Biochemical analysis determined that the UK variant (Alpha) could suppress a key innate immune mechanism for 1 to 2 days, and Indian variant (Delta) replicates about 10 times more strongly in the upper respiratory track. That seems increased fitness and explain why these two dominated over most other variants. Alpha less, but Delta ruled briefly supreme.
(I do agree that this obsession with S1 mutations is unwarranted. That is likely just a continuing result of the antibodies = immunity fallacy.)
So I'm not sure why you'd claim it doesn't have increased fitness. These low-data point graphs are not that convincing IMHO. Plus the amount of immune hosts also increased and are affected by testing rates which were all over the map.
But even if I grant you this, if not fitness and plenty of hosts, then why does a virus "decide" to no longer infect non-immune targets and simply give way to a new variant that isn't more fit but just different?
Without a convincing alternative, that still leaves me leaning towards fitness, even if we don't fully understand why VOC 1 was more fit than VOC2.
I do think however you are digging in the right place, as this is an area understudied. It seems to me this is a key opportunity to understand viral mutation and transmission mechanisms and greatly add to our general understanding. If anything, what I learned from your series so-far plus the preceding flu-series is how little we do know, and how much we just assume in the medical/scientific community. And likely there are some key aspects of this area we miss.
Hence why my point is about the aggregate - there were duds. So if "fitness" explains Alpha and Delta, well, what explains the others? Maybe my use of aggregate is a bad choice actually. So, it's like you can say "The VOC school has generated millions of dollars per pupil! (but only two pupils actually became rich, the others are hobos now)" - so is the school really doing that great?
First as far as theory, piling on more innate suppression late in the infection cycle might help kick butt even harder in a cell culture, but in vivo could be a too much of a good thing. The virus needs to optimize not just the early stages of infection but the part after S, N, maybe E antibodies start to arrive. If Alpha's Orf8 fatal stop is leading to over-expression of other subgenomic RNAs, that could be essentially a defect - Orf8 could be there to modulate.
Second as far as practical concerns, what if the "loser" VOCs also turn out to have the same effect on sgRNA and interferons in vitro (meaning, it was from some other mutation, like the nsp6 deletion)? Sadly the paper didn't try any other VOCs so assuming a link between the findings and Alpha's middling-good performance IRL is hazardous.
Glad he covers the sequence stuff. So yeah, that's basically why I'm trying to layout an argument for continual release that isn't tied up completely with swarms or RNA infidelity - the virus's genome is very stable!
To continue my past 2 posts, I should clarify. If I understood Fleming correctly, and if indeed his observation was correct, that the variants are morphing the "virus" back to its original wild form (I have no way of figuring out if he's correct on this, but I'm sure some of you could!) , then what that might mean is that indeed the viruses are as a whole sentient and do have a purpose, which according to Smith's communication with them is to bring all life forms into balance. This is perhaps not so farfetched given how much of our DNA did come from viruses as we evolved! This is exciting and hopeful, because it means that no matter the degree of human ignorance and hubris, no matter our ability to wreak destruction and imbalance, there are more powerful and beneficient forces at work. I realize I am going seriously astray from the more technical flavor of this conversation, so please forgive me if so.
I am clearly a novice at this commenting and somehow posted my comment before finishing! To continue: ......I believe the following observation came from one of his talks. He was showing and discussing some of the early variants and his conclusion was that the changes he was seeing in the variants were significantly focused in the same areas where changes had been made in the lab to the original natural virus. In other words, the variants were moving the virus back towards it's non- chimeric form. He made no big deal out this, but it struck me because I had also been reading Penelope Smith's Animal Communicator Blog where there are a few articles on the true nature and purpose of viruses. This admittedly is a spiritual look at what's going on, but I think an important part of the big picture. If you are at all interested I can go back and find some exact links for you, which might otherwise be hard to find. Thanks again for your integrity, your sense of humor, and your work!
Interesting. Off hand I would imagine those comments were based off of P681 in the spike protein, though these mutations in the variants are still tangential to the really weird, unnatural cg-enriched FCS site.
Hi Brian and Sage, thanks for what both of you are contributing to healthy dialogue. I wish I could follow and understand more of it, but regardless, I have a perspective that you might be interested in regarding the variants and the general direction of their evolution. This perspective is absolutely non-technical. It speaks to the bigger opportunities, that is, the bigger learnings that we might gain out of all of this craziness.
I have listened to a number of Peter Fleming interviews and talks, and I have read his book, "Is Covid-19 a Bioweapon?" I believe the following observation came from one of his talks.
One explanation for clades that appear and then fade out is that they were intentionally "seeded" within a population. I'm assuming this is where you are headed with this logic, and I almost suggested the same thing in my comment on your last post.
I'm curious, though, whether this phenomenon (many short-lived, local/regional evolutionary clades which fail to exhibit greater fitness on a global scale) is the exception or the rule in viral evolution - or even in evolutionary contexts more broadly.
The vast majority of mutations will be deleterious and will not be passed on from the host where they arise. A select few will confer greater fitness and will eventually gain dominance across the global viral population.
What lies in between these outcomes, though?
1. Mutations that confer a selective advantage *only within the host where they arise*. Perhaps they are better at infecting cells or making more copies but terrible at being transmitted. Presumably this explains many of the "one-off" sequences that are detected.
2. Mutations that confer a selective advantage within a particular spatiotemporal context, but not globally/permanently. It's quite possible to imagine, for example, a strain that could outcompete existing strains (and cause a wave of infection) in Manaus but not in New York City, or vice versa - in the context of differing innate/adaptive immunity in the populations (from past exposure to different pathogens/antigens) and different environmental and social conditions influencing transmission. It's also possible to imagine a strain that has an advantage in northern hemisphere winter but not in northern hemisphere spring/summer.
One of the main challenges here is that we have more detailed sequence data for SARS-CoV2 across space and time than for any other virus or organism ever, and so it's not always easy to find parallel comparisons to assess what is simply revealing the micro-, meso-, and macro-dynamics of natural selection and what is evidence of artificial intervention.
Right, there's certainly possibilities for unremarkable causes of the washout effect. In fact it might be totally consistent with what the default model is - variant arrives (advantage^), gets "recognized" by immunity (advantagev), repeat. The difficulty for Delta is that leaving India should have been like a bonanza, if its starting growth was in a place that already had high immunity. And if Delta was in fact innately compromised for the sake immune evasion, then why don't the lingering ancestral clades take off.
But yes, this is where I'm leading to as far as a "Gain of Purity" argument that doesn't assume total RNA instability. Instead, what if any given model of the virus is always in fatal mutagenesis - there *is* no valid optimum to stabilize at - and so after ~3/4 transmissions, it is nearly defective. Would that match what we saw? at least before BA.2 and 5, which are interesting for being more naturalistic in general. I don't think I can compellingly argue the case for believing in the model over something else but I want to put the model out there, backed with pointing out how "variants should happen" was always an unfounded assumption.
"A non-sterilizing vaccine WILL cause variants to emerge, as this is doing!"
So this is Paul channeling GVB, and Paul and GVB are quasi-homies or at least simpatico on this theme.
-----
Brian, I will confess to diligently trying to read through the first post in the series. I was doing pretty good through the Tony Hawk part and stuff. My head exploded, which is not unusual.
If my comments on Alexander's post are requested, the vaccines were already "around" this time last year - so why didn't the BA.1/2/5 subvariants emerge immediately when the Omicron update was "published" a year ago? Nor do they suddenly appear after the bivalent roll-out; they were already gaining steam just before then.
The change is rising natural immunity. So there's nothing that the vaccine really adds to the classic, down-to-earth, "virus infections make human immunity, so virus changes spike protein a bit to get around human immunity" model [even if the classic immune escape model is totally insufficient to explain all the previous variants, as in Pt 3 of this series]. But I'm not sure if you are requesting my comments or just baiting me into calling PA and GvB themselves, or their substack footprint, ops to distract from continual release, lol.
I would never! (they probably are)
I am skeptical about my ability to communicate the Tony Honk model coherently, so I apologize for likely not having done so. There are loads of analogies that are probably better! But I did my best to not veer into even worse ones (ok, so it's ancient Rome, and most wealthy families are no longer wealthy two generations down the line, and yet, someone still lives in their home, there are still "nobles", ohnoI'musingoneoftheevenworseanalogies).
Who are the parties in your "we"? If I am one of them, it is impossible to be polar opposites, since I sit at the middle of the scale.
The footprint question concerns whether output in this community is influenced by, well, artificially propping up certain influencers. As opposed to the same influencers actually being "in on" the op.
Of course, it's totally possible that intrinsic factors explain why more writers and readers on substack obsess over the "vaccines cause variants" idea, while literal "official narrative" evobio wonks like Rambaut and Bedford are dropping these *huge* bread-crumbs for repeated lab-derived updates that are *hugely* unlikely to derive from mutation, and no one here makes anything of it. For one thing, there's just a big lack of skill in this field. So, no one really has a lot of depth in RNA genomics, so they just parrot night-time news tropes about evolution / resistance instead of actually processing the data.
Brian, do you think that the gov't. scientists (like Baric, or Shi, say) are further ahead of the various anointed experts and those in the trenches, say you, or JJ, or Geert?
Have they possibly figured some stuff out that is not well understood outside the Security Clearances?
Or another way to phrase, is there a ceiling of what can be known, that is broken by collections of scientists behind the DARPA (et. al) veil?
Baric, absolutely. Lots of Chinese teams, lots of Japanese teams. Isn't it funny that Baric publishes an IC of SARS-CoV-2 in MAY, 2020 (https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8034761/), lots of Chinese and Japanese teams do afterward, no one flips out until the Boston University "Omicron chimera" study this October? So the real heavy-hitters are able to do whatever they want because no one on Earth, no one, in 8 billion people, grasps or cares about what they are doing. It's insanely asymmetric.
This is why I think Couey's clone videos are extremely positive development, even if my model for perpetual release is less "throw the PCR out with the bathwater."
At the same time, I don't think anyone really understands things on the level of "oh, this variant I am cooking up is going to make Steve in Pittsburg get sick." That part is still more like spaghetti at the wall, which is consistent with the VOCs dropping updates in a manner akin to "experiments."
Biochemical analysis determined that the UK variant (Alpha) could suppress a key innate immune mechanism for 1 to 2 days, and Indian variant (Delta) replicates about 10 times more strongly in the upper respiratory track. That seems increased fitness and explain why these two dominated over most other variants. Alpha less, but Delta ruled briefly supreme.
(I do agree that this obsession with S1 mutations is unwarranted. That is likely just a continuing result of the antibodies = immunity fallacy.)
So I'm not sure why you'd claim it doesn't have increased fitness. These low-data point graphs are not that convincing IMHO. Plus the amount of immune hosts also increased and are affected by testing rates which were all over the map.
But even if I grant you this, if not fitness and plenty of hosts, then why does a virus "decide" to no longer infect non-immune targets and simply give way to a new variant that isn't more fit but just different?
Without a convincing alternative, that still leaves me leaning towards fitness, even if we don't fully understand why VOC 1 was more fit than VOC2.
I do think however you are digging in the right place, as this is an area understudied. It seems to me this is a key opportunity to understand viral mutation and transmission mechanisms and greatly add to our general understanding. If anything, what I learned from your series so-far plus the preceding flu-series is how little we do know, and how much we just assume in the medical/scientific community. And likely there are some key aspects of this area we miss.
Hence why my point is about the aggregate - there were duds. So if "fitness" explains Alpha and Delta, well, what explains the others? Maybe my use of aggregate is a bad choice actually. So, it's like you can say "The VOC school has generated millions of dollars per pupil! (but only two pupils actually became rich, the others are hobos now)" - so is the school really doing that great?
The Alpha paper (https://www.nature.com/articles/s41586-021-04352-y) has limits, besides.
First as far as theory, piling on more innate suppression late in the infection cycle might help kick butt even harder in a cell culture, but in vivo could be a too much of a good thing. The virus needs to optimize not just the early stages of infection but the part after S, N, maybe E antibodies start to arrive. If Alpha's Orf8 fatal stop is leading to over-expression of other subgenomic RNAs, that could be essentially a defect - Orf8 could be there to modulate.
Second as far as practical concerns, what if the "loser" VOCs also turn out to have the same effect on sgRNA and interferons in vitro (meaning, it was from some other mutation, like the nsp6 deletion)? Sadly the paper didn't try any other VOCs so assuming a link between the findings and Alpha's middling-good performance IRL is hazardous.
https://anandamide.substack.com/p/quasi-species-swarms-in-sars-cov?utm_medium=email
Are you aware of Kevin McKernan’s substack?
Glad he covers the sequence stuff. So yeah, that's basically why I'm trying to layout an argument for continual release that isn't tied up completely with swarms or RNA infidelity - the virus's genome is very stable!
Correction: I'm referring to Dr. Richard Fleming, not Peter! Sorry bout that.
To continue my past 2 posts, I should clarify. If I understood Fleming correctly, and if indeed his observation was correct, that the variants are morphing the "virus" back to its original wild form (I have no way of figuring out if he's correct on this, but I'm sure some of you could!) , then what that might mean is that indeed the viruses are as a whole sentient and do have a purpose, which according to Smith's communication with them is to bring all life forms into balance. This is perhaps not so farfetched given how much of our DNA did come from viruses as we evolved! This is exciting and hopeful, because it means that no matter the degree of human ignorance and hubris, no matter our ability to wreak destruction and imbalance, there are more powerful and beneficient forces at work. I realize I am going seriously astray from the more technical flavor of this conversation, so please forgive me if so.
In expansion pack terms, it's not exactly on the level of Lord of Destruction. But it does add some nice content.
Always over promise and under deliver, that's the rule around here
I am clearly a novice at this commenting and somehow posted my comment before finishing! To continue: ......I believe the following observation came from one of his talks. He was showing and discussing some of the early variants and his conclusion was that the changes he was seeing in the variants were significantly focused in the same areas where changes had been made in the lab to the original natural virus. In other words, the variants were moving the virus back towards it's non- chimeric form. He made no big deal out this, but it struck me because I had also been reading Penelope Smith's Animal Communicator Blog where there are a few articles on the true nature and purpose of viruses. This admittedly is a spiritual look at what's going on, but I think an important part of the big picture. If you are at all interested I can go back and find some exact links for you, which might otherwise be hard to find. Thanks again for your integrity, your sense of humor, and your work!
Interesting. Off hand I would imagine those comments were based off of P681 in the spike protein, though these mutations in the variants are still tangential to the really weird, unnatural cg-enriched FCS site.
Hi Brian and Sage, thanks for what both of you are contributing to healthy dialogue. I wish I could follow and understand more of it, but regardless, I have a perspective that you might be interested in regarding the variants and the general direction of their evolution. This perspective is absolutely non-technical. It speaks to the bigger opportunities, that is, the bigger learnings that we might gain out of all of this craziness.
I have listened to a number of Peter Fleming interviews and talks, and I have read his book, "Is Covid-19 a Bioweapon?" I believe the following observation came from one of his talks.
One explanation for clades that appear and then fade out is that they were intentionally "seeded" within a population. I'm assuming this is where you are headed with this logic, and I almost suggested the same thing in my comment on your last post.
I'm curious, though, whether this phenomenon (many short-lived, local/regional evolutionary clades which fail to exhibit greater fitness on a global scale) is the exception or the rule in viral evolution - or even in evolutionary contexts more broadly.
The vast majority of mutations will be deleterious and will not be passed on from the host where they arise. A select few will confer greater fitness and will eventually gain dominance across the global viral population.
What lies in between these outcomes, though?
1. Mutations that confer a selective advantage *only within the host where they arise*. Perhaps they are better at infecting cells or making more copies but terrible at being transmitted. Presumably this explains many of the "one-off" sequences that are detected.
2. Mutations that confer a selective advantage within a particular spatiotemporal context, but not globally/permanently. It's quite possible to imagine, for example, a strain that could outcompete existing strains (and cause a wave of infection) in Manaus but not in New York City, or vice versa - in the context of differing innate/adaptive immunity in the populations (from past exposure to different pathogens/antigens) and different environmental and social conditions influencing transmission. It's also possible to imagine a strain that has an advantage in northern hemisphere winter but not in northern hemisphere spring/summer.
One of the main challenges here is that we have more detailed sequence data for SARS-CoV2 across space and time than for any other virus or organism ever, and so it's not always easy to find parallel comparisons to assess what is simply revealing the micro-, meso-, and macro-dynamics of natural selection and what is evidence of artificial intervention.
Right, there's certainly possibilities for unremarkable causes of the washout effect. In fact it might be totally consistent with what the default model is - variant arrives (advantage^), gets "recognized" by immunity (advantagev), repeat. The difficulty for Delta is that leaving India should have been like a bonanza, if its starting growth was in a place that already had high immunity. And if Delta was in fact innately compromised for the sake immune evasion, then why don't the lingering ancestral clades take off.
But yes, this is where I'm leading to as far as a "Gain of Purity" argument that doesn't assume total RNA instability. Instead, what if any given model of the virus is always in fatal mutagenesis - there *is* no valid optimum to stabilize at - and so after ~3/4 transmissions, it is nearly defective. Would that match what we saw? at least before BA.2 and 5, which are interesting for being more naturalistic in general. I don't think I can compellingly argue the case for believing in the model over something else but I want to put the model out there, backed with pointing out how "variants should happen" was always an unfounded assumption.
https://palexander.substack.com/p/ba5-covid-sub-variant-being-replaced?pos=1
------
"A non-sterilizing vaccine WILL cause variants to emerge, as this is doing!"
So this is Paul channeling GVB, and Paul and GVB are quasi-homies or at least simpatico on this theme.
-----
Brian, I will confess to diligently trying to read through the first post in the series. I was doing pretty good through the Tony Hawk part and stuff. My head exploded, which is not unusual.
----
How far apart are we here on the Expert Scale?
Polar opposites?
If my comments on Alexander's post are requested, the vaccines were already "around" this time last year - so why didn't the BA.1/2/5 subvariants emerge immediately when the Omicron update was "published" a year ago? Nor do they suddenly appear after the bivalent roll-out; they were already gaining steam just before then.
The change is rising natural immunity. So there's nothing that the vaccine really adds to the classic, down-to-earth, "virus infections make human immunity, so virus changes spike protein a bit to get around human immunity" model [even if the classic immune escape model is totally insufficient to explain all the previous variants, as in Pt 3 of this series]. But I'm not sure if you are requesting my comments or just baiting me into calling PA and GvB themselves, or their substack footprint, ops to distract from continual release, lol.
I would never! (they probably are)
I am skeptical about my ability to communicate the Tony Honk model coherently, so I apologize for likely not having done so. There are loads of analogies that are probably better! But I did my best to not veer into even worse ones (ok, so it's ancient Rome, and most wealthy families are no longer wealthy two generations down the line, and yet, someone still lives in their home, there are still "nobles", ohnoI'musingoneoftheevenworseanalogies).
Who are the parties in your "we"? If I am one of them, it is impossible to be polar opposites, since I sit at the middle of the scale.
No baiting!
Just trying to learn. There is a stark contrast in ideas. Way way above my paygrade. I'm not a science person.
You have presented a paradigm that does make sense.
The parties in the "We" are the "recognized experts" that publicly opine about viruses.
Perhaps the polar opposite of the scale then would be the Not a Viruses, like Cowan and Bailey.
If it's correct. That means that some of the most accomplished people in the field are mistaken.
That is fascinating to me.
I don't really care about Substack footprints, and all that. At all. At all. At all.
The footprint question concerns whether output in this community is influenced by, well, artificially propping up certain influencers. As opposed to the same influencers actually being "in on" the op.
Of course, it's totally possible that intrinsic factors explain why more writers and readers on substack obsess over the "vaccines cause variants" idea, while literal "official narrative" evobio wonks like Rambaut and Bedford are dropping these *huge* bread-crumbs for repeated lab-derived updates that are *hugely* unlikely to derive from mutation, and no one here makes anything of it. For one thing, there's just a big lack of skill in this field. So, no one really has a lot of depth in RNA genomics, so they just parrot night-time news tropes about evolution / resistance instead of actually processing the data.
Brian, do you think that the gov't. scientists (like Baric, or Shi, say) are further ahead of the various anointed experts and those in the trenches, say you, or JJ, or Geert?
Have they possibly figured some stuff out that is not well understood outside the Security Clearances?
Or another way to phrase, is there a ceiling of what can be known, that is broken by collections of scientists behind the DARPA (et. al) veil?
Baric, absolutely. Lots of Chinese teams, lots of Japanese teams. Isn't it funny that Baric publishes an IC of SARS-CoV-2 in MAY, 2020 (https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8034761/), lots of Chinese and Japanese teams do afterward, no one flips out until the Boston University "Omicron chimera" study this October? So the real heavy-hitters are able to do whatever they want because no one on Earth, no one, in 8 billion people, grasps or cares about what they are doing. It's insanely asymmetric.
This is why I think Couey's clone videos are extremely positive development, even if my model for perpetual release is less "throw the PCR out with the bathwater."
At the same time, I don't think anyone really understands things on the level of "oh, this variant I am cooking up is going to make Steve in Pittsburg get sick." That part is still more like spaghetti at the wall, which is consistent with the VOCs dropping updates in a manner akin to "experiments."
Do they know? Baric and the like?
Do they know that they are cooking up shit to murder the world?
*edit: I look up that Scripps Kristian Andersen team and they are like fresh faced types who I am sure think they are saving people!
Like the UNC team. Do they have any doubts, I wonder?