Here are four facts about SARS2 that are surprising under the natural emergence scenario but are no brainer under the lab escape one.
the fact that the pandemic broke out precisely in Wuhan, the very city in China where gain of function experiments on bat coronaviruses were ongoing.
the fact that right at the start the virus was well adapted to human cells
the fact that unlike all known SARS-related beta-coronaviruses, the SARS2 spike protein has a furin cleavage at the S1/S2 junction, just the right place for infectivity.
the fact that the furin cleavage site comprises a double arginine codon also unknown among beta-coronaviruses.
Of course, none of these independent facts taken in isolation would be very convincing but it is their accumulation that is quite telling.
Now, according to you, what are the evidences supporting the natural emergence scenario?
You say this is surprising on natural emergence, but why? Where should it have broken out under a natural emergence?
This is addressed by Edward Holmes in the presentation: Go to the video at about 44:20 and he addresses that claim.
What does it mean to be âwell adaptedâ to human cells? Itâs apparently even more adapted to mustelids such as ferrets and mink (leading to the total collapse of the Danish ermine industry when it got into the Mink population here and the government decided to have them all exterminated).
And as Edward Holmes also states, even the pangolin*(ant-eater, also found in asia and china) coronavirus does really well in human cells.
And itâs evolving better transmission in humans, as we can see with how things like much more transmissable variants are dominating the populations circulating worldwide. If it was already âwell adaptedâ(whatever that means) itâs not clear why it can still experience mutations that facilitate such huge increases in transmissibility.
The spike protein from a bat corona virus(SCH014) is known to be able to facilitate successful infection of human cells.
You yourself have argued extensively in your defense of Sanfordâs GE idea that zoonotic transmissions from natural reservoirs is a common source of viral pandemics.
But this just isnât a fact. Did you watch the presentation by Edward Holmes? He addresses this exact point in the Q/A period (question is posed about an hour in).
Hereâs a transcription of the relevant portion:
Questioner: Weâve got a question, uhm - what is the evolutionary role of the furin cleavage site? How did it get inserted into the SARS-Cov2 virus? Edward: So this furin cleavage site, this has been the most contentious, four amino acids of such absolute contention, so thereâs been an argument that itâs been deliberately inserted. Edward: If you look at viruses, lots of them have furin cleavage sites. Itâs very very common, uhm, serious influenza viruses have them. In corona viruses they are all over the place - they come and go all the time in evolution, okay? Edward: Weâve actually found some bat ones that have quite similar sites, so I think itâs an evolutionary, I think itâs a hotspot in evolution that changes all the time. In itself it means absolutely nothing. Edward: It appears to increase transmission, uhm, transmission of the virus, okay? But I think no more than that. Edward: Also, one other point. If you use cell culture, if you try to grow the lab[sic] in cell lines, you only ever lose the site, you donât gain it, okay? So if itâs a lab, if itâs engineered in a lab, you would not, the result youâre getting is the opposite you actually get cause you tend to lose it in a lab. Edward: So I think itâs a natural piece of coronavirus and virus evolution and no more than that. Thereâs not, thereâs no engineering going on there Iâm pretty certain of.
What is it about double arginine codon sites that make them more expected on a lab escape theory, as opposed to being the consequence of a zoonotic transmission through an intermediate host like mustelids or pangolins where that same cleavage site is also advantageous to the virus?
Presence of a furin CS at the S1/S2 junction is not uncommon in human coronaviruses; while half of human seasonal coronaviruses as well as MERS-CoV contain furin CSs, the remaining strains and SARS-CoV do not6,16. Thus, furin-mediated cleavage of spike is not an absolute requirement for efficient human respiratory transmission. Monitoring animal coronaviruses will probably be important in predicting and preventing future pandemics. We suggest that gain of a furin CS in the wider SARS-related coronaviruses is a cause for concern. The polybasic insertion to the S1/S2 CS provides a significant fitness advantage in TMPRSS2-expressing cells and is probably essential for efficient human transmission. We also note that the SARS-CoV-2 CS remains suboptimal for furin cleavage. It is unclear if this is a trade-off (that is, with stability of spike) or whether further optimization of this site could result in higher transmissibility. In this regard, multiple SARS-CoV-2 variants have recently emerged and spread rapidly, including some, such as the B.1.1.7 âUKâ variant, that have mutations proximal to the S1/S2 CS predicted to enhance furin cleavage. This further emphasizes the role of this site for virus transmission and the importance of continued monitoring as SARS-CoV-2 circulates in the human population53.
My bolds.
Though not the topic of this thread I also canât resist pointing this out since youâve been something of a chloroquine-fan:
Our study also confirms the limitations of relying on Vero E6 cells as a system for developing classes of drugs such as entry inhibitors as they do not accurately reflect the preferred entry mechanism of SARS-CoV-2 into human airway cells51,52. Indeed, the data here explain why chloroquine is ineffective in clinic against SARS-CoV-2 (ref. 51), since during replication in the human airway WT SARS-CoV-2 has evolved to enter cells without the need for endosomal acidification.
I posted the same paper on the presence of furin cleavage sites in MERS-CoV (which was discovered as far back as 2012 after it caused a small disease outbreak in humans) earlier on in the thread, but Gil ignored it and went ahead to still declare the presence of it in SARS-CoV-2 surprising.
More, this is exactly the scenario that epidemiologists have been warning about for many years. Itâs the reason the NIH was funding research there, because Wuhan is a known hotspot for new disease outbreak, and it makes sense to have a lab nearby.
This is one of those tricky âcorrelation is not causationâ problems, like the amazing coincidence that firemen always seem to show up at the location of a fire. Firemen respond to need - itâs not their job to start fires to put out. Much like the need for a laboratory in Wuhan where virus jumping species has been observed before.
Iâm not saying we shouldnât take laboratory safety practices seriously (we should), but the location of the lab in Wuhan should not be taken as causal evidence - itâs not.
There have been very good explanations for this already. It is critical to be aware of the difference between correlation and causation.
This argument doesnât make any sense. If a virus accumulates mutations that allow it to cross over from one species to another, then that virus becomes âwell adaptedâ to the new species. You are aware this happens routinely, correct? There are many examples within the last dozen years or so.
This is inaccurate. There are several beta coronaviruses that have S1/S2 furin cleavage sites.
There are 10 other beta coronaviruses in this single diagram that have S1/S2 furin cleavage sites. @Michael_Okoko has already shared with you the presence of the S1/S2 furin cleavage site in the MERS-CoV (another beta coronavirus).
I donât know all of the furin cleavage site sequences in the other beta coronaviruses, but these sequences are variable. There is no reason to suspect that a PRRAR cleavage sequence is somehow evidence of accidental lab release.
Virus spillover between species occurs routinely. We notice this, of course, when the spillover results in an emerging disease, as weâve seen in SARS and MERS, but it happens much more frequently than that. Infectious disease specialists warned for years that the probability of a pandemic due to such an event was quite high.
The sequence similarity between SARS-CoV-2 and the RaTG13 bat virus is 96%, although the RaTG13 is missing the furin cleavage site. Several pangolin viruses have a stronger sequence similarity in the receptor binding domain (RBD) of the spike protein. Furin cleavage sites can be acquired through recombination, followed by mutation. There are very plausible explanations for how the SARS-CoV-2 acquired its unique sequences. (see more here - The proximal origin of SARS-CoV-2 | Nature Medicine)
In addition to the highly plausible explanation for the origin of the virus, we have the circumstances around the investigation of the Wuhan lab. In Moranâs words:
Why is this a conspiracy theory? Because the speculation has been investigated by WHO scientists who found no evidence to support it. They saw that the lab protocols at the Institute were very good, as you would expect for a world class lab that was studying dangerous viruses that were known to cause pandemics. Futhermore, none of the workers at the lab tested postive for COVID-19 and none of them were studying any virus that resembled SARS-CoV-19. So, in order for the lab leak hypothesis to be true there has to have been a massive coverup by a very large number of people. Thatâs what makes it a conspriacy theory.
Moranâs piece also includes testimony (and a video link) from Professor Eddy Holmes, who is an expert in the field, explaining why he believes the natural origin of the virus is the more plausible of these two explanations.
Btw, regarding that double arginine furin cleavage site supposedly unique in beta-coronaviruses? From Edward Holmes presentation:
Top sequence is part of the SARS-Cov2 spike protein, with the arrow pointing to the furin cleavage site with itâs double arginines (âRRâ).
All the sequences below are other beta-coronaviruses spike proteins.
Sequences 3, 4, and 5 each have two double arginines in their furin cleavage site. Sequence 6 has four possible single nucleotide G â C substitutions possible that would gain it one too.
If this argument doesnât make any sense, you should inform Robert Redfield, former CDC director that has spent his all carrier in virology, for it is precisely the argument he uses to support the lab escape scenario.
The interesting point here that you failed to mention is that the two arginines of the furin CS of SARS2 spike protein are both coded by a CGG codon, the least popular coronavirusâ arginine codon. Indeed, according to Wade, only 5 percent of SARS2âs arginine codons are CGG, and the double codon CGG-CGG has not been found in any other beta-coronavirus. And Wade to pursue: for the lab escape scenario, the double CGG codon is no surprise. The human-preferred codon is routinely used in labs. Anyone who wanted to insert a furin cleavage site into the virusâs genome would synthesize the PRRA-making sequence in the lab and would be likely to use CGG codons to do so.
Okay so now weâve moved on from âno other coronaviruses have furin cleavage sitesâ - which was false, through âno beta-coronaviruses have double-arginine (RR) cleavage sitesâ - which was also false, to âbut the furin cleavage site is using CGG codons which have the lowest frequency among arginine codons and is preferred by researchersâ.
Considering the multiple falsehoods Iâm tempted to start asking for actual references.
Reference to the frequency of CGG-arginine codons among coronaviruses generally, and in their apparently very real, natural furin cleavage sites specifically.
Reference to the claim that theyâre âhuman preferredâ, and to what extend?
Are CGG codons actually 5% of arginine codons in all coronaviruses generally, or SARS-Cov2âs only? And is that also true among all coronavirus furin cleavage site codons? And just how significant is that really, considering that all the other arginine codons are a single nucleotide substitution away from a CGG codon?
To be fair I donât think @Giltil has said that SARS-Cov2 was released from the lab intentionally. I think heâs saying it was made able to infect humans intentionally though not with any aim of releasing it. I assume he thinks itâs hypothesized escape from a lab was accidental. He could of course just clarify.
I didnât say that he was saying that. He is claiming that it was constructed intentionally, a hypothesis for which there is little evidenceâso little that Gil resorted to the false claim about SARS-CoV-2 being the only one of
For those needing clarification, I invite them to go back to what I wrote at the incipit of this thread.
Note also that I am not saying that the virus has been cooked up in the lab through gain of function experiments and then accidentally escape from the lab, only that it is a plausible hypothesis that, as far as I can see, best explains the data than natural emergence.
It is surprising if Wade is right when he says that of all known SARS-related beta-coronaviruses, only SARS2 possesses a furin cleavage site. Granted, MERS-cov is a beta coronavirus, but since it is not a SARS-related beta coronavirus, it seems that Wade may be correct here.
Wade doesnât say that other beta coronaviruses beside SARS2 donât have a S1/S2 furin CS, only that among the SARS-related beta-coronaviruses, only SARS2 has one. Not being an expert in the field, I canât say if he is correct here, but I guess he has done his homework.
Iâve never said that « no other coronaviruses have a furin CS »
I should have been more precise here and said that no other known beta coronavirus has a double CGG arginine codon. But this should have been obvious for anyone who would have read Wade piece.
As shown above, the multiple falsehoods you are referring to are imaginary.
