Greetings! No argument on the "mess" remark, haha - but I don't see how my argument is very different from yours at first glance? The "years of evolution without sequences showing up" is Ethical Skeptic's theory, and my post is addressing why that is implausible for several reasons related to the evolutionary branching of BA.1 and BA.2 and yet their simultaneous geographically co-located emergence. So I am very much against the theory that Omicron came from actual transmission or infection as opposed to a lab origin.
Yikes, I never encountered Schmidt, et al. before. Recombination would need to have been with an mRNA vaccine or plasmid/pseudovirus construct that didn't use codon optimization, otherwise Omicron spike would be even more unrecognizable especially with silent mutations. Instead "BA.0"/1/2 are all 100% NS in spike. So Schmidt et al.'s plasmids were optimized, Moderna's mRNA likewise. But it's at least something to consider possible.
I'm somewhat agnostic about whether Omicron's spike was created in a "bespoke" synthetic fashion or simply the result of lab-setting escape-passage through immunized mice. Martin, et al. might be an argument for the latter, since it seems like a lot of the resulting spike changes wouldn't have been intentionally added but hypothetically still could have resulted from forced immunity escape (https://www.biorxiv.org/content/10.1101/2022.01.14.476382v1).
It was clearly not exactly the Schmidt et al paper that led to Omicron, it just proves that virologists would build such GoF mutation-enriched spikes outside of BSL4. Gritstone was testing some next gen. self replicating spike mRNA vaccines in humans if I'm not mistaken. such a study would also explain BA1, BA2, BA3..., always different parts of a super-infectious spike recombining w/ different SC2 strains in different people...
The methodology in this paper -- for reconstructing phylogenetic tree by an ordering method that does not rely on a "clock" (eg as Trever Bedford does) -- might be interesting applied to the Omicron data. The paper gives what seems likely to be a much more accurate picture of the original root (which they find preceded original Wuhan strain) for the 2020 tree. Would like to see what the method finds for Omicron lineages. https://academic.oup.com/mbe/article/38/8/3046/6257226
Haven't seen this before - indeed, I like the idea of not defaulting the earliest sequence as root, and wonder as I am reading if B.1 is going to make a cameo. Thanks!
Substack is where the conversation went that used to take place in the scientific literature, I guess. It's reassuring to see such thinking and explaining going on, as it includes self-doubt and allows for future correction based on more data. When contrasted with the top-down edicts of recent years, it makes one realize how amazingly corrupt it's become, as predicted by President Eisenhower in his Farewell Address.
I'm actually curious what you mean by a cover for spike. I've tried to rationalize GvB's position, but the more I think about it the more I don't find it is validated by the current events. I think his model fits too closely that he may be looking for data and using it to validate his theory, rather than predicting it beforehand based on the information already present.
If that sentence seems confusing, what I mean is that GvB doesn't appear to have predicted Omicron, including the reduced tropism for the lower airway. I think such a prediction would actually lend a lot of credibility to his theory on Ba.4/Ba.5 (note that it was never Ba.4/Ba.5- his theory considered a more "virulent" strain that escapes immunity and Ba.4/Ba.5 just so happened to fit the bill). But as of now it just seems too coincidental in how things just happen to fit into his model.
at some point the sh#t will hit the fan ... many casualties and so on. issue becomes would they admit was because of the spike injected in trillions? dont think so .... a convenient explanation would be bossche's theories of virus mutations etc. those could well be true, but in my opinion not at the scale to justify who knows how many victims ... cover story is being prepared in advance for what could happen ... will see.
If I had a farm I would be reluctant to bet it on spike being worse than currently appears. If the Omicron siblings are a preview of yearly super-mutant-releases, it results in a paradox where reinfections are purchased with changes to the spike protein which potentially mitigate toxicity. It also just slots into the normal math for aging, where everyone will be on a different spot and rate of decline based on exercise, stress, amount of health-boosting hard liquor intake, etc... Humans don’t live forever as is, which seems to be semi-news to Chestnut.
This is all very interesting Brian. Like I stated in a comment from one of my posts, I wished I kept up with looking into Omicron. As soon as it appeared that things would end soon I stopped looking. Well, that was probably the wrong position to take!
I've been trying to relate Omicron and the current issue with the whole "immune invasion" or the more virulent nature of Ba.4/Ba.5. I think one of the only ways is to conceptualize Wuhan and Omicron lineages (being used loosely here) as distinct and to essentially decouple them from one another in order to address what's going on. That creates all sorts of problems, but I suppose that's what makes it a working model.
Anyways, great work! I think I should look deeper into the orf mutations- and mostly things outside of the spike as well.
Incredible posts like this is why I subscribe to your substack. Well done!
Are you familiar with the viral quasispecies theory? According to this theory, an infection is really an infection with many related viruses, which coexist in varying proportions. So if Ba.1 is predominant in the Qs, it mostly shows in sequencing and you may miss the lower prevalent ba.2 and ba.4 and ba.5.
But once immune landscape changes, other Qs members may gain higher prominence.
So, it is possible that they were all released as one quasispecies?
A good point. Not sure it explains the current BA.* zoo completely.
Quasi-species are ubiquitous and changes in the environment (like immune landscape) would lead to a (variable) dominance of a genome with the highest fitness.
However, a quasi-species infection should show >1 species (or VOCs) in a patient at the same time.
BTW, while GISAID is touted as raw data here, it is not. All genomes in there are assembled (so no co-existing mutations are seen). For a glimpse of real raw data one needs to analyze sequencing reads at the NCBI SRA. One can theoretically see presence of substitutions from different VOCs in different reads from one patient sample - that would be a quasi-species infection.
I've looked at 1000s of samples and only seen a few with such simultaneous presence of divergent virus genomes. They could either be co-infections/quasispecies or could also be contaminated samples (mixup can occur at any stage up to the sequencing). In any case, they are very rare and usually show much lower difference compared to different favors of BA.*, only 1-2 substitutions.
BA.* likely began divergence from BA.0 via the quasi-species infection but have already deviated much further beyond that stage before being detected.
That is what I think describes the story for the omicron siblings. I discuss the swarm aspect more in my original post, especially how the mouse serial passage studies seem to demonstrate that B.1 is not present in Wuhan isolates. And in the link in this post for my BA.4/5 comments at Modern Discontent’s post I discuss how Omicron self-competition defines the sequence of dominate variants
"And in the link in this post for my BA.4/5 comments at Modern Discontent’s post I discuss how Omicron self-competition defines the sequence of dominate variants"
-as well as in an immune landscape shaped by prior variants and massive Wuhan vaccinated individuals, no less, which likely aided in the selection for Ba.1. At least that's what my working model is (and I believe you've commented about this somewhere as well earlier on), which led to the Ba.1 -> Ba.2 -> Ba.4/Ba.5 pipeline.
If some group is deliberately releasing variants, that might explain the extreme COVID policies. The lab leak theory is not new, but this sounds like a form of warfare. The COVID policies have seemed like a biological warfare defense plan activated by NATO, etc. If there are multiple deliberate releases, then maybe the censorship and propaganda and lockdowns and mandates start to seem understandable?
Everything that's happened since 2020 is perfectly understandable, and completely predictable, if you assume "The world is run by Bond villains, and 007 works for them."
Not only that, but once you assume that, history for the past 120 years comes out much better illuminated, too.
Your writing is not plain. Dickensian mostly. Not that there's anything wrong with that!
So a bat virus, never found in a bat in the wild, has caused the madness. Meanwhile, a sister virus is also circulating, and folks' immune systems deal with that one. Because its a coronavirus that most people everywhere have been exposed to coronaviruses, but the original non-wild bat virus is still hovering and takes the weak/elderly/immunocompromised. But the immune system is key to mortality/hospitalization.
Thanks for this post. You were one of the original substackers when hell broke loose. You are a bonafide source - thanks Brian.
I'm not quite sure how I abducted any of Brian's work.
My post in no ways contradicted the timelines of Omicron's passage. In my post I mentioned that Ba.1 and Ba.2 and antigenically different based on a few studies that I cited. Brian commented in a prior post suggesting that he believed Ba.4 and Ba.5 did not derive from Ba.2, but may be distinct as well. In one of my footnotes for a separate Omicron post I referenced sequencing information from South Africa which suggested that Ba.1 and Ba.2 were sequenced last year and that Ba.4/Ba.5 were sequenced in January (similar to Brian's comment above).
I'm unsure about Ba.4/Ba.5's lineage, however I commented that all of them emerging from a similar geographical regions should raise some idea that there may have been some "Omicron Big Bang (don't remember my actual comment)". Brian is unsure as well, but his working model leans towards distinct emergences rather than divergence from Ba.2.
For clarity, I took Brian's comment above to refer to the general atmosphere around Omicron which seemed to have forgotten the questionable origins and possible lab association, all of which was memory-holed in the public eye. I haven't kept up with information on Omicron, but I tried citing people in my posts, including mentioning that Brian believed Ba.4/Ba.5 were distinct from Ba.2 in my "In Regards to Omicron" post.
I just wanted to provide some context and rebut your assumption that I have abducted his work. I greatly admire Brian as he tends to be one of the people I generally believe have read the papers that he cites. There's been a growing issue in which people are either not reading studies they cite or they are reaching too far in their assumptions, and it's usually someone like Brian who provides his own perspective without grossly bastardizing a study in order to do so.
Modern Discontent - I mis-read and I was wrong to state you abducted Brian's work. I am very very sorry. I have removed that statement and I feel terrible about the consequences of my error. You went to a lot of trouble defending and clarifying, which you never should have had to do. I am very sorry, and very embarrassed about putting you in that position.
Honestly, no hard feelings. I would be remiss if I didn't tell you I was responding at midnight, saw your comment and wanted to pull a "who do you think you are?!" type of comment. And quite honestly, it at least provides me some space to "check myself" so to speak and not try to react impulsively to comments that would otherwise be denigrating or belittling.
Anyways, don't feel terrible. I suppose it should just be a reminder to be careful and read before making assumptions- it's a general lesson I think many (including myself) need to learn when reading posts on Substack. Lord knows plenty of misreadings are already happening!
So honestly try not to worry yourself too much over this! It's done and that's how it goes. No harm on both of our parts!
I don't take it personally, nor would I want people to castigate Sunshine for the remarks. I just wanted to provide my position. I hope people don't consider me to be plagiarizing other people's works, and if so I hope they [the authors] at least make an effort to tell me that that's what they believe is happening (hopefully not through email- I have trouble checking that already!).
None of those criticisms do not also apply to genomics of other life-forms. The article is arguing that genomics are not a "proof" of viruses. Fine, who cares. That doesn't render it meaningless in virology. The existence of sports gear does not "prove" that football exists. You still use it.
Answered by the football analogy. If you don't think genomics "proves" viruses, fine. That doesn't falsify or render void analysis of variants of viruses, just as sports gear is still useful despite not proving that "variants" of sports exist. The fact that we can "see" sport is not what makes sports gear useful.
my friend, I love your work, but honestly, this post is a mess.
years of omicron evolution without sequences showing up, really?
Take a look at my blog if you you are interested in IMO more likely origin scenarios
https://www.stopgof.com/english/omicron-origin/
feedback appreciated!
Greetings! No argument on the "mess" remark, haha - but I don't see how my argument is very different from yours at first glance? The "years of evolution without sequences showing up" is Ethical Skeptic's theory, and my post is addressing why that is implausible for several reasons related to the evolutionary branching of BA.1 and BA.2 and yet their simultaneous geographically co-located emergence. So I am very much against the theory that Omicron came from actual transmission or infection as opposed to a lab origin.
agreed. so how do you think omicron managed to copy at least 25 consecutive nonsynonymous mutations out of pubmed?
leaked polymutant spike or recombination w/ self-replicating pan-variant mRNA vaccine?
Yikes, I never encountered Schmidt, et al. before. Recombination would need to have been with an mRNA vaccine or plasmid/pseudovirus construct that didn't use codon optimization, otherwise Omicron spike would be even more unrecognizable especially with silent mutations. Instead "BA.0"/1/2 are all 100% NS in spike. So Schmidt et al.'s plasmids were optimized, Moderna's mRNA likewise. But it's at least something to consider possible.
I'm somewhat agnostic about whether Omicron's spike was created in a "bespoke" synthetic fashion or simply the result of lab-setting escape-passage through immunized mice. Martin, et al. might be an argument for the latter, since it seems like a lot of the resulting spike changes wouldn't have been intentionally added but hypothetically still could have resulted from forced immunity escape (https://www.biorxiv.org/content/10.1101/2022.01.14.476382v1).
It was clearly not exactly the Schmidt et al paper that led to Omicron, it just proves that virologists would build such GoF mutation-enriched spikes outside of BSL4. Gritstone was testing some next gen. self replicating spike mRNA vaccines in humans if I'm not mistaken. such a study would also explain BA1, BA2, BA3..., always different parts of a super-infectious spike recombining w/ different SC2 strains in different people...
The methodology in this paper -- for reconstructing phylogenetic tree by an ordering method that does not rely on a "clock" (eg as Trever Bedford does) -- might be interesting applied to the Omicron data. The paper gives what seems likely to be a much more accurate picture of the original root (which they find preceded original Wuhan strain) for the 2020 tree. Would like to see what the method finds for Omicron lineages. https://academic.oup.com/mbe/article/38/8/3046/6257226
Haven't seen this before - indeed, I like the idea of not defaulting the earliest sequence as root, and wonder as I am reading if B.1 is going to make a cameo. Thanks!
Substack is where the conversation went that used to take place in the scientific literature, I guess. It's reassuring to see such thinking and explaining going on, as it includes self-doubt and allows for future correction based on more data. When contrasted with the top-down edicts of recent years, it makes one realize how amazingly corrupt it's become, as predicted by President Eisenhower in his Farewell Address.
so basically, all those bossche theories are just that ... a cover for spike protein.
I'm actually curious what you mean by a cover for spike. I've tried to rationalize GvB's position, but the more I think about it the more I don't find it is validated by the current events. I think his model fits too closely that he may be looking for data and using it to validate his theory, rather than predicting it beforehand based on the information already present.
If that sentence seems confusing, what I mean is that GvB doesn't appear to have predicted Omicron, including the reduced tropism for the lower airway. I think such a prediction would actually lend a lot of credibility to his theory on Ba.4/Ba.5 (note that it was never Ba.4/Ba.5- his theory considered a more "virulent" strain that escapes immunity and Ba.4/Ba.5 just so happened to fit the bill). But as of now it just seems too coincidental in how things just happen to fit into his model.
at some point the sh#t will hit the fan ... many casualties and so on. issue becomes would they admit was because of the spike injected in trillions? dont think so .... a convenient explanation would be bossche's theories of virus mutations etc. those could well be true, but in my opinion not at the scale to justify who knows how many victims ... cover story is being prepared in advance for what could happen ... will see.
If I had a farm I would be reluctant to bet it on spike being worse than currently appears. If the Omicron siblings are a preview of yearly super-mutant-releases, it results in a paradox where reinfections are purchased with changes to the spike protein which potentially mitigate toxicity. It also just slots into the normal math for aging, where everyone will be on a different spot and rate of decline based on exercise, stress, amount of health-boosting hard liquor intake, etc... Humans don’t live forever as is, which seems to be semi-news to Chestnut.
This is all very interesting Brian. Like I stated in a comment from one of my posts, I wished I kept up with looking into Omicron. As soon as it appeared that things would end soon I stopped looking. Well, that was probably the wrong position to take!
I've been trying to relate Omicron and the current issue with the whole "immune invasion" or the more virulent nature of Ba.4/Ba.5. I think one of the only ways is to conceptualize Wuhan and Omicron lineages (being used loosely here) as distinct and to essentially decouple them from one another in order to address what's going on. That creates all sorts of problems, but I suppose that's what makes it a working model.
Anyways, great work! I think I should look deeper into the orf mutations- and mostly things outside of the spike as well.
Orf1, the polyprotein, is where all the cool kids mutate their coronaviruses.
Man, and here I was thinking I wanted to be Spike all along!
Incredible posts like this is why I subscribe to your substack. Well done!
Are you familiar with the viral quasispecies theory? According to this theory, an infection is really an infection with many related viruses, which coexist in varying proportions. So if Ba.1 is predominant in the Qs, it mostly shows in sequencing and you may miss the lower prevalent ba.2 and ba.4 and ba.5.
But once immune landscape changes, other Qs members may gain higher prominence.
So, it is possible that they were all released as one quasispecies?
A good point. Not sure it explains the current BA.* zoo completely.
Quasi-species are ubiquitous and changes in the environment (like immune landscape) would lead to a (variable) dominance of a genome with the highest fitness.
However, a quasi-species infection should show >1 species (or VOCs) in a patient at the same time.
BTW, while GISAID is touted as raw data here, it is not. All genomes in there are assembled (so no co-existing mutations are seen). For a glimpse of real raw data one needs to analyze sequencing reads at the NCBI SRA. One can theoretically see presence of substitutions from different VOCs in different reads from one patient sample - that would be a quasi-species infection.
I've looked at 1000s of samples and only seen a few with such simultaneous presence of divergent virus genomes. They could either be co-infections/quasispecies or could also be contaminated samples (mixup can occur at any stage up to the sequencing). In any case, they are very rare and usually show much lower difference compared to different favors of BA.*, only 1-2 substitutions.
BA.* likely began divergence from BA.0 via the quasi-species infection but have already deviated much further beyond that stage before being detected.
That is what I think describes the story for the omicron siblings. I discuss the swarm aspect more in my original post, especially how the mouse serial passage studies seem to demonstrate that B.1 is not present in Wuhan isolates. And in the link in this post for my BA.4/5 comments at Modern Discontent’s post I discuss how Omicron self-competition defines the sequence of dominate variants
"And in the link in this post for my BA.4/5 comments at Modern Discontent’s post I discuss how Omicron self-competition defines the sequence of dominate variants"
-as well as in an immune landscape shaped by prior variants and massive Wuhan vaccinated individuals, no less, which likely aided in the selection for Ba.1. At least that's what my working model is (and I believe you've commented about this somewhere as well earlier on), which led to the Ba.1 -> Ba.2 -> Ba.4/Ba.5 pipeline.
If some group is deliberately releasing variants, that might explain the extreme COVID policies. The lab leak theory is not new, but this sounds like a form of warfare. The COVID policies have seemed like a biological warfare defense plan activated by NATO, etc. If there are multiple deliberate releases, then maybe the censorship and propaganda and lockdowns and mandates start to seem understandable?
Everything that's happened since 2020 is perfectly understandable, and completely predictable, if you assume "The world is run by Bond villains, and 007 works for them."
Not only that, but once you assume that, history for the past 120 years comes out much better illuminated, too.
Your writing is not plain. Dickensian mostly. Not that there's anything wrong with that!
So a bat virus, never found in a bat in the wild, has caused the madness. Meanwhile, a sister virus is also circulating, and folks' immune systems deal with that one. Because its a coronavirus that most people everywhere have been exposed to coronaviruses, but the original non-wild bat virus is still hovering and takes the weak/elderly/immunocompromised. But the immune system is key to mortality/hospitalization.
Thanks for this post. You were one of the original substackers when hell broke loose. You are a bonafide source - thanks Brian.
I'm not quite sure how I abducted any of Brian's work.
My post in no ways contradicted the timelines of Omicron's passage. In my post I mentioned that Ba.1 and Ba.2 and antigenically different based on a few studies that I cited. Brian commented in a prior post suggesting that he believed Ba.4 and Ba.5 did not derive from Ba.2, but may be distinct as well. In one of my footnotes for a separate Omicron post I referenced sequencing information from South Africa which suggested that Ba.1 and Ba.2 were sequenced last year and that Ba.4/Ba.5 were sequenced in January (similar to Brian's comment above).
I'm unsure about Ba.4/Ba.5's lineage, however I commented that all of them emerging from a similar geographical regions should raise some idea that there may have been some "Omicron Big Bang (don't remember my actual comment)". Brian is unsure as well, but his working model leans towards distinct emergences rather than divergence from Ba.2.
For clarity, I took Brian's comment above to refer to the general atmosphere around Omicron which seemed to have forgotten the questionable origins and possible lab association, all of which was memory-holed in the public eye. I haven't kept up with information on Omicron, but I tried citing people in my posts, including mentioning that Brian believed Ba.4/Ba.5 were distinct from Ba.2 in my "In Regards to Omicron" post.
https://moderndiscontent.substack.com/p/in-regards-to-omicron
I just wanted to provide some context and rebut your assumption that I have abducted his work. I greatly admire Brian as he tends to be one of the people I generally believe have read the papers that he cites. There's been a growing issue in which people are either not reading studies they cite or they are reaching too far in their assumptions, and it's usually someone like Brian who provides his own perspective without grossly bastardizing a study in order to do so.
Modern Discontent - I mis-read and I was wrong to state you abducted Brian's work. I am very very sorry. I have removed that statement and I feel terrible about the consequences of my error. You went to a lot of trouble defending and clarifying, which you never should have had to do. I am very sorry, and very embarrassed about putting you in that position.
Honestly, no hard feelings. I would be remiss if I didn't tell you I was responding at midnight, saw your comment and wanted to pull a "who do you think you are?!" type of comment. And quite honestly, it at least provides me some space to "check myself" so to speak and not try to react impulsively to comments that would otherwise be denigrating or belittling.
Anyways, don't feel terrible. I suppose it should just be a reminder to be careful and read before making assumptions- it's a general lesson I think many (including myself) need to learn when reading posts on Substack. Lord knows plenty of misreadings are already happening!
So honestly try not to worry yourself too much over this! It's done and that's how it goes. No harm on both of our parts!
dont worry about people ... who knows ... internet.
brian gave you credit right at the top and that is what matters ... keep up the good work and thank you to you all !!
this is survival times .... no time to claim credit etc. now we all got to work together!!
I don't take it personally, nor would I want people to castigate Sunshine for the remarks. I just wanted to provide my position. I hope people don't consider me to be plagiarizing other people's works, and if so I hope they [the authors] at least make an effort to tell me that that's what they believe is happening (hopefully not through email- I have trouble checking that already!).
Nice font.
None of those criticisms do not also apply to genomics of other life-forms. The article is arguing that genomics are not a "proof" of viruses. Fine, who cares. That doesn't render it meaningless in virology. The existence of sports gear does not "prove" that football exists. You still use it.
Answered by the football analogy. If you don't think genomics "proves" viruses, fine. That doesn't falsify or render void analysis of variants of viruses, just as sports gear is still useful despite not proving that "variants" of sports exist. The fact that we can "see" sport is not what makes sports gear useful.