Brain Cells Share Information With Virus-Like Capsules

The Arc gene, which is critical for animals’ ability to learn from experiences, has an incredible origin story.

Virus-like shells budding off from one neuron and moving to another. Chris Manfre

Ed Yong
Jan 12, 2018

Updated: January 12, 2018, 5:05 P.M. ET

When Jason Shepherd first saw the structures under a microscope, he thought they looked like viruses. The problem was: he wasn’t studying viruses.

Shepherd studies a gene called Arc which is active in neurons, and plays a vital role in the brain. A mouse that’s born without Arc can’t learn or form new long-term memories. If it finds some cheese in a maze, it will have completely forgotten the right route the next day. “They can’t seem to respond or adapt to changes in their environment,” says Shepherd, who works at the University of Utah, and has been studying Arc for years. “Arc is really key to transducing the information from those experiences into changes in the brain.”

Despite its importance, Arc has been a very difficult gene to study. Scientists often work out what unusual genes do by comparing them to familiar ones with similar features—but Arc is one-of-a-kind. Other mammals have their own versions of Arc, as do birds, reptiles, and amphibians. But in each animal, Arc seems utterly unique—there’s no other gene quite like it. And Shepherd learned why when his team isolated the proteins that are made by Arc, and looked at them under a powerful microscope.

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.

As if that wasn’t weird enough, other animals seem to have independently evolved their own versions of Arc. Fruit flies have Arc genes, and Shepherd’s colleague Cedric Feschotte showed that these descend from the same group of gypsy retrotransposons that gave rise to ours. But flies and back-boned animals co-opted these genes independently, in two separate events that took place millions of years apart. And yet, both events gave rise to similar genes that do similar things: Another team showed that the fly versions of Arc also sends RNA between neurons in virus-like capsules. “It’s exciting to think that such a process can occur twice,” says Atma Ivancevic from the University of Adelaide.

This discovery has medical implications, too. Arc has been implicated in many brain disorders, like Alzheimer’s, schizophrenia, and Fragile X syndrome. It might also be involved in the mental declines that accompany aging. Shepherd says that young mice produce lots of Arc protein, and old mice make much less. If he artificially boosts Arc protein levels in the visual centers of the brains of old mice, he can make them as responsive to new experiences as those of younger rodents.

“This may be the tip of a giant iceberg,” says Harmit Malik from the Fred Hutchinson Cancer Research Center. It’s entirely possible that animals which lack Arc genes, such as fish, “use entirely different domesticated gag proteins to achieve the same purpose.” Indeed, the human genome has more than 100 gag-derived genes. What are they all doing?

This is part of a broader trend: Scientists have in recent years discovered several ways that animals have used the properties of virus-related genes to their evolutionary advantage. Gag moves genetic information between cells, so it’s perfect as the basis of a communication system. Viruses use another gene called env to merge with host cells and avoid the immune system. Those same properties are vital for the placenta—a mammalian organ that unites the tissues of mothers and babies. And sure enough, a gene called syncytin, which is essential for the creation of placentas, actually descends from env. Much of our biology turns out to be viral in nature.

* This article has been corrected to reflect the fact that Arc genes were co-opted by animals from a group of genes that also gave rise to retroviruses, and are not directly descended from retroviruses, as originally stated. We regret the error.

Mammals Made By Viruses

If not for a virus, none of us would ever be born.

In 2000, a team of Boston scientists discovered a peculiar gene in the human genome. It encoded a protein made only by cells in the placenta. They called it syncytin.

The cells that made syncytin were located only where the placenta made contact with the uterus. They fuse together to create a single cellular layer, called the syncytiotrophoblast, which is essential to a fetus for drawing nutrients from its mother. The scientists discovered that in order to fuse together, the cells must first make syncytin.

What made syncytin peculiar was that it was not a human gene. It bore all the hallmarks of a gene from a virus.

Viruses have insinuated themselves into the genome of our ancestors for hundreds of millions of years. They typically have gotten there by infecting eggs or sperm, inserting their own DNA into ours. There are 100,000 known fragments of viruses in the human genome, making up over 8% of our DNA. Most of this virus DNA has been hit by so many mutations that it’s nothing but baggage our species carries along from one generation to the next. Yet there are some viral genes that still make proteins in our bodies. Syncytin appeared to be a hugely important one to our own biology. Originally, syncytin allowed viruses to fuse host cells together so they could spread from one cell to another. Now the protein allowed babies to fuse to their mothers.

It turned out that syncytin was not unique to humans. Chimpanzees had the same virus gene at the same spot in their genome. So did gorillas. So did monkeys. What’s more, the gene was strikingly similar from one species to the next. The best way to explain this pattern was that the virus that gave us syncytin infected a common ancestor of primates, and it carried out an important function that has been favored ever since by natural selection. Later, the French virologist Thierry Heidmann and his colleagues discovered a second version of syncytin in humans and other primates, and dubbed them syncytin 1 and syncytin 2. Both virus proteins seemed to be important to our well-being. In pre-eclampsia, which gives pregnant women dangerously high blood pressure, levels of both syncytin 1 and syncytin 2 drop dramatically. Syncytin 2 also performs another viral trick to help its human master: it helps tamp down the mother’s immune system so she doesn’t attack her baby as a hunk of foreign tissue.

In 2005, Heidmann and his colleagues realized that syncytins were not just for primates. While surveying the mouse genome, they discovered two syncytin genes (these known as A and B), which were also produced in the same part of the placenta. This discovery allowed the scientists to test once and for all how important syncytin was to mammals. They shut down the syncytin A gene in mouse embryos and discovered they died after about 11 days because they couldn’t form their syncytiotrophoblast. So clearly this virus mattered enormously to its permanent host.

Despite their name, however, the primate and mouse syncytins didn’t have a common history. Syncytin 1 and 2 come from entirely different viruses than syncytin A and B. And the syncytin story got even more intricate in 2009, when Heidmann discovered yet another syncytin gene–from an entirely different virus–in rabbits. While they found this additional syncytin (known as syncytin-Ory1) in a couple different species of rabbits, they couldn’t find it in the close relative of rabbits, the pika. So their own placenta-helping virus must have infected the ancestors of rabbits less than 30 million years ago.

Now Heidmann has found yet another virus lurking in the ancient history of mammals. This one is in dogs and cats–along with pandas and hyenas and all the other mammals that belong to the so-called carnivoran branch of the mammal tree. In every carnivoran they’ve looked at, they find the same syncytin gene, which they named syncytin-Car1. In every species it is strikingly similar, suggesting that it’s experienced strong natural selection for an important function for millions of years. But it’s missing from the closest living relative of carnivorans, the pangolins. The diagram here, from the authors, shows how they see this evolution having unfolded. After the ancestors of carnivorans split from other mammals 85 million years ago, they got infected with a virus which eventually came to be essential for their placenta.

The big picture that’s now emerging is quite amazing. Viruses have rained down on mammals, and on at least six occasions, they’ve gotten snagged in their hosts and started carrying out the same function: building placentas. The complete story will have to wait until scientists have searched every placental mammal for syncytins from viruses. But in the meantime there is something interesting to consider. Some mammals that scientists have yet to investigate, such as pigs and horses, don’t have the open layer of cells in their placenta like we do. Scientists have come up with all sorts of explanations for why that may be, mainly by looking for differences in the biology of each kind of mammals. But the answer may be simpler: the ancestors of pigs and horses might never have gotten sick with the right virus.

(For more information on our inner viruses, see this 2010 story I wrote for the New York Times and my book from last year, A Planet of Viruses.)

[Top image: Leonardo da Vinci’s sketch of a human fetus. From Universal Leonardo]