Carrie Arnold is a contributing writer for Noema based in Virginia.
Sixty-six million years ago, a massive space rock collided with Earth and turned our planet into a smoking hellscape. This millennia-spanning cataclysm spelled the end of the dinosaurs, creating an opening for a small group of survivors — a hairy, warm-blooded group of critters that we call mammals. The catastrophic extinctions that enveloped the planet left an opening that the surviving mammals exploited.
But another event in deep history time also had a major impact on mammals, although it would never leave evidence in the fossil record. It happened when a small mammal got a virus. Compared to the surrounding apocalypse, a shrew-like being with the sniffles would normally be a pretty insignificant event. But something weird would happen with this virus, changing life on Earth almost as much as the dinosaur-ending asteroid.
This shrew-like mammal had been infected with a retrovirus, so named because they use a special enzyme to transform their RNA back into DNA (the opposite of the usual DNA-to-RNA direction). Like all viruses, a retrovirus depends on the cellular machinery of its host to copy itself. Unlike other viruses, however, the retrovirus must elbow its way into the genome of a host cell before it can begin replicating.
This process allows the virus to create long-term, smoldering infections, churning out trillions of tiny facsimiles during the host’s life. As long as the virus only infects standard body cells, the genetic intrusion ends with the infected cells’ death. The retrovirus infecting the ailing proto mammal, however, managed a rare feat and instead inserted itself into its sperm or egg cells. When the shrewish being had offspring, it passed along its own DNA, with a small viral bonus thrown in.
These types of evolutionary extras are usually harmful. If I were handed a wrench or crowbar and asked to do something to my car, the chances that I would improve it by giving it a random metallic thwack are slim. Sometimes, however, the stars align. The extra viral proteins provided some extra raw materials that natural selection could tinker with, ultimately leading to one of the mammals’ most iconic features. The placenta resembles a meaty pillow and provides a connection between the fetus and mother, but this connection was not yet complete. A retroviral protein that appeared from the sick shrew-like entity helped maternal and fetal cells merge in a single layer, increasing the nutrient transfer to the next generation. Tens of millions of years later, the syncytin gene hasn’t changed and still functions as a merge machine.
Anyone who reads papers about natural selection gets used to thinking, “WTF, evolution?!?” Some species of orchid look like female wasps to trick males into pollinating them while the insects try to mate with the flower. Peacock feathers and other ostentatious avian plumage make daily life cumbersome for males but are also irresistible to potential mates. Some types of sea cucumbers breathe with their anus.
Over the years, I had come to accept that the trillions of microbes that live in and on our bodies are an inextricable part of our own biology. I knew that our ability to withstand infection played an outsize role in how we evolved. But the placenta? Something as essential as the placenta existed because of a virus? Nearly a decade after I first stumbled across this fact, it still blows my mind. And syncytin is no oddity. As much as 8% of the human genome is actually from retroviruses.
“Endogenous retroviruses can be viewed almost as fossils that tell us something about how viruses have impacted the genomes of humans and other animals. It’s data where you can look into the past, just like bones and tools embedded in rock,” Welkin Johnson, an evolutionary virologist at Boston College, told me.
Scientists have begun learning that not only do the viruses in our genomes capture the history of human evolution, but they also continue to play a role in everything from infection control to neurons, from our earliest hours as fertilized eggs to our last breaths before death. Viruses, then, aren’t just temporary infections we contract. They aren’t an anomaly. Viruses are our default state. Emerging research is showing that much of our biology and physiology depend on these genetic fossils littering our genomes, and it’s changing the way we think of viruses — and ourselves.
“Bacteria have viruses. Even some viruses have viruses,” says Aris Katzourakis, an evolutionary virologist at the University of Oxford. “It’s viruses all the way down.”
“A shrew-like being with the sniffles would normally be a pretty insignificant event. But something weird would happen with this virus.”
Inheritance Goes Viral
Scientists have long turned to mice, rats and fruit flies to answer fundamental questions about biology. In the 1960s, chickens were also popular research subjects. For one, our feathered friends were easy to breed and keep in labs. As a bonus, their importance in the meat industry made understanding their genetics and physiology an economically crucial endeavor.
Solving these problems wasn’t just a boon for farmers — work on chickens resulted in major scientific breakthroughs. In the early 1900s, an elderly Long Island woman showed up on the doorstep of pathologist Francis Peyton Rous of New York’s then Rockefeller Institute for Medical Research, her gnarled, arthritic hands clutching a barred Plymouth Rock hen that had grown a tumor on its right breast. Rous was unable to save the bird, but his work in understanding what had killed it led to the discovery of infectious viruses that could cause cancer.
Although the Rous sarcoma virus, as it’s known, was the first such virus discovered, plenty of others would soon join its ranks, including the human papillomavirus (HPV, implicated in cervical cancer), the feline leukemia virus, and hepatitis B and C (which can cause liver cancer in humans).
These viruses and the cancers they caused were transmitted horizontally, passed from individual to individual via blood or body fluids. Vertical transmission — inheritance from parent to offspring — didn’t happen. So, scientists expected a similar pattern of horizontal transmission of the avian leukosis virus, which caused leukemia (a cancer of the white blood cells) in egg-laying hens.
By the 1960s, farmers were trying to breed flocks free of avian leukosis. At the time, Robin Weiss was studying retroviruses for his doctorate at University College London and thought this would be a good subject for his thesis. But as Weiss pored over the breeder’s meticulous records, he noticed something unusual: The patterns of which chickens got sick didn’t look like it was caused by an infection but rather something heritable. What he had discovered was the first endogenous retrovirus — viral genes that became incorporated into the host genome and were passed along just like any other gene.
The discovery opened the floodgates. Less than two decades later, researchers would find endogenous retroviruses in the human genome, too. As researchers raced to unscramble the billions of As, Ts, Gs, and Cs that make us, well, us, it became clear that virus-like elements were not only not rare, but that they actually comprised nearly half our genome. Aside from the nearly 10% of DNA that was from endogenous retroviruses, researchers found other repetitive, viral-derived elements such as transposons and retrotransposons (so-called “jumping genes”) that comprised a whopping 44% of our genome.
“These elements are often in a race to replicate more quickly than they can be inactivated,” says Katzourakis.
Initially, scientists wrote these elements off as “junk DNA.” Any once-functional sequence had accumulated so many mutations that it became the heritable equivalent of alphabet soup. Our chromosomes merely lugged these base pairs along like genomic baggage, generation after generation, never fully able to divest themselves of these viral parasites. Then came another chance discovery that would change everything.
How To Build A Placenta
As a pharmaceutical researcher, John McCoy had a single goal: He wanted to find the proteins and molecules secreted by cells. If these were linked to disease, they might be amenable to pharmaceutical treatment. Since McCoy wasn’t looking for a specific protein, he did the scientific equivalent of flinging a plate of pasta at the wall and seeing what would stick. One of the first signals he found was of a protein secreted by placental cells. Scientists were, just then, finishing up the draft sequence of the human genome, and although that data could pinpoint the location of the gene that coded for this placental protein to somewhere on chromosome 7, no one knew more than that.
Even to McCoy’s trained eye, the gene sequence was an unintelligible series of nucleotides. It told him nothing about what the protein did. To learn more about what the protein did, he performed a BLAST search, a kind of ersatz Google for the genomics crowd. He was hoping biologists working in mice or worms or fruit flies had found something similar. Indeed, the BLAST search turned up genes that were nearly identical to McCoy’s mystery find. But the genes weren’t from mammals or even vertebrates. They were from viruses.
“Viruses, then, aren’t just temporary infections we contract. They aren’t an anomaly. Viruses are our default state.”
“This was a retrovirus,” McCoy said. “And it’s expressed like gangbusters in the placenta.” Flanking it were two other viral genes (known as Gag and Pol) that had racked up so many mutations that they were nearly unrecognizable. But there sat a retroviral gene scientists called Env, short for “envelope,” nary a change in site. McCoy immediately recognized that our bodies were actively using this gene to do something. And McCoy needed to find out what.
In a retrovirus, the Env protein allows the virus to attach to a host cell, fusing with the host cell membrane and dumping the viral machinery. Since the gene McCoy found hadn’t really changed, he knew it had to be doing something similar in humans. He purified the protein and then added it to human cells growing in a tube. After letting the cultured cells marinate, McCoy took a peek under the microscope.
The changes were obvious. Instead of a layer of discrete cells jammed together, McCoy saw a single flat ur-cell with thousands of nuclei in a single membrane. Further experiments revealed that the forces of natural selection in the placenta had MacGyvered the viral protein into helping to fuse maternal and fetal cells in a layer called the syncytiotrophoblast. McCoy called the protein syncytin, in a nod to its function.
His results were mind-boggling, even unbelievable. When he submitted his findings to the journal Nature, editors initially rejected it, asking for more experiments that McCoy was unable to perform. It took over a year for the paper to finally be accepted and published in 2000.
“This paper has sparked a lot of work, and it’s been kind of cool to watch it grow,” says McCoy.
Perhaps the most incredible part of the syncytin story, Katzourakis says, is that it has happened several times. Humans carry two syncytin genes, from two different viruses. All told, scientists estimate that mammals evolved a virus-derived syncytin protein at least seven times over the course of evolution, with different viruses giving rise to different syncytins and, consequently, different placentas. And lest Y-chromosome carriers feel left out of the syncytin game, French scientists found that the presence of the syncytin protein increases muscle size in male mice. It makes sense, says McCoy, since building muscle mass involves a merging of cells not unlike what occurs in the placenta.
If syncytin alone were the only example of a viral influence on humanity, it would still be a pretty big deal. From an evolutionary standpoint, it’s harder to get more crucial than reproduction. But the influence of these endogenous retroviruses is larger and more nuanced than McCoy ever anticipated.
New Viruses On The Block
The first signs of disease are easy to miss, even for a watchful farmer. Affected sheep begin panting and show difficulty breathing. These symptoms can indicate anything from a mild respiratory infection to something more serious. The disease caused by Jaagsiekte Retrovirus is one of the latter. Infections don’t cause pneumonia but rather an infectious lung cancer known as ovine pulmonary adenocarcinoma.
Like all retroviruses, Jaagsiekte inserts itself into the genome of the cells it infects. The virus can cause cancer because the Env protein it uses to enter lung cells can also cause these same cells to replicate out of control. From a viral perspective, rapidly multiplying host cells is an all-you-can-infect buffet of vulnerable targets. To the unlucky sheep, however, the out-of-control dividing lung cells mean cancer.
Jaagsiekte is passed from animal to animal primarily by respiratory droplets formed during sneezing and breathing, not unlike the common cold or Covid-19. Each infected sheep develops cancer anew, from the virus it was unfortunate enough to inhale. The disease is fantastically lethal, slowly suffocating affected sheep and goats. For farmers, it became crucial to identify sheep that are resistant to Jaagsiekte.
Initially, virologists guessed that those few sheep that didn’t get sick after infection carried a mutation that prevented the virus’s genetic key from picking their cellular lock. What they found in the DNA of these resistant sheep, however, was a copy of the Jaagsiekte retrovirus itself.
The endogenous version of the Jaagsiekte retrovirus remains functionally intact, continuing to produce active copies of the virus. And these internally produced viruses protect the animal from the externally-circulating version by occupying the molecular lock the virus uses to enter the cell. If enough sheep inherit this gene, then it could drive the exogenous, infectious Jaagsiekte virus to extinction.
“As it turns out, our immune systems, our synapses, our placentas and embryos, are all driven by viruses.”
John Coffin, a retrovirologist at Tufts University in Boston, suspects that something analogous happened in humans. While we share many endogenous retroviruses with our ancestors, a small number of viral elements littering our genome appear to be uniquely human. These elements are members of a group known as HERV-K and HERV-H (for Human Endogenous RetroVirus) and unlike most of their relatives, don’t appear in the genomes of chimps and bonobos, our nearest relatives. This must mean infection of the genome occurred in the last million-plus years.
Infection with these human-specific HERV-K elements, in particular, is so recent (scientists estimate that it happened around 200,000 years ago — an evolutionary eyeblink) that the gene can still produce functional virus protein if it’s switched on. But when virologists tried to find relatives of the culprit among currently circulating retroviruses, they came up empty. Nothing like it seemed to exist. Coffin knew it had to exist at some point, otherwise, how would it have ended up in our DNA? He suspects the answer is that the HERV-K’s infiltration of our genome spelled the doom of the circulating version of the virus.
“That may be the reason that we no longer have any of these viruses infecting us,” he says.
From an evolutionary perspective, it was a win-win situation. Humans got immunity from a pathogen, and the virus’s genetic material could infect every human on the planet. To virologist Cedric Feschotte of Cornell University, this phenomenon is another example of how viruses continue to mold our physiology. Besides bolstering immune function, a 2018 paper showed that a neuronal protein called Arc, found in fruit flies and humans alike, originated as a retroviral Gag protein.
In animals, Arc regulates the formation of connections between neurons known as synapses. This synaptic plasticity is key to our ability to think and form memories. And developmental biologists have found that, in the hours after fertilization, waves of activation of the endogenous retroviruses buried in our genomes help to transform a humble sperm and egg cell into one that can — and will — give rise to every type of the body’s over 400 different varieties of cell. A paper published by Feschotte’s lab in April 2024 on bioRxiv, which has yet to be peer-reviewed, shows that development can’t occur without the activity of these viral elements.
“They are surprisingly required for some very fundamental developmental processes,” Feschotte told me.
But a piece of DNA with the ability to make infinite copies of itself and shove its way at random into the genome can be a dangerous thing. Interrupt the wrong gene, as with Jaagsiekte retrovirus or Rous Sarcoma Virus, and cancer can occur. Other errors can kill a cell outright if it can no longer perform its basic functions. As a result, most animals keep these segments of DNA hidden away from the molecular machinery that turns genes into proteins.
Sometimes, though, mistakes happen. Aging cells and those that have become cancerous are more likely to have endogenous retroviruses that are actively being transcribed. These viral fragments are innocuous — they don’t create an infectious virus and they can’t make copies of themselves.
But these protein pieces still hearken back to their viral origins and can trick the immune system into thinking the cell has been infected and should be eliminated, a process known as viral mimicry. Cancer biologist Charles Spruck at La Jolla’s Sanford Burnham Prebys Medical Discovery Institute found that activating viral mimicry in mouse tumor cells would make tumor cells ideal targets for both anti-cancer drugs and for targeting for death by the body’s own immune system.
“These discoveries are changing how we think of many diseases,” says Zsuzsanna Izsvák, a biologist at the Mex Delbrūck Center in Germany.
Forged By Viruses
As it turns out, our immune systems, our synapses, our placentas and embryos, are all driven by viruses. And though the biologist in me will never not geek out about this fact (the mother-freaking placenta is due to a virus!), another part of me wants to know “So what?” Especially as the world begins to emerge from the havoc still being wreaked by Covid-19, it directly contradicts the viruses-are-bad paradigm to which we’ve become accustomed.
Our discussions of viruses are filled with martial metaphors. We do battle with pathogens that breach our defenses. They are the enemy, and our bodies must outwit and outlast their attacks. My inbox is filled with pitches from PR professionals trying to sell antiviral hand sanitizers and air purifiers. The bottle of cleaning spray I use on my countertops advertises that it kills 99.9% of bacteria and viruses. If we want to stay alive, then viruses and bacteria need to be dead.
“If you want to look for new biology, you have to look at viruses.”
The thousands of viral relics in our genome tell a much different story. Our massive noggins — including the one I’m using to write this piece — can do so much thinking because viruses have enabled our neurons to make and break connections. Humans have used these folded, wrinkly, virus-driven gobs of goo to invent everything from calculus to Chia Pets. Yes, we get colds and gastrointestinal bugs and meningitis, but we wouldn’t be able to care about viruses without the help of a virus. Despite their outsized importance, little real estate in introductory biology classes is devoted to the subject.
“There’s no chapter in a textbook about this. It might get a brief mention, and they’ll certainly discuss how viruses themselves evolved, but there’s less attention paid to how viruses have influenced the evolution of life,” Johnson says.
It’s a major oversight, agrees Feschotte.
Our viral past is a permanent reminder of our deep histories, of how so much of evolution’s inventions emerged from biological junk drawers filled with spare genes and proteins.
“Viruses are the motor of genetic novelty. If you want to look for new biology, you have to look at viruses,” Feschotte says. “They need the host, but we are finding more and more that the host needs them as well.”
