Recently, scientists inserted two new letters into the genomic alphabet in E. coli bacteria, creating the first organism that can replicate man-made genetic data.
It’s a process 15 years in the making, led by scientists at the Scripps Research Institute in California. Their work began with a simple thesis: Why is every living thing is programmed in a simple lexicon of four letters and not, say, six? And why those four?
The two extra letters may begin to help answer the question.
In 1999, researcher Floyd Romesberg and his group started by synthesizing the original letters that make up the base pairs of DNA. All known DNA before this experiment consisted of four letters that determine what proteins a cell makes. These proteins are what allow the cell to function.
The researchers wanted to make sure that inserting the new letters, which they’ve dubbed X and Y, didn’t come at a cost of screwing up the existing alphabet. In order to prevent X and Y from bonding with the other letters, they used a different kind of chemical bond—one that’s more oil-like than the bond that typically pairs G, C, A, and T, the existing bases.
“It took a couple years of banging on it to figure out how good it was,” said Romesberg. “We wanted to optimize it in the test tube first. If it wasn’t going to be done in a test tube, it wouldn’t work in the much more complex environment of the cell.”
Not only did the insertion work, the extra base pair was kept by offspring of the original bacterium. They didn’t hurt the ability of the bacteria to grow, and as the E. coli replicated, the new bacterial cells kept the synthetic base pairs.
The group is working on inserting the unnatural base pairs in more than one spot in the cell. Today’s work represents only one new base pair at one position, and since then, the group has inserted the pair in a variety of positions and contexts, Romesberg said.
In the past 10 years, experiments with man-made biology have mostly rearranged protein pathways within a cell, teaching them to perform a new function. In 2010, a research group led by Craig Venter created a new bacterium by rearranging the four existing letters of the genetic code. That technique allows scientists to assemble genomes from scratch.
Pairing Venter’s technique with the unnatural base pairs could lead researchers to create other organisms using X and Y as base pairs, Romesberg said. However, several other challenges need to be addressed before the techniques can be combined, said Ross Thyer, a biologist at the University of Texas at Austin, who wrote an editorial accompanying the Scripps finding.
“The base pair right now is present but it doesn’t serve any particular function,” Thyer said. “The next step is engineering dependence mechanisms so X and Y do really become a part of the cell’s machinery and not just something we’ve thrown in there.”
Meanwhile, both Romesberg and Thyer agree that further development of these letters of the genetic alphabet may explain why nature settled on four codons.
“Now we have a tool to figure out what happens when you have more than four,” Thyer said. “Maybe there are unknown reasons why four is a good thing, it’s a good number before processes get too complicated.”
While some people may be unnerved by the technology, it’s not yet a threat, Thyer said. The bacteria are dependent on the nutrients being supplied to them in the lab.
The next step is to see if the extra information stored in the cells, using the new letters, could be decoded by RNA to create proteins. If the information can be both stored and decoded, the resulting proteins may aid in creating better protein-based drugs, Romesberg said.
“Retrieving that information, that’s the really exciting thing,” said Romesberg.
If the cells learn to process the new base pairs and create new proteins, the unnatural components may allow for powerful drug development. But that’s not the only possibility. Man-made genetics might allow for material appellations like stronger spider silk.
What’s more, triggering DNA to do other things, or retrieving genetic information in an unnatural manner might improve information storage.
“I hope that people read this paper and pursue other ideas I haven’t been thinking about,” Romesberg said. “We’ve been so focused on getting the proteins. I’m excited to see other people come up with new ideas for uses.”
But manipulating the bacteria to store extra information is only the first step. The next one will be to teach cells to decode the information.
Romesberg’s group is already hard at work on this aspect. He expects “serious progress” on this project in the next year or two, leading to the creation of a complete semi-synthetic cell that doesn’t just store information but retrieves it.