Scientists used painstaking research, genomics, and clever statistics to definitively track two distinct strains of the virus back to a wet market in Wuhan.
AUG 4, 2022 7:00 AM (wired.com)
IN OCTOBER 2014, virologist Edward Holmes took a tour of the Huanan Seafood Wholesale Market in Wuhan, a once relatively overlooked city of about 11 million people in the central Chinese province of Hubei. The market would have presented a bewildering environment for the uninitiated: rows of stalls selling unfamiliar creatures for food, both dead and alive; cages holding hog badgers and Siberian weasels, Malayan porcupines and masked palm civets. In the southwest corner of the market, Holmes found a stall selling raccoon dogs, stacked in a cage on top of another housing a species of bird he didn’t recognize. He paused to take a photo.
Eight years on, that photo is a key piece of evidence in the painstaking effort to trace the coronavirus pandemic back to its origins. Of course, it’s been suspected since the early days of the pandemic—since before it was even a pandemic—that the Wuhan wet market played a role, but it’s been difficult to prove it definitively. In the meantime, other origin theories have flowered centered on the Wuhan Institute of Virology, a biological research lab which, it’s argued, accidentally or deliberately unleashed the virus on the city and the world.
The overwhelming scientific consensus is that Covid originated in a similar way to related diseases such as SARS, which jumped from bats to humans via an intermediate animal. Figuring out exactly what happened with Covid-19 could prove immensely valuable both in terms of finally disproving the lab leak theory and by providing a source of information on how to stop the next pandemic. “This is not about placing blame,” says Kristian Andersen, a professor of immunology and microbiology at the Scripps Research Institute in California. “This is about understanding in as much detail as we can the origins of the Covid-19 pandemic.”
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For the last two years, an international team of scientists including Andersen and Holmes has been trying to pinpoint the epicenter of the pandemic, using methods ranging from genetic analysis to social media scraping. Their research, which attracted widespread coverage in preprint before being published in its final form last week, reads as much like a detective report as an academic study.
First: the scene of the crime. Where exactly in this city of 11 million people did the virus first jump from animals to humans? To find out, the team—led by University of Arizona biologist Michael Worobey—scoured a report published by the World Health Organization in the summer of 2021, which was based on a joint investigation the public health body conducted with Chinese scientists. By cross-referencing the different maps and tables within the report, the researchers obtained coordinates for 155 of the earliest Covid cases in Wuhan, people who were hospitalized from the disease in December 2019.
Most of those cases were clustered around central Wuhan, particularly on the west bank of the Yangtze river—the same area as the Huanan market. “There was this extraordinary pattern where the highest density of cases was both extremely near to and very centered on the market,” says Worobey, lead author on the paper, which was published in Science. Statistical analysis confirmed that it was “extremely unlikely” that the pattern of cases seen in the early days of the pandemic would have been so clustered on the market if Covid had originated anywhere else: A random selection of similar people from around Wuhan were very unlikely to have lived so close to the market.
Even early patients who didn’t work or shop at the market were more likely to live close to it. “This is an indication that the virus started spreading in people who worked at the market, but then started to spread into the local community, as vendors went to local shops, infected people who worked in those shops, and then local community members not linked to the market started getting infected,” says Worobey.
But a high level of transmission centered on the market doesn’t, in and of itself, imply that the entire outbreak started there. Snapshots from later in the pandemic might have found similar patterns centered on superspreader events in Italy or Seattle, for instance. To strengthen their case beyond the WHO data, the researchers turned to the Chinese microblogging service Weibo.
People who posted asking for help on a Covid-19 app within Weibo in January and February 2020 were clustered not around the market, but to the west, in more densely populated areas of the city, and in areas with more older people—hinting at how the pandemic began to shift from an isolated outbreak linked to the market to one with the potential to explode around the world. A few months in, it had started to mirror the population density of the city. Historical location-based “check-ins” on Weibo also show that the Huanan market was a relatively unlikely destination for most people in the city—in other words, it was unlikely to be the location of a superspreader event unless the virus originated from there.
To trace the pandemic in the other direction, toward its source, the researchers turned to swab samples collected by Chinese scientists from around the Huanan market just before it was shut down by the authorities in January 2020. Those swabs returned a cluster of positives in the south-western corner of the market—on a glove found on one of the stalls, from a grate under one of the cages. Five of the positive samples came from a single stall—a stall that was known to be selling live animals in late 2019, and the same stall where Holmes had taken his photograph of the raccoon dogs five years earlier.
This layering of indirect evidence has helped to settle the question of where Covid jumped into humans, but the question of timing has also been a subject of fierce debate. A companion paper explores this using Covid’s molecular clock—what Joel Wertheim, a virologist at the University of California, San Diego and coauthor on the paper, calls “that steady drumbeat of mutations accumulating in SARS-CoV-2,” or how the virus shifts over time.
It had been assumed that a virus jumping from animals into humans was a piece of cosmic bad luck—a one-off amplified by bad decisionmaking in the days and months that followed. But the genetic data tells a different story. There were actually two strains of Covid circulating in Wuhan in late 2019: Lineage A and Lineage B, which are just two letters apart in their genetic code, according to Jonathan Pekar, a researcher at UC San Diego and another of the study’s coauthors.
As Pekar delved deeper into what scientists call the “phylogeny” of SARS-CoV-2—its family tree—it became clear that their understanding of how the disease had crossed over might be wrong. “We eventually figured out that it was better explained by multiple introductions than a single one,” he says. The researchers now think Lineage A—which is more genetically similar to bat coronaviruses, and so appears earlier in the virus’s family tree—was actually introduced into humans after Lineage B. Lineage B ended up becoming the dominant global variant: both persisted for a while, but Delta, Omicron, and the rest of the variants that swept the globe are descended from B, not A.
Pekar now thinks there were actually up to a dozen separate crossover events, because in order for a disease like Covid to “take”—to go beyond its initial human host and start an epidemic—it needs to infect someone who’s going to spread it widely, and not everyone does. “Roughly 70 percent of introductions go extinct, so you need eight introductions to have two that persist,” Pekar says.
It might seem unlikely that a once-in-a-generation event happened twice within the space of a couple of weeks, but actually, says Wertheim, once all the conditions were in place—a zoonotic virus capable of human infection in close proximity to humans—it would have been surprising if it had only happened once. The barriers to spillover had been lowered. “We failed to climb Mount Everest for thousands of years, and then in one day two people did,” says Andersen.
The fact that the virus likely crossed over twice in quick succession is significant for two reasons: first, because multiple introductions damage the lab leak hypothesis—although like all conspiracy theories, it will likely contort itself into some new variant that hand-waves this away; and secondly, because it rules out Covid being introduced into the market from a human who caught it elsewhere. “This is so concordant with what we’ve seen with other epidemics that it makes any other scenario implausible, because you’d have to have an introduction of one virus and then we’d have to wait a week or two and have an introduction of another virus that is kind of similar but not the same,” Pekar says.
There’s been a narrative throughout the pandemic of Chinese obfuscation making matters worse—fueled by the same political tensions and mistrust that have made the lab leak theory so compelling to some. And while Chinese authorities undoubtedly made mistakes and obstructed access to information at times, it’s only the data collected by Chinese scientists that has made such detailed analysis of the origins of Covid possible at all. If, as these papers indicate, SARS-CoV-2 first crossed over in late November 2019, it took just a matter of weeks for doctors to figure out there was an epidemic, compared to several months for the 2014 Ebola outbreak and a year and a half for Zika. “The fact is we have an unprecedented view of the early picture of this pandemic compared to any pandemic in human history,” says Worobey. “There’s nothing like it.”
It means we have environmental sampling data that can place the spillover event precisely in the southwestern corner of the Huanan market, and genetic testing of virus samples from the first patients to give us a date: around November 18, 2019, for the introduction of Lineage B, with Lineage A following a week or so later. After that, though, the trail runs cold.
The researchers know which animals were being sold in the market in late 2019, and which ones were susceptible to coronaviruses, but they don’t have the smoking gun. “They don’t have samples from animals that had the virus. That’s what they’d like to have, and they’d like to be able to trace those animals back to the farms from which they came and see whether people in those farms had been exposed to the virus or viruses,” says Jonathan Stoye, a virologist at the Francis Crick Institute in the UK, who was not involved in the research.
That’s unlikely to be possible. There are theories on how infected animals may have reached the market: Wuhan is in Hubei province, and to the west of the region there are caves that are home to horseshoe bats, close to farms that once housed millions of raccoon dogs and civets. The most likely course of events is something like: A bat infected with a novel coronavirus flies over a farm where animals are being reared for meat. It poops, and viral particles infect one of the animals below, sparking an unseen wave of infections at the farm. Maybe the virus crosses over to the farmworkers but fizzles out because there’s not enough population density to sustain a human epidemic. Days or weeks later, in November 2019, some of the infected animals are shipped to the Huanan Seafood Wholesale Market, where they’re sold at stalls in the southwestern corner. The virus crosses over to humans at least eight times, maybe more. The majority of those infections fizzle out without spreading to anyone else, but two take hold, start to spread. Not long after that, dozens of people in the area start to come down with a mysterious viral pneumonia.
But the animal or animals that carried coronavirus are almost certainly long dead: shipped off and sold for meat, or killed in one of the mass culls that took place in early 2020 as the Chinese authorities clamped down on the live animal trade. “It is very possible that we will never have that sample, that we may have missed our opportunity,” says Worobey.
But there are still leads to follow: tracing the supply chains for the stalls in the southwestern corner of Huanan market and finding out which farms supplied them; poring over the paperwork from the culls to find out where the animals from that farm were buried; exhuming the animals and sequencing their DNA to look for remnants of a coronavirus that looks almost identical to SARS-CoV-2.
It will need patient work and international cooperation in a difficult environment—but it could be the only way to stop the next pandemic. “These things are not impossible,” Worobey says. “So let’s look at all the options. Let’s connect every single possible dot that we can.”
Image updated on 8/4/22 at 11:17AM PST to include the Wuhan Huanan Wholesale Seafood Market.
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Amit Katwala is a senior writer at WIRED with a focus on longform features, science, and culture. He graduated from the University of Oxford with a degree in experimental psychology, and is the author of two books: The Athletic Brain, about the rise of neuroscience in sport, and a WIRED… Read more