This is a more detailed version of the long article co-written with Alina Chan on the origin of the virus causing the covid pandemic which was published in the Telegraph on 6 February.
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The covid-19 pandemic has killed two million people and counting. It has created medical, social, psychological, and economic misery on a scale unprecedented in peacetime. So tracking down the origins of SARS-CoV-2, the virus that causes covid-19, is vital to prevent a recurrence.
Begin with a simple question: why Wuhan? As far as scientists can confidently tell, all of the earliest cases in late 2019 were in the city of Wuhan or nearby within the province of Hubei, China. The first officially reported cases in Thailand, Japan, America, France, Canada, Australia, Germany, India, Italy, Spain, Russia and Sweden had traveled from Wuhan, or been exposed to individuals who had traveled from Wuhan. Persistent attempts by the Chinese government and scientists to play up possible origins in frozen food imports and pre-Wuhan cases in Europe have been unpersuasive so far.
At first, the answer to “why Wuhan?” seemed easy: 27 of the first 41 cases had visited a seafood market selling exotic wildlife. The Chinese government moved quickly to close the market on 1 January 2020. Covid looked like a rerun of the 2002-4 SARS epidemic, which had first infected food handlers. That virus had been quickly traced to infected animals at markets, including, most famously, palm civets. Evidence collected by May 2003 pointed to the considerable exposure of local animal traders to SARS viruses despite being underrepresented among epidemic cases. By mid-2005, scientists had tracked SARS-like viruses to their natural reservoir in horseshoe bats.
So the story that SARS-CoV-2 had similarly spilled over from animals at a Wuhan market was one that sounded familiar. On 22 January 2020, the director of the Chinese Centers for Disease Control, Dr Gao Fu “confirmed the source of the new coronavirus, saying it was transmitted via wild animals illegally sold at a seafood market in Wuhan.”
Within a month, four different Chinese research groups reported they had found a similar virus in smuggled pangolins confiscated in 2019 in Guangdong, a southern China province, which was also where the 2003 SARS outbreak had started. Pangolins are among the most illegally trafficked animals globally, captured in Africa and south-east Asia and destined largely for China and Vietnam. Needless to say, these reports led the media and public to speculate that pangolins, illegally trafficked into Wuhan, were the culprits that had conveyed SARS-CoV-2 from bats into humans.
But there was another possible answer to “Why Wuhan?”. On 6 February 2020, a short article was released by two Wuhan scientists, Botao Xiao and Lei Xiao, pointing out that Wuhan laboratories had mounted expeditions across China to collect and study bat viruses, and stating that “in addition to origins of natural recombination and intermediate host, the killer coronavirus probably originated from a laboratory in Wuhan.”
That paper was withdrawn, but others were already investigating. For some, it was too coincidental that the outbreak began so close to the Wuhan Institute of Virology (WIV), China’s foremost research centre for SARS-like coronaviruses, which hosted a now missing database of more than 20,000 pathogen samples from wild animals across China, mostly bats and rodents. From these, diverse SARS-like coronaviruses had been genetically sequenced, isolated, manipulated, and used in cell or animal infection experiments.
Yet public statements from some scientists in early 2020 were confident that lab-based scenarios of SARS-CoV-2’s origins could be ruled out. “We stand together to condemn conspiracy theories suggesting that COVID-19 does not have a natural origin,” announced 27 prominent scientists in the Lancet on 19 February. “Our analyses clearly show that SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus,” proclaimed experts in Nature Medicine on 17 March. These statements have continued to appear, portraying an accidental lab leak hypothesis as a conspiracy theory or claiming as late as November last year that “months of genetics research has already concluded that the pandemic started with what’s known as a zoonotic spillover.”
“Could they have come from our lab?”
Now rewind the tape to the year 2012. After many years of work, Dr Shi Zhengli of the WIV has tracked down a cave in Yunnan where Chinese horseshoe bats are infected with coronaviruses that resemble SARS. She receives news of an outbreak of unusual, severe pneumonia in Mojiang county, Yunnan.
In April 2012, six men clearing bat droppings in a disused copper mine, fell ill and were hospitalized in Kunming, Yunnan’s capital. Three died. Antibiotics and antifungals did not help and the famous physician who originally figured out how to treat SARS patients, Dr Zhong Nanshan, was consulted in June 2012. He inferred that a SARS-like virus might be responsible and advised identifying the bat species in the mine and testing the patients for SARS. Some of these tests were performed at the WIV.
The doctors treating the miners deduced that their illness was “caused by SARS-like CoV or bat SARS-like coronavirus that has been isolated from the Chinese rufous horseshoe bat.” Over the next few years, Dr Shi sent at least seven expeditions to the Mojiang mine to catch and sample bats. These expeditions reportedly brought back to Wuhan at least nine different SARS-like coronaviruses. Other top Chinese labs also went to sample viruses from this mine.
On 30 December 2019, by her own account, Dr Shi was at a conference in Shanghai when she heard of the outbreak of infectious pneumonia in her home city of Wuhan. She rushed back on an overnight train. Dr Shi told Scientific American, “I had never expected this kind of thing to happen in Wuhan, in central China,” wondering “could they have come from our lab?” She concluded they did not.
Dr Shi found that part of the sequence of the novel coronavirus (SARS-CoV-2) closely resembled a short sequence from a bat virus her lab had collected in Mojiang in 2013. However, in publishing this finding in her first Nature paper on covid-19 in February 2020, Dr Shi made no reference to Mojiang or the miners, and published the bat virus under a different name, RaTG13, from the one used previously. Nor did she mention that her laboratory had sequenced and studied RaTG13 as early as 2017, and not after the outbreak of covid as readers of the Nature paper had understood.
These details were revealed through the diligence of Rossana Segreto of the University of Innsbruck and Yuri Deigin of Youthereum Genetics; a medical thesis from Kunming Medical University unearthed by an anonymous Twitter user, “The Seeker”, who tipped off Monali Rahalkar and Rahul Bahulikar at the Agharkar Research Institute and the Central Research Station, India; and a group of internet sleuths who go by the name of DRASTIC. Their connection of RaTG13 to the Mojiang miners was eventually confirmed by Dr Shi in an addendum to her Nature paper in November 2020, which also revealed the existence of eight other SARS-like viruses collected from the mine. Yet no genetic data for these were provided and the WIV’s virus database had been taken offline at the beginning of 2020, which Dr Shi told the BBC was for “security reasons.”
As these tantalizing details emerged, BBC and Associated Press journalists tried to visit the Mojiang mine but were tailed by police and stopped by impromptu roadblocks. Bloomberg reporters were prevented from speaking with vendors from the Wuhan seafood market. When shown this history of obfuscation, some senior scientists respond to us that, China being under a communist regime, it is hardly surprising that a laboratory has not fully shared what it knows. We do not find this argument reassuring.
“The market is more like a victim”
On 15 January 2021, the US State Department released a statement that “WIV became a focal point for international coronavirus research after the 2003 SARS outbreak and has since studied animals including mice, bats, and pangolins”; “U.S. government has reason to believe that several researchers inside the WIV became sick in autumn 2019, before the first identified case of the outbreak, with symptoms consistent with both COVID-19 and common seasonal illnesses”; and “WIV has collaborated on publications and secret projects with China’s military. The WIV has engaged in classified research, including laboratory animal experiments, on behalf of the Chinese military since at least 2017.”
Scientists are waiting to see if supporting intelligence will be declassified or if we will hear more from the incoming administration. However, the public scientific consensus had been slowly shifting even before the announcement. A growing number of top experts including (ordered alphabetically by last name) Drs Francois Balloux, Ralph S. Baric, Trevor Bedford, Jesse Bloom, Bruno Canard, Etienne Decroly, Richard H. Ebright, Michael B. Eisen, Gareth Jones, Filippa Lentsoz, Michael Z. Lin, Marc Lipsitch, Stuart A. Newman, Rasmus Nielsen, Megan Palmer, Nikolai Petrovsky, Angela Rasmussen, and David A. Relman have stated publicly (several in early 2020) that a lab leak remains a plausible scientific hypothesis to be investigated, regardless of how likely or unlikely. We informed and obtained consent from each expert for their inclusion in this list.
Information about what went on in the WIV laboratories remains scarce. Given that, as Dr David Relman of Stanford University points out, it has the world’s largest repository of bat coronaviruses, the lack of transparency and openness about their research, and inconsistencies in the information that has been released are bound to fuel speculation. This now includes whether there are clues to an accident in 2019 or to changes in bio-safety procedures. Meanwhile, in contrast to SARS, the anticipated evidence for the natural origin hypothesis has failed to materialise over an entire year.
On 25 May 2020, the Chinese CDC director announced that none of the animal samples from the Wuhan market had tested positive: “At first, we assumed the seafood market might have the virus, but now the market is more like a victim. The novel coronavirus had existed long before.” This statement followed months of speculation that the market was not the site of spillover. Independent analyses had shown that some of the earliest patients had no links to the market; that an ancestral version of the virus had not passed through the market; and that virus sequences from “environmental” samples at the market (such as sewage) did not point to cross-species spillover of the virus at the market.
It remains possible, Dr Maciej Boni of Pennsylvania State University reminded us, that “there was a positive group of animals in mid or early December 2019 but they were not tested.” He notes that some cities in China and neighbouring countries have hundreds of markets, “and thousands when you count small roadside sellers or temporary stalls.” He argues that “human-animal contact at many different interfaces is very high in many parts of Asia. And lab escapes are much more rare.”
“The pangolin samples are a mess”
The pangolin connection was put to the test when one of us (Chan, alongside a highly skilled collaborator, Dr Shing Hei Zhan of the University of British Columbia) discovered that for the pangolin viruses that most resembled SARS-CoV-2 in the key section of its spike protein, all four studies used the same dataset from a single batch of pangolins intercepted in Guangdong in March 2019. The journal Nature has since attached an editor’s note to one of the papers to alert readers that “concerns have been raised about the identity of the pangolin samples reported in this paper and their relationship to previously published pangolin samples.”
Dr Linfa Wang of the Duke-NUS Medical School in Singapore, one of the scientists who discovered that bats were the natural reservoir of SARS viruses, told the Associated Press that “the search for the coronavirus in pangolins did not appear to be ‘scientifically driven.'” Dr Angela Rasmussen, of the Georgetown Center for Global Health Science and Security, said simply “the pangolin samples are a mess and likely not relevant.”
Furthermore, when one of us (Chan, in collaboration with Zhan) scrutinized the evolution of SARS-CoV-1 and SARS-CoV-2 in the early months of their respective epidemics, the former was observed to have mutated rapidly in early human cases as the virus adapted to its new host, while the latter had not. "The virus was well adapted to human transmission from the moment it was first detected," the World Health Organization's global study on the origins of the virus commented in November.
There are three possible explanations: the virus circulated undetected in people for months while accumulating adaptive mutations; it was already highly adept at human transmission while in bats or another animal; or that it had become adapted in human cells or humanised animals in a laboratory.
That such viruses circulate in Wuhan seems unlikely. Dr Shi and colleagues have been sampling people as well as bats in rural Southern China and used the Wuhan population as a negative control in one of their studies in 2015. Of hundreds of people tested in Wuhan, none had antibodies against SARS-like viruses.
There is still no sign of an original animal source of SARS-CoV-2 in Wuhan or the rest of Hubei. Dr Shi told Science Magazine in July 2020 that her team had not found bats in Hubei that carry close relatives of SARS-CoV-2, saying “I don't think the spillover from bats to humans occurred in Wuhan or in Hubei Province.” A WHO global study commented in November: “there is no evidence to demonstrate the possible route of transmission from a bat reservoir to human through one or several intermediary animal species.”
Controversially, right in the middle of the spike gene of SARS-CoV-2 lurks a surprise. Unlike other SARS-like coronaviruses so far described, including RaTG13 and the pangolin viruses, SARS-CoV-2 has an extra 12 digits inserted, creating a “furin cleavage site”. This is a feature found in other pathogenic coronaviruses such as Middle Eastern Respiratory Syndrome (MERS), and is known to make viruses more capable of infecting different tissues in the body. Yet, this remarkable insertion was not mentioned in either of the WIV’s first covid-19 papers despite a close analysis of the spike gene. It will be near impossible to definitively determine whether this furin cleavage site arose naturally or artificially. However, its omission from key WIV covid-19 papers is curious.
The practices of building chimera coronaviruses (made from parts of multiple viruses), sometimes leaving no trace of manipulation, or inserting a furin cleavage site into the spike protein of SARS virus, are not new. These experiments have been conducted in select laboratories such as at the WIV for the purpose of understanding how novel SARS viruses could spill over into humans. The ultimate goal is to create a universal vaccine for all SARS-like viruses.
The scientists might find it unbearable if they instead caused a pandemic. But they did not find it unthinkable. In a 2015 article co-authored by Dr Shi and Dr Ralph Baric of the University of North Carolina at Chapel Hill (the heads of two leading SARS coronavirus research groups) these words appear: “scientific review panels may deem similar studies building chimeric viruses based on circulating strains too risky to pursue… the potential to prepare for and mitigate future outbreaks must be weighed against the risk of creating more dangerous pathogens.”
Matt Ridley’s book “Viral”, on the origin of the pandemic, will be published in 2021. Alina Chan is a postdoc at the Broad Institute of MIT and Harvard.
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