How a pandemic begins

5 min readDec 8, 2024

Rhinolophus malayanus is a small bat from Southeast Asia. It lives inside limestone caves, feeds on insects, and holds an unfortunate record: a specimen of this species was found to harbor the closest known relative of SARS-CoV-2. Its name is BANAL-20–52, which was sampled in northern Laos in July 2020. Not only does its genome share a 96.8% identity with the pandemic virus, but the key region of the spike protein (the RBD domain) is practically identical to that of SARS-CoV-2. It is so similar, in fact, that just like its more famous relative, BANAL-20–52 can bind with high affinity to the human ACE2 receptor.

This Laotian virus is, in fact, only one representative of a pretty large family. We have other viruses from Laos, some of which are even more similar to SARS-CoV-2 in certain regions of their genome. Similar viruses were found in bats from Vietnam, Cambodia, and Thailand. Then we have the pangolin viruses, which are the sole outsiders in this bat-dominated list. And, of course, there are the relatives identified in Yunnan, China, the most famous of which is certainly RaTG13. For a long time, this virus attracted global attention, first because it was collected by researchers of the Wuhan Institute of Virology, located in the city where the pandemic began, and second, because it was the closest known relative of SARS-CoV-2 until the discovery of BANAL-20–52. The question haunted us for a long time: were the Wuhan researchers to be blamed for the COVID pandemic? Today, the spotlight on virologist Shi Zhengli’s lab is dimming, partly because the hotspot of this virus family appears to be in Southeast Asia, shifting attention away from RaTG13, and partly because other evidence clearly points elsewhere.

Michael Worobey and colleagues analysed the earliest known COVID cases, and found a strong geographic link to the Huanan seafood market — not just among those who reported direct contact with the market (which is unsurprising), but also among those who had no known connection to it (more surprising). The clustering of early cases in that area strongly suggests that the outbreak started there. For a long time, it was hypothesized that the market was not the origin but merely a key step in the epidemic — a super-spreading event that amplified infections. However, further data analysis (in this case, geolocation data from social media) highlighted that many other locations in Wuhan, such as shopping malls, places of worship, hospitals, and nursing homes, could have served as super-spreader sites due to their high number of visitors. Honestly, it would be an extraordinary coincidence if the first super-spreader event of a novel epidemic had occurred in the Huanan market, which was a relatively less crowded location, but had a key feature that has been historically associated with spillover events: the prolonged proximity between wildlife and humans. To be fair, another hypothesis has been proposed involving the Wuhan Center for Disease Control (WCDC), which was relocating to a new site just a few hundred meters from the market at that time. Since the new site was not yet fully operational and experiments were not being conducted there, it is hard to imagine that SARS-CoV-2 originated from this location. It is even less likely that it came from Shi Zhengli’s laboratory, over 30 kilometers away. Indeed, it doesn’t seem very realistic that an infected researcher could have sparked an epidemic in that area without leaving a trail of other infection clusters behind.

The clues, in any case, do not end here. Shortly after the market’s closure, teams of experts collected hundreds of samples from surfaces, drains, and animal carcasses. While the carcasses tested negative for SARS-CoV-2, those collected near the stalls of wildlife traders were particularly rich in positive samples. Similar to how the spatial analyses described above pointed to the market, the analyses conducted inside the market clearly indicated the area where wildlife was sold. The species for sale were many: foxes, minks, ermines, Himalayan marmots, hog badgers, hoary bamboo rats, Amur hedgehogs, Malayan porcupines, the infamous masked palm civets (from which SARS originated), as well as raccoon dogs, which are susceptible to SARS-CoV-2 infection. There is no proof that these animals were infected by the virus, but we know that some of them were unwell, as reported by Angela Rasmussen at a recent conference in Japan: the samples showed traces of ongoing infection, evidenced by the activation of genes involved in immune response. We can also add the fact that both virus lineages (A and B) were present in the Huanan market, quite an unlikely coincidence if it had merely been a super-spreading event.

So what about Shi Zhengli and her lab, then? It is difficult to give a definitive answer, as the intermediate host animal is still unknown, and perhaps will never be identified. However, it is undeniable that all the available data points in one direction, and that direction does not lead to the Wuhan Institute of Virology. Shi Zhengli has drawn doubts and suspicions for a long time due to her institute’s location and her history of experiments with bat coronaviruses. The initial opacity of Chinese authorities did not help, nor did the mysterious furin cleavage site that made SARS-CoV-2 so efficient. Nonetheless, one should reconsider his or her ideas in light of new data and evidence. Kristian Andersen and Edward Holmes did so very quickly. Within a few days, they shifted from suspecting the virus had been engineered to writing in Nature Medicine that any lab scenario was implausible. Michael Worobey, too, was unconvinced of a natural origin, and he even co-signed an appeal in Science calling for further investigation. And yet, it was one of his later publications that convinced me the simplest explanation for the origins of COVID was to be found in the wildlife trade.

Compared to four years ago, when I wrote my latest article on this topic, we now have much more information. Above all, we have discovered that SARS-CoV-2 is ultimately not that special. Southeast Asian bats are a reservoir of very similar viruses: just a few mutations and the right conditions could be enough for triggering an epidemic among our species. In other words, there’s no need to invoke complex and risky genetic engineering experiments; nature already has everything it needs to cause a pandemic. It is up to us, as humans, to learn from this experience and prevent it from happening again.

How a pandemic begins

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Written by Moreno Colaiacovo

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