Very interesting post Brian. I do wonder if the search for answers may make accrue a hint of a spike hypochondriac mentality and assume that the spike is the most nefarious thing known to man. It could very well be, but sometimes this search may pollute other endeavors by lumping everything into an "all-spike" narrative.
It can sometimes feel like the search for prions is one area where every little prion-like study means that many people may suffer from dementia. I haven't looked too deeply into the prions issue but I think having a back and forth discussion should help find the nuance in-between.
And speaking of not using the tools properly, I wonder what you thought of the BLAST study trying to link the spike insertion to the MSH3 protein.
I tried rebuking the paper but I think my post didn't cover some of my concerns in-depth:
I brought this up because I find no association between the insertion and the MSH3 protein aside from "this insertion was in here, this whole 19 nucleotide section which we really didn't account for since we were only looking at the 12 nucleotide insertion also appears in this protein. This protein helps repair DNA mismatches. Therefore, this insertion of only a few amino acids means that the spike is causing cancer!" It's been cited a ton and even appeared in some interviews/conferences and I can't figure out why.
Whether this should be considered evidence that the FCS insert came from moderna's cells (I think no; letters are letters, and this smells more like an op), it wouldn't magically transfer any of those cells properties to the (negative) sequence. PRRA is just... PRRA. Like, biology doesn't need humans to figure out PRRA. So most of the hyping of this is a substitution fallacy - "There's mathematically no way this nucleotide sequence could appear at random; so something is special about this aa sequence."
Further, it's superfluous to the question of human intent. We already know that the aa sequence is "special" in that it's exactly where you want bases for furin to cleave and activate fusogenicity; it's exactly where you want a P to create a putative NLS. It has an obvious, though maybe not 100% conclusive artificial codon choice fingerprint (CGG). And as I said at the time, since we already know humans would want to put these bases here, they would have been able to pick any sense-matching nucleotide sequence they wanted; for them to come up with the Moderna sequence probably means they searched in advance for a matching sequence as some kind of brag or op.
Was I there? Whoops I guess I'm reaching the point where I am forgetting these things! Must be residual spike from earlier this year I suppose?
Yes this does sound familiar! Within the context of prion everything I guess it's worth remembering that we are treading into territory that we should probably be a bit hesitant about when making bold assertions. I appreciate that you are providing pushback since I tend to conceptualize better when I see different aspects of the argument.
I'm kind of bristling at the characterization of my prion post as "contribution" and "pushback," haha. Like, in this case, I showed up to the scene of the spike prion panic, and found there was no actual evidence to push back against. All anyone had to do, at any point, was put these proteins into the PLAAC tool for themselves...
Well I suppose I'll say that I haven't spent a lot of time looking into the prion issue so I've sort of stayed away to some degree including looking deeper into papers. So on the surface seeing someone say, "hey maybe you should use the tool" wasn't on my radar. I will say though that the idea that the furin cleavage site of only a few amino acids long somehow is acting as the swiss army knife of all things cytotoxic doesn't quite make sense to me.
The FCS just being a frat bro boogeyman was my initial instinct, before learning the spike protein design. So the FCS is basically the safety of fusion proteins. When it's there, the safety is open - they can fire, leading to fusion; when it's gone, the safety is closed - no firing, endocytosis only.
And so you have regular avian flu spike glycoprotein (HA) and then you have highly pathogenic avian flu (HPAI) spike glycoprotein, and the difference is the FCS. Presumably there's some intrinsic promotion of insertion of appropriate nucleotides built into the RNA molecule secondary structure and the flu polymerase complex, but it's way beyond human understanding. Human A influenzas all have FCS-equipped HAs as far as I understand, so they all are intrinsically "pathogenic" but there are no adults without immune experience so it's fine.
Likewise for meaner animal coronaviruses vs friendly human coronaviruses. The difference is FCS. And with SARS-CoV-2, now that there is adult immune experience, it is just a flu.
Presumably there's tradeoffs from the viruses point of view. Fusion might not be worth it if premature loss of the S1 subunit leads to lower viability in outdoor, longer-range transmission. In that case you want a non-firing spike protein that will be more durable.
So if a human wants to make a SARS1 template more pathogenic they add an FCS (I say "template" because I am suspicious that SARS1 didn't just lose its FCS somewhere between infections and sequencing). And if there's a tradeoff in transmission, no problem, they can just release more from stock.
Downloading is encouraged. Though maybe more the original version as linked. I hate the one with the names. When I have to figure out chemical names I feel like a CEO being forced to learn a cashier's name. I just wince.
I have not - I have no talent for data/base analysis, so I am not sure our work can fit in the same pet carrier. Typically my collabs are just in the nature of me consulting back-end on interpreting the bio.
Very interesting post Brian. I do wonder if the search for answers may make accrue a hint of a spike hypochondriac mentality and assume that the spike is the most nefarious thing known to man. It could very well be, but sometimes this search may pollute other endeavors by lumping everything into an "all-spike" narrative.
It can sometimes feel like the search for prions is one area where every little prion-like study means that many people may suffer from dementia. I haven't looked too deeply into the prions issue but I think having a back and forth discussion should help find the nuance in-between.
And speaking of not using the tools properly, I wonder what you thought of the BLAST study trying to link the spike insertion to the MSH3 protein.
I tried rebuking the paper but I think my post didn't cover some of my concerns in-depth:
https://moderndiscontent.substack.com/p/rebuking-the-moderna-patent-paper
I brought this up because I find no association between the insertion and the MSH3 protein aside from "this insertion was in here, this whole 19 nucleotide section which we really didn't account for since we were only looking at the 12 nucleotide insertion also appears in this protein. This protein helps repair DNA mismatches. Therefore, this insertion of only a few amino acids means that the spike is causing cancer!" It's been cited a ton and even appeared in some interviews/conferences and I can't figure out why.
I commented on the Moderna patent controversy at the time. You were there... https://unglossed.substack.com/p/the-moderna-patent-controv
Whether this should be considered evidence that the FCS insert came from moderna's cells (I think no; letters are letters, and this smells more like an op), it wouldn't magically transfer any of those cells properties to the (negative) sequence. PRRA is just... PRRA. Like, biology doesn't need humans to figure out PRRA. So most of the hyping of this is a substitution fallacy - "There's mathematically no way this nucleotide sequence could appear at random; so something is special about this aa sequence."
Further, it's superfluous to the question of human intent. We already know that the aa sequence is "special" in that it's exactly where you want bases for furin to cleave and activate fusogenicity; it's exactly where you want a P to create a putative NLS. It has an obvious, though maybe not 100% conclusive artificial codon choice fingerprint (CGG). And as I said at the time, since we already know humans would want to put these bases here, they would have been able to pick any sense-matching nucleotide sequence they wanted; for them to come up with the Moderna sequence probably means they searched in advance for a matching sequence as some kind of brag or op.
Was I there? Whoops I guess I'm reaching the point where I am forgetting these things! Must be residual spike from earlier this year I suppose?
Yes this does sound familiar! Within the context of prion everything I guess it's worth remembering that we are treading into territory that we should probably be a bit hesitant about when making bold assertions. I appreciate that you are providing pushback since I tend to conceptualize better when I see different aspects of the argument.
I'm kind of bristling at the characterization of my prion post as "contribution" and "pushback," haha. Like, in this case, I showed up to the scene of the spike prion panic, and found there was no actual evidence to push back against. All anyone had to do, at any point, was put these proteins into the PLAAC tool for themselves...
Well I suppose I'll say that I haven't spent a lot of time looking into the prion issue so I've sort of stayed away to some degree including looking deeper into papers. So on the surface seeing someone say, "hey maybe you should use the tool" wasn't on my radar. I will say though that the idea that the furin cleavage site of only a few amino acids long somehow is acting as the swiss army knife of all things cytotoxic doesn't quite make sense to me.
The FCS just being a frat bro boogeyman was my initial instinct, before learning the spike protein design. So the FCS is basically the safety of fusion proteins. When it's there, the safety is open - they can fire, leading to fusion; when it's gone, the safety is closed - no firing, endocytosis only.
And so you have regular avian flu spike glycoprotein (HA) and then you have highly pathogenic avian flu (HPAI) spike glycoprotein, and the difference is the FCS. Presumably there's some intrinsic promotion of insertion of appropriate nucleotides built into the RNA molecule secondary structure and the flu polymerase complex, but it's way beyond human understanding. Human A influenzas all have FCS-equipped HAs as far as I understand, so they all are intrinsically "pathogenic" but there are no adults without immune experience so it's fine.
Likewise for meaner animal coronaviruses vs friendly human coronaviruses. The difference is FCS. And with SARS-CoV-2, now that there is adult immune experience, it is just a flu.
Presumably there's tradeoffs from the viruses point of view. Fusion might not be worth it if premature loss of the S1 subunit leads to lower viability in outdoor, longer-range transmission. In that case you want a non-firing spike protein that will be more durable.
So if a human wants to make a SARS1 template more pathogenic they add an FCS (I say "template" because I am suspicious that SARS1 didn't just lose its FCS somewhere between infections and sequencing). And if there's a tradeoff in transmission, no problem, they can just release more from stock.
"Guasine-Rich RNA" does not exist, it is called guanine-rich RNA...
Thanks. I had some editing in the wrong post issues after I decided to split the post in two.
I'm looking forward to the Guanine post - your molecule map in this one intrigued me so I downloaded it for more future enjoyment.
Downloading is encouraged. Though maybe more the original version as linked. I hate the one with the names. When I have to figure out chemical names I feel like a CEO being forced to learn a cashier's name. I just wince.
Thanks for this contribution to the discussion. 👍🏽
Thank you, Brian. I always look forward to your posts.
Thank you!
Have you shared this with Jessica Rose?
I have not - I have no talent for data/base analysis, so I am not sure our work can fit in the same pet carrier. Typically my collabs are just in the nature of me consulting back-end on interpreting the bio.
It would still be worth it to see what she thinks. People send her stuff all the time--she welcomes it.