A PhD student at the Gladstone Institutes nearly gave up on finding the DNA that was supposed to run a bacterial defense. Karen Zhang and senior author Seth Shipman had a retron, a kind of antiviral system in bacteria, that appeared to make almost none of the molecule that normally drives the process. The team’s description of the system, published in Molecular Cell, is that it is the strangest retron anyone has come across.
Save more, waste less: The Cool Down’s newsletter sends smart, simple changes that help you and the planet in your everyday life.
We may earn a commission if you sign up.
Zhang recalled that the results were so odd the group wondered whether the system was broken. It was not. The defense works almost completely backward compared with the retrons described so far.
How ordinary retrons guard a cell
Retrons are bacterial immune systems that make short stretches of single-stranded DNA by reverse transcription. In the versions studied before, a toxic protein is already present in healthy cells, held in check by that DNA. When a bacteriophage, a virus that infects bacteria, invades and disrupts the arrangement, the toxin is released. The infected cell dies, and the virus cannot spread to its neighbors.
The retron design is a loaded trap: the weapon exists all the time and the DNA acts as the safety catch. Zhang described the type the team found as almost the mirror-image version of how retrons are traditionally viewed, according to the Gladstone Institutes announcement. The News-Medical report from October 13 carried the same finding on the day the paper came out.
Type VI retrons: DNA first, toxin second
The new group, called type VI retrons, sets up the sequence the other way round. In healthy cells the team detected very little DNA and essentially no toxin. Once a phage arrives, DNA production rises substantially. That DNA binds an RNA molecule that had been blocking synthesis of the toxin, which lifts the block and lets the cell make the protein quickly.
The toxin appears to be a very small protein that inserts into the cell membrane and destabilizes it, killing the infected cell and halting the spread of the virus. The full study, “Reverse transcribed ssDNA derepresses translation of a retron antiviral protein,” was published October 13 and is available through its Molecular Cell DOI. Its authors include collaborators at the University of Copenhagen and the University of California, San Francisco, led on the Copenhagen side by Rafael Pinilla-Redondo and Guillermo Montoya.
A preprint of the work on bioRxiv supplies the molecular detail. The defense system studied, Retron-Vpa2, comes from the bacterium Vibrio parahaemolyticus, and the experiments ran in E. coli. It was tested against a panel of 92 phages and defended broadly against several families, and triggers were traced to phage genes involved in DNA recombination. The toxin is encoded in a transcript of about 470 nucleotides, and its water-repelling tail is essential for killing the cell.
Finding DNA that was barely there
The low baseline is what nearly stalled the project. Zhang said the group had just about given up hope that any DNA was being made when conventional methods came up empty. The team turned to Spacer-seq, a technique from Shipman’s lab that uses CRISPR-Cas components to record molecular activity, and it revealed DNA at very, very low levels in uninfected cells.
Shipman said the retrons operate with Rube Goldberg-level complexity, a reference to the chain of steps between infection and the death of the cell. ScienceDaily’s coverage of the release notes that the article gives no quantitative measurements of the DNA levels, so the size of the rise after infection is described only in words.
Sensors, antibiotics and a gene-editing tool
Gladstone says the group is building synthetic DNA and RNA sensors and switches from this machinery. The tiny, potent toxins are also being explored as starting points for antimicrobial therapies against disease-causing bacteria. Retrons more broadly are under study as tools for rewriting disease-causing mutations in human cells, though that work remains in development. Shipman put the philosophy simply: what evolution has produced can serve as a starting point. The study was funded by a long list of sources including the National Science Foundation, the Moore Foundation, the Novo Nordisk Foundation and the European Research Council.
The preprint puts figures on how faint the signal was. No DNA from the retron showed up on a standard gel at baseline, and sequencing found a truncated fragment of 63 nucleotides and a full-length version of 86 nucleotides that appeared when a phage protein called Gam was present. Mutating one regulatory region raised sequencing coverage about fivefold. In a split-GFP assay the toxin signal rose more than 10,000-fold above the negative control. The preprint also notes that a covariance search found 81 type VI retron sites, so the group is not a one-off curiosity.
The open question, per Gladstone, is where type VI sits in evolutionary history. The group does not yet know whether these retrons are older or newer than the other types, or a stepping stone between them, which would reveal whether the reversed design is an ancient original or a later refinement.
This article was produced with the assistance of AI and reviewed by Morning Overview editors prior to publication.
Save more, waste less: Subscribe to The Cool Down →
We may earn a commission if you sign up.
More from Morning Overview
