Probing Evolution

Is Memory a Virus? How Retroviruses Shaped the Human Mind

When brains evolved by virtue of viruses.

All land animals have an Arc gene in their brain. This gene serves as the “master regulator” that determines how neuronal synapses (i.e., neuronal connections) form in the brain.

Two independent research groups [1,2] have published their findings in the prestigious academic journal, Cell, in 2018 — showing that Arc behaves like viruses and has ancestral roots in retroviruses.

Function of Arc

In a sense, the Arc gene moulds and sculpts the brain connections — forming the mind — making amphibians think like amphibians, birds like birds, reptiles like reptiles, monkeys like monkeys, and humans like humans.

As the experts in the field, Dr. Nicholas Parrish and Prof. Keizo Tomonaga put it: “These processes underlie brain functions ranging from classical operant conditioning to human cognition and the concept of ‘self’.”

If there are any genetic issues with the Arc gene, brain development and learning capacity become jeopardized. “Arc has previously been implicated in autism and other neurodevelopmental disorders,” as Dr Parrish and Prof Tomonaga stated.

Mice with defective Arc genes cannot learn new stuff, indicating faulty synaptic connections. “If you take the Arc gene out of mice, they don’t remember anything,” explains Jason Shepherd, associate professor of neurobiology at the University of Utah, and a pioneer in the study of Arc. “I can see what people are thinking: Is memory a virus?” Shepherd laughed.

Origin of Arc

Shepherd then led a team to conduct evolutionary analyses to probe the origin of the Arc gene. After extensive bioinformatics work, they showed that Arc arises — or has descended — from the Gag gene of retroviruses, a class of viruses encompassing human immunodeficiency virus (HIV), lentivirus, and others.

“These findings suggest that Gag retroelements have been repurposed during evolution to mediate intercellular communication in the nervous system,” the study authors, led by Shepherd, wrote in Cell.

Retroelements are also known as “jumping genes” that are capable of integrating themselves into the genome of other organisms. What an “astonishing contribution of retroelements to even the most complex physiological functions of multicellular organisms,” Parrish and Tomonaga added. And, if the human brain isn’t enough, retroviruses have aided the evolution of the mammalian placenta as well:

And their analysis also revealed that the Arc gene is only found in the brain of land and not marine animals. “One explanation is that when animals moved onto land, there were all these new environments they had to adapt to — so you needed a smarter brain and a more plastic brain. Perhaps that is why Arc is so useful: It can give that extra plasticity or some sort of advantage,” Shepherd hypothesized.

Arc in Action

To form neuronal synapses or connections, information must be passed from neuron to neuron so that they know where to connect. This information is called the messenger RNA (mRNA) that instructs the neuron on what to do.

Upon receiving the Arc mRNA, neurons do something that is unseen in other mammalian proteins — it builds capsids. The capsid is also a term given to the outer shell of viruses.

This capsid enables the neuron to safely move around [in the extracellular space] and enter into another neuron, passing the Arc mRNA into it. This receiver neuron then does the same. And neuronal connections form one by one until the brain is formed.

Importantly, this Arc gene’s action in the brain has an uncanny resemblance to how viruses infect cells. It resembles how viruses make protective capsids around them to move around and infect other cells. It resembles how viruses integrate their genetic elements into the infected cell. It resembles how viruses instruct the infected cell on what to do — that is to make more copies of the same viruses — as viruses don’t have sophisticated machinery to replicate on their own.

In other words, the Arc gene “infects” neurons via capsid formation — exactly like how viruses infect cells. And the infected neurons receive instructions to form synapses.

“When we [first] looked at them, we thought: What are these things?” asked Shepherd. “Here was a brain gene that makes something that looks like a virus.” Later, to the shock of many, several HIV experts saw the picture of the Arc gene and thought it was HIV trying to infect cells. If Arc and viruses bear functional similarities, it’s not a surprise that they are evolutionarily related.

“Beforehand, if I had said to any neuroscientist that this gene sort of acts like a virus, they would have laughed at me,” Shepherd further commented. “We knew this was going to take us in a completely new direction.”

Future of Arc

Knowing the origin of the Arc gene may not do much. But understanding its function as a means of how neurons communicate and connect to one another may unravel new forms of treatments in the future.

Shepherd has also previously led a study in 2017 demonstrating that older mice have lower activities of the Arc gene than younger mice. Artificially enhancing the Arc gene activities — via genetic overexpression — in the brain, in turn, made the older mice more responsive to novel experiences or visual cues in their surroundings, just like the younger mice.

“These findings provide a mechanism for the loss of excitatory plasticity with age, and suggest that Arc may be an exciting therapeutic target for modulation of the malleability of neuronal circuits,” the 2017 study authors wrote in PNAS, another reputable academic journal.