On January 30, Arkansas senator Tom Cotton tweeted that although he didn’t know where the novel coronavirus, SARS-CoV-2, originated, he wanted to point out that “Wuhan has China’s only biosafety level-four super laboratory that works with the world’s most deadly pathogens to include, yes, coronavirus.”
He was implying, as other conspiracy theorists have continued to do, that the new virus was intentionally made and released (ignoring the fact there are many “level-four super laboratories” around the world). Politicians, including Donald Trump, continue to call SARS-CoV-2 the “Chinese virus” or “Wuhan Virus.”
But the origins of viruses, and how they come to infect humans, are almost always more complicated than a couple of evil geniuses secretly creating infectious killers. Viruses mutate constantly, playing the equivalent of a genetic slot machine until they chance upon the winning genetic sequences to allow them to jump from animals into humans, and be infectious enough to spread their genetic information far and wide.
While there’s still so much uncertainty about the COVID-19 pandemic—how long it will last, what treatment options might work, when a vaccine will arrive, there are actually a lot of things that we do know about the virus, through genetics and structural biology—including where it came from.
In a new paper in Nature Medicine, scientists from the U.S., Australia, and the U.K. analyzed the virus closely—outlining its likely origins and exactly how and why it seems to be more infectious than previous coronaviruses, like SARS or MERS. Their research also provides a resolution to the “made-in-a-lab” speculation. Kristian Andersen, an associate professor of immunology and microbiology at Scripps Research, said in a press release: “We can firmly determine that SARS-CoV-2 originated through natural processes.”
“Seeing that kept me up all night”: This virus is different from other coronaviruses
You can tell a lot about a virus from its genome—what kind of virus it is, and how closely related it is to viruses you already know about. The genetic sequence to SARS-CoV-2 was made available very quickly by Chinese scientists, allowing researchers all over the world to see what made the new virus tick.
Coronaviruses get their name from spikes that cover their surface that look a bit like the sun’s corona. Those spikes are key to how the virus infects a human cell and two integral parts of the new virus’s spikes are slightly different from those of previous coronaviruses. These differences could help us understand how it’s spreading farther and infecting more people.
The first change is in the receptor-binding domain. This is part of the spike that binds to a human cell—for this virus it attaches to ACE-2, a cell membrane enzyme that regulates blood pressure.
We already knew that the 2003 SARS binding could bind pretty tightly to ACE-2. But in a Science paper this month, researchers using cryo-electron microscopy revealed that the new virus’s spike was better. It binds to the ACE-2 receptor 10 times more tightly than a SARS virus does. This difference is made possible by small variations in structure to the receptor binding domain.
The second adaptation in the new coronavirus is a part of the spike called the cleavage site. The spike is a folded up-bundle, and it has to be cleaved, or cut, in a specific place to pop open, like releasing a spring. After being cleaved, the spike is used to grab onto a human cell.
The cleavage site is made up of small amino acid sequences that are recognized by cellular enzymes called proteases, enlisted to do the cutting. These molecular scissors are different for each coronavirus. SARS-CoV-2’s cleavage site is made of amino acids that attract an enzyme called furin. Our bodies make furin in a lot of different tissues, but in particular, in the upper respiratory and lower respiratory tract.
When a virus has a cleavage site that attracts furin to do the cutting, it becomes more dangerous. To compare, influenza viruses are often cleaved and activated by enzymes called trypsin, “which are typically restricted to certain tissues and organs,” said Jean Millet, a microbiologist at the Molecular Virology and Immunology unit of INRAE, located in France, who wasn’t involved in the paper.
Experiments with avian influenza virus have shown that if they evolve a furin cleavage site, they become much more infectious. Having a furin cleavage site means that the virus is able to replicate more, and in different tissues. It can easily go into the lower respiratory tract. It may be one of the reasons that people develop pneumonia—though this hasn’t been proven for certain.
“Seeing that in the new SARS-CoV-2 when those sequences came out for the first time actually kept me up all night,” said Bob Garry, an assistant professor of microbiology and immunology at Tulane University School of Medicine and co-author of the Nature paper.
We know it didn’t come from a lab because it’s more effective than anything any human could have come up with
These changes may be alarming, but they’re also how we know this virus wasn’t designed in the lab. Simply put, the adaptations—specifically the binding to ACE2—are just too good for a human to have come up with it.
Computer programs that scientists use to model the interactions between a virus’s spike and ACE-2 don’t predict that the receptor SARS-CoV-2 has would work very well. And yet, it does—as Wrapp found, 10 times better. It’s an indication that the alterations in the binding were selected for through natural selection, not genetic engineering.
“You couldn’t predict that with any computer program,” Garry said. “Nature usually is better at doing things than we can figure out with a computer these days. That’s pretty good evidence that this virus did evolve to bind to human ACE-2 on its own. Nobody helped it. If somebody had designed it, they would have used a different solution.”
I asked if there was any possibility some evil-genius person out there, with a different computer algorithm, could have come up with it. “Like in the comic books? It doesn’t seem likely,” Garry said.
“This is a convincing argument,” Millet confirmed. “SARS-CoV and SARS-CoV-2 do bind the same receptor but they do so in different ways that is most likely through an evolutionary process whereby each virus has ‘figured out’ different ways to do so…This goes against the notion that someone or a group would have intentionally used the SARS-CoV sequence to generate a new virus.”
Additionally, if someone wanted to make a coronavirus, they would use another virus as a building block, Garry said. But the virus that is closest to SARS-CoV-2 is a bat virus that wasn’t discovered until after the outbreak. There’s no evidence from the SARS-CoV-2 genome that any other virus was used as a backbone to make something new.
Where and when it came from
Viruses mutate at a steady rate, and so as they spread, researchers can look at how many adaptations they’ve acquired and count back in time to figure out when it appeared. Co-author Andrew Rambaut, professor of Molecular Evolution at University of Edinburgh, did this, and found that SARS-CoV-2 sprung up in humans in either late November or early December—which makes sense given it was December 31 that Chinese authorities told the World Health Organization about the outbreak.
That’s the “when,” but it doesn’t tell us where exactly it came from. In the SARS epidemic from the early 2000s, the virus transferred directly from a civet cat to humans. “It didn’t have to adapt,” Garry said. “It was already good to go.” With MERS, it was a similar story—the same virus that infected camels got passed to humans.
SARS and MERS didn’t transmit between people as well as the new coronavirus does. That could be because SARS-CoV-2 has adapted more to humans—meaning it didn’t just jump from an animal, but first adapted to infect us better. “I could be proven wrong tomorrow,” Garry said. “Somebody could find an animal out there that has a virus that’s identical to SARS-CoV-2. I don’t think that’s going to happen.”
The closest virus to the new coronavirus is a bat virus, RaTG13, which is 96 percent similar. Yet it’s missing one crucial thing: its spike has a different receptor binding domain, not the defining one that SARS-CoV-2 has. Intriguingly, another recently discovered virus, from the pangolin, a scaly anteater, is less like SARS-CoV-2 overall, but does have a strongly similar receptor binding domain.
Garry said that because of this, he and his co-authors think it’s possible that SARS-CoV-2 is a recombinant virus, meaning it’s a combination of two different viruses that shared their genetic information. This is like a couple moving in together and combining their kitchen appliances. Suddenly they have access to tools they didn’t before—a Vitamix and a food processor. A coronavirus might have been able to gain the enhanced receptor binding and then mutated further until genetic luck brought it the furin cleavage site.
What we don’t know is the specifics of where or when this recombination and other mutation occurred. It could have happened while the virus was still in an animal—then, after the furin cleavage adaptation, it was able to jump into humans and spread rapidly afterwards. Another possibility is that a previous non-pathogenic version of the virus was circulating in people for some time before the mutation at the cleavage site occurred and it started spreading rapidly. What we can say is that it’s more complicated than just a “Chinese” or “Wuhan” disease. It’s a virus that has changed and mutated many times, possibly from different animal sources, or within our own bodies, and with genetic good fortune, happened upon the right adaptations to take hold.
How all this information helps us
We won’t know the virus’s origins for sure until we have more data, but the answer could be a predictor of what’s to come. If SARS-CoV-2 achieved its adaptations in animals, there’s more of a risk for future similar outbreaks. If it adapted while already in humans, it’s less likely those same mutations will happen again—just based on probability. Either way, we learn more about the many ways viruses make it into our lives.
“The significance is that now we know that there’s a new way you can get a pathogenic coronavirus through recombination,” Garry said. “Spread or passage doesn’t have to be a direct jump from an animal.”
Figuring out the origins of SARS-CoV-2 and how it works will be important the next time another new coronavirus emerges.
If we can understand what types of coronaviruses—with what types of features—are in animals now, it would make it easier to look at a virus’s genome sequence and determine where it got its features from, or how its spike might bind to our cells. One way to do this would be to start gathering information about the coronaviruses that are in many kinds of animals now. Bat coronaviruses, for example, are incredibly under-sampled, Garry said. “We know that the diversity of coronaviruses in bats is a lot more than what we know about right now. Just figuring that out would be important.”
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