He saw that these Arc proteins assemble into hollow, spherical shells that look uncannily like viruses. “When we looked at them, we thought: What are these things?” says Shepherd. They reminded him of textbook pictures of HIV, and when he showed the images to HIV experts, they confirmed his suspicions. That, to put it bluntly, was a huge surprise. “Here was a brain gene that makes something that looks like a virus,” Shepherd says.
That’s not a coincidence. The team showed that Arc descends from an ancient group of genes called gypsy retrotransposons, which exist in the genomes of various animals, but can behave like their own independent entities.* They can make new copies of themselves, and paste those duplicates elsewhere in their host genomes. At some point, some of these genes gained the ability to enclose themselves in a shell of proteins and leave their host cells entirely. That was the origin of retroviruses—the virus family that includes HIV.
So, Arc genes are the evolutionary cousins of these viruses, which explains why they produce shells that look so similar. Specifically, Arc is closely related to a viral gene called gag, which retroviruses like HIV use to build the protein shells that enclose their genetic material. Other scientists had noticed this similarity before. In 2006, one team searched for human genes that look like gag, and they included Arc in their list of candidates. They never followed up on that hint, and “as neuroscientists, we never looked at the genomic papers so we didn’t find it until much later,” says Shepherd.
The similarities don’t end there. When genes are activated, the instructions encoded within their DNA are first transcribed into a related molecule called RNA. Shepherd’s colleague Elissa Pastuzyn showed that the Arc shells can enclose RNA and move it from one neuron to another. And that’s basically what retroviruses do—they use protein shells to protect their own RNA as it moves between cells in a host.
So our neurons use a viral-like gene to transmit genetic information between each other in an oddly virus-like way that, until now, we had no idea about. “Why the hell do neurons want to do this?” Shepherd says. “We don’t know.” One wild possibility is that neurons are using Arc (and its cargo) to influence each other. One cell could use Arc to deliver RNA that changes the genes that are activated in a neighboring cell. Again, “that’s very similar to what a virus does—changing the state of a cell to make its own genes,” says Shepherd.
“We have way more questions now than when we started out,” he says. “What is the RNA cargo? What is the signal [that the Arc shells] are carrying? When Arc is released by a neuron, how far can it travel?” And perhaps more importantly, how does all of this influence the brain? If the team stops neurons from releasing Arc, how does that affect an animal’s ability to learn or to form new memories? “I can see what people are thinking: Is memory a virus?” Shepherd says, laughing.