Thursday, in the journal Science, Church’s group described how it deleted all 314 instances of a particular codon in the genome of living E. coli and replaced them with another codon. The work was co-led by Farren Isaacs, now assistant professor of molecular biology at Yale University. The process involves making small-scale genetic changes in multiple strains of E. coli, then combining them.
Researchers at the J. Craig Venter Institute have previously demonstrated a different to edit a whole genome. This is the same group that made the first “synthetic living cell” last year. The Venter group edits the genome on a computer, and then synthesizes the entire thing using a combination of machinery and yeast cells; after that, the genome is transplanted into a recipient cell.
Church’s method introduces changes in living cells. He believes the advantage of this approach is that it’s possible to correct mistakes as they happen on the way toward making larger changes. Church hopes his latest work will convince other researchers of the value of “genome-scale” engineering. Both his method and that developed at the Venter Institute involve using DNA synthesizer machines to make large amounts of DNA for the engineered cells to take up. DNA synthesis is still expensive. And the time involved in both techniques, though it’s getting shorter, is another expense. “We need to bring costs down, and think about ease of use,” he says.
Making proteins with unnatural components is so useful that biologists have been doing it, albeit inefficiently, for decades, says David Tirrell, professor of chemical engineering at Caltech. Tirrell is not affiliated with the Harvard group.
Two companies—Allozyme, which Tirrell is associated with, and Ambrix—are both making protein drugs that incorporate unnatural amino acids. In both cases, they have engineered bacteria that can make proteins that include just one unnatural amino acid. Making organisms that can use more of these unnatural chemicals to produce new kinds of molecules would open up new frontiers for protein drugs, he says. Proteins with unnatural components might also be able to cross barriers in the body that are not easily breached today, such as the blood-brain barrier. Church’s group is beginning a collaboration with Ambrix.