site with their synonyms (Nature 2019, DOI: 10.1038/s41586-019-1192-5). Now they have further engineered that strain and deleted the genes for the corresponding transfer RNA molecules (Science 2021, DOI: 10.1126/science.abg3029). The bacteria still made the full set of natural proteins and therefore grew normally.

Viruses infect cells by co-opting the cells’ machinery to reproduce. Without the full set of tRNAs, the bacteria could not properly read viral genomes and thus became resistant to viral infections.“This is an important discovery” because over 10% of industrial biotechnology processes are compromised by contamination, often by viruses, says Michael C. Jewett, a bioengineer at Northwestern University, causing expensive losses.

In another set of experiments, Chin and his coworkers incorporated engineered tRNAs into the engineered E. coli that reassigned the removed codons to other monomers. The researchers then introduced a DNA sequence that used the deleted codons to direct the bacteria to synthesize genetically encoded linear polyamides and macrocycles four to six units long (example shown) using these monomers.

“This is the first example of cells being able to make completely synthetic polymers and macrocycles that are genetically encoded,” Chin says. “But the polymers and macrocycles are still linked by amide bonds. The next goal will be to combine these advances with advances in ribosome engineering to allow us to expand the chemical scope of polymerization beyond α-l-amino acids.”