Prehistoric Viruses and the Function of the Brain

The exceedingly strange story of learning, memory and the “Arc” gene

Prehistoric Viruses and the Function of the BrainYou might be forgiven for having never heard of the NotPetyacyberattack. It didn’t clear out your bank account, or share your social media passwords, or influence an election. But it was one of the most costly and damaging cyberattacks in history, for what it did target: shipping through ports. By the time the engineers at Maersk realized that their computers were infected with a virus, it was too late: worldwide shipping would grind to a halt for days. Imagine a similar situation, in which the target was another port: the synapse, the specialized port of communication between neurons. Much of our ability to learn and remember comes down to the behavior of synapses. What would happen then, if one neuron infected another with malware?

Ports and synapses both run on rules, meant to ensure that their cargo can be exchanged not only quickly and reliably, but also adaptably, so that they can quickly adjust to current conditions and demands. This ‘synaptic plasticity’, is fundamental to the ability of animals to learn, and without it we would no more be able to tie our shoes than to remember our own names. Just as shipping rules are determined by treaties and laws, the rules of synaptic plasticity are written into a multitude of genes in our DNA. For example, one gene might be involved in turning up the volume on one side of the synapse, while another gene might ask the other side of the synapse to turn up the gain. Studying the function of these genes has been one of the core approaches to understanding what it is, at the microscopic level, to learn and to remember.

One of these genes, known as Arc, is so critical to these processes that it has often been called a ‘master-regulator’ of synaptic plasticity. Without Arc, synapses fail to adapt, and animals fail to learn. Nevertheless, exactly how Arc is involved in these processes has remained frustratingly mysterious—at least until now. The key insight in the Arc story comes from a careful study of the DNA sequence of the Arc gene, which contains stretches that look eerily similar to those found in ancient viruses. This by itself is no great surprise: roughly half of the human genome seems to have a similar evolutionary origin. What is surprising though, is that Arcstill seems to act like a virus. Viruses are tiny infectious agents that invade cells, bringing foreign genetic material with them. Arc works in a similar way: rather than simply asking the other side of the synapse to turn up the gain, Arc packages the raw genetic material to do so, and then visits the other side of the synapse in person. Effectively, Arc ‘infects’ other neurons with the raw materials of memory.

If it sounds strange, that’s because it is. This groundbreaking discovery, reported earlier this year by two groups in Cell, is undoubtedly the first in a new line of research on learning and memory. Scores of laboratories all over the world are focused on understanding the rules controlling how neurons communicate across the synapse. This finding challenges our basic understanding of that communication, and its reverberations might therefore be felt in every field in neuroscience. To return to the analogy of ports, this would be like discovering that the most precious containers on the docks had been unloaded not only in the dead of night, but by submarines.

Here’s what we know so far about how it works: After a neuron is stimulated, the Arc gene gets turned onArc produces a protein that takes on a shape like a virus. Let’s call it the Arc-virus. The Arc-virus soaks up genetic material—in a sense, biological software from around the activated neuron. Once full, the Arc-virus is secreted by the activated neuron and taken up by other neurons in the neighborhood. Then it ‘infects’ them with whatever biological software it carries. It could be the raw material for memory. It could just as easily be biological malware. At this point, we don’t know exactly what the Arc-virus is delivering, or whether it could be delivering different cargo at different times. But this function seems to be ancient, in the evolutionary sense: Arc works in a similar fashion right across the tree of life, from flies to humans. In other words, the ability of Arc to act like a virus may be fundamental to the ability of animals to learn.

More broadly, the discovery of a new means by which neurons can exchange genetic information has no shortage of important implications. For starters, this discovery demands an investigation into whether and to what extent the Arc story might generalize. It could be that Arc is the only gene with this behavior; or it could be just the tip of the genomic iceberg. Regardless of whether or not Arc ends up being a curiosity or a new rule, it offers an incredible new therapeutic angle—our bodies are making something like their own viruses, and harnessing them could provide a new vehicle to deliver medicine (including snippets of genetic material) without the danger of rejection by our immune systems. Then there’s the fact that Arc has been implicated in a variety of neurological diseases and conditions, ranging from Fragile X syndrome to Alzheimer’s disease. The Arc study will be an invaluable corner piece for those puzzles.

Today we know that much of learning, from the synaptic to the behavioral levels, comes down to the detection of coincidences—and it is the type and degree of coincidence that differentiates a sticky idea from one that is truly infectious. How apt then, that the Arc story begins with prehistoric viruses and ends with another coincidence: in the summer of 2017, while NotPetya was spreading like wildfire through the world’s shipping infrastructure, the Arc studies were packing their bags to head to press, ready to go viral. You might even remember hearing about it at the time; if so, Arc had something to do with it.