Caenorhabditis elegans germ cells constantly scan their contents looking for unfamiliar genetic material.

For a cell, the past informs the present. We humans have search engines like Google and Yahoo to sift through the Internet’s gobs of historical information and learn from others’ mistakes and successes. In some cells of the worm Caenorhabditis elegans, it turns out, a type of RNA, called Piwi-interacting RNA (piRNA), and its partner, an Argonaute protein called Piwi, run a similar search. The piRNA and protein continuously peruse the cell’s library of data and detect how it previously dealt with a particular molecule—whether an invading virus or a cell’s own genetic material.

That historical review determines the cell’s next step, according to research by HHMI investigator Craig Mello of the University of Massachusetts Medical School. piRNA—short stretches of 21 to 36 nucleotides—exists in tens of thousands of different sequences in germ cells (those that become eggs and sperm) of many animals including humans, but scientists have struggled to understand its purpose. Mello’s lab has now uncovered the reason the molecules are so ubiquitous and exist in so many forms in C. elegans: so they can pair with essentially any genetic sequence they encounter during their endless scanning.

“The Internet is full of information, yet we can navigate it pretty efficiently because we have search engines,” says Mello. “Argonaute proteins are like cellular search engines, and their small RNA cofactors are like the short search queries we type into Google.” The piRNAs have a huge capacity for scanning, explains Mello, because they allow imperfect pairing—like when you misspell a search query, but still find what you’re after. In short, Mello has discovered, the piRNA-based search engine can find everything out there, like running many millions of two- or three-word searches in Google to assemble every Web page on the Internet.

Mello’s findings suggest that to make sense of this massive search process, the piRNA system interfaces with two other pathways that serve as cellular memories of “self” and “non-self” RNA. Sequences that were seen before in a previous generation (“self” RNAs) are thought to be protected from piRNA silencing by a pathway involving an Argonaute protein called CSR-1. Sequences not seen before lack this pathway’s protection and so they are recognized by the Piwi/piRNA complex. In this case, the complex recruits a different Argonaute, dubbed WAGO, to create a permanent memory of the “non-self” RNA sequence.

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The Mello lab stumbled upon this system while attempting to introduce foreign genes into C. elegans. When scientists insert a new gene into the worm’s germline—the genetic material passed down to future generations via germ cells—the gene is sometimes expressed and sometimes silent. Mello’s lab group wanted to know why expression is so unpredictable, even when genes are inserted into exactly the same corresponding spot in the genome.

To follow expression, the team attached coding sequences for jellyfish green fluorescent protein (GFP) to the foreign genes. By identifying worms whose germlines glowed green, they could easily see whether the associated gene was silenced. Then, they began crossing worms—those that had silenced the gene and those that hadn’t—with each other. In the resulting offspring, they expected to see half the brightness of the green fluorescence—the gene inherited from one parent would be on, the second gene off. But the germlines of cross progeny were dark.

Illustration: Nicholas Blechman

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