Biologists Create Cells With 6 DNA Letters, Instead of Just 4

Cells with an expanded genetic alphabet could potentially make a wider range of proteins. Image: Synthorx

One of the first things you learn in Biology 101 is that the genetic code consists of four letters: A, T, C, and G. Each represents a chemical building block of DNA, the molecule that encodes the information necessary to build life as we know it. But what if we didnt have to settle for just four letters? Now, scientists have accomplished something once thought impossible: Theyve created cells with an expanded genetic alphabet that includes two more letters.

We now have a cell that survives and lives with more information in its genome, said Floyd Romesberg, the synthetic biologist at the Scripps Research Institute in La Jolla, California who led the work.

Having more letters to work with potentially opens the door to a huge range of novel molecules. (A rough analogy: Just think how many crazy new words you could spell with 39 letters instead of the usual 26). With further refinements, synthetic cells might one day be used to createor evolveproteins that dont exist in nature, as well as new sequences of DNA and RNA, any of which could be useful for research, diagnosing disease, or creating new therapies. But thats still a ways off.

Romesberg says his lab spent 15 years developingDNA with two extra letters. In chemical terms, the letters are nucleotides, the components of DNA whose sequences spell out instructions for making proteins. Cells, you may remember, make proteins by transcribing DNA into RNA and using the RNA as a template to string together amino acids into proteins. Cells also have to copy their DNA each time they divide to make more cells. The biggest challenge, Romesberg says, was making sure the two new nucleotides played nice with the enzymes that do all this copying and transcribing.

In 2012, the scientists reported a breakthrough: They showed that six-letter DNA theyd created could be successfully copied and transcribed into RNA in test tube experiments.

In a new study, scientists put six-letter DNA into E. coli bacteria. Image: Database Center for Life Science (DBCLS)

But could six-letter DNA actually function in the far more complex and chaotic environment of a living cell?

The new study suggests it can. Romesberg and colleagues managed to coax E. coli bacteria into taking up their six-letter DNA and making copies of it. The cells enzymes copied the two new letters, which the scientists call X and Y for short (not to be confused with the X and Y chromosomes that differentiate boys from girls), along with the usual four. The cells grew a little more slowly than normal, but otherwise seemed no worse for wear, the team reports today in Nature.

The work is a major accomplishment, says Steven Benner, a synthetic biologist at the Foundation for Applied Molecular Evolution in Gainesville, Florida. He says its the first time anyone has shown that living cells can replicate alien DNA built from parts other than the four letters that occur in nature.

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Biologists Create Cells With 6 DNA Letters, Instead of Just 4