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Glowing E. coli bacteria
Bacteria express a green fluorescent protein that’s produced from DNA instructions with unnatural chemical “letters” added. (Scripps Research Institute Photo / Bill Klosses)

Researchers have reached a new milestone in their effort to expand the genetic alphabet of life by designing a strain of E. coli bacteria that creates proteins unlike anything cells can produce naturally.

The technique, detailed in a paper published today in the journal Nature, could lead to the production of totally new types of protein-based medicines, plastics and biofuels.

It could also stretch the definition of natural vs. artificial life.

“I would not call this a new lifeform — but it’s the closest thing anyone has ever made,” study leader Floyd Romesberg, a biochemist at the Scripps Research Institute, said in a news release. “This is the first time ever a cell has translated a protein using something other than G, C, A or T.”

Those four letters stand for guanine, cytosine, adenine and thymine, chemicals that serve as the alphabet for the coded instructions in DNA molecules. The instructions are used to produce all the amino acids and proteins that cells require for life’s processes.

Three years ago, Romesberg and his colleagues successfully inserted two other chemicals, dubbed X and Y, into DNA molecules. Since then, the researchers have developed ways for bacteria to store the augmented DNA and pass it along as they reproduced.

In their newly published paper, the team reports that the six-letter DNA coding could be transcribed into RNA molecules, and then translated into amino acids and proteins that don’t occur naturally.

The technique was used to customize a set of genetic instructions for manufacturing a variant of green fluorescent protein, or GFP, that incorporated unnatural amino acids. When E. coli bacteria were genetically engineered to include those instructions, the organisms produced the protein, which glowed bright green under ultraviolet light. That signaled that the bacteria could make use of the “alien” DNA.

“This was the smallest possible change we could make to the way life works — but it is the first ever,” Romesberg said.

The study also demonstrated that life’s molecular machinery could make use of linkages other than the hydrogen bonds that bind G, C, A and T. The X and Y bases were designed to avoid hydrogen bonds, to make sure they didn’t get mixed up with the other molecular letters.

That has implications in the search for “weird life” beyond the earthly variety we all know and love.

“It’s very hard to ask questions about the origins of life. It’s hard to ask questions about why we are the way we are, why we are built the way we are, because we have nothing out there to compare ourselves to,” Romesberg said. “We’ve now given the field a comparison. It’s a small step, but it’s the first successful step.”

He and his colleagues emphasized that the semi-synthetic organisms couldn’t live or reproduce outside the lab, because the chemicals required for producing the X and Y bases had to be provided externally.

Romesberg is among the founders of a biotech venture called Synthorx, which is developing protein therapeutics that make use of X and Y.

In addition to Romesberg, the authors of the Nature paper, titled “A Semi-Synthetic Organism That Stores and Retrieves Increased Genetic Information,” include Yorke Zhang, Jerod Ptacin, Emil Fischer, Hans Aerni, Carolina Caffaro, Kristine San Jose, Aaron Feldman and Court Turner.

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