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Cave Coronavirus in Wuhan Lab Seeded COVID – The Truth Has Always Been Out There, in the Genetics

When former Director of the National Institute of Allergy and Infectious Diseases, Anthony Fauci testified before a House Select Subcommittee on the coronavirus pandemic on June 3 to share his thoughts about the possible origin of SARS-CoV-2, the idea that sampling from nature and alteration at the Wuhan Institute of Virology returned to the headlines.

For those of us who consider viral genome sequences instead of tea leaves, rumors, and politically expedient explanations, the cave origin-lab leak hypothesis is hardly a surprise – the genetic puzzle pieces have fit for quite some time.

Ruling Out Alternate Explanations Requires Logic and Science

Soon after Fauci’s grilling, Alina Chan, a molecular biologist at the Broad Institute of MIT and Harvard, succinctly explained the converging evidence in a compelling Opinion piece in the June 9 New York Times. Through graphics and five main points, Chan countered the wet market scenario of the pandemic’s beginnings. Her points:

1. The virus SARS-CoV-2 emerged in Wuhan, home of a premiere research institute that focuses on viruses.

2. A year before the initial outbreak, Wuhan researchers proposed nurturing a coronavirus with enhanced ability to attach onto, and enter, human cells. Shortly thereafter, some workers became sick. That, Chan wrote, was not initially reported.

3. Experiments at the Wuhan facility were done at the lowest two of the four standard biosafety levels, which were established at the dawn of recombinant DNA research in the 1970s. An altered virus could have escaped.

4. The evidence supporting viral origin at the Huanan seafood market was never compelling – it just seemed possible.

5. Evidence that the virus emerged, or escaped, from the wildlife trade is lacking.

But the list leaves out the most likely scenario, which is where Chan’s discussion begins: the virus was present, or arose, more than a decade ago in a mineshaft in Yunnan Province in China and/or a cave in Laos – as a virus called RaTG13. It, or perhaps a similar viral contemporary or descendant not yet recognized, was the lump of clay from which SARS-CoV-2 would be molded.

The most compelling evidence for the origin lies in the RNA genome sequence similarities between RaTG13 and SARS-CoV-2 – specifically, a part that encodes the “furin binding site” of the spike protein with which the virus adheres to host cells. And a change to one specific part of the virus enabled it to locate and glom onto our cells, then slip inside and take over the protein production line. Coincidence? I’ve never thought so. Perhaps more likely is that one type of coronavirus gave rise to another with a little help in the lab.

The Likely Predecessor of SARS-CoV-2 – From my Past Blog Posts

I wrote 100+ DNA Science blog posts during the pandemic about the virus. It’s interesting to look back now, as much of the guesswork, infighting, accusations, motives, and scenarios have lost intensity. I tuned much of that out, focusing on clues in the science. (I edited a bit and comment in italics.)

On April 15, 2021, I posted “3 Possible Origins of COVID: Lab Escapee, Evolution, or Mutator Genes?”

Researchers discovered RaTG13 in droppings of the horseshoe bat Rhinolophus affinis in an abandoned mineshaft near a cave in Yunnan, China, in 2013, shortly after six miners fell ill and three of them died of an unspecified pneumonia. (Bats harbor many viruses without becoming sick, which I explained here.)

RaTG13 shares about 96.1% of its genome sequence with that of SARS-CoV-2. For perspective, SARS-CoV-2’s genome is only about 80% similar to that of the original SARS coronavirus from 2003.

A key difference between RaTG13 and SARS-CoV-2 is in part of the receptor binding domain where the spike protein latches onto human cells. This differing part matches the RNA sequence from viruses in the Malayan pangolin, a spiny anteater-like creature that may be an intermediate host between bats and people.

Clues to the transition from bat RaTG13 to human SARS-CoV-2 may lie within the smidgeon of the genome sequences that diverge. Evolutionary biologists estimate it would have taken at least 50 years for the bat virus to have mutated into SARS-CoV-2, considering known, natural mutation rates of viral genomes. A bioweapon could have been created much faster.

A leap from RaTG13 from bat muck in 2013 to the emergence of SARS-CoV-2 in 2019 is like reading the first and last chapters of a novel: there’s not enough of a plot to reconstruct a story. But as more chapters are revealed, it increasingly seems that SARS-CoV-2 arose from a poop soup of viruses – and continues to evolve as new mutations appear.

RaTG13 likely wasn’t the only stop on the evolutionary road to SARS-CoV-2. Nor was China the only home of novel coronaviruses. Consider reports:

Cambodia, January 26, 2021 Excrement and saliva from two horseshoe bats sampled in Cambodia in 2010 yielded coronaviruses that share 92.6% of their genome sequences with SARS-CoV-2. The viruses differ at one end of the gene that encodes the spike protein.

Thailand, February 9, 2021 Blood from five bats in a cave in Thailand yielded coronaviruses similar to those from Yunnan, and also had antibodies against SARS-CoV-2, attesting to the similarities of the two viruses. The antibodies were also detected in a pangolin. Whatever the progenitor virus was, its realm extends beyond China.

China, March 8, 2021 a report expanded coverage to 411 coronavirus samples from 23 bat species, collected from May 2019 to November 2020, over 2700 acres in Yunnan province. SARS-CoV-2 and its closest relative among the samples, dubbed RpYN06, share 94.5% of the genome sequence.

More important than genome similarity, though, is the correspondence between individual genes, which can better predict the effect of a novel virus on a host. And RpYN06 indeed has key genes that encode the proteins that:
• protect the viral genetic material
• provide the tools to replicate
• enable entry into host cells
• take over the cell’s protein synthetic machinery

The investigation also identified three other coronaviruses whose genomes are very similar and resemble the pangolin virus.

So did SARS-CoV-2 chug along, in diverse bats for years, mixing its RNA with that of other coronaviruses, yet retaining genes that had served it well?

The title of an article in PLoS Biology from March 12, 2021, summed up the forces that likely, at some early point at least, molded the novel virus: “Natural selection in the evolution of SARS-CoV-2 in bats created a generalist virus and highly capable human pathogen.”

So ended my 2021 blog post a month later. Yet even then, inklings arose that something else nudged the fledgling virus into becoming a killer – and it had a boost in the lab.

Dr. Chan and many other sources blame a research project called Defuse from US-based EcoHealth Alliance, the Wuhan Institute for Virology, and Ralph Baric of the University of North Carolina “The Defuse project proposed to search for and create SARS-like viruses carrying spikes with a unique feature: a furin cleavage site – the same feature than enhances SARS- CoV-2’s infectiousness in humans, making it capable of causing a pandemic,” Chan wrote. The US did not fund Defuse.

My DNA Science post from December 1, 2022, fleshed out the story of how the virus likely became a killer.

We still do not, and may never, know the immediate predecessor of SARS-CoV-2. I suspect many other geneticists share my opinion that the origin is unfathomable, but have been loathe to speak out because of politics and a public uncomfortable with the reality that science is inherently uncertain.

Clues to the origin lie in what to the virus is the most important part of its anatomy: the triplets of spike proteins that festoon the surface. Each spike has a part that grabs a cell, and another that slips the virus inside.

A spike attaches with its receptor binding domain (RBD), which gloms onto receptors (ACE2) on many host cell types, like in our lungs. A small part of the RBD, the “furin cleavage site,” holds the halves of a spike together, until a host’s enzyme cuts it. That jettisons the virus into the cell like an arrow shot from a bow.

Key to the power of the furin cleavage site is a specific sequence of four contiguous amino acids. This is where looking at other viruses provides compelling clues to where SARS-CoV-2 may have come from.

The first SARS virus, from 2003, doesn’t have a furin cleavage site, but HIV, the Ebola virus, and the MERS coronavirus do. That’s why the furin cleavage site in SARS-CoV-2 is dubbed a “gain-of-function.” Altering this viral Achilles heel can and has changed the speed of transmission.

How did the furin cleavage site enter SARS-CoV-2, when its nearest known relative doesn’t have it? Did pieces of RNA altering the furin cleavage site swap into the genomes of the recent ancestors of SARS-CoV-2

(a) in a bat cave?
(b) in an abandoned mine shaft?
(c) in a “wet market?”
(d) at the Wuhan Institute of Virology? And, if so, accidentally or purposely?

Consider the extent of change to the furin cleavage site: four contiguous amino acids. That represents twelve RNA bases, because RNA or DNA triplets encode the amino acids that make up proteins.

Was the sequence altered one amino acid at at a time, and we just haven’t identified the intermediates? Or all at once? Stretches of genetic material that move among genomes are well known for organisms, from bacteria to humans. But they are rare among viruses.

So how did the exact stretch of amino acids that catapult the viruses into our cells get there?

Occum’s razor might suggest that someone engineered the four amino acids into the furin cleavage site, perhaps by accident, perhaps to create a bioweapon. Then came a “lab leak.”

The cave-to-lab-manipulation makes even more sense now. Dr. Chan points out that lab workers were sickened months before the first reported cases.

I look forward to finally learning the truth to how COVID began.


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