Origins of Covid

[Skeptic Ginger]

I agree with this: Another Metzl Tweet:

Quote:

This phylogenetic analysis of the #SARSCoV2 virus makes clear that @carlzimmer's @nytimes cover story re the #COVID19 preprints was misreported. It is simply not plausible that the Worobey & Pekar papers present "dispositive evidence" of market origins.

Louis R Nemzer, Associate Professor at Nova Southeastern University commented he also concluded Gao's paper ruled out the market spillover and he highlighted the same passages I quoted. I hesitated to post this because he thinks the NYT's biases were showing in their reporting.

Nemzer's reply to Metzl's Tweet

Quote:

They had rush to finish it, because the other preprint by the head of China's CDC (Gao 2022) was about to say the market was NOT the source.

Gao's paper with the highlights is embedded in Nemzer's Tweet.

[angrysoba]

Originally Posted by Skeptic Ginger

So Gao should have an opinion on the market being a spillover event but the Worobey group can't possibly address the Gao et al paper because they came out a day apart?

It's easy to focus on something pedantic and miss the bigger picture.

Worobey overstated the findings of their study. Nothing about being interpreted by anyone else.

More than a few Western researchers and experts have a confirmation bias toward finding a natural event, not a lab accident for the origin. I brought this up a couple posts upthread. The implications of a lab accident could have repercussions that affect the whole viral research field.

Gao has a clear motive to find an origin of the pandemic outside of Wuhan, outside of China. Why would he consider a possible spillover event at the market? That makes no sense.


None of these people except Gao are necessarily aware of their biases.


That's why the TopHap study is so important. It's also important to look at what these coronavirus researchers were doing before the pandemic. There is a lot of evidence to be found there.

You asked "Does the Worobey study address the findings in the Gao paper? Why not?"

I told you why the study does not address it.

Then you ask what did the group say?

So, you want me to track that down as well...

Worobey finds it interesting that both lineages were found in Huanan when I think they only knew of one being detected there.

Link


One complaint that comes up is that because all the swabbing seems to have been done in January, and in some cases mid-January, there is the obvious problem of destruction of a lot of evidence that could have taken place then. The market was apparently scrubbed to contain the outbreak. Clearly someone thought the Huanan market was a possible spillover zone all the way back then.

[angrysoba]

For what it is worth I don't find the Worobey et al paper to be anywhere near conclusive.

In fact, I think it has been massively overhyped.

[angrysoba]

Also, I am now confused about what some of the lab leakers believe.

It seems there have been some splits in Drastic.

Am I wrong or does Rosanna Segreto seem to be claiming that the TopHap analysis suggests that the lab from which Covid leaked was actually in the US???!??

Link

[W.D.Clinger]

Originally Posted by angrysoba

Am I wrong or does Rosanna Segreto seem to be claiming that the TopHap analysis suggests that the lab from which Covid leaked was actually in the US???!??

Link

That does appear to be what she is claiming, judging from her tweet's hand-written "USA" next to the nu1 and nu2 mutations in the TopHap paper's Figure 3. I see no support for that conclusion in the TopHap paper; indeed, Figure 7 of the TopHap paper and its discussion clearly indicate that Caraballo-Ortiz et al. (the authors of the TopHap paper) do not regard the nu1 and nu2 mutations as viable candidates for MRCA (most recent common ancestor).

Figure 5 (Spatiotemporal dynamics of 172,480 SARS-CoV-2 genomes (December 2019–2020)) of the Kumar et al. paper (which was the immediate context for Segreto's tweet, but she seems to be confused about that) shows genomes in Asia well before the appearance of genomes in Europe or North America.

Originally Posted by Skeptic Ginger

I'm not sure why you think your interpretation of the paper is superior to the 2 PhDs' interpretation of the paper.

Originally Posted by angrysoba

TWO PhDs!!!!

I guess 2 PhDs can't be wrong.

Jonathan Latham "has published scientific papers in disciplines as diverse as plant ecology, plant virology, genetics and genetic engineering." Allison Wilson "has published scientific research on plant hormones and flowering time in Arabidopsis, Tetrahymena molecular biology, and plant genetic engineering."

Let's not forget that Kumar et al. (8 PhDs) and Caraballo-Ortiz et al. (7 of the 8 from Kumar et al. plus one new co-author) published their findings in refereed journals. Latham and Wilson stated their opinions in a blog article.

[angrysoba]

Originally Posted by W.D.Clinger

That does appear to be what she is claiming, judging from her tweet's hand-written "USA" next to the nu1 and nu2 mutations in the TopHap paper's Figure 3. I see no support for that conclusion in the TopHap paper; indeed, Figure 7 of the TopHap paper and its discussion clearly indicate that Caraballo-Ortiz et al. (the authors of the TopHap paper) do not regard the nu1 and nu2 mutations as viable candidates for MRCA (most recent common ancestor).

Figure 5 (Spatiotemporal dynamics of 172,480 SARS-CoV-2 genomes (December 2019–2020)) of the Kumar et al. paper (which was the immediate context for Segreto's tweet, but she seems to be confused about that) shows genomes in Asia well before the appearance of genomes in Europe or North America.

Jonathan Latham "has published scientific papers in disciplines as diverse as plant ecology, plant virology, genetics and genetic engineering." Allison Wilson "has published scientific research on plant hormones and flowering time in Arabidopsis, Tetrahymena molecular biology, and plant genetic engineering."

Let's not forget that Kumar et al. (8 PhDs) and Caraballo-Ortiz et al. (7 of the 8 from Kumar et al. plus one new co-author) published their findings in refereed journals. Latham and Wilson stated their opinions in a blog article.

Certainly I find Latham and Wilson's discussions of various arguments to be difficult to take at face value. I would think their Mojiang Mine Serial Passage of RaTG13 theory to be even more obviously refuted than the Huanan spillover theory given the discovery of BANAL-52.

That said, I am sure that Kumar et al / Caraballo-Ortiz et al have viable claims for their analyses of the emergence of SARS-CoV2 or its progenitor.

The thing is, I have no way of judging that.

This appears to be one of the key points:

Quote:

In all the three equally most parsimonious scenarios (A, B and C), the addition of mutation x pushes back the MRCA of SARS-CoV-2 by one mutation compared to the proCoV2 sequence of Kumar et al. (2021). In these cases, the number of differences between Wuhan-1 and the MRCA is four (Fig. 7). With a mutation rate range of 6.64 × 10−4 to 9.27 × 10−4 substitutions per site per year (Pekar et al., 2021), we can estimate that proCoV2 existed 7.7–10.8 weeks before the December 24, 2019 sampling date of Wuhan-1. This places the progenitor of SARS-CoV-2 to have evolved in mid-September to early-October 2019, many weeks earlier than the mid-November 2019 date proposed by Pekar et al. (2021). For their analysis, Pekar et al. (2021) used the rooting from scenario D in which the lineage containing α2–α3 and β1–β3 (PANGO B) is a sister group of the lineage containing α1 and ν1–ν2 (PANGO A) (Fig. 7d). As noted above, this scenario receives lower bootstrap support than the alternative in which PANGO B arose from the ancestor containing α1. In this sense, Pekar et al. (2021) have likely dated an event that occurred downstream of the MRCA.

Link

Pekar et. al (2001) appears to be an earlier paper (rather than the more recent pre-print that came out as the companion paper to Worobey et. al's paper that looked at the cases spreading from the Huanan market.) in which they argued that lineage A and lineage B were separate emergences and hence making it more likely that it was due to spillover rather than lab leak.

Presumably even if the spillover occurred back in mid-September or early-October, it still doesn't answer the question of whether or not it was spillover or lab leak, and doesn't even, in my humble opinion, rule out the market as the emergence site.

But this is just my opinion. I don't even have one PhD, let alone two.

[Skeptic Ginger]

Originally Posted by angrysoba

You asked "Does the Worobey study address the findings in the Gao paper? Why not?"

I told you why the study does not address it.

Then you ask what did the group say?

So, you want me to track that down as well...

I was being sarcastic given you have been droning on about what Gao didn't say which to you has some special significance.

Seriously, it's time you stopped these pedantic distractions and actually deal with the issues. Worobey ignores the earliest cases and instead maps out the ones that essentially occurred after the super-spreading event at the market.

Originally Posted by angrysoba

Worobey finds it interesting that both lineages were found in Huanan when I think they only knew of one being detected there.

Link

From that link:

Quote:

As such, it was sampled within just 8 days of the very first SARS-CoV-2 sequence known to date, a lineage B virus sampled from a deliveryman at the Huanan market.

"[T]he very first SARS-CoV-2 sequence known to date," is exactly my point. So cases China knows about (they admitted to early on) but which they refuse to share the details about simply don't count in Worobey's "known to date".

That is not likely to get by the peer reviewers.

Originally Posted by angrysoba

One complaint that comes up is that because all the swabbing seems to have been done in January, and in some cases mid-January, there is the obvious problem of destruction of a lot of evidence that could have taken place then. The market was apparently scrubbed to contain the outbreak. Clearly someone thought the Huanan market was a possible spillover zone all the way back then.

Or they were simply doing due diligence because there was a cluster of cases around the market.

[Skeptic Ginger]

Originally Posted by angrysoba

For what it is worth I don't find the Worobey et al paper to be anywhere near conclusive.

In fact, I think it has been massively overhyped.

Some of your posts reflect that and some don't. I find it confusing that your posts put so much weight on the Worobey paper if this is indeed your opinion of it.

Can we move on now to the TopHap research?

[Skeptic Ginger]

Originally Posted by angrysoba

Also, I am now confused about what some of the lab leakers believe.

It seems there have been some splits in Drastic.

Am I wrong or does Rosanna Segreto seem to be claiming that the TopHap analysis suggests that the lab from which Covid leaked was actually in the US???!??

Link

I'll have to look into that.

As for what the lab origin proponents believe, I wasn't aware we were supposed to be moving in lock-step.

[angrysoba]

“Aha! Gao says X in his paper!”
*looks at paper again* “No, he doesn’t.”
“You’re so pedantic!”

[angrysoba]

“Aha! Worobey says X in his paper!” X 10
*looks at paper again* “That doesn’t look accurate!”
“Why you always going on about Worobey?”

[Skeptic Ginger]

I've been going on about Worobey because their conclusions are not only overstated, they've been taken, falsely, by the news media and many others as some sort of smoking gun.

As for Gao said the market was a super-spreader event, yes he said that early on. You want his latest paper to negate that, it doesn't. End of pedantry.

Back to areas of substance. I'm looking into the claim the TopHap study implicates a beginning outside of Wuhan. I saw nothing of the kind in the further analysis of the MOA results using the TopHap methodology. Most of the TopHap paper is concerned with testing its reliability.

I need to look further

[Skeptic Ginger]

Originally Posted by angrysoba

Also, I am now confused about what some of the lab leakers believe.

It seems there have been some splits in Drastic.

Am I wrong or does Rosanna Segreto seem to be claiming that the TopHap analysis suggests that the lab from which Covid leaked was actually in the US???!??

Link

I'm not seeing the "splits" you refer to. I did look at Segreto's Twitter and following leads came across this: BMJ Opinion piece: Waiting for the truth: is reluctance in accepting an early origin hypothesis for SARS-CoV-2 delaying our understanding of viral emergence?

The authors make a case for not ruling out very early circulation of SARS CoV2 in countries other than China. I don't think there's a case that is stronger than a leak from a lab in Wuhan for the main reason it doesn't explain China's reluctance to share data on the earliest cases and they've yet to release their coronavirus genome library.

But the point of leaving a very early origin in a country besides China on the table is a reasonable point.

[angrysoba]

Originally Posted by Skeptic Ginger

I'm not seeing the "splits" you refer to. I did look at Segreto's Twitter and following leads came across this: BMJ Opinion piece: Waiting for the truth: is reluctance in accepting an early origin hypothesis for SARS-CoV-2 delaying our understanding of viral emergence?

The authors make a case for not ruling out very early circulation of SARS CoV2 in countries other than China. I don't think there's a case that is stronger than a leak from a lab in Wuhan for the main reason it doesn't explain China's reluctance to share data on the earliest cases and they've yet to release their coronavirus genome library.

But the point of leaving a very early origin in a country besides China on the table is a reasonable point.

Whereas you think the virus came from the WIV (or the CCDC), derived from RaTG13 (or one of the Laos viruses), Segreto clearly thinks there is a stronger case for saying it came from the USA.

Link

Now, to be sure. She doesn't say, "It's from the US" but only says "to say that "The evidence is against a US lab-based origin of Covid-19" is clearly unscientific."

[Skeptic Ginger]

We had a problem early on in the WA State outbreak of COVID, because of a shortage of tests testing was restricted to cases of pneumonia in people with a known exposure to a positive case. It took an ED Dr taking things in his own hands to find out they were seeing fatalities from the Life Care nursing home in people with COVID.

It looks like there was significant bias in the Chinese recognition of cases to only those with a history of exposure to the market.

There are lots of details about that in this archived Twitter run down.

Quote:

The first sign of (PCR and seroconversion) global spread is found in the end of November 2019 to about 01 December 2019. This is at least a week before the Huanan market environmental samples or case cluster. ...

Severe underreporting of cases, market-centered “retrospective case search”, and market-only standard of diagnosis formed the basis of the WHO 2019 dataset of “173 cases in December 2019, centered around the Huanan market”. Other cases were ignored and covered up.

Alina Chan reply:

Quote:

A good find by @TheSeeker268: doctors in Wuhan said that unless pneumonia cases were linked to the Huanan market, they did not meet Wuhan Municipal Health Commission standards and were often not reported or counted.

It's a long exchange citing lots of data and is well worth reading.

[Skeptic Ginger]

Originally Posted by angrysoba

Whereas you think the virus came from the WIV (or the CCDC), derived from RaTG13 (or one of the Laos viruses), Segreto clearly thinks there is a stronger case for saying it came from the USA.

Link

Now, to be sure. She doesn't say, "It's from the US" but only says "to say that "The evidence is against a US lab-based origin of Covid-19" is clearly unscientific."

Besides you are misstating my position the virus came directly from any of the distant viruses in Yunaan and Laos, I'm not sure why you are repeating what Segreto said given I commented on it already in post 3013 right above your post.

[angrysoba]

Originally Posted by Skeptic Ginger

Besides you are misstating my position the virus came directly from any of the distant viruses in Yunaan and Laos, I'm not sure why you are repeating what Segreto said given I commented on it already in post 3013 right above your post.

Why am I repeating what Segreto said? Because what she says contradicts your interpretation of her...

Look again at her Tweet that specifically refers to a "US lab-based origin of Covid-19".

That is in contradiction to this, "The authors make a case for not ruling out very early circulation of SARS CoV2 in countries other than China. I don't think there's a case that is stronger than a leak from a lab in Wuhan for the main reason it doesn't explain China's reluctance to share data on the earliest cases and they've yet to release their coronavirus genome library."

No, not "very early circulation". She is explicitly saying "US-based lab origin".

Segreto is here arguing with Alina Chan (Alina believes it is a WIV origin, clearly, and Segreto thinks the US strains are shown to be the earliest according to the TopHap).

Also, interesting is that when I click on the link to that Twitter thread I find it is populated with people like Daoyu, Segreto and Charles Rixey.

You may want to look at their Twitter feeds. Lots of claims that monkeypox either came from a lab or is spreading due to ADE thanks to the Covid vaccines.

Daoyu

Charles Rixey on Monkeypox

[Skeptic Ginger]

Originally Posted by angrysoba

Why am I repeating what Segreto said? Because what she says contradicts your interpretation of her...

Look again at her Tweet that specifically refers to a "US lab-based origin of Covid-19".

That is in contradiction to this, "The authors make a case for not ruling out very early circulation of SARS CoV2 in countries other than China. I don't think there's a case that is stronger than a leak from a lab in Wuhan for the main reason it doesn't explain China's reluctance to share data on the earliest cases and they've yet to release their coronavirus genome library."

No, not "very early circulation". She is explicitly saying "US-based lab origin".

Segreto is here arguing with Alina Chan (Alina believes it is a WIV origin, clearly, and Segreto thinks the US strains are shown to be the earliest according to the TopHap).

Also, interesting is that when I click on the link to that Twitter thread I find it is populated with people like Daoyu, Segreto and Charles Rixey.

You may want to look at their Twitter feeds. Lots of claims that monkeypox either came from a lab or is spreading due to ADE thanks to the Covid vaccines.

Daoyu
[snipped off-topic Monkey Pox citations. We have enough on this plate already without expanding it to an unrelated virus outbreak]

Funny you mention Daoyu. I was just about to cite that Twitter feed.

Here's a long feed with lots of evidence that not only did the pandemic start before the market cases, there's evidence the military games were indeed connected to spreading the virus to the EU and elsewhere.

We seem to be circling back to earlier on in the thread where you dismissed the spread via the military games.


Why should I buy into one person's claim the pandemic started in the US? I'm not sure what you expect me to take away from that? This is what I said about Segreto:

Originally Posted by SG

I don't think there's a case that is stronger than a leak from a lab in Wuhan for the main reason it doesn't explain China's reluctance to share data on the earliest cases and they've yet to release their coronavirus genome library.

I also don't think she's right about the MOA/TopHap analysis showing the virus started outside of Wuhan. She might have circled what she thought was what the analysis showed, but the authors did not state that was their findings. One would think such a finding would be in their abstract or conclusion.

I've been waiting to see if they reply to Segreto. I'll post it here if they do.

Chan and Ridley build a thorough case for the Wuhan lab-leak hypothesis in their book, Viral, and their testimony to the Parliament in the UK that I cited earlier.

Here's Segreto's book review of Viral. She describes a lot of things about the book and other reviews of it. She essentially remains on the fence (her words) about the origin of the pandemic and didn't find Viral to be a game changer.


Back to what you seem to think is so important, she circled places in the phylogenetic tree from the MOA/TopHap work. That isn't exactly a detailed case for the virus starting outside Wuhan. Compare that to a number of very detailed accounts of evidence supporting the Wuhan lab-leak origin. I'm not impressed by Segretto's circles.

From the TopHap paper:

Quote:

These trends are consistent with the clonal evolution without recombination of SARS-CoV-2 during the early stage of the pandemic. ...

IOW ready to go from the first cases. That's hard to explain using the spillover hypothesis. The ACE insertion site and the FC would be unlikely to have evolved in an animal species, especially one leaving no detectable traces. Adaptation in a lab, OTOH, explains how the virus came to be ready out of the box when it infected the true patient zero.

Quote:

... In these cases, the number of differences between Wuhan-1 and the MRCA is four (Fig. 7). With a mutation rate range of 6.64 × 10−4 to 9.27 × 10−4 substitutions per site per year (Pekar et al., 2021), we can estimate that proCoV2 existed 7.7–10.8 weeks before the December 24, 2019 sampling date of Wuhan-1. This places the progenitor of SARS-CoV-2 to have evolved in mid-September to early-October 2019, many weeks earlier than the mid-November 2019 date proposed by Pekar et al. (2021). ...

The analysis rules out the market as the origin. It rules out 2 spillover events. Starting in Sept is consistent with the Chinese removal of their coronavirus databases from open access. It is consistent with early spread of the virus via the military games. And given how China sought to minimize the COVID problem during the winter olympics, it makes sense they mistakenly thought they had things under control in Oct 2019 so gave no warning to the incoming visitors to the military games.

When Segreto has an explanation for the secrecy China as invoked surrounding the earliest cases of COVID she might make her case stronger. I suspect she is misinterpreting the phylogenic tree roots.

[Chris_Halkides]

Originally Posted by Chris_Halkides

I looked up the sequences of some DNA binding proteins that fall into the class of leucine zippers. Because DNA carries a negative charge, one expects the protein to have some positively charged amino acid side chains. A portion of the sequence for Jun reads RRMR. That is three positive charges out of four amino acid residues (M is uncharged). A few residues away is a second sequence KCRKRK. That is four positive charges in a row, and 5 out of 6 (C is uncharged). Some of the residues of Fos are in a special kind of alpha-helix called a coiled-coil. In the one-letter code, K is lysine, and R is arginine.

I would point out that being close in sequence is not quite the same thing as being close in three dimensions. A typical alpha-helix makes one full revolution every 3.6 amino acids. One can consult a diagram of a helical wheel to see how the side-chains are dispersed in the standard alpha helix (although a coiled coil is slightly different). In a beta-sheet, each side chain points in an approximately opposite direction to the last one. I am not saying that the claim that 4 positive charges in a row is rare is incorrect, but I am saying that I am not convinced.

By accident I found another example, namely NPLLLKRRKKARALEAAA. KRRKK is five positively charged amino acids in a row. This is a portion of the sequence of the protein MAPKAPK2 and MAPKAPK3 has a nearly identical peptide sequence in this region. MAPKAPK2 stands for MAPK-activated protein kinases. These are signal transduction proteins, and I found these sequences and two more that have four positively charged residues in a row, in this paper Tanoue T et al., Nature Cell Biology 2(2):110-116 2000. PubMed
doi: 10.1038/35000065
EDT
My recollection is that this issue was raised because of a claim that having four positively charged amino acid residues in a row was impossible, or at the very least, never occurred in nature. K stands for lysine, and R stands for arginine; both amino acid residues have positively charged side chains. We can now be certain that having even four or five positively charged amino acid residues does occur in nature.

[dudalb]

IMHO it was bad bungling by the Chinese Government in the early stages rather then some evil plot.
The Chinses Government secrecy is a exercise in CYA more then anything else.

[Skeptic Ginger]

Originally Posted by dudalb

IMHO it was bad bungling by the Chinese Government in the early stages rather then some evil plot.
The Chinses Government secrecy is a exercise in CYA more then anything else.

No one of significance is arguing evil plot. They are arguing covering up the lab error. And it's a no brainer, nothing to hide, no coverup. Being the country responsible for a worldwide deadly pandemic, intolerable, coverup would be mandatory. And the involvement of scientists outside China who were involved in some of the research is also intolerable to admit. Thus we get things like Fauci playing word games with gain or function research.

And there is a reason so many researchers are embracing a natural spillover. They are (whether they admit it to themselves or not) concerned about the public backlash that will encompass lab research around the world, involved in connected research or not. People will be outraged to find out COVID originated in a lab.

[Skeptic Ginger]

Originally Posted by Chris_Halkides

By accident I found another example, namely NPLLLKRRKKARALEAAA. KRRKK is five positively charged amino acids in a row. This is a portion of the sequence of the protein MAPKAPK2 and MAPKAPK3 has a nearly identical peptide sequence in this region. MAPKAPK2 stands for MAPK-activated protein kinases. These are signal transduction proteins, and I found these sequences and two more that have four positively charged residues in a row, in this paper Tanoue T et al., Nature Cell Biology 2(2):110-116 2000. PubMed
doi: 10.1038/35000065
EDT
My recollection is that this issue was raised because of a claim that having four positively charged amino acid residues in a row was impossible, or at the very least, never occurred in nature. K stands for lysine, and R stands for arginine; both amino acid residues have positively charged side chains. We can now be certain that having even four or five positively charged amino acid residues does occur in nature.

There are a lot of arguments about this and that being the smoking gun. One can take any one of those arguments and find a rebuttal.

Some may be more valid than others, some might not be valid at all. I can do the same thing with the natural spillover arguments. The latest one many people are latching onto is the Worobey study and it's being treated in the news media like it is the smoking gun.

His argument is based on patient proximity to the market but that can easily be explained by the fact the market was the location of a super-spreader event.

The claim A&B lineages represent two market spillover events is no stronger than those whose analysis show B is a variant of A and it had more transmissibility. The A lineage would still have been ready out of the box if it was the lab leak strain.

The strongest lab-leak origin argument based on certain unexpected findings in the genome is that of the furin cleavage site. Yes it can be found in distant coronaviruses in the wild and yes (IIRC) that was supposed to be the result of a recombination event.

As for coming from a pangolin coronavirus, there were no pangolins around the market, and none were found in the sarbecoronavirus subgenus. Many would argue not enough bat coronaviruses have been sampled.

But there are no other furin cleavage sites in the subgenus sarbecoronaviruses and it offers no benefit that it would be naturally selected in any SARS-like CoVs. It provides one of the stronger bits of evidence of human intervention in the evolution of SARS CoV2.

Could it be from a natural recombination event in the wild? Sure. Is it likely? No.

We are back to no smoking gun on either side and a lot of wannabe smoking guns that can each be argued against.


I'm waiting to hear the arguments against the HapMap/MOA studies which identified the early evolution of SARS CoV2 beginning more likely in Oct/Nov of 2019. That fits with other evidence like when the Chinese took their database of coronavirus genomes offline blocking public access. They wouldn't have done that if it had been a natural spillover event.

Have you looked at that research?

[angrysoba]

Originally Posted by Skeptic Ginger

But there are no other furin cleavage sites in the subgenus sarbecoronaviruses and it offers no benefit that it would be naturally selected in any SARS-like CoVs. It provides one of the stronger bits of evidence of human intervention in the evolution of SARS CoV2.

Could it be from a natural recombination event in the wild? Sure. Is it likely? No.

A new paper has just been published that apparently shows how the FCS could have evolved naturally in SARS-CoV2.

https://www.nature.com/articles/s42003-022-03421-w.pdf

Also, I don’t understand your argument that an FCS “offers no benefit”. I mean the pandemic itself looks like perfectly good evidence for the benefit of FCS. It managed to replicate all over the world and ultimately that is the only “benefit” that matters to evolution.

[angrysoba]

As for the Top/Hap, I read the paper but don’t have any way to judge whether it is accurate or not. I have no knowledge of the field and have no way to assess the science.

The paper merely states that the likely emergence is somewhere between mid-September and early November. I mean, okay, we have to put it on the pile of papers that suggest various other times of emergence such as the Pekar paper that said it likely originated in November. Why or how am I to pick one over another?

[lomiller]

Originally Posted by dudalb

IMHO it was bad bungling by the Chinese Government in the early stages rather then some evil plot.
The Chinses Government secrecy is a exercise in CYA more then anything else.

It was not even bungled all that badly from the details I've seen. Physicians see a lot of cases of pneumonia and even when it "looks different" they don't immediately jump to the conclusion it's caused by a completely new virus. The outbreak was identified in hospitals in the 3rd week of Jan from just a handful of cases and virus was isolated and sequenced in under 2 weeks from that point.

Originally I was swayed by the argument regional authorities dragged their feet a bit in raising an alert, but when you have 5 identified cases and no known deaths in a city of 10 million people causing a panic normally wouldn't have been a wise idea.

The problem is the stealth nature and high R value of covid. By the time you had 10 people in hospital and were still at zero known deaths (~Jan 20) there were probably 1000 people who had been infected. By the time you started to see a significant numbers of deaths in early Dec that was more like 25K and there was no hope of containing it. The result would have been the same anywhere IMO.

[lomiller]

Originally Posted by angrysoba

A new paper has just been published that apparently shows how the FCS could have evolved naturally in SARS-CoV2.

https://www.nature.com/articles/s42003-022-03421-w.pdf

Also, I don’t understand your argument that an FCS “offers no benefit”. I mean the pandemic itself looks like perfectly good evidence for the benefit of FCS. It managed to replicate all over the world and ultimately that is the only “benefit” that matters to evolution.

There is also the fact that we have found similar and even more advanced FCS in other wild Corona Viruses. Also worth reminding everyone that Covid only has a partial FCS rather than a full FCS which would have made it even more ineffective. If you were trying to make a human optimized Corona Virus you'd have used a full FCS not a partial FCS. It's also out of frame, which no lab would do.

[lomiller]

Originally Posted by angrysoba

As for the Top/Hap, I read the paper but don’t have any way to judge whether it is accurate or not. I have no knowledge of the field and have no way to assess the science.

The paper merely states that the likely emergence is somewhere between mid-September and early November. I mean, okay, we have to put it on the pile of papers that suggest various other times of emergence such as the Pekar paper that said it likely originated in November. Why or how am I to pick one over another?

If it jumped to earlier than Nov that early case numbers would have been much much higher in Dec unless it was limping along with very low Transmissibility for a month or so while it adapted to humans. This would undermine the argument that the virus was "ready to go" in humans and make the chances of it successfully making the jump very low.

[Skeptic Ginger]

Originally Posted by angrysoba

A new paper has just been published that apparently shows how the FCS could have evolved naturally in SARS-CoV2.

https://www.nature.com/articles/s42003-022-03421-w.pdf

Also, I don’t understand your argument that an FCS “offers no benefit”. I mean the pandemic itself looks like perfectly good evidence for the benefit of FCS. It managed to replicate all over the world and ultimately that is the only “benefit” that matters to evolution.

That paper was submitted in Sept 2021 even if it was only recently published. It doesn't say anything new. It says the same thing, they showed that it's possible the FCS entered the horseshoe bat coronavirus genome naturally.

We know it could have evolved naturally. I said so. I said all the 'smoking gun wannabes' can be explained regardless of which theory of origin they are supposed to support.

As for a benefit to the organism, well yeah, think about what you said there: it has a great benefit in human infections.


You can pick apart any lab-leak evidence and I can pick apart any spillover evidence. That was the point of my post to Chris. You have to look at the bigger picture.

As for dueling battles over the significance of the FCS, this paper is of interest:
The Difficulty of Determining the Origin of the SARS-CoV-2 FCS

Quote:

Jack Nunberg, whose group first inserted an S1/S2 FCS into the spike of SARS-CoV, said: “there is no way to know whether humans or nature inserted the site” in SARS-CoV-2 (Cyranoski 2020). ...

Whittaker recently (August 2021) published a comment describing the SARS-CoV-2 FCS as “highly unusual” (Whittaker 2021). Similar studies on MERS-CoV had also determined that its S1/S2 FCS is required for efficient entry into human lung and intestine cells, and influences the cell tropism of the virus (Park et al. 2016; Kleine-Weber et al. 2018). In September 2021, it was reported that an international group of scientists (including from the Wuhan Institute of Virology) had, in March 2018, proposed a roadmap for detecting novel proteolytic cleavage sites (including FCSs) in the spike sequences of novel sarbecoviruses and inserting these novel cleavage sites into the appropriate parental strain (Daszak 2018; Lerner and Hibbett 2021). ... The virologist David Baltimore commented that “these features make a powerful challenge to the idea of a natural origin for SARS2,” later clarifying that “you can't distinguish between the two origins from just looking at the sequence” (Caltech Weekly 2021).

That last bit was when the paper was taken as a smoking gun and it had to be clarified that it wasn't.

Quote:

As more bat CoVs are sampled, it is possible that another SARSr-CoV will be discovered with an S1/S2 FCS insertion. FCSs have evolved naturally in other non-sarbecovirus families of betacoronaviruses (Wu and Zhao 2020). Therefore, an S1/S2 FCS emerging in a sarbecovirus is consistent with natural evolution. Even so, the knowledge that scientists had a workflow for identifying novel cleavage sites in diverse SARSr-CoVs and experimentally characterizing these cleavage sites in SARSr-CoVs—likely in a manner that makes the resulting recombinant SARSr-CoV practically indistinguishable from a rare SARSr-CoV with a naturally emerging FCS—makes it challenging to rule out an artificial origin of the SARS-CoV-2 S1/S2 FCS

So emergence naturally looks to be exceedingly rare if it occurs at all. While scientists had been working experimentally on inserting the FCS in SARS-like CoVs prior to the pandemic.

[Skeptic Ginger]

Originally Posted by angrysoba

As for the Top/Hap, I read the paper but don’t have any way to judge whether it is accurate or not. I have no knowledge of the field and have no way to assess the science.

The paper merely states that the likely emergence is somewhere between mid-September and early November. I mean, okay, we have to put it on the pile of papers that suggest various other times of emergence such as the Pekar paper that said it likely originated in November. Why or how am I to pick one over another?

An earlier emergence pretty much makes Worobey's hypothesis unsupportable.

It fits with why the Chinese took the genome database down and also with the military games being the reason the virus showed up so early in Italy and the rest of Europe. I'm not sure why we haven't heard more about testing the attendees of the games for COVID. If none of them had COVID we should have heard that by now yet we haven't.

And it addresses the two lineages with B being a variant derived from A.

[Skeptic Ginger]

Too late to edit my posts but I referred to HapMap in a couple posts because I was reading articles in the technique that used that term. I should have been referring to TopHap.

[angrysoba]

Originally Posted by Skeptic Ginger

That paper was submitted in Sept 2021 even if it was only recently published. It doesn't say anything new. It says the same thing, they showed that it's possible the FCS entered the horseshoe bat coronavirus genome naturally.

We know it could have evolved naturally. I said so. I said all the 'smoking gun wannabes' can be explained regardless of which theory of origin they are supposed to support.

As for a benefit to the organism, well yeah, think about what you said there: it has a great benefit in human infections.


You can pick apart any lab-leak evidence and I can pick apart any spillover evidence. That was the point of my post to Chris. You have to look at the bigger picture.

As for dueling battles over the significance of the FCS, this paper is of interest:
The Difficulty of Determining the Origin of the SARS-CoV-2 FCSThat last bit was when the paper was taken as a smoking gun and it had to be clarified that it wasn't.

So emergence naturally looks to be exceedingly rare if it occurs at all. While scientists had been working experimentally on inserting the FCS in SARS-like CoVs prior to the pandemic.

Can you stop using the words "smoking gun"? Nobody is using the term except you. The spillover argument does not rely on "smoking guns".

[angrysoba]

Originally Posted by Skeptic Ginger

An earlier emergence pretty much makes Worobey's hypothesis unsupportable.

It fits with why the Chinese took the genome database down and also with the military games being the reason the virus showed up so early in Italy and the rest of Europe. I'm not sure why we haven't heard more about testing the attendees of the games for COVID. If none of them had COVID we should have heard that by now yet we haven't.

And it addresses the two lineages with B being a variant derived from A.

I don't think that is true. It could have emerged in the market in September and/or October and simply taken that long to become more transmissable.

Worobey's paper is based on epidemiology.

The paper that would be contradicted by the TopHap analysis is the Pekar paper.

But I have no way to judge whether the TopHap paper or the Pekar paper is more likely to be correct.

We should not just choose the paper based solely on which theory it fits better.

But as you say, it seems unusual if you could determine whether or not there were earlier outbreaks in the US or Italy without being able to blame Chinese obstructionism.

There seem to be a few possibilities, and one of those is simply that there was no pre-December spread to Italy (incidentally, that seems most parsimonious to me), but the theory most consistent with a lab leak, would have to then assume that Italy and/or the United States is involved in some kind of cover-up.

This is one of the reasons why, for me, it is difficult to posit a lab leak that doesn't also end up with ad hoc conspiracy theories being fashioned to paper over the cracks in the theory.

[Skeptic Ginger]

Originally Posted by angrysoba

Can you stop using the words "smoking gun"? Nobody is using the term except you. The spillover argument does not rely on "smoking guns".

Sure if it bothers you. What term would you like to use for any piece of evidence that is conclusive?

I should probably go back to see what you used describing the Worobey study.

[angrysoba]

Originally Posted by Skeptic Ginger

I should probably go back to see what you used describing the Worobey study.

Feel free.

[Skeptic Ginger]

Originally Posted by angrysoba

I don't think that is true. It could have emerged in the market in September and/or October and simply taken that long to become more transmissable.

Worobey's paper is based on epidemiology.

The paper that would be contradicted by the TopHap analysis is the Pekar paper.

But I have no way to judge whether the TopHap paper or the Pekar paper is more likely to be correct.

You are quite defensive of the Worobey paper. His study relies entirely on looking at how the cases cluster around the market. He ignores the fact earlier cases are not included.

Originally Posted by angrysoba

We should not just choose the paper based solely on which theory it fits better.

But as you say, it seems unusual if you could determine whether or not there were earlier outbreaks in the US or Italy without being able to blame Chinese obstructionism.

There seem to be a few possibilities, and one of those is simply that there was no pre-December spread to Italy (incidentally, that seems most parsimonious to me), but the theory most consistent with a lab leak, would have to then assume that Italy and/or the United States is involved in some kind of cover-up.

You are way off base here.

Originally Posted by angrysoba

This is one of the reasons why, for me, it is difficult to posit a lab leak that doesn't also end up with ad hoc conspiracy theories being fashioned to paper over the cracks in the theory.

No one is covering up early cases except the Chinese. Not sure where you are getting that. There are posts here with citations about early cases in Italy and some suspected early cases have been uncovered in the US.

Here's an example.
Reuters: Coronavirus came to Italy almost 6 months before the first official case, new study shows

Quote:

COVID-19 was circulating in Italy from September 2019, according to a study by the Italian National Cancer Institute.
Italy’s first official COVID-19 case was detected on February 21st.
The new study which re-examined samples from a lung cancer screening trial between September 2019 and March 2020, suggests otherwise.
It showed that of the 959 healthy volunteers enrolled in the trial, 11% had developed coronavirus antibodies well before February.
A study by the University of Siena also supports this theory. ...

A further specific SARS-CoV-2 antibodies test was carried out by the University of Siena for the same research titled “Unexpected detection of SARS-CoV-2 antibodies in the pre-pandemic period in Italy”.

It showed that four cases dated back to the first week of October were also positive for antibodies neutralizing the virus, meaning they had got infected in September, Giovanni Apolone, a co-author of the study, told Reuters.

It would be interesting to see if this had any connection to the first cluster of cases in Italy in one city. I'll look into it.


As for the US, here's an example, also a Reuters article: Five U.S. states had coronavirus infections even before first reported cases -study

Quote:

At least seven people in five U.S. states were infected with the novel coronavirus weeks before the states reported their first cases, a large new government study showed, pointing to the presence of the virus in the country as early as December 2019.

Participants who reported antibodies against SARS-CoV-2 were likely exposed to the virus at least several weeks before their sample was taken as the antibodies do not appear until about two weeks of infection, the researchers said.

The samples came from Illinois, Massachusetts, Mississippi, Pennsylvania and Wisconsin, and were part of a study of more than 24,000 samples taken for a National Institutes of Health research program between Jan. 2 and March 18, 2020....

Of the seven samples, three were from Illinois, where the first confirmed coronavirus case was reported on Jan. 24, while the remaining four states had one case each. Samples from participants in Illinois were collected on Jan. 7 and Massachusetts on Jan. 8.

These were not as early as the cases in Italy.

[Skeptic Ginger]

Originally Posted by angrysoba

Feel free.

You didn't suggest an alternative to smoking gun. Do you have one?

[angrysoba]

Originally Posted by Skeptic Ginger

You are quite defensive of the Worobey paper. His study relies entirely on looking at how the cases cluster around the market. He ignores the fact earlier cases are not included.

I am not "defensive". I just try to be accurate. They do not "ignore" earlier cases. Rather they work with those cases they know about.

Which specific cases are being "ignored"?

[angrysoba]

September infections of Covid?

That makes no sense.

This has clearly not reached the level of established fact otherwise it would be part of any working theory of the origins of Covid.

Besides, if the cases were in September it would torpedo your claim the Wuhan Games led to the outbreaks in Italy.

[W.D.Clinger]

Originally Posted by angrysoba

As for the Top/Hap, I read the paper but don’t have any way to judge whether it is accurate or not. I have no knowledge of the field and have no way to assess the science.

The paper merely states that the likely emergence is somewhere between mid-September and early November. I mean, okay, we have to put it on the pile of papers that suggest various other times of emergence such as the Pekar paper that said it likely originated in November. Why or how am I to pick one over another?

All three of these papers were published in refereed journals:

• Jonathan Pekar, Michael Worobey, Niema Moshiri, Konrad Scheffler, Joel O Wertheim. Timing the SARS-CoV-2 index case in Hubei province. Science 372(6540), pages 412-417, 18 March 2021. https://doi.org/10.1126/science.abf8003
  
  
• Sudhir Kumar, Qiqing Tao, Steven Weaver, Maxwell Sanderford, Marcos A Caraballo-Ortiz, Sudip Sharma, Sergei L K Pond, Sayaka Miura. An Evolutionary Portrait of the Progenitor SARS-CoV-2 and Its Dominant Offshoots in COVID-19 Pandemic. Molecular Biology and Evolution, 38(8), pages 3046-3059, August 2021. https://doi.org/10.1093/molbev/msab118
  
  
• Marcos A Caraballo-Ortiz, Sayaka Miura, Maxwell Sanderford, Tenzin Dolker, Qiqing Tao, Steven Weaver, Sergei L K Pond, Sudhir Kumar. TopHap: rapid inference of key phylogenetic structures from common haplotypes in large genome collections with limited diversity. Bioinformatics 38(10), pages 2719-2726, 15 May 2022. https://doi.org/10.1093/bioinformatics/btac186

The papers were published in the order shown above. The second and third papers in that list refer to and cite all previous papers in that list. There is considerable overlap between the authors of the second and third papers in that list.

Allow me to suggest that all three papers should be regarded as credible, with each succeeding paper building upon and refining/improving the previous papers. That's how science usually works.

Originally Posted by angrysoba

The paper that would be contradicted by the TopHap analysis is the Pekar paper.

But I have no way to judge whether the TopHap paper or the Pekar paper is more likely to be correct.

All three of these papers use statistical methods and simulations to infer the timing of variants. Caraballo-Ortiz published their paper more than a year after Pekar et al., so the Caraballo-Ortiz results are more recent and appear to use more sophisticated methods. It seems likely that the more recent papers improve upon the earlier one.


ETA:

Originally Posted by angrysoba

September infections of Covid?

That makes no sense.

This has clearly not reached the level of established fact otherwise it would be part of any working theory of the origins of Covid.

Besides, if the cases were in September it would torpedo your claim the Wuhan Games led to the outbreaks in Italy.

On my reading of the paper by Caraballo-Ortiz et al., they are not suggesting any humans had been infected with SARS-CoV-2 in September 2019, or even in October. So far as I can tell, their methods are incapable of determining when the first human infections occurred. In the following quotation, they are talking about the evolution of the Most Recent Common Ancestor (MRCA) of SARS-CoV-2. With my highlighting:

Originally Posted by Caraballo-Ortiz et al.

With a mutation rate range of 6.64 × 10⁻⁴ to 9.27 × 10⁻⁴ substitutions per site per year (Pekar et al., 2021), we can estimate that proCoV2 existed 7.7–10.8 weeks before the December 24, 2019 sampling date of Wuhan-1. This places the progenitor of SARS-CoV-2 to have evolved in mid-September to early-October 2019, many weeks earlier than the mid-November 2019 date proposed by Pekar et al. (2021).

[Skeptic Ginger]

Originally Posted by angrysoba

I am not "defensive". I just try to be accurate. They do not "ignore" earlier cases. Rather they work with those cases they know about.

You put a lot of weight into Worobey's report because it's the main source of specific spillover evidence. But it really isn't any stronger than what we already know about the spillover hypothesis. There is still no animal source and no outbreaks anywhere else except Wuhan where these viruses were being studied and that included live cultures, a fact that I believe was denied at first. 'Of all the gin joints in China ...'

Originally Posted by angrysoba

Which specific cases are being "ignored"?

The ones China at first admitted to then later refused to share any of the demographic data about. Demographic as in the things an epidemiologist would look at to track down the source of an outbreak.


Worobey used convenient confirmation bias data that was readily available. He ignored the rest. Quay used a similar approach noting that the hospitals taking COVID patients followed the metro line that connected the WIV to the city proper and you dismissed that analysis out of hand. Interestingly some of the the hospitals are near the market as well.

Wherever data was missing Worobey chalked it up to asymptomatic and mild cases. That's valid if you have dots to connect the cases. In Seattle and surroundings researchers at Fred Hutch (Bloom's lab) connected the dots between the first known patient who had come straight from Wuhan, to a Seattle resident that was picked up in a flu surveillance study, and to an outbreak at the nursing home near me. We don't know who passed the virus on in between, but the genetics showed the cases were connected.

Worobey concluded A&B lineages represented 2 separate spillover events both occurring at the seafood market. Other researchers think the A&B lineages have a direct connection with B being a variant of A.


Here's an example of fitting the evidence to existing bias: Paper by Worobey in Science: Dissecting the early COVID-19 cases in Wuhan

Quote:

Samples from the earliest COVID-19 patients in Wuhan have been sequenced, and two distinct SARS-CoV-2 lineages, A and B, have been identified. Given that the elderly couple at HPHICWM was the WHO report’s cluster 1, it follows that the husband, illness onset 26 December (1), must be the source of the earliest lineage A sequence, Wuhan/IME-WH01/2019 (GenBank accession number MT291826) (see fig. S1), which he most likely got from his wife, who became ill 15 December. This raises the possibility that the Yangchahu Market that they visited may have been a site of a separate animal spillover.

Yes the earliest cases we have genome and other demographic data for. In the paper he uses the fact the hospital that had this patient was the first to identify the virus and raise the alarm. This was about the same time the Chinese had suppressed the ophthalmologist who reported seeing several cases of an unknown pneumonia in the hospital he worked in. So there were several cases in the hospitals that I didn't see Worobey addressing.

And he soon drops the other market as a spillover site:

Quote:

However, the earliest known lineage A genomes have close geographical connections to Huanan Market: one from a patient (age and gender not reported) who stayed in a hotel near Huanan Market in the days before illness onset in December (15) and the other from the 62-year-old husband in cluster 1 who visited Yangchahu Market, just a few blocks north of Huanan Market (1), and lived just to the south (see the figure). Therefore, if lineage A had a separate animal origin from lineage B, both most likely occurred at Huanan Market, and the association with Yangchahu Market, which does not appear to have sold live mammals, is likely due to community transmission starting in the neighborhoods surrounding Huanan Market.

Sure, and coincidentally the Yangchahu market had not been cleared out and it could be tested. But it turns out there's no evidence there.

Maybe that's the other market the WHO report noted, IIRC they said a drain at another market had tested positive but the report doesn't name the market. This is the report a number of researchers claimed supported the conclusion spillovers occurred at multiple markets in Wuhan. I have asked numerous times in this thread to show us how the WHO report supported that conclusion. So far crickets. But I'm still open to someone finding it in the report.

The reason multiple market sources is important is it supposedly decreases the odds the virus coincidentally emerged where such viruses were being studied. Of all the gin joints in China ...

Getting back to Worobey:

Quote:

Thus, 10 of these hospitals’ 19 earliest COVID-19 cases were linked to Huanan Market (∼53%), comparable both to Jinyintan’s 66% (of 41 cases) (4) and to the WHO-China report’s 33% of 168 retrospectively identified cases within Wuhan across December 2019 (1). ...

... there was a genuine preponderance of early COVID-19 cases associated with Huanan Market.

He goes on discussing how all the cases not connected to the market could have been infected by the virus circulating undetected.

Sure, but in addition, the cluster of cases could also be explained by a super-spreader event at the market.