Researchers make two genetic codes work in a cell-free system

A genetic code usually runs the whole protein-making shop. In George Church’s laboratory, researchers have now made two genetic codes operate in parallel—but only in a cell-free translation system, not inside a living cell. That distinction is the headline and the limit.

The obstacle is built into biology’s basic machinery. DNA is copied into messenger RNA, then a ribosome reads that message three bases at a time. Transfer RNAs, or tRNAs, match those three-base units and carry the corresponding amino acids; enzymes “charge” each tRNA with the right molecular building block. Changing the code means changing some combination of genes, tRNAs and charging enzymes, or rewriting the genome to compensate.

The team’s workaround targets a recognition step rather than the ribosome’s protein-making core. A small sequence on the ribosome normally pairs with a matching sequence on every tRNA. The researchers altered that sequence in one tRNA population and made the corresponding change in a separate ribosome population. The two engineered partners could then recognize each other while remaining distinct from the ordinary system.

In cell-free experiments, the altered tRNAs could generally still be charged with amino acids, although the efficiency depended on the exact sequence and was typically lower than for normal tRNAs. Ordinary ribosomes ignored them, while ribosomes carrying the matching alteration used them to make proteins. The work combined cell-free translation, robotics, next-generation sequencing and analytical chemistry.

So what, concretely? Synthetic-biology researchers could test alternative genetic codes without immediately having to re-engineer every gene in a bacterial genome. That could make experiments with artificial amino acids and redesigned protein systems less laborious. For now, the result remains a laboratory demonstration: no living cell has been tested, and the authors’ system might encounter problems there.