In a landmark feat of genetic engineering, researchers at the MRC Laboratory of Molecular Biology (LMB) in Cambridge have created a strain of Escherichia coli that functions with just 57 codons, down from the 64 used by virtually all known life.<\/p>\n
The synthetic bacterium, named Syn57, has the most radically compressed genetic code ever built, opening the door to future organisms that can create unnatural materials, virus-resistant biofactories, and advanced polymers.<\/p>\n
The genetic code is the universal system life uses to build proteins. <\/p>\n
It reads DNA and RNA in three-letter sequences called codons, which specify amino acids or signal when to stop making a protein.<\/p>\n
Rewiring the genetic playbook<\/p>\n
Life typically uses 64 codons to encode just 20 amino acids and three stop signals, meaning there\u2019s built-in redundancy.<\/p>\n
By removing some of these duplicated codons, scientists can reclaim space in the genome to reassign new biochemical functions.<\/p>\n
Jason Chin\u2019s team at LMB previously created Syn61, a fully synthetic E. coli strain using only 61 codons. <\/p>\n
That earlier version has already been reprogrammed to include non-canonical amino acids\u2014chemical building blocks not found in nature\u2014to create entirely novel polymers.<\/p>\n
Now, Syn57 takes the concept further, eliminating seven additional codons: four for serine, two for alanine, and one stop codon. <\/p>\n
In total, the team replaced over 101,000 codon instances across the bacterium\u2019s 4-megabase genome.<\/p>\n
To manage the scale of this rewrite, the genome was divided into 38 synthetic DNA fragments, each around 100,000 bases long.<\/p>\n
These fragments were built using homologous recombination and assembled using a tool called uREXER (Replicon Excision Enhanced Recombination), a technique that combines CRISPR-Cas9 and viral enzymes to swap out DNA precisely in a single step.<\/p>\n
Problematic genome regions that resisted recoding or stunted bacterial growth were identified during stepwise testing. <\/p>\n
The team addressed these issues by refactoring overlapping genes, tweaking codon choices, and optimizing the N-terminal coding sequences to improve gene expression.<\/p>\n
Synthetic cells, real impact<\/p>\n
The resulting fragments were merged using bacterial mating into a sequence of semi-synthetic strains, which were then convergently assembled into the final, fully synthetic Syn57 organism.<\/p>\n
Despite its radically altered code, Syn57 grows and functions. <\/p>\n
Freed-up codons can now be repurposed to introduce even more non-canonical amino acids, enabling the synthesis of custom synthetic polymers, macrocycles, and potentially new materials with programmable properties.<\/p>\n
Crucially, Syn57 may also be immune to many viruses<\/a>, which rely on the host\u2019s standard genetic code to replicate. That could make industrial drug-making<\/a> safer and cheaper by eliminating a major source of biomanufacturing disruption.<\/p>\n \u201cIt\u2019s a radically recoded genome,\u201d said lead researcher Wes Robertson. \u201cWith today\u2019s technology, this is likely the most compressed code life can use.\u201d<\/p>\n