Thoughts on Hong Kong Virologist Warning
So I guess I am wondering if this isn’t just the outcome that happens when you insert a polybasic furin cleavage site in just the right spot?
If this virus is zoonotic then we are not dealing with core virus A + core virus B = COVID, we would be dealing with multiple layers of recombinant evolution. For example, the second-closest match to hCoV-2019 is from a Malaysian Pangolin MP789 virus. The specific Pangolin in question had no less than 9 viruses in its blood, one of which being Yellow Fever, which happens to have a polybasic RSRR motif in its cleavage site. The coronavirus discovered had a 88.4% RdRp match to SARS-CoV-HGZ8L1-A and a 91.31% RdRp match to hCoV-2019. More importantly, this coronavirus discovered in this now deceased Pangolin perfectly matched the key six amino acids identified for hACE2 docking affinity. This Pangolin is not our source animal as it died in Guangdong, China in March 2019 and does not contain a furin cleavage site. The bigger point here is that over time a Pangolin infected with a SARS-like coronavirus, Yellow Fever, and perhaps others would likely bring us to something nearly identical with what we are seeing. Within that dead Pangolin was the possibility to evolve to hCoV-2019. The 6 key amino acids for hACE2 docking affinity, the RxRR cleavage site from Yellow Fever and a very virulent Spike protein.
If we take a horseshoe bat that has a similar naturally occurring virus, like we see in 4991/RaTG13 then introduce that beta coronavirus to a Malaysian Pangolin already infected with Yellow Fever, HIV, and some other viruses, we have the potential of being at 99.8% similarity to hCoV-2019. Then we infect a human host and allow the virus to culture and we would expect specific homo-sapien mutations that would dock best with humans as opposed to other animals. Why? The coronavirus in our example bat does a pretty bad job docking to human ACE2 but perhaps to other animals. The Pangolin would gain its cleavage site from other viruses and reshape a newly evolved virus. As this virus is novel it has no “natural” host to dock with but since it contains sections of Yellow Fever it would naturally have an affinity to human ACE2. That affinity would then be mutated/strengthened when cultured in the human host, regardless of the survival rate of that patient zero. By the time we sequence the genome of a human patient, this person is not patient zero and is likely patient 10+ and by now we have a stabilized virus with potentially various modes of attack.
Every aspect of the genome of hCoV-2019 can be explained by zoonosis and potentially explains the existence of a polybasic furin cleavage site in our virus, as it was more than likely adapted by another virus. That being said, the natural creation of this virus is a one in a billion chance. There is nothing to suggest that a magic bat in nature directly infected a human. We have two possible paths here. Either this was created in a lab, and yes we can tinker in such a way to ensure the virus has these modes of attack or we use zoonosis with just the right bat infecting just the right Pangolin, and then infecting a human. The problem is that we have not been able to identify any host animals.
This publication in June refers to a bat coronavirus that was recently discovered to also have a polybasic furin cleavage site at the S1/S2 junction of its Spike protein. The virus in question is RmYN02 (Rhinopolus malayanus YUNNAN province, sample 2). This find shows us that this type of insertion is possible in nature. We had either just never seen it before with bat coronaviruses or they had not yet previously evolved to this point. Now the cleavage site in question is pretty weak and the insertion is P-AA compared to PRRA. The RBD and Spike protein of this bat virus are pretty boring and do not warrant much research. The virus in question is RmYN02 and the publication can be found here. For our hCoV-2019 the existence of an RxRR motif is more than likely to have been adapted from a similar virus-like Yellow Fever during zoonotic recombination.
Her timing coincides with the abrupt closure of the Houston consulate; maybe there is no connection, but the timing is there.
I think you are not seeing the bigger picture of mortality. SARS mortality should also not be trusted. If China is not being transparent about their cases now, why then do you believe they were being transparent with SARS-CoV? So you are building on a foundation of sand and not realizing that the data you are working with cannot be trusted. What was the actual CFR of SARS-CoV? We have absolutely no clue because, if you look back in history, China initially covered up the SARS outbreak. Shocking, right?
Right, yes, SARS1 data cannot be trusted because it came mostly out of China, and I guess also that far fewer people got tested because only severely sick people would have a good reason to.
The lack of honest reporting coming out of Spain should have you realize that Spain is not unique in this approach. Turkmenistan claims there are zero cases yet has filed a national public health emergency..that claim has the WHO concerned about what may actually be happening. So we can debate if the actual confirmed cases are higher or less but we need to firmly understand is the mortality count is not only exceptionally low but cannot be trusted when we factually know that countries like North Korea, Turkmenistan, China, and Spain have stopped reporting mortality. Do you see what I mean? Your data is all wrong, so you are reaching the wrong conclusions. Was the CFR of SARS-CoV worse than this? Absolutely not! Why? The numbers you see before you are all lies. That needs to become obvious in order to you to see the bigger picture. Even my government in Germany is lying about the situation. We have a fantastic health care system but there are many cases and deaths that are not being reported. 93% recovery of all patients?
Yes, we expect dictatorships like China, DPRK and Turkmenistan to lie, but that Spain has also become a dictatorship isn’t well-known (outside of Spain and maybe Venezuela and Bolivia) as of today. Even in democracies, real or fake or no-longer-real, government groups will have either a net motive to downplay or exaggerate mortality and alarm level, depending on the political circumstances of each country. For example in the case of the US and Belgium, there’s a strong motive to make it look worse than it is, while in Spain it’s the opposite. In some more-democratic countries like say Sweden, there’s also obvious motives to downplay the severity of the pandemic, but they might not be as corrupt and therefore coverups are limited, the official data more trustworthy.
Can we combat the virus? Absolutely! Can we prepare our bodies to significantly limit the impact? Absolutely! Will billions of humans do that? No, and perhaps many billions are not in the position to do such a thing. I highly doubt the citizens in the slums of Dhaka, Bangladesh have the ability to purchase the right balance of vitamins to strengthen their immune system prior to infection. So there is no doubt here that we can combat this virus. But there are over 7 billion people out there and at least 1 billion were already starving to death and living in poverty. So, the bigger picture, this is a problem.
I think you don’t need to buy vitamin D supplements if you live in Bangladesh, you just need abundant Sun exposure. There are others they might be deficient in like iodine, magnesium… but clearly the #1 parameter is vitamin D blood levels. So if the recommendation to get sunshine were #1 as it should be, especially when lockdowns are involved, then mortality would go far down. So we have to ask ourselves, who is more responsible for those easily preventable excess deaths: the virus itself or government/supranational “health authorities”?
[…] That is the difference between taking a crappy PCR test for a possible RdRp match and having us Scientists sequence the entire genome of a virus sample from your cells. That PCR test can only see if you might be positive for a coronavirus. It could be this coronavirus. It could see OC43 as a close enough match and say you are positive. But having your genome sample in a lab, we can tell the exact strain family (clade) you have and denote every single mutation in every protein of that virus. While there are 15 million “confirmed cases”, there are only around 100,000 sequenced genomes from patients. That means that we, as Doctors, have confirmed only 0.6% of the global “confirmed cases”.
That is part of what I am doing every day. I am reviewing new patient data and reviewing the provided genome to determine exact mutations. This helps us track various mutations in the virus and we can use that data to help determine when the patient was likely infected.
Fascinating info, thanks. So indeed PCR tests can easily be detecting the common hCoV-OC43 (or theoretically any other betacoronavirus like hCoV-HKU1, SARS-CoV and MERS-CoV)? (That’s in addition to them detecting virion RNA sequences only, not whether they’re from active virions or just dead residues the body has already neutralized and is shedding!). That sounds like a crazy number of false positives must be happening! What’s your estimation of false positives rate?
You are confusing ACE2 and the virus. hACE2 has a cleavage site that can (it is not required) be activated, whereas the Spike protein of the novel virus has a cleavage site that requires cleavage. Two different things. TMPRSS2 is typically the preferred protease for hACE2 cleavage, however, sometimes it chooses to use ADAM17. Whereas the novel coronavirus prefers Furin. So there is no overlap here. Two different conversations. Scientists are suggesting that the virus has somehow hijacked ADAM17 and makes it select for cleavage priority over TMPRSS2, forcing cleavage of hACE2, this, in turn, weakens the structure of hACE2 and as the virus docks to hACE2, that then facilitates the breakdown of the cell.
Right, so TMPRSS2 doesn’t cleave the Spike protein into S1 and S2 subunits, or doesn’t “prime” the Spike protein, as many articles have reported, and like MERS requires? Instead it’s only furin that does this? What’s the difference between a cleaved/activated vs. non-cleaved hACE2 receptor? Lowered/increased affinity for angiotensin II or (1-7), and increased affinity for the Spike protein?
So let’s see if I’m getting this right:
– TMPRSS2 or otherwise ADAM17 can cleave hACE2 to make it easier for Spike-S1 to bind and dock to hACE2 receptors (but doesn’t cleave SC2-Spike as happens with MERS-CoV)
– the virus may somehow make ADAM17 more likely to do the cleavage, which weakens the structure of hACE2 facilitating cell membrane breakdown and thus cell entry
– furin cleaves Spike protein into S1 and S2 subunits to make it functional allowing it to bind and dock to hACE2 receptors (does it have negligible affinity for hACE2 without this step?)
– Cathepsin L (CatL or CTSL) then is required to mediate the cleavage of the S1 subunit to allow virion-cell endosome membrane fusion for RNA payload release
These two images may help readers in picturing this:
I can make strong arguments for both and provide the detailed science for both outcomes. Given the existence of a few specific beta coronaviruses, it seems highly probable that this was zoonotic. Bat RmYN02/2019 also helps explain the existence of our polybasic furin cleavage site. In my professional opinion, I would say it is 85% probable to have been of zoonotic origin. I can explain virtually every aspect of the genome but cannot explain its ability to instantly use so many host receptors. That is why this is so novel. Nonetheless, the fact that we have not positively identified either the primary or secondary hosts after 9+ months is exceptionally troubling.
Right, so what do you think could’ve been the role of GoF researchers? They introduced gains-of-function from other viruses into bat coronaviruses and infected bat populations and at some point bats passed it over (ACE2 affinity mutated) to an intermediate animal (like pangolin) and then to hACE2? Or they took a zoonotic hCoV and added some gains-of-function and it escaped a lab? Or they modified/increased affinity for hACE2 without leaving clues thus made it look like zoonosis?
Regarding Bangladesh, the air quality is exceptionally poor and the sky is mostly a haze. Citizens would nonetheless be getting vitamin D but a nice dose of toxins and dirt on a daily basis. Paved roads are not a common component of Bangladesh infrastructure
So we have to ask ourselves, who is more responsible for those easily preventable excess deaths: the virus itself or government/supranational “health authorities”?
That cannot even be a debate. Governments are responsible for nearly every death and every medical condition that survivors now need to live with. Here is an exceptionally important point that most people do not talk about. Irrespective of where this virus came from when it was first detected in Wuhan, China kept things quiet. This was likely to avoid panic and ensure the CNY holiday would not be impacted. There was a point when China internally had confirmed that the virus was transmissible from human to human. China then banned all domestic flights and began harshly locking down each province. All great (albeit authoritarian) measures, but then China intentionally allowed (promoted) international outbound flights to continue. Regardless of why they did this, the act needs to be condemned as a war crime against humanity. If we play devil’s advocate and say that the USA intentionally released the virus within China, then the USA is responsible for the spread of the virus within china. That is a localized epidemic. China then intentionally created a global pandemic. That fact is irrefutable. Next, we move on to other countries. Which kills more people within a nation, a pandemic or an economic depression? The depression wins every time. Not only did the lockdowns not work, but it also ensured global depressions which will ultimately lead to the collapse of many nations. Next, we blame the WHO, CDC, NIH, and all virologists that initially worked on this outbreak. It was government agencies that labeled this as a SARS outbreak. Emphasis on the RS in that acronym! So how would a physician treat a respiratory syndrome? They would treat it as a respiratory syndrome. Yet this is not a respiratory syndrome at all. I was screaming to deaf ears about ventilators back in February. I just cannot believe how stupid Doctors are. We have a virus that highly effectively targets ACE2. Just stop there. Does ACE2 hijacking cause ARDS or cytokine storms? The short answer is no. How about focusing on the role of ACE2 and the RAS system? How was all of this ignored and every physician in the world went? Well, it’s called SARS, so let’s get that ventilator because RESPIRATORY SYNDROME. Just ranting. Quite absurd. I would think pathologists would have been ripping their hair out. It is really bad that I knew this in February and the world figured this out in May 🙁
Fascinating info, thanks. So indeed PCR tests can easily be detecting the common hCoV-OC43 (or theoretically any other betacoronavirus like hCoV-HKU1, SARS-CoV and MERS-CoV)?
Only if the RdRp in question is a relatively close match. The ORF1ab of MERS is exceptionally different from hCoV-2019 because there are two different subgenus of betacoronaviruses. MERS fall under something called Merbecovirus and hCoV-2019 (and SARS) are in Sarbecovirus. The genomes of these two viruses are exceptionally different. Merbecovirus genomes tend to be longer than Sarbecovirus genomes and that is saying something! I went and manually checked and OC43 is a 66% RdRp match. That would be close enough pairing with a bad testing unit
That’s in addition to them detecting virion RNA sequences only, not whether they’re from active virions or just dead residues the body has already neutralized and is shedding!
Correct, we are reading either RdRp from ORF1ab or a specific segment from the (E) Envelope protein. But this is a virus, not a virion. The virion has already assembled and infected the cell, hence the host being infected. Yes a host can have virions in them and not have an infection but this typically would not show up in their blood as the assembly from ORF was never completed. Your second part is spot on! The test could pick up residues in the swab and the patient would still test positive. No hospital in the world can tell a patient if they have recovered from the virus past 90%. Meaning there is no way to tell the patient they have a 100% recovery and can go home. This is because of residues that would cause them to test positive. President Bolsanaro tested positive three times, then tested negative. The easiest conclusion is that their testing is faulty. Using a crappy test on world leaders is very shortsighted. Sequence that genome!!!
That sounds like a crazy number of false positives must be happening! What’s your estimation of false positives rate?
I would say no less than 40% of those 15 million “confirmed cases” are false positives. Even if we bring the confirmed cases down to 8 million, there are still billions of people that have not been tested. So..since the data is wrong and only a fraction of people have been “tested” this is an exercise in futility.
Right, so TMPRSS2 doesn’t cleave the Spike protein into S1 and S2 subunits, or doesn’t “prime” the Spike protein, as many articles have reported, and like MERS requires?
Correct and so why is that? Why is this virus specifically requesting Furin? We do not know. This is not unprecedented for coronaviruses, just unprecedented for bat coronaviruses.
Instead it’s only furin that does this? What’s the difference between a cleaved/activated vs. non-cleaved hACE2 receptor? Lowered/increased affinity for angiotensin II or (1-7), and increased affinity for the Spike protein?
Correct again! Forced cleavage is making the binding domain of ACE2 more susceptible to attack. The most logical conclusion here is that our virus is hijacking ADAM17 and forcing it to cleave ACE2 cells in order to help secure its own entry. That being said, this conclusion has not yet been backed up by science and is in peer review.
furin cleaves Spike protein into S1 and S2 subunits to make it functional allowing it to bind and dock to hACE2 receptors (does it have negligible affinity for hACE2 without this step?)
If Furin (or nothing) cleaves that site then the Spike protein is rendered useless. Researchers are trying to find a way to prevent the cleavage site from forming, which in turn would the virion starve as it would never infect a cell and form into a virus. I want to be clear about that point. For this virus, proteolytic cleavage is REQUIRED for the Spike assembly to FOLD into a protein. The assembly must progress step-by-step! If this step is not completed, the assembly HALTS and the entire virion will break down and “die”. Got that? Assembly instructions MUST be completed. Only when completed can any polypeptide chain be folding into a protein. Since we are referring to the Spike protein here, no protein, no completed assembly, death to the virion! Scientists are trying to stop Furin from cleaving. Other scientists are trying to stop the virion at ORF1a altogether (good luck with that).
* Everything else in your protease breakdown is correct. Looking at those photos I start to feel bad for the ER as its troops fall by the wayside during endocytosis.
Right, so what do you think could’ve been the role of GoF researchers? They introduced gains-of-function from other viruses into bat coronaviruses and infected bat populations and at some point bats passed it over (ACE2 affinity mutated) to an intermediate animal (like pangolin) and then to hACE2?
This infers malintent to mutate entire wild bat populations and it seems far-fetched to me. I believe the research is exactly as they stated. With SARS, the bat could not direct “infect” hACE2. Once horseshoe bats were revealed to be the primary host and scientists began researching bats, they saw how prevalent SARS-like viruses were in bats. That meant another SARS outbreak WILL occur at some point in the future. Dr. Shi and colleagues deduced it was probable that some of these SARS-like viruses will naturally evolve, primarily because they are mixing with other viruses in the bats, and eventually bat viruses would emerge that could directly dock to hACE2. Nothing wrong so far. So the teams went into jungles and samples tens of thousands of bats to see if they might find a needle in a haystack. No luck. So they played GOD and created a chimeric to prove their point that this was possible. While I understand the point, the risk far outweighs the reward. So her research was condemned (as it should be). What happened after that is speculation. So I need not speculate over what function they may have worked on. There is absolutely no evidence to even suggest that GoF research was conducted jointly on bats and pangolins. It is pure speculation to even suggest this. I am not saying this did not occur. We simply have zero proof.
Or they took a zoonotic hCoV and added some gains-of-function and it escaped a lab?
In terms of potential GoF research, this is more probable. Not a lab release but playing with a zoonotic hCoV.
Or they modified/increased affinity for hACE2 without leaving clues thus made it look like zoonosis?
The world may never know. We have been able to erase those clues for well over 20 years now. It upsets me when other virologists say “it was not made in a lab because..we would be able to tell if it was made in a lab”. Borrowing an analogy from technology this would be like saying it is impossible for a human to create anonymous hacking virus that hacks into the FBI database. FBI counter-hacking experts would say “well if someone hacked us, we would know who it is!”. I fully believe that statement, in 1970. All I can say is the jury is out as evidence either way is missing.
Her timing coincides with the abrupt closure of the Houston consulate; maybe there is no connection, but the timing is there.
Sorry but this is a non-starter. She fled Hong Kong in April after having worked on this virus since late December. The two stories are unrelated and the timing is off by 3 months.
The relevant timing refers to her arrival and being interviewed in the US. Your bias may be showing.
Please refrain from Making disparaging comments about Dr. Mayer. His contribution has been unparalleled in trying to unravel the facts. His only bias is toward the truth. His patience with lay people is unusual…and this community strives to be worthy of his shared expertise.
The timing of flight to Hong Kong (when it was still a safe haven with no extradition) to her exit from Hong Kong after the CCP takeover makes some sense. The timing of closure of the Houston consulate was the puzzle as their activity there has been known for years.
I was involved in the successful containment of SARS when I had my regional directors(MD) hat on, and it pains me to have seen the absence of memory and willful ignorance of lessons learned(?). I had mentally been prepared for the pandemic and its origins in early January, just not believing the lack of our governments intelligence (unlike New Zealand) and systematic falsehoods (Canada).
Obviously it took some time prior to that to put the article together. Also Trump banned flights from China on June 3. So how does her flight date (probably before June 3rd) relate to the shut down of the Houston embassy on July 22nd. Why would the two events be related????
First, the woman did not flee from China. She has lived with her husband and worked in Hong Kong for some time. Her flight to safety was from Hong Kong to the U.S. It would seem likely that she did not speak publicly to the media until after her application for asylum / immigration in the U.S. had been processed and approved. However she did tell all she knew to the Immigration officials and FBI upon landing in the U.S. on April 28, so the government would have been in receipt of her knowledge on this subject long before her public statement and before the closure of the Consulate.
Second, it’s not quite clear how your second paragraph relates to the question of the timing of the arrival of the virologist in the U.S. and the closure of the Houston consulate.
Third, I agree with Olive Oil – there is no excuse for rudeness to Dr. Mayer.