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Inside the puzzle to reconstruct the history of SARS-CoV-2 and how it spilled over into humans
As the Covid-19 pandemic disrupts the lives of billions around the world, two questions continue to linger: Where did the virus come from, and how did it find its way into humans?
Scientists have been hunting for those answers since the first cluster of unusual pneumonia cases emerged in China in December 2019. Investigating the origin of the novel coronavirus is a daunting task that can be compared with assembling a difficult jigsaw puzzle with most of its pieces missing. But mapping out the virus’s spread is of crucial importance to prevent new epidemics. Discovering where the virus came from could teach scientists and leaders how to avoid the situations where viruses are most likely to be introduced into humans.
The initial puzzle pieces of the Covid-19 pandemic were put together when whole genome sequencing of the virus showed that it shared 79.5% of its RNA with SARS-CoV, the coronavirus that had been responsible for the 2003 SARS outbreak, and was even more similar (96.2% identical) to another coronavirus called RaTG13, which had been previously found in a bat. This strongly suggested that the newly identified SARS-CoV-2 also came from bats.
Some of the earliest cases of Covid-19 were connected to a local seafood market in the city of Wuhan, which seemed to indicate that the market was where the virus made its leap from the winged mammals to humans. But it soon became clear that not all of the early cases could be traced back to the market. Only 66% of the initial 41 patients had been exposed to the location. Notably, the first patient identified (who is not necessarily the first to have acquired the disease) had not been to the market.
Patient zero: a fruitless quest?
At that point, the quest to find the very first person who came down with Covid-19 — the pandemic’s “patient zero” — became quite an unrealistic endeavor, according to scientists. With the majority of people infected with Covid-19 suffering from mild symptoms or no symptoms at all, the virus could have been circulating silently in the population before it garnered the attention of health authorities.
“There’s a window for that. You could look for it when you had very few cases by searching for people that have immunity to the virus,” says Vineet D. Menachery, PhD, assistant professor in the Department of Microbiology and Immunology at the University of Texas Medical Branch. The issue is that now millions of people around the world have been exposed to the virus, so the window for that kind of tracing is closing for the Covid-19 pandemic.
“No matter how good we are as scientists, we may never find it.”
That doesn’t mean scientists aren’t trying. One of the only ways to identify the first infection at this point would be searching through old samples predating the pandemic. “There are biobanks for tissues, blood, nasal swabs… I guarantee that where those collections are, people are looking for SARS-like viruses,” says virologist Robert F. Garry, PhD, a professor of microbiology and immunology at Tulane Medical School. He and his team, for example, are looking into blood samples collected in West Africa, where they’ve been studying Lassa fever and Ebola for 15 years, to try to find antibodies to the new coronavirus to see if it could’ve been circulating there before the pandemic. “So far, nothing to report.”
There are circumstances where finding patient zero is possible. In the 2014 Ebola outbreak in West Africa, for example, scientists reported having found the presumed first person to have been infected, a two-year-old child who died from the disease in a village in Guinea. “Ebola is a highly fatal disease,” says David M. Morens, MD, a medical virologist and a senior adviser to Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases. “If a first Ebola infection happens, it’s probably going to be a serious illness, and everybody in that village is going to know about it.”
Morens says that scientists don’t use the term “patient zero,” because it gives people a false sense that if scientists looked hard enough, they would find that first case. “No matter how good we are as scientists, we may never find it,” he says.
Discarding the possibility of lab manipulation
Although patient zero is an elusive character, scientists have already uncovered other important facts about the origin of the novel coronavirus, particularly about its evolutionary history, adding new pieces to the puzzle.
Garry was one of the authors of an early report about the proximal origin of SARS-CoV-2. “Our group spent quite a bit of time with those original genome sequences, comparing them to other viruses,” he says. The team looked specifically into the spike protein of the novel coronavirus, a large protein that sticks out from the surface of the virus, giving it the appearance of a crown (or “corona” in Latin).
By analyzing the sequence of the spike corresponding to the receptor-binding domain — a part of the spike that binds to the cells it infects — it became apparent that the virus was binding to a receptor (a protein that works like the keyhole that the virus unlocks to get inside the cells) called ACE2, present in various cells of the human body, particularly in the respiratory tract.
This was one of the first scientific articles to state that the virus could not have been constructed in a laboratory, but was a clear result of natural selection. In fact, scientists working on this field think theories that claim the virus was a result of laboratory manipulation are silly. “Why would you spend millions of dollars and months of work to have a team of scientists create something that you could just go to a cave and get from a bat?” Morens asks.
Although patient zero is an elusive character, scientists have already uncovered other important facts about the origin of the novel coronavirus.
When Garry and his colleagues were analyzing the SARS-CoV-2 genome, sequences emerged of coronaviruses found in pangolins, a scale-covered mammal that resembles an armadillo. “The pangolin viruses are kind of interesting because their receptor-binding domain is remarkably similar to the SARS-CoV-2.” This led to initial speculation that the pangolin could have acquired SARS-CoV-2 from bats and then transmitted it to humans, acting as an intermediate host. But, intriguingly, the rest of the genome is not that similar. Garry — who keeps in his office a small pangolin model that showed up in his mailbox one day without a return address — says it’s probably safe to exonerate the scaly anteater from the responsibility of the pandemic.
Taking ‘recombination’ into account
After Chinese scientists released the first SARS-CoV-2 genome sequences in January 2020, a diverse group of researchers working from Belgium, Scotland, China, Texas, and Pennsylvania coalesced in a website called Virological, where they had been posting their own analyses of the data. “It was the quickest international collaboration I’ve ever worked on,” says Maciej F. Boni, PhD, associate professor of biology at Penn State University.
While analyzing the sequence of SARS-CoV-2 and comparing it to other similar viruses to investigate the origin of the pandemic, this group carefully considered the fact that coronaviruses are especially adept at recombination, which is when a virus genome breaks apart and recombines with other viruses to form a completely new virus.
“Coronaviruses are essentially recombining all the time,” says David L. Robertson, PhD, one of the scientists in this collaboration and professor of computational virology and head of bioinformatics at the MRC-University of Glasgow Centre for Virus Research.
He explains what the recombination process looks like: When bats, for example, are infected by different viruses, these distinct viruses can potentially end up replicating in the same cell. Then the viral genome ends up as a mixed-up version of those different viruses. “The problem is that it confounds your ability to look at the evolutionary history of a virus,” Robertson says.
To disentangle which part of the virus genome came from where is no easy job. According to Boni, the scientists took genome sequences from different viruses within the same subgenus of SARS-CoV-2, called the sarbecoviruses, and went through all of them, trying to recreate all possible evolutionary histories where the viruses are mixing and matching different parts of the genome. “It is computationally very intensive, and it requires a lot of computing tricks,” Boni sums up. They also calculate the virus’s evolutionary rate, which is the number of mutations that occur per year. That allows them to determine the point in time when two viruses shared a common ancestor.
By using those techniques, Boni, Robertson, and their colleagues were able to understand the relationship between the novel coronavirus and its closest known relatives: RaTG13 (the aforementioned bat virus sampled in 2013) and a couple pangolin viruses sampled in 2017 and 2019 — the ones whose receptor-binding domain is almost identical to SARS-CoV-2.
The analysis showed that despite the genetic closeness, RaTG13 and SARS-CoV-2 split up quite a long time ago, possibly in 1969. It also suggested that the explanation for the similar pangolin virus receptor-binding domain is that this characteristic was present in the common ancestors of all these related viruses in bats, but it got lost in the lineage leading to RaTG13 due to recombination.
One of the important findings of this study is that the virus probably evolved in bats, where the virus developed the ability to infect humans, as well as other animals, like the pangolin. “The virus is not specifically human-adapted. It’s a bit of a generalist, so it’s able to exploit other species,” Robertson says.
This means SARS-CoV-2 didn’t have to evolve in humans for a long time to gain its current infecting abilities, indicating that its leap into people happened not too long before the outbreak in Wuhan. “We can’t be sure it’s not been in humans for longer, but given how successful it’s been, I think we’d have known about it.”
Another group of scientists reached very similar conclusions by also taking into account the virus recombination proneness. The team led by Rasmus Nielsen, PhD, professor in the Department of Integrative Biology at the University of California, Berkeley, concluded that the bat coronaviruses RATG13 and RmYN02 (another recently discovered virus that is genetically close to SARS-CoV-2) split up from SARS-CoV-2 at roughly 52 and 37 years ago, respectively. “For viruses, it’s actually a pretty long time, as they can change a lot in this time span,” Nielsen says.
He notes that he doesn’t know what happened in the 40 to 50 years since those viruses diverged from SARS-CoV-2, and the missing link between those related coronaviruses found in bats and the novel coronavirus infecting humans remains a mystery. The simplest explanation for the data is that the virus spilled over from bats into humans, but it’s not known when and how that happened. Samples of the similar viruses were found in caves geographically far from Wuhan. Did a person infected by bats — possibly through contact with the bat’s body fluids, like saliva, urine, or feces — travel to Wuhan? Was an infected bat (or another animal that got the virus from bats) brought to live animal markets in that region? So far, these are still unanswered questions.
In an ideal world, scientists would be able to identify pandemic-causing viruses even before they emerged.
More data is required to dig deeper
Like other researchers investigating the origin of SARS-CoV-2, Nielsen believes scientists have done their best to trace the origins of the virus with the data that’s currently available.
“There’s only one way really to get those questions answered now. It’s to go out and sample more, presumably in China, especially in Wuhan and Yunnan, the province where the bats that carry the most related viruses were found,” he says. If scientists can find viral sequences that are more closely related to SARS-CoV-2, they might provide more insights.
One of the greatest experts in that type of work is virologist Shi Zhengli, PhD, director of the Center for Emerging Infectious Diseases at the Wuhan Institute of Virology. She has been conducting virus-hunting expeditions in bat caves in China for the past 16 years, activity for which she earned the nickname “bat woman.”
Ever since the new coronavirus emerged, Shi and her colleagues have collected samples from various animals in different locations, including the Wuhan seafood market and farms in the region, she told Science in July. According to Shi, many groups in China are carrying out studies like these and publishing their results. “We are tracing the origin of the virus in different directions and through multiple approaches,” she told Science.
Although China has been accused of lack of transparency on coronavirus data, scientists interviewed for this story don’t believe the country has been systematically withholding information from the international scientific community — at least this wasn’t the case in the first months of the epidemic. “In January and February, the Chinese public health and virology communities were very forthcoming with all their data,” Boni says. “Since March, it’s changed a little bit. And that’s all because of politics.”
In an ideal world, scientists would be able to identify pandemic-causing viruses even before they emerged. While it may take a lot of time for the SARS-CoV-2 origin puzzle to be completed, scientists are already working to find the next viruses that could jump into people. For Menachery and his team, that means identifying the key elements that allow a virus to successfully infect humans. With that knowledge, it would be possible to look for viruses with those characteristics in the wild and take the necessary precautions to keep them away from the population.
Menachery has been studying the potential emergence of coronaviruses for years. Back in 2015, he and his colleagues published a paper about the risk of the human emergence of a bat coronavirus circulating in China. Sound familiar? He thinks there will be an increased interest in broader coronavirus research in the next few years, but he warns that it’s important to explore the science of other viruses as well to prepare for what might come next.
“Hopefully now society will invest more in exploring these questions,” he says. “But it’s also easy for people to forget and move on to the next thing.”
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