Thread by @Kevin_McKernan

I wonder what could go wrong codon optimizing a virus that is already adapted to its host?

What made them think maximum expression was desirable?

Top Track- SARs-CoV-2 GC content over spike.

Bottom- BNT162b2 GC content.

They certainly weren’t thinking about secondary structure.

This type of stuff matters to RNAses and other components of the innate immune response (Toll Like Receptors).

Yes, their goal was to evade innate detection with pseudouridine but at what cost?

These types of modifications create stop codon ablations and many translation errors.

Has anyone see protein sequence data of the spike protein expressed in vaccinated people?

This seems like a major regulatory oversight.

The assumption that codon optimized mRNA is a bio equivalent to the natural spike protein is a pharma narrative.

The mRNA should be considered a pro-drug and proof of the active metabolite needs identification and quantification (spike protein generated in the host)

Not some ELISA or antibody test.

Protein sequencing to a depth that can see rare variants.

The paucity of RNA and Protein sequencing the Vax is deafening.

GC content is simply the GC/AT count in the RNA.
G and C make 3 hydrogen bonds
A and T make 2 hydrogen bonds.

GC rich RNA is stickier and makes much different secondary structure.

Think of knots on a coiled telephone cable. Think Telomeres and gene regulation.

Pseudouridines are used to camouflage the mRNA from your Toll Like Receptors and certain RNAses.

But… they are sloppy bases. Promiscuous.
U should Bind to A
Their replacement binds to G and A and C a bit too.
And itself.
Error Prone.

pnas.org/content/116/46…

Base pairing party with Pseudouridine (pitch fork symbol)

This confuses the hell out tRNAs trying to translate this sloppy message into proteins. It’s particularly bad at stop codons.

What happens when you miss stop codons?

I hope their UTRs are clean

ncbi.nlm.nih.gov/pmc/articles/P…

So what happens to a mRNA that is folded differently and knotted up with much higher GC content?

Something called Quadruplex G

DNA and RNA begin to form Hoogstein base pairing instead of Watson Crick base pairing.

This stalls translation and often results in misfolds/errors.

And the codon “optimizers” were optimizing at warp speed and make a rookie mistake.

They codon optimized but forgot to ablate the quadruplex Gs(G4’s).

Oops. The viral mRNA has 4 G4’s.
Pfizer now has 9 and Moderna has 19. Regions in yellow =G4.

What happens to cells that express bucket loads of G4 RNA?

G4’s are important in senescence.
Telomeres are all G4’s.

Stabilizing G4s can inhibit telomerase.

P53 often binds to G4’s.

These are really important features of RNA they must be oblivious to.

There pursuit of maximizing expression levels of toxic spike came at all costs.

They used dirty bases like N1-methylpseudouridine, strong Globin promoters and very sloppy codon optimization that is likely very error prone. Did they ever ask if more was better?

So again,
This begs the question, should a codon optimized mRNA be considered a bio equivalent with another viral mRNA that is only 73% identical at the sequence level?
Should the protein they theoretically code for be assumed equivalent without proof?
Promiscuous pseudouridine?

Seems to me the mRNA field wants its cake and to eat it too.

They want a base that tricks the immune system but they don’t want to admit the translational error that invites.. and they don’t want any attention on the fact that this mutagenesis may occur over bioweapon SEB motif

There is a good Dark Horse podcast going over the mistake of Bio equivalence on Telomeres in mice. Warp speed science is most prone to making these false equivalences.

@BretWeinstein

Let’s have a look at the sacrifice they paid.
This is Pseudouridine.
It should bind A.
But it binds G….and C ….and sometimes itself.
No fidelity.
How is a tRNA/Ribosome supposed to read this sentence when the speaker is slurring every 4th word?
You are going to get errors.

There is a certain Hubris on display here.
Why did they think they needed to improve upon the viruses codon usage when expressing spike?

Did it occur to them that the virus may have adapted a particularly scarce codon usage to limit damage to its host?
Mobile hosts spread.