Synthorx

. Adding, deleting, and splicing genes has become routine, and some researchers are now even designing DNA for creatures. While many are hard at work rearranging letters on the page, a new experiment is redefining the concept of synthetic biology by writing new letters.

As they reported today in the journal Nature, a team of biologists led by Floyd Romesberg at the Scripps Research Institute have expanded the genetic alphabet of DNA—the As, Cs, Gs, and Ts that write the book of life—to include two new letters. The scientists showed that their letters could be integrated into the DNA of a living creature (an E. coli bacterium) and increase exponentially the amount of information the genetic code can store.

"This is a very major accomplishment in our efforts to inch towards a synthetic biology," says Steven Benner, a synthetic biologist at the Foundation for Applied Molecular Evolution who was not involved in the study. "Many in the broader community thought that Floyd's result would be impossible to achieve."

With a Little Help From My Fungus

The history of these new letters—which the scientists call X and Y—can be traced back to 1998 when Rosmeberg and his colleagues first tinkered with the idea. They sought to develop a pair of genetic letters that were similar enough to the letters life already uses that they could function (and wouldn't be rejected by) the existing framework of DNA. Yet the letters had to be different enough that they wouldn't be accidentally mispaired with the original four letters—and effectively forgotten.

The letters saw many, many failed incarnations before they morphed into what the researchers presented today. "After 14 years we had developed, made, and optimized over 300 of these nucleotides," Rosmeberg says. Then came the bigger hurdle: getting a real cell to reproduce X and Y after scientists spliced them in. While cells come stock with the machinery to churn out the original four letters, the scientists had no way to easily alter their bacteria to likewise synthesize X and Y.

Credit: Synthorx

Romesberg's team found a way to steadily feed their bacterium the X and Y nucleotides it would need. The researchers took a line of genetic code from a species of fungus—which saves energy by gobbling up nucleotides anywhere around it and using those when it needs to replicate its DNA—and spliced it into their bacteria's loop of DNA.

"As soon as we cut in that DNA, it was remarkable. The issue of producing these nucleotides just vanished as a problem," Romesberg says.

As long as their bacteria was fed the X and Y nucleotides, the researchers found that even after 15 hours it would replicate them over and over again just as it would any other line of DNA. And if the bacteria tried to reproduce without them, it would get stuck until it mutated out the new code, essentially reverting back to its natural state.

It's an open question why the bacteria cell doesn't reject the strange nucleotides as fatal errors in genetic replication—the genetic framework of life has many inspection and failsafe mechanisms to prevent errors or foreign debris from gunking up DNA. Romesberg hypothesizes that his expanded genetic alphabet is either so foreign that the genetic framework simply doesn't recognize it as an error, or, more likely, it does see an error but has no way to fix or change the X and Y letters.

Failsafe

Understandably, there's growing concern about these kinds of modified organisms, and what would happen if they were to somehow spread beyond the lab. "I'm worried people might think is our only concern is to make Frankenstein," Romesberg says, "but I'd like to emphasize that we have a failsafe mechanism built into this system. If you take this bacteria out of the lab [it] converts back to its normal state."

Although Rosemberg's modified E. coli replicated his X and Y nucleotides in the DNA, the bacteria did not use that customized clip of genetic code to build proteins, so the new letters were not expressed in new genes. While DNA stores genetic information in its double helix, it is not until that info is transcribed to RNA that the cell begins to use it in three-letter chunks called codons. This was intentional, Rosemberg says. His X and Y nucleotides are hidden away on a length of DNA that essentially functions as empty code.

New Letters, New Possibilities

But the prospect of using these new nucleotides to craft new (and more) codons is perhaps the most exciting aspect of this discovery. While all possible combinations of G, T, C, and A are already in use—AAG for example, creates an amino acid called lysine, and TAA signifies the end of a code of DNA—new letters exponentially increase the number of possible codons and give researchers the ability to recode the genetic framework without needing to rewrite or erase what life has already created. Codons like XYA or TGX, for example, could be programmed to build new types of amino acids, which could configure new proteins.

Expanding the suite of possible cell-made proteins would have an immediate impact in the pharmaceutical industry, which is increasingly using the protein synthesis of cells—rather than step by step molecular configuration—to produce medicines. And while this sounds like little more than science fiction, researchers have already proven the ability to recode how DNA is expressed with the original four nucleotides. "There is still much to do to achieve such goals, but this is an exciting early step," says Sri Kosuri, a molecular biologist at UCLA, who was not involved in the research.

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