Brother - you piss me off occasionally but I ain’t never gonna unsubscribe. You have very important thoughts that need to be shared. My only criticism of you ever (what pisses me off) is when you use bad data (e.g., your state death data) to then do “good” analyses. It’s still garbage in garbage out, no matter how good your analysis. But when you are breaking down the genetic code stuff, the signatures and patterns, and describing what’s happening biochemically, you’re at the top of your game. You ask the right questions. Just gotta be careful w those data sets; it can become a modeling circle jerk real fast.
Is "Protein Simple" tool CFR Part 11 compliant? If not, its use is not acceptable for FDA data/document submission due to not being compliant with the "digital audit trail" requirements. We had to validate Microsoft Office products when using them to generate data submissions in our workflow to the pharma clients and FDA.
I couldn't guess. It might be in that any image, however easily faked, can be cross-checked with the source blots? So validation-compliability is built-in.
Well, there are very specific requirements for pharma reg compliance on this, it's not just that something can be cross checked. It has to be documented in the Pfizer Quality System, and if they are using vendors to do this, then in those vendors' systems, who would have had to run a bunch of testing, verify, document, etc. and Pfizer would have had to audit this and keep auditing it. The FDA would need to be able to audit every "prettified" graph to the raw data down to every click on the computer that was made, and know who made them.
This is such a gigantic pain that it is only worth it if absolutely necessary, and to generate a couple of pretty graphs is not worth this at all. And if I were an honest regulator, I would still require them to send real images.
This suggests that Bio-Techne isn't interested in making trial compliant products, generally, though I didn't see the same language in the user manual for Jess so it could just be a legal shotgun disclaimer.
Unless otherwise expressly stated in writing by Bio-Techne, (i) Purchaser may not use Products for Commercial Purposes; and (ii) all Products are for research use only, and not for human or animal therapeutic or diagnostic use. “Commercial Purposes” means any activity by a party for consideration and may include, but is not limited to: (1) use of Products or their components to provide a service, information, or data; (2) use of the Products or their components for therapeutic, diagnostic or prophylactic purposes or in connection with any Phase III clinical trials, pivotal trials or post registration clinical trials;"
Yes, exactly, this language is to clarify that they are not making software for regulatory compliance purposes. The research market application for software is a very small market to justify the investment otherwise.
I see what you mean - there's downside, no real upside, even if it is compliant. For all we know that was intentional - Pfizer could have known that just haggling over the use of SimpleWestern would deplete regulator manhours.
Yeah I am increasingly leaning to this theory of the "fraud." Pfizer used the Simple Western to increase cross-talk and paperwork. But it's just a guess.
Jan 17, 2023·edited Jan 17, 2023Liked by Brian Mowrey
Properly understanding the science at this level is a bit above my pay grade to say the least, but I wonder if it's a 'limited hangout' and the real story is elsewhere - or is this the real story?
For example what happens when the mRNA gets broken down, does it remain soluble or does it aggregate into something insoluble:
Nonetheless it's puzzling why they don't publish the original blots and why didn't the regulators request them, would they show inconsistencies to the trained eye?
Edited to add: I don't like to be conspiratorial but for example it looks like the bilvalent boosters got approval on the back of some key omission, which should have been picked up by the regulators.
That is an extremely cool paper, thanks for the link. What they are showing is that a lot of proteins, even without known RNA binding properties, need RNA to remain soluble. That makes sense since RNA is everywhere so so proteins are going to evolve "needing" it in that it wouldn't make sense to design proteins to operate in a "RNA sterile" context.
But RNAse is ubiquitous, RNA is always being degraded, it's probably a question of homeostasis there, so I don't think transfection RNA will be dangerous in this regard when it breaks down (which apparently takes days and days, of course). On the other hand it might be dangerous and protein-deforming before then, thanks to the novel secondary structures created by codon optimization as others have pointed out https://unglossed.substack.com/i/76344824/prion-risk-factor-vaccine-g-rich-mrna
Limited hangout indeed. If Pfizer wanted to fake these experiments with "real blots," it would have been trivially easy. Just run a mock protein / antibody to show "spike," run empty lanes to show "no truncated spike," etc. Though I still feel like it seems like they have limited access to Covid vaccine and aren't actually making it themselves. We know that scale-up isn't plausible and this makes it look like they could barely conduct experiments on prototype.
"Omission" - you mean the "FDA is angry" story? I mean the FDA is the one rushing things, they can't blame that on Moderna. "FDA is angry at the Blockbuster clerk because it rented the wrong Matrix sequel and now the kids ARE SCREAMING"
Well the FDA (or Paul Offit at least) may be angry, but he doesn't realize the problem is the FDA are far too close to the pharma companies, and it appears the latter can strongly influence the former to allow trial endpoints which flatter their product the most. When it turns out the product is less effective in real world use, the FDA doesn't have a leg to stand on, since they accepted the trial endpoints which the product fulfilled. (antibodies in 8 mice??? 🙄)
A great example is the Tamiflu investigation by Peter Doshi of the BMJ among others, where governments spent billions of $ without properly looking at the trial data because they were desperate for a 'cure' for swine flu. In the end it turned out that it only reduced symptoms for a day or so, with no significant effects on hospitalization:
I'm not quite sure what the "worry window" is that you are referring to, but I will say you put us in a very difficult position when our unsubscribing becomes contingent upon our purchasing of chicken bakes!
Worry Window isn't widely promoted, but uptake in the "collective skeptic unconscious" is extreme. Basically it is a handful of easily disputable arguments about rapid vaccine induced negative efficacy that lead people to assume that the widespread convention of not counting people as "fully vaccinated" until X timepoint poisons efficacy data (as opposed to having no meaningful impact in most contexts).
Brian, you've written before about feeling your work doesn't make much of a difference and your low popularity compared to more sensationalist narratives. Obviously that's because of your pesky cold water pouring - but some people appreciate it. I have enough scientific training to know the importance of the 'ugly fact' so please keep those irritating observations coming!
Thank you for this comment (and I "liked" it) so I don't need to make another one similar to it. I always worry that Brian will think I've got a crush on him or something. 😄👍
We're already dealing with "spaghetti at the wall" hypothesis and lack of actual reading of studies, so anyone who spends time dwelling on studies does more in engaging with actual science than cursory glances that may leave readers having to relegate to just trusting what they read.
Thank you! I very much appreciate the support for the party pooper content.
As always, even though no posts are locked I pick topics based on returning value to donors / supporters so the unpopular reality checks will certainly continue.
To the people who may be outraged at the incompetence of the regulators, and may enter in a depressing pattern of thinking involving how should they be prosecuted, I say this: What incentive does any Government in the World have in prosecuting itself?
There.
You cannot go lower than that.
Dear Depression, I win today!
People, I have saved you a few cycles of misery in your brains. Go out and play.
😅 I love the poll.
Brother - you piss me off occasionally but I ain’t never gonna unsubscribe. You have very important thoughts that need to be shared. My only criticism of you ever (what pisses me off) is when you use bad data (e.g., your state death data) to then do “good” analyses. It’s still garbage in garbage out, no matter how good your analysis. But when you are breaking down the genetic code stuff, the signatures and patterns, and describing what’s happening biochemically, you’re at the top of your game. You ask the right questions. Just gotta be careful w those data sets; it can become a modeling circle jerk real fast.
Thank you! - glad to hear support for the code stuff. It's still what I spend a lot of my not-on-the-page time on, but eureka moments never come easy
Still no sequence data either.
Is "Protein Simple" tool CFR Part 11 compliant? If not, its use is not acceptable for FDA data/document submission due to not being compliant with the "digital audit trail" requirements. We had to validate Microsoft Office products when using them to generate data submissions in our workflow to the pharma clients and FDA.
I couldn't guess. It might be in that any image, however easily faked, can be cross-checked with the source blots? So validation-compliability is built-in.
Well, there are very specific requirements for pharma reg compliance on this, it's not just that something can be cross checked. It has to be documented in the Pfizer Quality System, and if they are using vendors to do this, then in those vendors' systems, who would have had to run a bunch of testing, verify, document, etc. and Pfizer would have had to audit this and keep auditing it. The FDA would need to be able to audit every "prettified" graph to the raw data down to every click on the computer that was made, and know who made them.
This is such a gigantic pain that it is only worth it if absolutely necessary, and to generate a couple of pretty graphs is not worth this at all. And if I were an honest regulator, I would still require them to send real images.
This suggests that Bio-Techne isn't interested in making trial compliant products, generally, though I didn't see the same language in the user manual for Jess so it could just be a legal shotgun disclaimer.
https://www.bio-techne.com/terms-and-conditions
Product Use and Restrictions.
Unless otherwise expressly stated in writing by Bio-Techne, (i) Purchaser may not use Products for Commercial Purposes; and (ii) all Products are for research use only, and not for human or animal therapeutic or diagnostic use. “Commercial Purposes” means any activity by a party for consideration and may include, but is not limited to: (1) use of Products or their components to provide a service, information, or data; (2) use of the Products or their components for therapeutic, diagnostic or prophylactic purposes or in connection with any Phase III clinical trials, pivotal trials or post registration clinical trials;"
Yes, exactly, this language is to clarify that they are not making software for regulatory compliance purposes. The research market application for software is a very small market to justify the investment otherwise.
I see what you mean - there's downside, no real upside, even if it is compliant. For all we know that was intentional - Pfizer could have known that just haggling over the use of SimpleWestern would deplete regulator manhours.
They haggle over every small thing. Ask me how I know. Pfizer is one of the worst.
Yeah I am increasingly leaning to this theory of the "fraud." Pfizer used the Simple Western to increase cross-talk and paperwork. But it's just a guess.
Properly understanding the science at this level is a bit above my pay grade to say the least, but I wonder if it's a 'limited hangout' and the real story is elsewhere - or is this the real story?
For example what happens when the mRNA gets broken down, does it remain soluble or does it aggregate into something insoluble:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534620/
Nonetheless it's puzzling why they don't publish the original blots and why didn't the regulators request them, would they show inconsistencies to the trained eye?
Edited to add: I don't like to be conspiratorial but for example it looks like the bilvalent boosters got approval on the back of some key omission, which should have been picked up by the regulators.
That is an extremely cool paper, thanks for the link. What they are showing is that a lot of proteins, even without known RNA binding properties, need RNA to remain soluble. That makes sense since RNA is everywhere so so proteins are going to evolve "needing" it in that it wouldn't make sense to design proteins to operate in a "RNA sterile" context.
But RNAse is ubiquitous, RNA is always being degraded, it's probably a question of homeostasis there, so I don't think transfection RNA will be dangerous in this regard when it breaks down (which apparently takes days and days, of course). On the other hand it might be dangerous and protein-deforming before then, thanks to the novel secondary structures created by codon optimization as others have pointed out https://unglossed.substack.com/i/76344824/prion-risk-factor-vaccine-g-rich-mrna
Limited hangout indeed. If Pfizer wanted to fake these experiments with "real blots," it would have been trivially easy. Just run a mock protein / antibody to show "spike," run empty lanes to show "no truncated spike," etc. Though I still feel like it seems like they have limited access to Covid vaccine and aren't actually making it themselves. We know that scale-up isn't plausible and this makes it look like they could barely conduct experiments on prototype.
"Omission" - you mean the "FDA is angry" story? I mean the FDA is the one rushing things, they can't blame that on Moderna. "FDA is angry at the Blockbuster clerk because it rented the wrong Matrix sequel and now the kids ARE SCREAMING"
Well the FDA (or Paul Offit at least) may be angry, but he doesn't realize the problem is the FDA are far too close to the pharma companies, and it appears the latter can strongly influence the former to allow trial endpoints which flatter their product the most. When it turns out the product is less effective in real world use, the FDA doesn't have a leg to stand on, since they accepted the trial endpoints which the product fulfilled. (antibodies in 8 mice??? 🙄)
A great example is the Tamiflu investigation by Peter Doshi of the BMJ among others, where governments spent billions of $ without properly looking at the trial data because they were desperate for a 'cure' for swine flu. In the end it turned out that it only reduced symptoms for a day or so, with no significant effects on hospitalization:
https://www.bmj.com/content/348/bmj.g2545
I'm not quite sure what the "worry window" is that you are referring to, but I will say you put us in a very difficult position when our unsubscribing becomes contingent upon our purchasing of chicken bakes!
Worry Window isn't widely promoted, but uptake in the "collective skeptic unconscious" is extreme. Basically it is a handful of easily disputable arguments about rapid vaccine induced negative efficacy that lead people to assume that the widespread convention of not counting people as "fully vaccinated" until X timepoint poisons efficacy data (as opposed to having no meaningful impact in most contexts).
Ah, ok interesting! I look forward to that post! Now, the question remains if I should procure a churro along with my chicken bake...
Brian, you've written before about feeling your work doesn't make much of a difference and your low popularity compared to more sensationalist narratives. Obviously that's because of your pesky cold water pouring - but some people appreciate it. I have enough scientific training to know the importance of the 'ugly fact' so please keep those irritating observations coming!
Brian is an honest man. One of just a few science writers I trust, in the post-covid-hysteria world, with cranks running wild on both sides.
💯
Thank you for this comment (and I "liked" it) so I don't need to make another one similar to it. I always worry that Brian will think I've got a crush on him or something. 😄👍
Oh he knows I love him.
😄 👍
I also appreciate it! It’s only healthy to challenge on a regular basis any inherent confirmation bias in my viewpoint :)
We're already dealing with "spaghetti at the wall" hypothesis and lack of actual reading of studies, so anyone who spends time dwelling on studies does more in engaging with actual science than cursory glances that may leave readers having to relegate to just trusting what they read.
Thank you! I very much appreciate the support for the party pooper content.
As always, even though no posts are locked I pick topics based on returning value to donors / supporters so the unpopular reality checks will certainly continue.
To the people who may be outraged at the incompetence of the regulators, and may enter in a depressing pattern of thinking involving how should they be prosecuted, I say this: What incentive does any Government in the World have in prosecuting itself?
There.
You cannot go lower than that.
Dear Depression, I win today!
People, I have saved you a few cycles of misery in your brains. Go out and play.
It goes beyond the gov't. It goes with leaders and reformers who thrived in the same system, me thinks.
-----
"The system itself doesn't provide you with the tools or ideas that would allow you to change, escape or defeat it. All by design, of course."