Octopuses and squids can rewrite their RNA. Is that why they’re so smart?

When Inky the octopus escaped from his tank at New Zealand’s National Aquarium in April 2016, he squirmed through a six-inch-wide drainpipe and made off into the Pacific. He stole more than a few human hearts along the way, too. Inky fans celebrated the animal that outwitted the aquarium: “Please watch out – he is heavily armed,” one commentator quipped.

The intelligence of octopuses goes far beyond escape artistry. They can unscrew glass jars from the inside and solve other complex mechanical problems. They play. Some are capable of body-contorting mimicry. All of this is to say that cephalopods – the spineless, many-legged creatures including octopuses and cuttlefish – stand out among their fellow mollusks. Pity in comparison the oyster, a mollusk that, sadly, doesn’t even have a proper brain.

Cephalopods are unusual not only because they solve puzzles and clams cannot. Squids, cuttlefish and octopuses do not follow the normal rules of genetic information, according to research published in the journal Cell. Their RNA is extensively rewritten, particularly the codes for proteins found in the animals’ neurons.

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Put simply, that’s very weird. According to the central dogma of molecular biology, cells convert DNA sequences to RNA, which then creates proteins.

Imagine a library full of cookbooks, where you’re not allowed to check anything out. But you are allowed to copy recipes as you need them. The copies must almost always be verbatim, as though done by a faithful scribe. RNA plays the role of scribe.

Sometimes, cells edit RNA, plucking out the molecule adenosine and inserting a molecule called inosine. University of Utah biochemist Brenda Bass discovered RNA editing three decades ago. “Everything we have learned in the 30 years since these were discovered says that these type of editing events usually don’t change codons,” Bass tells The Washington Post, meaning that the edits to RNA did not change what proteins are created.

“The general view was that editing sites are being ‘expelled’ from the coding part of the RNA molecules,” Eli Eisenberg, a co-author of the new study and an expert in RNA editing at Tel Aviv University, writes in an email to The Post.

But, far from expelling the edited sites, cephalopods use the tweaked RNA to generate new proteins. Rather than one gene producing one protein, this type of RNA editing, called recoding, could allow a single octopus gene to produce many different types of proteins from the same DNA.

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“Recoding by editing effectively creates a new protein sequence, and thus it’s expanding the protein repertoire at the organism’s disposal,” Eisenberg says.

To return to the metaphorical library of cookbooks, it’s as though a chef has replaced the scribe. Perhaps the chef owns an oven that doesn’t heat up well, says Joshua Rosenthal, a neurobiologist at the Marine Biological Laboratory in Woods Hole, Massachusetts, and an author of the new study. The chef decides to write down a higher temperature than the printed recipe calls for. Or maybe the chef is in the mood for something sweeter, and alters how much sugar a recipe has.

These RNA changes can have a dramatic impact on squid or octopus biology. In a previous study, Rosenthal discovered that octopuses living in the Antarctic used RNA editing to keep their nerves firing in frigid waters.

In the new report, scientists measured rates of RNA recoding in several cephalopod species. They found that squids, cuttlefish and octopuses – the smartest kinds of cephalopods – frequently edit RNA, in about one out of every two transcribed genes. What’s more, RNA editing most often targeted cephalopod genes related to nervous system functions. “It was making tweaks that really make a neuron a neuron,” Rosenthal says.

There was one exception. A type of cephalopod called a nautilus lacked such high rates of RNA recoding. Nautiluses, though, aren’t known for their intelligence. Could “massive RNA-level recoding”, as the scientists write in their new study, be related to the animals’ smarts?

The study did not provide conclusive evidence that RNA recoding was the reason for cephalopod smarts. But it offered “tantalising hints toward the hypothesis that extensive recoding might have contributed to the exceptional intelligence”, Eisenberg says, of the squids, octopuses and cuttlefish. “Of course, at this point it’s just an enticing idea to think about, and we would need much more evidence to say anything definitive in this direction.”

Bass, who was not involved with this new research, agrees that the idea is enticing. It made “perfect sense” that the more sophisticated cephalopods would rely on recoding, she said, “because that would allow them to diversify their nervous system.”

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The cephalopod brain boost, after all, could use more explanation. “Of all the branches of life you have two that have real behavioural complexity,” Rosenthal says. There are vertebrates, such as birds and mammals, and there are cephalopods. “And that’s it.” (It’s been more than 500 million years since the last common ancestor of humans and octopuses).

Widespread RNA editing comes at a cost. If a mutation occurs at an editing site, the animals’ cells can no longer tweak it. “You can’t mess around with that underlying structure,” Rosenthal says. It turns out that these squids and octopuses have much lower rates of DNA mutation – which Rosenthal called the “currency of evolution” – than other organisms. In other words, while most animals adapt and evolve through changes in DNA, they seemed to prioritise RNA recoding.

To further investigate how the animals curb their DNA mutation rate in favour of RNA recoding, Rosenthal plans to manipulate cephalopod genetics using the CRISPR-Cas9 gene editing technique. He’ll just have to keep the octopus tank lids shut tightly each night.

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