Time to learn some new letters (Image: Synthorx)

They may look like any other microbe, but don’t be fooled. The bacteria growing in a Californian laboratory are the first organisms to have an expanded genetic code. Instead of four letters, their genetic alphabet has six, thanks to two artificial letters.

“We have created the first organism that stores increased genetic information,” says Floyd Romesberg of the Scripps Research Institute in La Jolla.

Life on Earth, from bacteria to humans, uses the same four “letters” or bases to build its DNA: A, T, C and G. But there are many alternative molecules. Romesberg previously built two artificial letters, d5SICS and dNaM, that work well with the natural enzymes that build DNA.


Now he has incorporated them into living E. coli bacteria. The cells naturally took them into their genome, making matching pairs that face each other on either side of the DNA double helix.

“It is astounding that it could work at all,” says Aaron Leconte of Claremont McKenna College in California, who helped to design the new genetic letters but was not involved in the current project.

Factory microbes

Surprisingly, other than adding a transporter protein that carried the new genetic letters into the bacteria, the team did not have to modify the cells at all. “We did nothing to the DNA replication machinery,” say Romesberg. That is unexpected because cells are good at correcting mistakes in their DNA. Somehow d5SICS and dNaM evaded these repair mechanisms – perhaps because they are so different from the natural versions that the machinery couldn’t do anything to them.

At first, the extra letters were slipped into the bacteria far from working genes, to avoid disrupting their function. But Romesberg is now trying to put the letters into those genes, to coax the cells into producing unnatural proteins.

Nature only provides 20 amino acids, the building blocks of proteins. Romesberg’s work makes it possible to incorporate an additional 152 artificial ones. That could lead to new materials like nanowires, which could help to make miniature versions of electrical components like batteries, and better drugs.

Ultimately, the idea is to build semi-synthetic cells that operate two separate genetic codes in parallel. The original genetic software would keep the cells alive, while a parallel synthetic or semi-synthetic genetic code would allow the cell to act as a micro-factory, producing useful materials.

Because they are alive, these microbial factories could harness the power of evolution to rapidly and automatically find the best material for a job. For instance, cells could produce thousands of variations on a successful antibiotic in a fraction of the time it would take traditional chemists.

Journal reference: Nature, DOI: 10.1038/nature13314