Rewritten genetic code allows bacteria to fend off viral attacks
Strategy could keep potentially dangerous genes from escaping from genetically modified organisms
Call it a genetic firewall. By partially rewriting the genetic code in bacteria, two groups of researchers have found they can thwart invading viruses, which must hijack the microbes’ genetic machinery to replicate. The strategy, described today in Science and in a preprint posted in July, could shield drug-producing bacteria from viral attacks and keep potentially dangerous genes from escaping from genetically modified organisms.
“These are important steps forward,” says synthetic biologist Ned Budisa of the University of Manitoba, who wasn’t connected to the research. “Both works have great technological promise.”
Nearly every living thing relies on the same genetic code. Various sequences of three DNA nucleotides, called codons, tell a cell which amino acid to install where in a protein. So-called transfer RNAs, or tRNAs, read the codons and act on their instructions. Each type of tRNA carries a specific amino acid that it adds to a growing protein strand only when it recognizes the correct codon. Cells also carry three kinds of stop codons that tell them when to stop making a protein.
Because organisms share this genetic programming language, they can gain new abilities by acquiring genes from other organisms. The common language also allows researchers to insert human genes into bacteria, coaxing the cells to manufacture drugs such as insulin. But a universal genetic code leaves cells vulnerable to interlopers such as viruses and plasmids, DNA snippets that reproduce inside bacteria and can ferry genes among them.
For years, researchers have tried to block this traffic. In 2013, synthetic biologist George Church of Harvard Medical School and colleagues genetically tweaked the bacterium Escherichia coli, replacing one of its stop codons with another version. The team modified the bacterium’s tRNAs so that when it reads the original stop codon—say, in the genome of an invading virus—it installs an inappropriate amino acid that impairs the viral protein. The modified microbe could safely synthesize its own proteins but was resistant to several kinds of viruses and plasmids.
Last year, synthetic biologist Jason Chin of the University of Cambridge and his team went a step further. They swapped out the same stop codon in E. coli, but they added another layer of protection. They replaced two of the codons for the amino acid serine in the microbe’s genome with two different serine codons. They then deleted the tRNAs that would recognize the original serine codons. This modified bacterial strain, dubbed Syn61Δ3, could not read two serine codons found in invaders, helping it shrug off bacteria-infecting viruses.
The group tested its improved Syn61Δ3 by exposing it to a pair of viruses fished out of the River Cam in Cambridge. Both killed the original Syn61Δ3 but spared upgraded versions, the scientists report this week in Science. They also showed that although the improved Syn61Δ3 cells could exchange a plasmid engineered to use their modified genetic code, they could not share the plasmid with other bacteria. “We have created a form of life that doesn’t read the canonical genetic code and that writes its genetic information in a form that can’t be read” by other organisms, Chin says.
Church’s and Nyerges’s team followed a similar strategy. The researchers endowed Syn61Δ3 with modified tRNAs that misread two of the serine codons carried by invading viruses, inserting leucine instead of serine. Compared with the original Syn61Δ3, the altered microbes became more resistant to the 12 viruses that scientists had plucked from environmental samples, the team revealed in July. The paper “shows a way to make any organism resistant to all viruses—and with one step,” Church says. (The team also made sure the microbes require an amino acid that doesn’t occur in nature, ensuring they can’t survive if they escape.)
Such recoding might help prevent viral outbreaks in factories that use bacteria to churn out drugs or other products. And by recoding genetically modified organisms, researchers might prevent other organisms from acquiring their DNA. The bacteria could also help biologists study the evolution of the genetic code itself, says synthetic biologist Chang Liu of the University of California, Irvine. Now, researchers can “ask why the genetic code is the way it is.”
Church says viruses are unlikely to evolve strategies for getting around this defense because it involves more than 200,000 changes to the microbes’ genome. And synthetic biologist Drew Endy of Stanford University says the researchers deserve credit for the rigor with which they tested the viral resistance of the bacteria. “One of the most beautiful things they’ve done here is they’ve gone out into the wild” to find viruses, he says.
Still, he and others aren’t so sure the bugs are genetically locked off from other living things. “We still need to be very careful,” Budisa says. “I can’t put my hand in a fire and say, ‘This is a perfect firewall.’” Endy agrees. “It’s an arms race between human ingenuity and natural biodiversity,” he says, “and we don’t know how long the race is yet to run.”
