Researchers have generated E. coli with a fully synthetic genome in which three codons have been replaced with their synonyms, reports a paper published yesterday (May 15) in Nature. The genome-recoded bacteria are a bit bigger and are slower growing than their wild-type counterparts. But, they are alive.

“It was completely unclear whether it was possible to make a genome this large and whether it was possible to change it so much,” Jason Chin, a molecular biologist at the UK’s Medical Research Council Laboratory of Molecular Biology and the scientist who led the project, tells The Guardian

A synthetic genome is one that scientists have created chemically, then inserted into cells. In 2010, Craig Venter and colleagues created the first organism with a fully synthetic genome by piecing together synthesized pieces of the bacterium Mycoplasma mycoides’s 1 million–base-pair-long genome. 

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A recoded genome is one in which one or more codons—the three-letter DNA or RNA sequence that tell the cell to add a particular amino acid to a nascent protein, or to stop translation altogether—have been replaced with synonyms or assigned to code for alternative molecules, such as amino acids that cells do not naturally use. In 2013, the lab of Harvard’s George Church recoded the E. coli genome by using gene editing to replace a stop codon with a synonym, STAT reports. Then in 2016, Church’s lab replaced seven codons in parts of the E. coli genome, this time by assembling pieces of synthetic DNA.

In the new study, Chin and his colleagues synthesized the 4 million base pairs of the E. coli genome, making more than 18,000 codon changes as they did so. Specifically, the team replaced two of the codons that encode the amino acid serine with a synonym and did the same for a stop codon, freeing up three codons for future alternative uses. 

“They have taken the field of synthetic genomics to a new level, not only successfully building the largest ever synthetic genome to date, but also making the most coding changes to a genome so far,” Imperial College London’s Tom Ellis, a synthetic biology researcher who was not involved in the study, tells The Guardian.

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