Monday, May 24, 2021

The origin of COVID: Did people or nature open Pandora’s box at Wuhan?

"We stand together to strongly condemn conspiracy theories suggesting that COVID-19 does not have a natural origin," a group of virologists and others wrote in the Lancet on February 19, 2020, when it was really far too soon for anyone to be sure what had happened. Scientists "overwhelmingly conclude that this coronavirus originated in wildlife," they said, with a stirring rallying call for readers to stand with Chinese colleagues on the frontline of fighting the disease.

Contrary to the letter writers' assertion, the idea that the virus might have escaped from a lab invoked accident, not conspiracy. It surely needed to be explored, not rejected out of hand. A defining mark of good scientists is that they go to great pains to distinguish between what they know and what they don't know. By this criterion, the signatories of the Lancet letter were behaving as poor scientists: They were assuring the public of facts they could not know for sure were true.

It later turned out that the Lancet letter had been organized and drafted by Peter Daszak, president of the EcoHealth Alliance of New York. Daszak's organization funded coronavirus research at the Wuhan Institute of Virology. If the SARS2 virus had indeed escaped from research he funded, Daszak would be potentially culpable. This acute conflict of interest was not declared to the Lancet's readers. To the contrary, the letter concluded, "We declare no competing interests."


A second statement that had enormous influence in shaping public attitudes was a letter (in other words an opinion piece, not a scientific article) published on 17 March 2020 in the journal Nature Medicine. Its authors were a group of virologists led by Kristian G. Andersen of the Scripps Research Institute. "Our analyses clearly show that SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus," the five virologists declared in the second paragraph of their letter.

Unfortunately, this was another case of poor science, in the sense defined above. 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.


First, they say that the spike protein of SARS2 binds very well to its target, the human ACE2 receptor, but does so in a different way from that which physical calculations suggest would be the best fit. Therefore the virus must have arisen by natural selection, not manipulation.

If this argument seems hard to grasp, it's because it's so strained. The authors' basic assumption, not spelt out, is that anyone trying to make a bat virus bind to human cells could do so in only one way.


Shi returned to her lab at the Wuhan Institute of Virology and resumed the work she had started on genetically engineering coronaviruses to attack human cells. How can we be so sure?

Because, by a strange twist in the story, her work was funded by the National Institute of Allergy and Infectious Diseases (NIAID), a part of the US National Institutes of Health (NIH). And grant proposals that funded her work, which are a matter of public record, specify exactly what she planned to do with the money.

The grants were assigned to the prime contractor, Daszak of the EcoHealth Alliance, who subcontracted them to Shi. Here are extracts from the grants for fiscal years 2018 and 2019. ("CoV" stands for coronavirus and "S protein" refers to the virus's spike protein.)

"Test predictions of CoV inter-species transmission. Predictive models of host range (i.e. emergence potential) will be tested experimentally using reverse genetics, pseudovirus and receptor binding assays, and virus infection experiments across a range of cell cultures from different species and humanized mice."

"We will use S protein sequence data, infectious clone technology, in vitro and in vivo infection experiments and analysis of receptor binding to test the hypothesis that % divergence thresholds in S protein sequences predict spillover potential."

What this means, in non-technical language, is that Shi set out to create novel coronaviruses with the highest possible infectivity for human cells. Her plan was to take genes that coded for spike proteins possessing a variety of measured affinities for human cells, ranging from high to low. She would insert these spike genes one by one into the backbone of a number of viral genomes ("reverse genetics" and "infectious clone technology"), creating a series of chimeric viruses. These chimeric viruses would then be tested for their ability to attack human cell cultures ("in vitro") and humanized mice ("in vivo"). And this information would help predict the likelihood of "spillover," the jump of a coronavirus from bats to people.

The methodical approach was designed to find the best combination of coronavirus backbone and spike protein for infecting human cells. The approach could have generated SARS2-like viruses, and indeed may have created the SARS2 virus itself with the right combination of virus backbone and spike protein.

It cannot yet be stated that Shi did or did not generate SARS2 in her lab because her records have been sealed, but it seems she was certainly on the right track to have done so.


On December 9, 2019, before the outbreak of the pandemic became generally known, Daszak gave an interview in which he talked in glowing terms of how researchers at the Wuhan Institute of Virology had been reprogramming the spike protein and generating chimeric coronaviruses capable of infecting humanized mice.

"And we have now found, you know, after 6 or 7 years of doing this, over 100 new SARS-related coronaviruses, very close to SARS," Daszak says around minute 28 of the interview. "Some of them get into human cells in the lab, some of them can cause SARS disease in humanized mice models and are untreatable with therapeutic monoclonals and you can't vaccinate against them with a vaccine. So, these are a clear and present danger…."


the long history of viruses escaping from even the best run laboratories. The smallpox virus escaped three times from labs in England in the 1960's and 1970's, causing 80 cases and 3 deaths. Dangerous viruses have leaked out of labs almost every year since. Coming to more recent times, the SARS1 virus has proved a true escape artist, leaking from laboratories in Singapore, Taiwan, and no less than four times from the Chinese National Institute of Virology in Beijing.

One reason for SARS1 being so hard to handle is that there were no vaccines available to protect laboratory workers. As Daszak mentioned in the December 19 interview quoted above, the Wuhan researchers too had been unable to develop vaccines against the coronaviruses they had designed to infect human cells.


Where we are so far. Neither the natural emergence nor the lab escape hypothesis can yet be ruled out. There is still no direct evidence for either. So no definitive conclusion can be reached.

That said, the available evidence leans more strongly in one direction than the other. Readers will form their own opinion. But it seems to me that proponents of lab escape can explain all the available facts about SARS2 considerably more easily than can those who favor natural emergence.


Proponents of natural emergence have a rather harder story to tell. The plausibility of their case rests on a single surmise, the expected parallel between the emergence of SARS2 and that of SARS1 and MERS. But none of the evidence expected in support of such a parallel history has yet emerged. No one has found the bat population that was the source of SARS2, if indeed it ever infected bats. No intermediate host has presented itself, despite an intensive search by Chinese authorities that included the testing of 80,000 animals. There is no evidence of the virus making multiple independent jumps from its intermediate host to people, as both the SARS1 and MERS viruses did. There is no evidence from hospital surveillance records of the epidemic gathering strength in the population as the virus evolved.

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