“The structure, that’s key to function,” Whiteley said. “The protein can’t change in structure. But it can change in sequence to try and disrupt all the ways the virus is trying to antagonize the system.”
The discovery of the structural similarity was surprise enough. But did these bacterial enzymes, like human cGAS, protect against foreign viruses? Yes. That same year, Sorek’s team showed that the bacterial cGAS enzymes did in fact work as an anti-phage defense.
Both teams eventually found STING in bacteria as well. When they confirmed that the bacterial STING functioned in immune defense much like the human STING, “all the dots really started to connect,” Kranzusch said. “Then we had everything.”
The hardest part of this work was neither solving the protein structures nor testing their functions. “The dogma in the field was that immune proteins should not be old. And that was the really hard part to overcome with the cGAS-STING pathway,” Kranzusch said.
“We knew it was conserved, and it was doing the same function, and it was maintained across billions of years of evolution,” he continued. “As the data became overwhelming, that broke down the barriers for all sorts of other findings in the field.”
Cast of Characters
Since the discovery of the uncanny correspondence between bacterial and human cGAS-STING, computational analysis of bacterial defense islands has predicted hundreds of distinct mechanisms of innate immunity. Some of the mechanisms cleave viral DNA or RNA transcripts to kill the viruses; others terminate the reproduction of new viral DNA. “Quite a few of these defense systems turn out to be suicidal,” said Eugene Koonin, an evolutionary biologist at the National Institutes of Health who published a foundational paper on defense islands in 2011. That is, they cause the cell to self-destruct, thereby preventing further spread in the viral population.
The evolutionary biologist Eugene Koonin led foundational research identifying clusters of antiviral genes in bacterial genomes.
National Library of Medicine
But over billions of years, phages have evolved ingenious countermoves to evade such defenses. For example, in response to bacterial cGAS-STING, phages deploy molecules that sponge up the cyclic dinucleotide signals (cGAMP) that connect the sensor (cGAS) to the effector (STING). This effectively short-circuits and overcomes the defense.
Countering that, bacteria evolved a mechanism called Panoptes — first described in 2025 by Whiteley, Morehouse, and their colleagues — which constantly generates cGAMP signals that are similar but not identical to those generated by cGAS. An invading phage then sponges up the cGAMP decoys, allowing the true signal to reach its target (STING) and trigger cellular self-destruction.
This trick works only because the cGAS and Panoptes dinucleotides are different enough for the cell to distinguish them and similar enough that the phage can’t tell the difference. It’s a dangerous balance — one that probably frequently misfires.
“This is the marvel of bacteria,” Whiteley said. “They’re replicating so rapidly that they can try a lot of things that don’t work in order to find the very few that do.”
Another example of fascinating moves and countermoves can be found in a bacterial defense mechanism that depletes NAD, an essential cofactor. NAD is an electron carrier that, every second, greases the wheels of millions of biochemical reactions in the cell. By quickly destroying all cellular NAD, bacteria grind biochemical reactions to a halt, preventing viral replication. But phages, not to be outdone, have evolved ways to reconstitute NAD and evade this bacterial defense, Sorek’s team has found.
Then there’s viperin, a human protein that makes modified nucleotides that quickly terminate viral replication; its mechanism of action was deciphered in 2018. Soon after, Aude Bernheim, who was a postdoctoral fellow in Sorek’s lab and now leads her own research group at the Pasteur Institute in Paris, found homologues of viperin in bacteria. She also showed that they work the same way human viperin does.
Gasdermins are immune proteins present in the cytosol that kill the cell when it senses an infection by piercing a hole in the cell membrane. The mechanism for gasdermins in humans was described in 2015. In 2022, Tanita Wein, who trained as a postdoc in the Sorek lab and now leads her own research group at the Weizmann Institute, discovered that gasdermins work the same way in bacteria as they do in humans.
Researchers initially made headway in the field by mapping existing knowledge of human immunity onto bacterial genomes. Now they are doing the opposite: investigating whether the hundreds of new bacterial immune systems can be used to predict still unknown mechanisms in humans and other eukaryotes.
This predictive framework has already borne fruit. For example, Sorek’s team discovered a bacterial protein that, upon sensing infection, depletes ATP (molecular energy) from the cell, thus preventing the virus from replicating. They later found it in the genomes of animals, including corals and insects (though not humans). When tested in living tissues, the coral and insect proteins worked the exact same way as they do in bacteria.
“This is a very strong revelation, because doing research in bacteria is much easier than doing research in humans,” Sorek said. “One of the most important influences of our research is this ability to use bacteria to study higher organism immunity.”
An Evolutionary Cauldron
Although there are hundreds of bacterial defense systems, most bacteria have only about a dozen. They are inherently costly and always carry the risk of triggering accidental self-destruction, which limits how many any single bacterium can have. Some mechanisms, like restriction-modification enzymes, are common, while others are relatively rare. CRISPR exists in about 40% of prokaryotic genomes; viperins are present in only about 0.5%.
Bacterial communities are like a cauldron where new molecular weapons are forged and are always evolving.
Many of the most common immune mechanisms in prokaryotes have not been inherited by eukaryotes, while some relatively rare ones have been inherited and have “flourished,” Koonin said. The question is: Why? Why don’t our cells have CRISPR? And why did cGAS-STING, a relatively rare immune mechanism in bacteria, become such a central tool in our arsenal?
In some cases, bacterial defense mechanisms could have been acquired by eukaryotes about 2 billion years ago, when an archaeal cell first engulfed a bacterial one — which eventually settled in as a mitochondrion organelle — and seeded the eukaryotic lineage. Other mechanisms may have been acquired later through horizontal gene transfer, a mechanism commonly used by bacteria to swap chunks of DNA, which occurs with less frequency in eukaryotes.
The acquisition “in itself is not such a big problem,” Koonin said. “How and why [rare defenses] replaced the most common prokaryotic defenses — that is more intriguing and, of course, not entirely clear.”
One possibility is that in bacteria, defenses often come with several genetic components organized in small arrays, or operons, that are regulated together. Restriction-modification enzymes, toxin-antitoxin genes, CRISPR and Cas, cGAS and STING — each is a system made of genes that sit next to each other in bacterial genomes. This makes it easy for bacteria to share the entire toolkit.
But in eukaryotes, because of the more complicated way our genomes are organized and regulated, genes’ operon organization is often disrupted. “Once you lose an operon, you are very unlikely to reacquire it by horizontal transfer,” Koonin said. “Once it is disrupted, it is effectively gone.”
The evolutionary immunologist Tera Levin studies how arms races between bacteria and viruses create new immune mechanisms.
When Tera Levin and Edward Culbertson, a postdoctoral fellow in her lab at the University of Pittsburgh, surveyed cGAS and STING proteins across a broad swath of eukaryotes, they found that it’s quite common to find one or the other missing. That begs the question of what one piece is doing when the other isn’t there.
“These components either aren’t there, or aren’t there in the combinations I expected — what are they possibly doing?” Levin said. “That is a question we encounter over and over again in this part of the field.”
It’s possible that the pieces evolved entirely new functions. For example, more than a decade ago, the evolutionary biologist L. Aravind showed that some restriction-modification enzymes became essential enzymes in eukaryotic epigenetics, where they place (or remove) epigenetic marks at specific locations on the chromatin. In 2025, his team showed that Wnt proteins, essential signaling molecules in animal development, also originate in bacterial conflict systems.
In this way, bacteria serve as a kind of “maker space” for accelerated evolutionary experimentation and innovation, generating novelty that then is seeded across life. This seeding is not just a thing of the distant past: Eukaryotes have continued to beg, borrow, and steal from bacteria and phages in more recent evolutionary time.
Several million years ago, the wild fruit fly Drosophila ananassae horizontally acquired a viral toxin gene that cuts DNA, probably from phages of endosymbiotic bacteria. In 2025, Noah Whiteman, a biologist at Berkeley, and his team discovered that the fruit fly uses this phage toxin not to kill viruses but rather to poison parasitic wasps that lay eggs inside fly larvae. Amazingly, the fly manages to wield this powerful new weapon without poisoning its own cells.
Unlike bacteria that can easily swap genes with their neighbors and evolve at warp speed, multicellular organisms are stuck with sexual reproduction — which means that evolution proceeds at a slower pace. By taking advantage of the rapid evolution of bacterial and viral weapons, insects and other eukaryotes can accelerate their own evolutionary process to stay a step ahead of their enemies.
“When you borrow a gene from another organism that’s evolving very rapidly, that’s a great strategy, because you can borrow tools at a faster rate than you could ever make them,” Whiteman said.
It’s now clear that bacterial communities are like a cauldron where new molecular weapons are forged and are always evolving. This microbial arsenal contains hundreds, perhaps thousands, of different defense systems.
Diverse eukaryotic lineages, from unicellular eukaryotes to plants and animals, have repeatedly borrowed, adapted, and lost defenses from this arsenal over evolutionary time. In this cauldron, the rules of all evolutionary warfare — microbial, animal, vegetal — continue to be written.