Octopuses are aliens living on Earth. They solve puzzles, use tools, and communicate with color. They also squirt ink, open jars, and occasionally pull a prank or two. Given their remarkable intelligence and cunning ways, it takes a lot to surprise the biologists who study these wonderful creatures and their equally weird cousins the squids and cuttlefish.

But when Stanford University geneticist Jin Billy Li heard about Joshua Rosenthal’s work on RNA editing in squid, his jaw dropped. That’s because the work, published today in the journal Cell, revealed that many cephalopods present a monumental exception to how living things use the information in DNA to make proteins. In nearly every other animal, RNA—the middleman in that process—faithfully transmits the message in the genes. But octopuses, squid, and cuttlefish (but not their dumber relatives, the nautiluses) edit their RNA, changing the message that gets read out to make proteins.

In exchange for this remarkable adaptation, it appears these squishy, mysterious, and possibly conscious creatures might have given up the ability to evolve relatively quickly. Or, as the researchers put it, "positive selection of editing events slows down genome evolution." More simply, these cephalopods don't evolve quite like other animals. And that could one day lead to useful tools for humans.

A Mystery of Omission

First, a primer. You can think of RNA as a copy of the genetic instructions for a protein. When an animal cell makes a protein, it starts by transcribing the DNA—duplicating the A, T, C, and G nucleotides into RNA strands of A, T, C, and U. The RNA, composed of ribonucleic acids, is a lot like DNA but without the double helix structure. It's shorter, too, often containing only the information needed to create one protein at a time. Ribosomes, the little machines that create proteins, read the RNA sequence like a blueprint.

Once the organism—a human, a praying mantis, a quokka, whatever—transcribes DNA into RNA, it often splices out large chunks of material called introns that aren't needed to produce the protein. But occasionally, a special sequence in the RNA lets it hook up with an enzyme that does true RNA editing. That enzyme can edit a single spot in the RNA, turning an A into an I, which the ribosome interprets as a G.

Subbing out one spot in the code may seem like a minor switcheroo, but it can change how—or whether—a protein functions. Theoretically, it changes the genome's level of complexity: Humans possess just two copies of a given gene, but add a few RNA editing sites and the number of protein variants rises exponentially. An animal could use RNA editing to change how its proteins work if its environment changes. For instance, some RNA in squid get edited when the weather changes so that their proteins work properly at different temperatures.

Although most organisms posses the enzyme needed for gene editing, it isn't widely used. In fact, University of Michigan evolutionary biologist Jianzhi George Zhang says RNA editing is, in most cases, deleterious. The consensus among folks who study such things is Mother Nature gave RNA editing a try, found it wanting, and largely abandoned it.

A Wayward Branch

Rosenthal, a neurobiologist at the Marine Biological Laboratory, was a grad student studying a specific protein in squid when he got an an inkling that some cephalopods might be different. Every time he analyzed that protein's RNA sequence, it came out slightly different. He realized the RNA was occasionally substituting A's for I's, and wondered if squid might apply RNA editing to other proteins. Rosenthal, a grad student at the time, joined Tel Aviv University bioinformaticists Noa Liscovitch-Braur and Eli Eisenberg to find out.

In results published today, they report that the family of intelligent mollusks, which includes squid, octopuses and cuttlefish, feature thousands of RNA editing sites in their genes. Where the genetic material of humans, insects, and other multi-celled organisms read like a book, the squid genome reads more like a Mad Lib.

So why do these creatures engage in RNA editing when most others largely abandoned it? The answer seems to lie in some crazy double-stranded cloverleaves that form alongside editing sites in the RNA. That information is like a tag for RNA editing. When the scientists studied octopuses, squid, and cuttlefish, they found that these species had retained those vast swaths of genetic information at the expense of making the small changes that facilitate evolution. “Editing is important enough that they’re forgoing standard evolution,” Rosenthal says.

He hypothesizes that the development of a complex brain was worth that price. The researchers found many of the edited proteins in brain tissue, creating the elaborate dendrites and axons of the neurons and tuning the shape of the electrical signals that neurons pass. Perhaps RNA editing, adopted as a means of creating a more sophisticated brain, allowed these species to use tools, camouflage themselves, and communicate.

That remains nothing more than a hypothesis. The researchers can't say precisely when and where the RNA is edited or to what end, although they have shown that editing key brain proteins changes the function of those proteins. Rosenthal hopes to discover what role RNA editing might play in the intelligence of these undersea predators, because he wonders whether it might lead to treatments and therapies for cystic fibrosis and other diseases. Given the ethical boundaries around genome editing with tools like CRISPR, he’s exploring how to use RNA editing instead. That remains a distant goal, but Rosenthal finds comfort knowing that these earthbound aliens have been doing it for millions of years and might one day share their secret.