by An illustration of viruses called phages infecting a bacterial cell. Researchers have developed a modified strain of Escherichia coli bacteria that is resistant to natural viral infections and has a low risk of entering the environment. This breakthrough in genetic engineering and synthetic biology aims to reduce the risk of viral contamination in the manufacture of medicines and other substances such as biofuels. At present, viral infections in bacteria can cause a production stop, jeopardize drug safety and cause high financial costs. Credit: Behnoush Hajian
create researchers[{” attribute=””>virus-resistant, safely restrained E. coli for medical, industrial applications.
In a step forward for genetic engineering and synthetic biology, researchers have modified a strain of Escherichia coli bacteria to be immune to natural viral infections while also minimizing the potential for the bacteria or their modified genes to escape into the wild.
The work promises to reduce the threats of viral contamination when harnessing bacteria to produce medicines such as
Learn more about how codon deletion works in this 2016 video on a related Church lab project. Credit: Rick Groleau
“We believe we have developed the first technology to design an organism that cannot be infected by any known virus,” said study lead author Akos Nyerges, a genetics research associate in George Church’s lab at the Blavatnik Institute in Harvard Medical School and the Wyss Institute for Biologically Inspired Engineering.
“We can’t say it’s completely virus-resistant, but so far, based on extensive laboratory experimentation and computer analysis, we haven’t found a virus that can break it,” Nyerges said.
The work also offers the first built-in safety measure that prevents modified genetic material from being incorporated into natural cells, he said.
The authors said their work proposes a general method for making any organism immune to viruses and preventing gene flow in and out of genetically modified organisms (GMOs). Such biocontainment strategies are of increasing interest as groups investigate the safe use of GMOs to grow crops, reduce the spread of disease, produce biofuels, and remove pollutants from open environments.
Building on what came before
The findings build on previous efforts by genetic engineers to develop a helpful, safe, virus-resistant bacterium.
In 2022, a group from the University of Cambridge thought they had made one E. coli tribe immune to viruses. But then Nyerges teamed up with research associate Siân Owen and graduate student Eleanor Rand in the lab of co-author Michael Baym, assistant professor of biomedical informatics at HMS’s Blavatnik Institute. When they sampled local websites with many E. coli, including chicken coops, rat nests, sewage and the Muddy River down the road from the HMS campus, they discovered viruses that could still infect the modified bacteria.
Discovering that the bacteria weren’t fully virus-resistant “was a bummer,” Nyerges said.
The original method involved genetic reprogramming E. coli to manufacture all of their life-sustaining proteins from 61 sets of genetic building blocks, or codons, instead of the naturally occurring 64. The idea was that viruses couldn’t hijack the cells because they couldn’t replicate without the missing codons.
However, the HMS team found that deleting codons was not enough. Some viruses brought their own gear to circumvent the missing pieces.
So Nyerges and colleagues devised a way to change what those codons tell an organism — something scientists hadn’t done on this scale in living cells.
Lost in translation
The key lay in transfer RNAs or tRNAs.
The role of any tRNA is to recognize a specific codon and add the appropriate amino[{” attribute=””>acid to a protein that’s being built. For instance, the codon TCG tells its matching tRNA to attach the amino acid serine.
In this case, the Cambridge team had deleted TCG along with sister codon TCA, which also calls for serine. The team had also removed the corresponding tRNAs.
The HMS team now added new, trickster tRNAs in their place. When these tRNAs see TCG or TCA, they add leucine instead of serine.
“Leucine is about as different from serine as you can get, physically and chemically,” said Nyerges.
When an invading virus injects its own genetic code full of TCG and TCA and tries to tell the E. coli to make viral proteins, these tRNAs mess up the virus’s instructions.
Inserting the wrong
