Rewritten genetic code allows bacteria to defend themselves against viral attacks | Sciences

Call it genetic firewall. By partially rewriting the genetic code of bacteria, two groups of researchers have found they can thwart invading viruses, which must hijack the genetic machinery of microbes to replicate. The strategy, described today in Science and in a preprint published in July, could protect drug-producing bacteria from viral attack and prevent 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 was not involved in the research. “Both works have great technological promise.”

Almost all living things are based 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 is added to a growing protein strand only when it recognizes the correct codon. Cells also carry three types 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, prompting the cells to make drugs like insulin. But a universal genetic code leaves cells vulnerable to intruders like viruses and plasmids, bits of DNA that replicate inside bacteria and can carry genes between them.

For years, researchers have tried to block this traffic. In 2013, synthetic biologist George Church of Harvard Medical School and his colleagues genetically modified 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 damages the viral protein. The modified microbe could safely synthesize its own proteins, but was resistant to various types of viruses and plasmids.

Last year, synthetic biologist Jason Chin of the University of Cambridge and his team went a step further. They swapped the same stop codon in E. coli, but added another layer of protection. They replaced two of the serine amino acid codons in the microbe’s genome with two different serine codons. They then removed the tRNAs that would recognize the original serine codons. This modified strain of bacteria, named Syn61Δ3, was unable to read two serine codons found on invaders, helping to fight off viruses that infect bacteria.

Still, Syn61Δ3 is not invincible. A team led by Church and his postdoc Akos Nyerges showed that it was susceptible to 12 types of viruses isolated from various sources, including pig manure and a chicken coop. So Chin and his colleagues added new protections. They devised tRNAs that actively mess up viral proteins by delivering the wrong amino acids, including proline and alanine, in response to foreign serine codons.

The group tested their improved Syn61Δ3 by exposing it to a pair of viruses extracted from the River Cam in Cambridge. Both killed off the original Syn61Δ3 but not the improved versions, the scientists report this week in Science. They also showed that although the enhanced Syn61Δ3 cells could exchange a plasmid designed to use their modified genetic code, they could not share the plasmid with other bacteria. “We’ve created a life form that doesn’t read the canonical genetic code and writes its genetic information in a way that can’t be read” by other organisms, says Chin.

Church and Nyerges’ team followed a similar strategy. The researchers provided Syn61Δ3 with modified tRNAs that misread two of the serine codons carried by invading viruses, inserting leucine instead of serine. Compared to the original Syn61Δ3, the altered microbes became more resistant to the 12 viruses that the scientists had extracted from environmental samples, the team revealed in July. The paper “shows a way to make any organism resistant to all viruses, and in one step,” says Church. (The team also made sure the microbes require an amino acid not found in nature, ensuring they can’t survive if they escape.)

Such recoding could help prevent viral outbreaks in factories that use bacteria to make drugs or other products. And by recoding genetically modified organisms, researchers could prevent other organisms from acquiring their DNA. The bacterium 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 develop strategies to get around this defense because it involves more than 200,000 changes to the microbe’s genome. And synthetic biologist Drew Endy of Stanford University says the researchers deserve credit for the rigor with which they tested the bacteria for viral resistance. “One of the most beautiful things they’ve done here is go out into nature” to find viruses, he says.

Still, he and others aren’t so sure that insects are genetically isolated from other living things. “We still have to be very careful,” says Budisa. “I can’t put my hand in the fire and say, ‘This is a perfect firewall.'” Endy agrees. “It’s an arms race between human ingenuity and natural biodiversity,” she says, “and we don’t know how long until the race.”

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