How Worms Remember Their Enemies: Transgenerational inheritance of avoidance behavior in C. elegans

Image courtesy of Rebecca Moore.

Imagine if your great-great-grandmother passed down a story that warned your family to avoid an enemy. Now, let’s propose that you never heard this message explicitly, and instead, it manifested in the form of a gut feeling, a biologically wired warning felt upon nearing that threat. C. elegans, a species of worm commonly studied in biology, uses a powerful intuition like this to avoid pathogens based on the lethal danger the pathogens posed to the worms’ ancestors.

Researchers Rebecca Moore, Rachel Kaletsky, and Coleen Murphy at Princeton University discovered that this “gut feeling” C. elegans inherit is pathogen avoidance behavior. The pathogen in this case is Pseudomonas aeruginosa (PA14), which kills C. elegans within two to three days upon exposure. 

In a paper published in Cell, the researchers were able to show that C. elegans used horizontal memory transmission—transfer of memory between members of an ecosystem—by observing that worms not yet exposed to the pathogen could learn this avoidance behavior through exposure to lysate from pathogen-trained grandmothers. 

By comparing worms exposed to PA14 with controls, the researchers discovered that worms learn to avoid PA14 after direct exposure to the pathogen for twenty-four hours. This avoidance behavior relies on P11, a small PA14 RNA that, when “read,” sends a signal from the worm’s germline to neurons, resulting in pathogen avoidance. With P11 still present in the worm’s reproductive cells, inheritance of this avoidance behavior is possible without direct exposure to the pathogen.

The researchers also discovered the molecular mechanism by which this horizontal transmission of memory occurs: transposons, segments of DNA that can jump to different locations in the genome. Usually, transposons are considered dangerous because their presence in genomes can lead to disease and the degradation of host fitness. However, the researchers found that the Cer1 retrotransposon expresses virus-like particles that can transfer memory of learned pathogen avoidance to other worms. 

Murphy believes that the most interesting discovery the team made was that when one set of animals is trained, they secrete these molecules into the media. “If you put that media onto untrained animals, they learn the information. So they’re literally transferring memories,” Murphy said. 

This mechanism of memory storage had been previously considered impossible due to the theorized Weismann barrier, a barrier between germline and somatic cells that preserves germ cells. Under this theory, hereditary information could move from germline to body cells, but never the reverse. The behavior of C. elegans, however, defied this hypothesis. “This is the way for an animal who doesn’t necessarily teach its young to transmit this information to its progeny. So, I think we have to come back and maybe re-evaluate the idea of the Weismann barrier,” Murphy said.

Interestingly, this memory transference ends after four generations. There is likely a biological reason for this limit. “[C. elegans] don’t always avoid [the pathogen] because sometimes Pseudomonas can be a nutritious food source depending on the temperature or other conditions,” Moore said.

Worms serve as a model system for mammalian species. The researchers’ discovery may therefore set the stage for discoveries about humans in the future. “Avoiding pathogens is something that we do,” Kaletsky said. “And in terms of the smaller RNA biology, I mean, our gut is loaded with bacteria. So it really opens up the possibility that we communicate with our gut microbiome through similar mechanisms.”