The Potential Lab Origin of COVID-19

[PointOfViewGun]

What a sad little game of definitions to play with people's opinions... Gain-of-function is not the devil people make it to be:
Recommendations for the Evaluation and Oversight of Proposed Gain-of-Function Research:

There are many types of GOF studies and not all of them have the same level of risks. Only a small subset of GOF research—GOF research of concern (GOFROC)—entail risks that are potentially significant enough to warrant additional oversight.

But what is gain-of-function? From the same document taken from NIH website:

Experimental techniques and approaches that modify microorganisms are routinely employed in pathogen research to ascertain the roles of genes and their functional products. Such studies are fundamental to the field of microbiology and facilitate correlation of genetic and phenotypic characteristics – a critical step in deciphering the complex nature of host-pathogen interactions that underlie transmission, infection, and pathogenesis. Such manipulations can result in either diminished (loss-of-function) or enhanced (gain-of-function) biological phenotypes (see Box 1)

Box 1. Gain-of-Function Research
Recently, the phrase “gain-of-function research” has become synonymous with certain studies that enhance the ability of pathogens to cause disease. However, gain-of-function studies, as well as lossof-function studies, are common in molecular microbiology and are essential to understanding molecular pathogenesis of infectious diseases. Changes to the genome of an organism, whether naturally occurring or directed through experimental manipulations in the laboratory, can result in altered phenotypes, as biological functions are lost or gained. Investigators routinely conduct loss- and gain-of-function experiments to understand the complex nature of host-pathogen interactions that underlie transmission, infection, and pathogenesis. The term “gain-of-function” is generally used to refer to changes resulting in the acquisition of new, or an enhancement of existing, biological phenotypes. This report further defines “gain-offunction research of concern” to describe the subset of studies that have been the subject of recent debate and have raised potential biosafety and biosecurity implications. These are gain-offunction studies with the potential to generate pathogens with pandemic potential in humans by exhibiting high transmissibility and high virulence. See Section 6 for a more rigorous description of GOF research of concern (GOFROC).

The document above is what Richard H. Ebright (the person sumskilz applied for his opinion earlier) was referring to. Now we know what a gain-of-function research is.

On the other hand, we have a NIH exposé. In an attempt at character assassination of Fauci, the Vanity Fair article religiously linked to in many places, points at NIH admitting to funding such a research. What's the research from NIH letter? Here:

The limited experiment described in the final progress report provided by EcoHealth Alliance was testing if spike proteins from naturally occurring bat coronaviruses circulating in China were capable of binding to the human ACE2 receptor in a mouse model. All other aspects of the mice, including the immune system, remained unchanged. In this limited experiment, laboratory mice infected with the SHC014 WIV1 bat coronavirus became sicker than those infected with the WIV1 bat coronavirus. As sometimes occurs in science, this was an unexpected result of the research, as opposed to something that the researchers set out to do. Regardless, the viruses being studied under this grant were genetically very distant from SARS-CoV-2.

Is this a gain-of-function research? Not really. There is no process describing the enhancement of the virus' capabilities. We merely have animal subjects being exposed to different types of the same virus.

So, it's not just that gain-of-function is not some spawn of the devil, NIH did not admit to funding one in the Wuhan lab as well. What's the whole fuss is about?

[Morticia Iunia Bruti]

There is a new patient zero after the study from Michael Woroby, who is strongly linked to the Huanan animal market:

Crucially, however, the now famous “earliest” COVID-19 case (1), a 41-year-old male accountant, who lived 30 km south of Huanan Market and had no connection to it—illness onset reported as 8 December—appears to have become ill with COVID-19 considerably later (12). When interviewed, he reported that his COVID-19 symptoms started with a fever on 16 December; the 8 December illness was a dental problem related to baby teeth retained into adulthood (12). This is corroborated by hospital records and a scientific paper that reports his COVID-19 onset date as 16 December and date of hospitalization as 22 December (13). This indicates that he was infected through community transmission after the virus had begun spreading from Huanan Market. He believed that he may have been infected in a hospital (presumably during his dental emergency) or on the subway during his commute; he had also traveled north of Huanan Market shortly before his symptoms began (12). His symptom onset came after multiple cases in workers at Huanan Market, making a female seafood vendor there the earliest known case, with illness onset 11 December (12). Notably, she reported knowledge of several possible COVID-19 cases in clinics and hospitals that were near Huanan Market from 11 December, and Huanan Market patients were hospitalized at Union Hospital as early as 10 December (see fig. S1).

https://www.science.org/doi/10.1126/science.abm4454

Notably is that Woroby is or was a former critics of the official WHO statement (no laboratory accident).

[swabian]

The only difference of the virus, not being laboratory made, and the virus coming from armadillos or bats that the Chinese chose to consume, does not really exist. It's coming from some form of Chinese disorganization.

We should refrain from assuming that anyone here on this subsection of a subsection of a forum is trying to engineer anything.

Can it be assumed that the virus has escaped from China, yes. It is a known fact.

Can it be assumed that China did this as a prelude to world war 3 because they are going to attack Taiwan? No. What is China's gain from being deceptive here?

They are not going to stop, if the supreme leader feels like attacking Taiwan.

If that happens, they are also going to attack Australia - and that means nuclear war and therefore the end of civilization and probably the existence of higher life, but who cares. I don't think corona is possibly a strategic advantage for the Chinese. They will face total destruction, much more than the rest of the the world. They will be utterly destroyed. And maybe aliens will carve out the accomplishments of the Chinese, millenia after they are extinct, because there will be no more human archaeology to be bothered with it.

[sumskilz]

But what is gain-of-function? From the same document taken from NIH website:

Experimental techniques and approaches that modify microorganisms are routinely employed in pathogen research to ascertain the roles of genes and their functional products. Such studies are fundamental to the field of microbiology and facilitate correlation of genetic and phenotypic characteristics – a critical step in deciphering the complex nature of host-pathogen interactions that underlie transmission, infection, and pathogenesis. Such manipulations can result in either diminished (loss-of-function) or enhanced (gain-of-function) biological phenotypes (see Box 1)

Box 1. Gain-of-Function Research
Recently, the phrase “gain-of-function research” has become synonymous with certain studies that enhance the ability of pathogens to cause disease. However, gain-of-function studies, as well as lossof-function studies, are common in molecular microbiology and are essential to understanding molecular pathogenesis of infectious diseases. Changes to the genome of an organism, whether naturally occurring or directed through experimental manipulations in the laboratory, can result in altered phenotypes, as biological functions are lost or gained. Investigators routinely conduct loss- and gain-of-function experiments to understand the complex nature of host-pathogen interactions that underlie transmission, infection, and pathogenesis. The term “gain-of-function” is generally used to refer to changes resulting in the acquisition of new, or an enhancement of existing, biological phenotypes. This report further defines “gain-offunction research of concern” to describe the subset of studies that have been the subject of recent debate and have raised potential biosafety and biosecurity implications. These are gain-offunction studies with the potential to generate pathogens with pandemic potential in humans by exhibiting high transmissibility and high virulence. See Section 6 for a more rigorous description of GOF research of concern (GOFROC).

The document above is what Richard H. Ebright (the person sumskilz applied for his opinion earlier) was referring to. Now we know what a gain-of-function research is.

On the other hand, we have a NIH exposé. In an attempt at character assassination of Fauci, the Vanity Fair article religiously linked to in many places, points at NIH admitting to funding such a research. What's the research from NIH letter? Here:

The limited experiment described in the final progress report provided by EcoHealth Alliance was testing if spike proteins from naturally occurring bat coronaviruses circulating in China were capable of binding to the human ACE2 receptor in a mouse model. All other aspects of the mice, including the immune system, remained unchanged. In this limited experiment, laboratory mice infected with the SHC014 WIV1 bat coronavirus became sicker than those infected with the WIV1 bat coronavirus. As sometimes occurs in science, this was an unexpected result of the research, as opposed to something that the researchers set out to do. Regardless, the viruses being studied under this grant were genetically very distant from SARS-CoV-2.

Is this a gain-of-function research? Not really.

Naturally, considering your expertise, we can assume that you understand the definition better than Ebright, but for the sake of balance, I'll repeat his assessment:

The materials show that the 2014 and 2019 NIH grants to EcoHealth with subcontracts to WIV funded gain-of-function research as defined in federal policies in effect in 2014-2017 and potential pandemic pathogen enhancement as defined in federal policies in effect in 2017-present.

The materials confirm the grants supported the construction--in Wuhan--of novel chimeric SARS-related coronaviruses that combined a spike gene from one coronavirus with genetic information from another coronavirus, and confirmed the resulting viruses could infect human cells.

The materials reveal that the resulting novel, laboratory-generated SARS-related coronaviruses also could infect mice engineered to display human receptors on cells ("humanized mice").

The materials further reveal for the first time that one of the resulting novel, laboratory-generated SARS-related coronaviruses--one not been previously disclosed publicly--was more pathogenic to humanized mice than the starting virus from which it was constructed...

...and thus not only was reasonably anticipated to exhibit enhanced pathogenicity, but, indeed, was *demonstrated* to exhibit enhanced pathogenicity.

The materials further reveal that the the grants also supported the construction--in Wuhan--of novel chimeric MERS-related coronaviruses that combined spike genes from one MERS-related coronavirus with genetic information from another MERS-related coronavirus.

The documents make it clear that assertions by the NIH Director, Francis Collins, and the NIAID Director, Anthony Fauci, that the NIH did not support gain-of-function research or potential pandemic pathogen enhancement at WIV are untruthful.

To someone who understands the science, the claim that it was a surprise that the resulting virus was more infective strains credibility, and it is apparent that such a claim represents an attempt by the NIH to weasel out of allegations of wrongdoing via "a sad little game of definitions" as you might say.

There is a new patient zero after the study from Michael Woroby, who is strongly linked to the Huanan animal market:

Crucially, however, the now famous “earliest” COVID-19 case (1), a 41-year-old male accountant, who lived 30 km south of Huanan Market and had no connection to it—illness onset reported as 8 December—appears to have become ill with COVID-19 considerably later (12). When interviewed, he reported that his COVID-19 symptoms started with a fever on 16 December; the 8 December illness was a dental problem related to baby teeth retained into adulthood (12). This is corroborated by hospital records and a scientific paper that reports his COVID-19 onset date as 16 December and date of hospitalization as 22 December (13). This indicates that he was infected through community transmission after the virus had begun spreading from Huanan Market. He believed that he may have been infected in a hospital (presumably during his dental emergency) or on the subway during his commute; he had also traveled north of Huanan Market shortly before his symptoms began (12). His symptom onset came after multiple cases in workers at Huanan Market, making a female seafood vendor there the earliest known case, with illness onset 11 December (12). Notably, she reported knowledge of several possible COVID-19 cases in clinics and hospitals that were near Huanan Market from 11 December, and Huanan Market patients were hospitalized at Union Hospital as early as 10 December (see fig. S1).

https://www.science.org/doi/10.1126/science.abm4454

Notably is that Woroby is or was a former critics of the official WHO statement (no laboratory accident).

Although this has been widely reported as "a new patient zero", Woroby made no such claim. The earliest known case is not believed to have been the first case nor is the first case believed to have occurred in December. Nobody disagrees that there was a cluster of cases connected to Huanan Market, but rather the disagreement is about whether or not it jumped from animals who were kept there or was spread there by an infected person. The reported hospitalizations of three researchers from the Wuhan Institute of Virology occurred a month earlier. Interestingly, Chinese scientists have been unanimous in arguing that the Huanan Market was not the source. While there is no direct evidence, live animal markets do offer the best explanation for how the disease could have begun in Wuhan via a natural spillover, which is the opinion of most scientists outside of China who endorse or lean toward natural origin.

[PointOfViewGun]

Naturally, considering your expertise, we can assume that you understand the definition better than Ebright, but for the sake of balance, I'll repeat his assessment:

To someone who understands the science, the claim that it was a surprise that the resulting virus was more infective strains credibility, and it is apparent that such a claim represents an attempt by the NIH to weasel out of allegations of wrongdoing via "a sad little game of definitions" as you might say.

No expertise, other than a basic knowledge of English, is needed here. The fact that you're not addressing my actual points but deciding to cover behind what somebody else said with a different parameter of points shows me that you too reached the same conclusion as I did. The claim was revolving around the NIH letter, that it admitted it funded gain of function. That was the claim in your post #196. It was a false claim. Now, you are free to produce the materials Ebright refers to and show us passages where it is described that the virus' functions were changed. However, there is a lesson to be had here. Showing that shouldn't take away from you to acknowledge that the NIH letter did not admit funding of gain of function research. You can do both.

[sumskilz]

The claim was revolving around the NIH letter, that it admitted it funded gain of function. That was the claim in your post #196.

I made no such claim. I didn't even mention the letter in post #196 (or anywhere else as far as I remember). The NIH letter to congress was an attempt to cover their asses after their funding of gain-of-function research was exposed via freedom of information act litigation, by claiming that it wasn't really gain-of-function because the researchers didn't know the result would be more infectious. They inserted various spike proteins into a SARS-CoV backbone creating chimeric viruses in order to see if they would be more infectious, but supposedly didn't know that they would be. The whole notion is absurd. Of course their hypothesis was that they would be.

Now, you are free to produce the materials Ebright refers to and show us passages where it is described that the virus' functions were changed.

They were already linked, but here.

Page 298, for example:

Using the reverse genetic methods we previously developed, infectious clones with the WIV1 backbone and the spike protein of SHC014, WIV16 and Rs4231, respectively, were constructed and recombinant viruses were successfully rescued. In Year 4, we performed preliminary in vivo infection of SARSr-CoVs on transgenic mice that express hACE2. Mice were infected with 105 pfu of full-length recombinant virus of WIV1 (rWIV1) and the three chimeric viruses with different spikes. Pathogenesis of the 4 SARSr-CoVs was then determined in a 2-week course. Mice challenged with rW IV1-SHC014S have experienced about 20% body weight loss by the 6th day post infection, while rWIV1 and rWIV-4231 S produced less body weight loss. In the mice infected with rWIV1-WIV16S, no body weight loss was observed (Fig. 35a). 2 and4 days post infection, the viral load in lung tissues of mice challenged with rWIV1-SHC014S, rWIV1-WIV16S and rWIV1-Rs4231 S reached more than 106genome copies/g and were significantly higher than that in rWIV1-infected mice (Fig. 35b). These results demonstrate varying pathogenicity of SARSr-CoVs with different spike proteins in humanized mice.

More opinions:

The Intercept consulted 11 scientists who are virologists or work in adjacent fields and hold a range of views on both the ethics of gain-of-function research and the Covid-19 origins search. Seven said that the work appears to meet NIH’s criteria for gain-of-function research.

One said that the experiment “absolutely does not meet the bar” for gain-of-function research. “You can’t predict that these viruses would be more pathogenic, or even pathogenic at all in people,” said Angela Rasmussen, a virologist with the Vaccine and Infectious Disease Organization at the University of Saskatchewan. “They also did not study transmissibility at all in these experiments,” meaning that the scientists did not look at whether the viruses could spread across a population.

Three experts said that, while they did not have enough knowledge of U.S. policies to comment on whether the research met NIH criteria, the experiment involving humanized mice was unnecessarily risky.

One virologist, Vincent Racaniello, a professor of microbiology and immunology at Columbia University, said while he considered the mouse experiment described in the document to clearly fall into the gain-of-function category, he didn’t see it as problematic. “You can do some kinds of gain-of-function research that then has unforeseen consequences and may be a problem, but that’s not the case here,” said Racaniello.

Robert Kessler, communications manager for EcoHealth Alliance, denied that the work on the humanized mice met the definition of gain-of-function research. Kessler insisted that bat viruses are not potential pandemic pathogens because, he said, “a bat virus is not known to be able to infect humans.” The proposal justified the work on WIV1 by explaining that it is “not a select agent” — referring to a list of closely monitored toxins and biological agents that have the potential to pose a severe threat to public health — and “has not been shown to cause human infections, and has not been shown to be transmissible between humans.”

But the group’s bat coronavirus research was focused on the very threat that bat viruses pose to people. Kessler did acknowledge that, while the original bat coronavirus in the experiment did not spread among humans, the research was designed to gauge how bat coronaviruses could evolve to infect humans.

All but two of the scientists consulted agreed that, whatever title it is given, the newly public experiment raised serious concerns about the safety and oversight of federally funded research. “In my point of view, the debate about the definition of ‘gain-of-function’ has been too much focused on technical aspects,” said Jacques van Helden, a professor of bioinformatics at Aix-Marseille Université. “The real question is whether or not research has the potential to create or facilitate the selection of viruses that might infect humans.” The experiments described in the proposal clearly do have that potential, he said.

At least one of the two (out of eleven) that disagreed that it "raised serious concerns about the safety and oversight of federally funded research" has a conflict of interest. Rasmussen has been involved in similar research regarding Ebola.

[PointOfViewGun]

I made no such claim. I didn't even mention the letter in post #196 (or anywhere else as far as I remember). The NIH letter to congress was an attempt to cover their asses after their funding of gain-of-function research was exposed via freedom of information act litigation, by claiming that it wasn't really gain-of-function because the researchers didn't know the result would be more infectious. They inserted various spike proteins into a SARS-CoV backbone creating chimeric viruses in order to see if they would be more infectious, but supposedly didn't know that they would be. The whole notion is absurd. Of course their hypothesis was that they would be.
They were already linked, but here.
Page 298, for example:
More opinions:
At least one of the two (out of eleven) that disagreed that it "raised serious concerns about the safety and oversight of federally funded research" has a conflict of interest. Rasmussen has been involved in similar research regarding Ebola.

In post #196, you linked to the Vanity Fair article. The name of that article is: In Major Shift, NIH Admits Funding Risky Virus Research in Wuhan. The main point of that widely circulated article was that NIH, in his letter, admitted to using gain of function research, when the letter contained no such information. My main post, #201, mainly addressed that article and the letter as I linked to them and quoted them. The letter also didn't portray any of the information you imply that it did in your first paragraph there. So, pardon me if I keep grounding you on the proper context.

[swabian]

@Sumskilz: I have a lot of respect for you and most of the time i soak up eagerly what you have to say, because it is always interesting, exciting and educating. But i think this time you're really on the wrong track. Yes, i have read all the stuff written by yourself and some of the articles you've linked, but there simply is no god damn proof and it's all annoying and irritating speculation. I t really makes me cringe what you're producing here. Sorry, man. No offense. I know we all have to suffer and we are all trying to make sense of of world events and emerging problems to protect ourselves. It's hard...

[sumskilz]

@Sumskilz: I have a lot of respect for you and most of the time i soak up eagerly what you have to say, because it is always interesting, exciting and educating. But i think this time you're really on the wrong track. Yes, i have read all the stuff written by yourself and some of the articles you've linked, but there simply is no god damn proof and it's all annoying and irritating speculation. I t really makes me cringe what you're producing here. Sorry, man. No offense. I know we all have to suffer and we are all trying to make sense of of world events and emerging problems to protect ourselves. It's hard...

You're correct in pointing out that there is no proof, which is why I consistently use the term hypothesis. Unfortunately, there is no solid evidence supporting any hypothesis, so it largely comes down to what one finds more or less plausible in the presence of very minimal evidence. The lack of any solid evidence for some time now has made me lose interest in the topic. What seems clear to me, is that whatever the origin is, the Chinese government is not interested in anyone knowing it, whether or not they even know themselves.

That said, the main point that I was making when I started the thread has been thoroughly vindicated, which was that the lab leak hypothesis is a legitimate and plausible scientific hypothesis, and that inquiry into that possibility was deliberately being suppressed by the Chinese government, a small group of western scientists with vested interests, and most of the western media (at the time, due to tribalism/ignorance). The once widely held notion that it is far-fetched to believe that a lab leak was the source of, or played a role in, the pandemic's origin is erroneous in light of the fact that SARS-CoV-1 jumped from nature twice but escaped from a lab six times, four times in China, and that was after it was already known how dangerous the virus is.

[Cyclops]

​To me the suppression is the scandal. I think politicians and scientists have tried to cover their arses instead of working for humanity.

[PointOfViewGun]

What's really problematic is relying on narratives that lie about basic facts about an issue. If there was ever a credit for the lab leak theory, its hurt by usage of such deceptive information and the inability to acknowledge basic facts and failures of one's own position. That, however, plagues all sects of life...

[Cyclops]

What's really problematic is relying on narratives that lie about basic facts about an issue. If there was ever a credit for the lab leak theory, its hurt by usage of such deceptive information and the inability to acknowledge basic facts and failures of one's own position. That, however, plagues all sects of life...

Indeed any serious academic research work into ivermectin and light therapies would have been skittled by Trumps trollish paw prints. Even when he was half right he sounded all wrong.

In a way I expect that, not condoning it. But Fauci's lies and misinfo around this, presumably to protect research funds from knee-jerk cancellation by association, is horrific.

[Heathen Hammer]

Indeed any serious academic research work into ivermectin and light therapies would have been skittled by Trumps trollish paw prints. Even when he was half right he sounded all wrong.

In a way I expect that, not condoning it. But Fauci's lies and misinfo around this, presumably to protect research funds from knee-jerk cancellation by association, is horrific.

This wouldn't be the first time CDC under Fauci would chose to sacrifice lives of people to save funding/image, just look up Fauci's role in AIDS crisis of the 80s.

[PointOfViewGun]

Lets not forget that Fauci was the mastermind behind Nazi experimentation on Republican babies during WWI under the supervision of Genghis Khan.

[Ludicus]

W. Post awarded Ted Cruz two Pinnochios
The repeated claim that Fauci lied to Congress about 'gain-of

the lab leak hypothesis is a legitimate and plausible scientific hypothesis

As a laboratory construct, it's not completely impossible, but what happens to the furin cleavage when the Sars-COV2 is replicated in a cell culture in a lab?

------

Ban on gain-of-function studies ends - The Lancet (2018)

Proponents of gain-of-function experiments argue that their work could facilitate vaccine development.
“We cannot even predict what the current seasonal influenza strains are going to do from one season to the next”, retorts Ian Mackay (University of Queensland, Brisbane, QLD, Australia). “We have vaccines, but they are not much good, and instead of concentrating on understanding these viruses and improving the vaccines, people prefer to worry about viruses that have not yet become transmissible and may never do so.”

That’s right...

[alhoon]

Please remember to stay topical. Further attempts to derail the thread from the potential lab origin of Covid-19 will result in deletions of entire posts and perhaps even penalties, according to the ToS

[Ludicus]

As a laboratory construct, it's not completely impossible, but what happens to the furin cleavage when the Sars-COV2 is replicated in a cell culture in a lab?

I'm waiting for an answer.

[sumskilz]

but what happens to the furin cleavage when the Sars-COV2 is replicated in a cell culture in a lab?

It's subjected to selection pressure, the specific response to that pressure would depend both on the nature of the cells and (to some degree) chance.

[Ludicus]

When the Sars-COV2 is replicated in a cell culture in a lab, the furin cleavage gets deleted; to replicate the virus while preserving the cleavage site- according to Stephen Goldstein- it would require doing things differently than everyone does them and, crucially, choosing cell cultures that replicate the virus more slowly; researchers would have had to make a series of inefficient and strange decisions to preserve a tiny protease enzyme.Another possibility, he says, is to use live animals to multiply and mutate the virus-using one sick animal to infect the next, and the next, and the next, until an evolved and efficient virus came out the other end.In the end he asks "How complicated can this get?”

We may never know where the virus came from. But evidence still suggests nature

From the moment the novel coronavirus, SARS-CoV-2, emerged in Wuhan, China, scientists and the broader public have sought answers to some fundamental questions: Where did this virus come from? How did the pandemic start? From the early days, experts have considered two possibilities. Either the virus somehow escaped from a laboratory, perhaps the Wuhan Institute of Virology, or, like countless viruses throughout history, it arrived through zoonotic spillover, jumping from animals to humans.

More than a year later, we still don’t know exactly what happened. Though governments and news organizations have focused more attention recently on the notion that the virus leaked from a lab, it’s unclear that we’ll ever identify a theory that satisfies everyone as to how SARS-CoV-2 emerged. Ironically, given the recent prominence of the lab escape theory, the questions the world wants answered about the virus — and the astonishingly fast development of the vaccines that can quash the pandemic — depend entirely on research conducted in labs like the Wuhan Institute of Virology and across the world over the past several decades. This fundamental research underpins our ability to prepare for and respond to pandemics. We need to know what’s out there and what kind of viral threats we face. The only way to do that is to go where the viruses are, with our colleagues who are already there.

In March 2020, a group of renowned evolutionary virologists analyzed the genome sequence of SARS-CoV-2 and found it was overwhelmingly likely that this virus had never been manipulated in any laboratory. Like the earlier coronaviruses SARS-CoV and MERS-CoV, they theorized, it “spilled over” from its natural reservoir host (bats) to a new one (humans). Viruses jump species frequently, with unpredictable consequences. Often a virus hits an evolutionary dead end if it cannot adapt to the new host rapidly enough to be transmitted again. Sometimes, however, it can. Clues that reveal this scenario can be found by analyzing the sequence of the virus genome, and that’s exactly what this study did.


The study carefully examined whether key elements of the virus, particularly the spike protein on its surface, appeared engineered. They did not. The spike didn’t optimally bind to its receptor, ACE-2, and the interaction between the two proteins was unpredictable even using the most advanced computer algorithms. Another key feature often cited as evidence of laboratory origin is the furin cleavage site, where the spike protein is cut in half to “activate” viral material for entry into cells. The viruses most closely related to SARS-CoV-2 don’t have this site, but many others do, including other human coronaviruses. The furin site of SARS-CoV-2 has odd features that no human would design. Its sequence is suboptimal, meaning its cleavage by the enzyme furin is relatively inefficient. Any skilled virologist hoping to give a virus new properties this way would insert a furin site known to be more efficient. The SARS-CoV-2 site has more of the hallmarks of sloppy natural evolution than a human hand. Indeed, a timely analysis last year showed convincingly that it is a product of genetic recombination, a natural feature of coronavirus replication and evolution.

Unfortunately, the pandemic has provided many opportunities to observe SARS-CoV-2 evolution in humans as it unfolds — and confidence in its natural origin has grown over time. The molecular handshake between SARS-CoV-2 and ACE-2, seemingly unique in early 2020, turns out to be found in several related viruses and has since evolved to be a better fit. Its ability to infect human cells also turns out to be unremarkable. A related virus discovered in pangolins infects human cells even more readily than SARS-CoV-2. The virus behind the pandemic may be special in its impact on our lives and the global economy, but the way it infects us isn’t unique at all.

The evolutionary trajectory of SARS-CoV-2 further undermines claims that the virus is obviously artificial and designed for human transmission. Early in the pandemic, a mutation called D614G took hold and spread rapidly around the world, showing that the virus was adapting to its host from the very beginning. Since then, mutations in the region of the spike protein that binds ACE-2, as well as near the furin cleavage site, show continued adaptation. Several of these are found repeatedly in different variants of concern and almost certainly contribute to increased transmissibility. SARS-CoV-2 continues to evolve. It wasn’t perfectly tuned for humans when it appeared, just good enough.

The epidemiological evidence in the World Health Organization’s origins mission report from this spring further bolsters the natural-origin hypothesis. Among early cases, 55 percent had had exposure to wildlife markets, and the growth of the outbreak over time, both in cases and excess deaths, clearly shows that the neighborhood surrounding the Huanan market was the initial center of the epidemic in Wuhan. It’s true that 45 percent of cases could not be linked to a market, but the silent spread of SARS-CoV-2 that has made it so hard to control also makes it difficult to rule out such connections.

Yes, the WHO’s mission was imperfect and hampered by political forces in China and elsewhere; even the organization’s director general, Tedros Adhanom Ghebreyesus, has nodded to those limitations by calling for a more thorough examination of the possibility of a lab escape. We don’t disagree about the benefits of doing so...but our priorities should be guided by what is most likely. There are still missing pieces of data, including those unlinked cases and inadequate animal sampling, but most of the data we do have points heavily toward natural origin.

Some of the public consideration of a lab escape has focused on a kind of research known as gain-of-function, and whether such experiments could have given rise to SARS-CoV-2. This work is defined by the National Institutes of Health as research on influenza, MERS-CoV or SARS coronaviruses with the potential to enhance transmissibility by aerosol droplet or pathogenicity in mammals. A subset of that research, done at the Wuhan Institute of Virology and some labs in the United States, has involved constructing “chimeric” coronaviruses, where the spike protein of one virus is inserted into the genetic backbone of another, typically the original SARS-CoV or a bat coronavirus called WIV1 used at the Wuhan lab. This allows scientists to study the properties of the spike protein within the context of a well-understood system and make direct comparisons about virulence with a known virus.These experiments carry some risk, as noted by researchers who have engaged in them, and it’s appropriate to consider the balance between that risk and their benefits.
Understandably then, some people have wondered whether these types of experiments could have produced SARS-CoV-2. The answer is, in this case, not really. In theory, if you had the right viruses in your catalogue, sure. But there are no indications that anyone had ever seen this virus nor any viruses similar enough to serve as its genetic building blocks before SARS-CoV-2 emerged in the population.

The Wuhan institute’s most recent chimeric virus used a very different coronavirus as its genetic backbone. Looking at the body of research produced there, it’s clear that scientists were laser-focused on the bat viruses related to SARS-CoV, which spurred research on coronaviruses worldwide after it emerged in 2003 because of its pandemic potential. There’s just no trace of SARS-CoV-2 in the lab, and if the SARS-CoV-2 progenitor or its building blocks weren’t in the lab before the pandemic, the pandemic could not have started there — even accidentally. This precludes the possibility that SARS-CoV-2 evolved via serial passage in cell culture, or repeated rounds of infection of other cells in a lab, as do other observations about the virus. In standard cell culture, features like the furin cleavage site that are crucial for transmission and disease in humans are rapidly lost as the virus begins adapting to the vervet monkey kidney cells typically used to grow it. For the past 18 months, virologists around the world have been studying SARS-CoV-2 in the laboratory, and they have not seen any evidence that it becomes more dangerous to humans in the lab. The opposite is true: The virus loses features key to transmissibility and virulence, forcing researchers to innovate new culture methods to allow the study of antivirals or vaccines.

It does seem like quite a coincidence that the pandemic started in Wuhan, which has one of the world’s leading coronavirus research labs, and that’s surely helped raise questions about a possible leak. But in addition to being a coronavirus research center, Wuhan is a city of 11 million people, home to a major transportation hub that is connected to every other part of China, as well as wildlife markets supplied by farms throughout the country. The presence of the lab in the city where the pandemic emerged is simply not suspicious enough on its own to outweigh what we know about the virus.

We agree that researchers should continue to study whether the virus could have emerged from a lab, but this cannot come at the expense of the search for animal hosts that could have transmitted SARS-CoV-2 to humans. Getting better answers will take rigorous scientific work — and cooperation from China. As frustrating as obfuscation by the Chinese government is, the answers are there. If we make accusations and demands that aren’t firmly grounded in evidence, we run the real risk of having no origins investigations at all.

The only reason we can evaluate the genomic and virological evidence in a scientifically informed way, and the only reason we have vaccines so quickly, is decades of research on coronaviruses. We’d be years behind the curve without this fundamental knowledge, which resulted from gain-of-function studies and surveys of coronaviruses in bats and other wild animals. How many are there? Where are they? Can they infect us? How might they compare with the original SARS-CoV, which caused a global epidemic in 2003? An even bigger question looms now: Can we design vaccines that might protect us against all related coronaviruses? Research is progressing, but testing vaccine candidates will require finding out what viruses are out there. Again, we have to work with colleagues in China, where the viruses are, to do that.

As the vaccines start to bring the pandemic under control in the United States, the fundamental truth about how to identify and fight dangerous viruses hasn’t changed: Preparing for pandemics, global crises by definition, demands a global response. We must approach this collaboratively — and objectively recognize what the data shows. This virus is more likely to be a product of nature than a product of a laboratory. Letting politics lead us toward other conclusions won’t help keep anyone safer.

One thing is certain-Furin cleavage sites naturally occur in coronaviruses
---
That said, 18 November 2021 Dissecting the early COVID-19 cases in Wuhan - Science

19 November 2021 - expert reaction to perspective looking at the early cases of ...

[sumskilz]

When the Sars-COV2 is replicated in a cell culture in a lab, the furin cleavage gets deleted; to replicate the virus while preserving the cleavage site- according to Stephen Goldstein- it would require doing things differently than everyone does them and, crucially, choosing cell cultures that replicate the virus more slowly; researchers would have had to make a series of inefficient and strange decisions to preserve a tiny protease enzyme.Another possibility, he says, is to use live animals to multiply and mutate the virus-using one sick animal to infect the next, and the next, and the next, until an evolved and efficient virus came out the other end.In the end he asks "How complicated can this get?”

We may never know where the virus came from. But evidence still suggests nature

The lead author on that article is Angela Rasmussen, whose conflict of interest I've already discussed. It's a series of strawman arguments and non-sequiturs.

But returning to what you asked:

but what happens to the furin cleavage when the Sars-COV2 is replicated in a cell culture in a lab?

It's such a vague and broad question that it made no sense. What cell culture? It was not unexpected that it was supposed to be some sort of silly gotcha moment, but this was my polite answer attempting to cover a very broad question:

It's subjected to selection pressure, the specific response to that pressure would depend both on the nature of the cells and (to some degree) chance.

I was correct of course.

This is what Rasmussen and Goldstein actually wrote (note what I bolded):

In standard cell culture, features like the furin cleavage site that are crucial for transmission and disease in humans are rapidly lost as the virus begins adapting to the vervet monkey kidney cells typically used to grow it.

Why did they only talk about vervet monkey kidney cells and never mention humanized mice cells when it's a matter of public record that the WIV was passaging through humanized mice cells? I can only assume that's because the article was meant for a general audience and they weren't arguing in good faith.

Now here was your non-sequitur takeaway:

When the Sars-COV2 is replicated in a cell culture in a lab, the furin cleavage gets deleted

But this is all very tedious, especially because the lab leak hypothesis wouldn't be falsified if the furin cleavage site turned out to be completely natural in origin.