One of the theories behind the Covid-19 outbreak is that a virus leaked out of the Wuhan Institute of Virology during 'gain of function' research | Photo: Commons
File photo of the Wuhan Institute of Virology | Representational image | Commons
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New Delhi: Over the last few weeks, voices that believe — and proffer scientific evidence in favour of — the hypothesis that the SARS-CoV2 virus leaked from a Chinese lab have grown stronger. 

There have been a series of factors that have elevated the lab leak theory from conspiratorial speculation to an increasingly plausible possibility. These include China’s reluctance to give foreign investigators full access to its laboratories and databases, and the seeming hesitation of the World Health Organization (WHO) to push the envelope with the Asian nation — refer to Republican Senator John Kennedy’s questioning of Dr Anthony Fauci, the chief medical adviser to US President Joe Biden, during a Senate hearing last month. 

Questioning the immunologist on the nature of research being conducted by the Wuhan Institute of Virology (WIV) on coronaviruses, Kennedy asked whether the WHO would fall out of Xi Jinping’s pocket if the Chinese President were to be held upside down. 

Then there is the flurry of scientific revelations over the last few weeks, some of them by amateur sleuths. A key aspect of this is a coronavirus sample collected by the WIV from a Chinese mineshaft in 2013 that has been linked to a pneumonia-like illness that afflicted six miners the year before. The bat-origin coronavirus — since identified as RaTG13 — has been found to be over 96 per cent similar to SARS-CoV-2, which causes Covid-19.

This has fuelled speculation that SARS-CoV-2 might have emerged from RaTG13 following gain of function research, which involves manipulating pathogens in a way that they gain an advantage in or through a function, such as increased transmissibility.

On 26 May, Biden announced a time-bound investigation by the country’s intelligence agencies into the origins of the virus. EcoHealth Alliance, a New York-based non-profit under fire for allegedly using US public money to fund dangerous research in Wuhan to create deadly viruses, is already set to lose a $1.5 million grant from the Bill and Melinda Gates Foundation to work with the Indian government. 

But no matter how compelling the evidence may seem, questions about the origins of the SARS-CoV-2 virus are by no means closed. There are theories and evidence, but there is also the other side — counter-arguments.


Also Read: Virus labs need more oversight, even if Covid lab leak theory isn’t found true


Suppression of pneumonia outbreak among miners

Global norms for reporting infectious diseases require countries to flag disease outbreaks to the WHO. In today’s world of easy air connectivity, diseases take very little time to travel from one country to another and lead to a pandemic — Covid-19 has been proof of that long-held hypothesis. If the outbreak is of a hitherto unknown disease, the urgency to report is even more.

That is why the belated unearthing of a 2012 disease outbreak among miners in the Yunnan district of China, and the fact that WIV researchers probed the outbreak, isolated a novel virus (RaTG13, a coronavirus), but did not report it to the WHO, has raised hackles.

In a paper published in the journal Frontiers in Public Health in October 2020, scientists Monali Rahalkar and Rahul Bahulikar of the MACS Agharkar Research Institute and BAIF Development Research Foundation, respectively, wrote: “It was found that RaTG13/CoV4991 was collected from Tongguan mineshaft in Mojiang, Yunnan, China, in 2013. Surprisingly, the same mineshaft was also associated with a severe pneumonia-like illness in miners in 2012 killing three of the six miners.”

The scientists said a “Master’s thesis (in the Chinese language) was found on the cnki.net website which described in detail the severe illness in miners”. 

“The thesis concluded that a SARS-like CoV originating from Chinese horseshoe bats (Rhinolophus) was the predicted causative agent. The cases were remotely monitored by a prominent pulmonologist in China. Retrospective analysis of the pneumonia cases shows striking similarities with Covid-19,” they added. 

China’s reluctance to let anyone approach the abandoned copper mines, or to collect samples from there, has added fuel to the conspiracy theories.

Counter: In a June 2020 conversation with Scientific American, WIV researcher Shi Zhengli — known as “bat lady” because of her work on zoonotic diseases of bat provenance — said the miners had died of a fungus found in bat faeces and not infection by the SARS-CoV-2 cousin.

In the same conversation, Shi also admitted that in the wake of the first Covid-19 cases being reported, she herself had entertained the possibility of a virus leak from her own lab and spent several sleepless nights before she was convinced otherwise.

It was only in a November 2020 addendum to a February 2020 article published in Nature that Shi and her team gave “information about the bat SARS-related coronavirus (SARSr-CoV) strain RaTG13” and linked it to the miners’ outbreak. Science has moved on since then, though. 

RaTG13, a coronavirus found in bats at Mojiang county in Yunnan province, is supposed to be the closest known relative of the SARS-CoV2 virus — the two have a 96.2 per cent similarity. It was collected from the faeces of the horseshoe bat there in 2013. One of the differences between RaTG13 and SARS-CoV2 is the furin cleavage site.

Furin cleavage site

Furin is an enzyme that is found in human cells. The SARS-CoV-2 virus has a unique orientation of amino acids in its spike protein, and cleaves into two at the site when it comes into contact with the enzyme. Nobel laureate virologist Professor David Baltimore has been quoted as saying:  “When I first saw the furin cleavage site in the viral sequence, with its arginine codons, I said to my wife it was the smoking gun for the origin of the virus. These features make a powerful challenge to the idea of a natural origin for SARS2 (sic).”

The furin cleavage site makes the virus uniquely suitable to infect human cells and is believed to make it more highly transmissible than some of its other relatives such as the RaTG13. It is widely speculated that the introduction of this site into the RaTG13 happened in a lab as part of the gain-of-function research being conducted at the WIV using funds from EcoHealth Alliance, through a grant to the non-profit from the US government’s National Institutes of Health (NIH).

Counter: The furin cleavage is by no means a novelty in nature. A January 2021 article in Science Direct, published by researchers at ShanghaiTech University, claimed that such a site is present in many coronaviruses. “Furin cleavage is critical to many viral diseases, including HIV, Ebola, and influenza H5 and H7 . Furin is a ubiquitously expressed protease. In human body, it has a wider distribution range than the major protease responsible for cleaving spike, TMPRSS2. Therefore, coronaviruses with spike containing furin cleavage site may have advantage in spreading,” they wrote.

Prof. Baltimore himself seems keen now to recalibrate his emphatic indictment of the furin cleavage site. In an email exchange with the Los Angeles Times, Baltimore conceded he had overstated the case and that he had an open mind on the matter.

“[I] should have softened the phrase ‘smoking gun’ because I don’t believe that it proves the origin of the furin cleavage site but it does sound that way.

“I believe that the question of whether the sequence was put in naturally or by molecular manipulation is very hard to determine but I wouldn’t rule out either origin.”


Also Read: US govt lab found it ‘plausible’ Covid-19 leaked from Wuhan lab, WSJ report says


Renaming of sample 4991 as RaTG13

The November 2020 addendum raised more questions than it answered. Because scientists suspect that a virus that had been sequenced earlier from the mine isolates and existed inside the Wuhan lab was renamed as RaTG13 to deflect blame for a possible leak. RaTG13 is 96.2 per cent similar to SARS-CoV-2 but 100 per cent similar to 4991.

“A total of 150 alphacoronaviruses and only two betacoronaviruses, of which only one was SARS-like betacoronavirus (CoV/4991), were detected. The same virus 4991 was renamed as RaTG13, which is the next genetic relative of SARS-CoV-2,” the scientist couple from Pune, who are part of a group called DRASTIC that is investigating the genesis of SARS-CoV2, wrote in their paper.

Alphacoronaviruses and betacoronavirues are two coronavirus genera that affect mammals.

Counter: In a July 2020 interview to Science, Shi said: “Ra4991 is the ID for a bat sample while RaTG13 is the ID for the coronavirus detected in the sample. We changed the name as we wanted it to reflect the time and location for the sample collection. 13 means it was collected in 2013, and TG is the abbreviation of Tongguan town, the location where the sample was collected.”

Around the same time, EcoHealth Alliance head Peter Daszak put out a series of tweets denying any links between RaTG13 and SARS-CoV2. “Most importantly RaTG13 is not SARS-CoV-2 by a long stretch. To provide a 7 yr ‘timeline’ from the mine to Covid is misinformation that pushes ‘blame China’ narrative. This virus prob. emerged mnths before we found it, around the border of Yunnan & neighboring countries. 

“Our work shows that hundreds of distinct viral genetic sequences exist in this region, that these viruses are infecting people prob. daily, so there will likely be dozens of illnesses, small outbreaks that go undiagnosed each year…” He was responding to an article in The Australian.

Daszak has been among the foremost backers of WIV and the prime mover on a February 2020 letter published by The Lancet — signed by several illustrious scientists — vouching for the natural origins of SARS-CoV-2. 

Removal of database

Months before the first cases of the novel coronavirus disease were reported in Wuhan, online databases of viral samples possessed by WIV started disappearing. The first of these disappeared on 12 September 2019; 15 others followed soon, according to researchers from DRASTIC.

Some of these were administered by Shi, while others had been developed using funds from the NIH.

In a paper that detailed the timelines of these disappearances, researchers from DRASTIC wrote: “There are estimated to be at least 100 unpublished sequences of bat betacoronaviruses in Batvirus.whiov.ac.cn (one of the deleted databases), which urgently need to be accessed by international scientists in order to investigate the origins of SARS-CoV-2:

“These include in particular:

1) WIV6 and WIV15 BatCov isolates that have never been made public, but whose existence can be deduced from gaps in the existing series of isolates mentioned in research papers.

2) 8 beta BatCoVs related to SARS, sampled from Yunnan, only recently mentioned by Shi Zhengli in the addendum to the Nature paper and in an online presentation and never published despite being of the highest relevance.”

Counter: In December 2020, Shi told the BBC that the database was taken off because there were security concerns. Her institute, she insisted, had “nothing to hide”. In various interviews before that and since, she has also maintained that all her work on virus genomes has been published or duly submitted to the GenBank, the NIH genetic sequencing database, and therefore her team has nothing to hide.


Also Read: EcoHealth of US, under fire for Wuhan lab link, is working with Modi govt since Aug 2020


Known safety concerns in Wuhan

One of the most shocking revelations in recent weeks has been the fact that Shi’s team carried out dangerous research that involved making viral pathogens more infectious or more lethal, in a laboratory that did not have sufficiently high safety levels. The highest possible safety level is in a bio safety level (BSL) IV laboratory, where researchers need to take utmost protection, don elaborate protective gear every time they enter, and follow very stringent protocol to prevent any pathogens from accidentally being transported outside.

Until recently, the WIV did not have a BSL IV facility. Shi is on record to say that her own coronavirus research was carried out in BSL II or III laboratories.

“The coronavirus research in our laboratory is conducted in BSL II or BSL III laboratories. After the BSL IV laboratory in our institute has been put into operation, in accordance with the management regulations of BSL IV laboratory, we have trained the scientific researchers in the BSL IV laboratory using the low- pathogenic coronaviruses as model viruses, which aims to prepare for conducting the experimental activities of highly pathogenic microorganisms,” she told Science in an email interview. 

“After the Covid-19 outbreak, our country has stipulated that the cultivation and the animal infection experiments of SARS-CoV-2 should be carried out in BSL-III laboratory or above,” she said.

The rush to rule out lab leak

For a disease and a pathogen that are both so little understood, early on, there was a rush of scientific publications that reposed unqualified faith in WIV scientists and their version of events, virtually foreclosing any further discussion on the topic, thanks to the heft of their voices. 

As understanding of the virus and its origins has become clearer, that apparent haste to declare “all is well” has started looking increasingly suspicious. Daszak, for example, orchestrated the letter in The Lancet that dismissed any hypothesis that might have existed at the time on the possibility of the SARS-CoV-2 having leaked from a Chinese laboratory. 

He was among the illustrious signatories, and the letter declared that they had “no conflict of interest”. But findings have since emerged suggesting the EHA had been funding gain-of-function research at the WIV.

Another article rejecting the laboratory origin of the SARS-CoV-2 virus appeared in Nature, with Kristian Andersen, an immunologist at the Scripps Research Institute, US, as the corresponding author. 

“It is improbable that SARS-CoV-2 emerged through laboratory manipulation of a related SARS-CoV-like coronavirus. As noted above, the RBD (receptor binding domain) of SARS-CoV-2 is optimised for binding to human ACE2 with an efficient solution different from those previously predicted. Furthermore, if genetic manipulation had been performed, one of the several reverse-genetic systems available for betacoronaviruses would probably have been used. However, the genetic data irrefutably show that SARS-CoV-2 is not derived from any previously used virus backbone,” it says.

Counter: Many of the arguments in favour of the natural origin of the virus have since been rejected or vociferously questioned. The fact that declarations of no-conflict-of-interest came from deeply interested parties has not helped WIV’s cause either. 

In his much-quoted article in Bulletin of the Atomic Scientists, journalist Nicholas Wade wrote: “True, some older methods of cutting and pasting viral genomes retain tell-tale signs of manipulation. But newer methods, called ‘no-see-um’ or ‘seamless’ approaches, leave no defining marks. Nor do other methods for manipulating viruses such as serial passage, the repeated transfer of viruses from one culture of cells to another. If a virus has been manipulated, whether with a seamless method or by serial passage, there is no way of knowing that this is the case. Andersen and his colleagues were assuring their readers of something they could not know.”

Scientists’ understanding of the origins of SARS-CoV-2 is changing rapidly and the question is still very much an open one. The coming months may reaffirm public faith in scientists or significantly damage it for many decades to come. Transparency will hold the key.

(Edited by Sunanda Ranjan)


Also Read: Story of how ‘amateur sleuths’ forced world to consider Wuhan lab leak theory about Covid


 

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