Pseudouridine: What is it and Why Should you Care?
The Nobel Prize in Physiology or Medicine was awarded for discovering use of Pseudouridine to suppress immune responses to synthetic mRNA, and use of that discovery in COVID-19 mRNA vaccines
Background
Natural RNA, including mRNA, consists of a polymerized string of four different compounds – A, U, G, C. U = Uridine. There are many different natural forms of RNA in cells, but in general, DNA makes mRNA, and mRNA makes protein (polypeptide).
In cells after polymerization, in some mRNA there are precisely controlled modifications to the “U” compounds (bases) to convert them to a different compound, called pseudouridine.
The presence of such precise pseudouridine modifications regulate many aspects of mRNA biology, including how long it persists in the cell before being degraded, the structures that it forms when folding, how efficiently it is turned into protein (translated), and the activity of certain cell types containing this modified mRNA when responding to inflammation.
Pseudouridine messages an anti-inflammatory (which is to say immunosuppressive) signal to cells.
Kariko and Weissman recently received the Nobel Prize in Physiology or Medicine for their their discovery that replacement of synthetic pseudouridine for uridine throughout synthetic mRNA reduces the inflammation triggered when this synthetic mRNA is delivered into the cells of animals using self-assembling cationic lipid delivery particles, and specifically the use of that discovery to enable the rapid development of the Pfizer/BioNTech and Moderna COVID-19 mRNA “vaccines” that have been deployed throughout the world.
In a break with standard regulatory practice, under the EUA process the FDA did not require rigorous assessment of the pharmacology, pharmacokinetics, safety, toxicity, reproductive toxicity or any other aspect of synthetic mRNA incorporating pseudouridine for human (or animal) use.
Furthermore, the synthetic pseudo-mRNA (which is very different in many ways from naturally produced mRNA) manufactured and dosed into humans throughout the globe does not even contain pseudouridine.
Instead, it incorporates a synthetic molecule which is even more potent that naturally occurring pseudouridine, called N1 Methyl pseudouridine, which is structurally more closely related to the molecule Thymidine, which is found in DNA (not RNA).
Chemical structure of Thymidine, one of the four key components of DNA (A, T, G, C)
As a consequence of this decision by FDA, which was then followed by the European Medicines Agency and regulatory agencies across the world, the effects of injection of these highly modified synthetic pseudo-mRNA have not been adequately investigated.
This includes effects on human immunology, autoimmunity, toxicity, pharmacokinetics (how long an active drug stays in the body), pharmacodynamics (study of the biochemical and physiologic effects of drugs), pharmacodistribution (where a drug goes in the body) and clearance (how long and by what mechanisms a drug takes to be broken down and removed from the body).
The willful avoidance and ignorance by FDA and Pharma concerning these key parameters is what underlies the misinformation propagated by FDA, Pharma, and mRNA vaccine advocates concerning where these molecules go in the body, how long they last, and how they are eliminated from the body.
All of these issues have become common questions and concerns asked by patients to physicians and other allied health practitioners. But there are no solid, rigorous, methodical prospective study data to which health practitioners can refer to when answering their patient’s questions.
All that is available are general platitudes promoted as propaganda by Pharma, the Government, and academic stakeholders such as Drs. Kariko and Weissman (and the Nobel Prize Selection Committee) who have repeatedly, and incorrectly asserted that these synthetic foreign pseudo-mRNA are rapidly degraded in the body after injection.
Subsequent research by laboratories from all over the world have demonstrated that this is a false statement – mis- or dis-information – and that these synthetic molecules persist in the bodies of injected persons for weeks to months, rather than the hours originally asserted.
The inconvenient truth in this matter is that current scientific understanding of the molecular biology, immunology and toxicology of both Pseudouridine – modified mRNA as well as N1-methyl-Pseudouridine – modified mRNA is still in development. In plain words, not well understood at this point.
What is clear is that these modified pseudo-mRNA have a wide range of biological effects, including immunosuppression. Which can be a good thing for overcoming one barrier (inflammatory response) to the medical administration of synthetic mRNA formulated into self-assembling lipid particles.
But may well be a bad thing for things like autoimmune disease and the ability of the immune system to control other infectious disease and cancer.
Of additional relevance is that these pseudouridine and N1-methyl-pseudouridine modifications of synthetic mRNA are not necessary for eliciting an immune response to the protein encoded by such synthetic mRNA.
This is clearly demonstrated in the initial reduction to practice (in mice) demonstrated by myself and others at the La Jolla startup biotech company Vical in 1990, and in the context of COVID-19 mRNA vaccine development by the initial clinical trial results of the European biotech startup CureVac.
The pseudouridine (or N1-methyl-Pseudouridine) may make synthetic mRNA-based drugs and vaccines more potent on a comparative dose-by-dose basis, but it is not necessary and this effect may be overcome by increasing the dose of non-pseudouridine modified synthetic mRNA.
What is clear is that, for some reason, the FDA suspended its normal processes and procedures which would typically require that a biologically active new chemical entity be thoroughly investigated prior to use in humans. The reason and logic behind this gross negligence should be thoroughly investigated and disclosed to the public.
Both those who have received these poorly characterized products, often after being subjected to a wide range of psychological manipulation, propaganda, compulsion and coercion (mandates), and all too often with dosing-associated adverse events (including severe AE including death) deserve to know what happened and why.
Pseudouridine Facts
•Pseudouridine is a modified nucleotide mRNA subunit that is prevalent in natural human mRNAs
•The biologic significance and regulation of the pseudouridine modification process is still being determined and understood.
•This modification occurs naturally in the cells of our body, in a highly regulated manner. This is in sharp contrast to the random incorporation of synthetic pseudouridine which occurs with the manufacturing process used for producing the Moderna and Pfizer/BioNTech (but not CureVac) COVID-19 “mRNA” vaccines.
•These modifications occur at locations associated with alternatively spliced RNA regions, are enriched near splice sites, and overlap with hundreds of binding sites for RNA-binding proteins.
•pre-mRNA pseudouridylation is used by human cells to regulate human gene expression via alternative pre-mRNA processing
•mRNA pseudouridylation may control mRNA metabolism in response to changing cellular conditions
•Incorporating RNA modifications, including pseudouridine, in foreign RNA allows for escape from innate immune detection
•Presence of modified nucleosides in viral genomic RNA could contribute to immune evasion during infection
•In vitro transcribed RNA is immunostimulatory when transfected into HEK293 cells engineered to express either TLRs and inclusion of Ψ in the RNA suppressed this response (most pronounced for TLR7 and TLR8).
• Inclusion of Ψ in a 5′-triphosphate capped RNA abolishes activation of RIG-I, providing another mechanism for pseudouridine-mediated suppression of innate immune activation.
•Pseudouridine likely affects multiple facets of mRNA function, including reduced immune stimulation by several mechanisms, prolonged half-life of pseudouridine-containing RNA, as well as potentially deleterious effects of Ψ on translation fidelity and efficiency.
See more here substack.com
Some bold emphasis added
Header image shows Uridine, one of the four key components of natural RNA and mRNA (A, U, G, C), shown together with the structures of Pseudouridine and N1-methyl-Pseudouridine
Please Donate Below To Support Our Ongoing Work To Expose The Lies About Covid 19
PRINCIPIA SCIENTIFIC INTERNATIONAL, legally registered in the UK as a company 
incorporated for charitable purposes. Head Office: 27 Old Gloucester Street, London WC1N 3AX.
Trackback from your site.
Saeed Qureshi
| #
Wow – chemistry in action (with dreaded chemical structures to impress the readers) from a non-chemical environment. I wonder if these mRNAs or pseudo-mRNAs have been isolated, purified, and characterized for studying the claims made, within or external to the vaccine. If so, please share their source or literature references.
This “science” seems to me as “valid” (fictional) as the claims of the virus’s existence. Wow, just wow!
Reply
Greg Spinolae
| #
There is nothing wrong with the CHEMISTRY. It’s CORRECT. ……
The POINT IS that pseudouridine CORRUPTS the RNA instruction set AND corrupts the natural catabolism of the PSEUDO-mRNA wherin it resides; leaving it to continue instructing the production of whatever proteins the pseudo-mRNA has been programmed to produce – FOR EVER – or until it is “cured” by, perhaps, some new profitable “medication”.
Reply
Saeed Qureshi
| #
This is the question: describe how and where the chemistry part is done. That is, “pseudouridine CORRUPTS the RNA instruction set AND corrupts the natural catabolism of the PSEUDO-mRNA wherin it resides;”
I would like to see the methodology (references) of using isolated, purified, and characterized components showing “the corruption of the natural catabolism of the PSEUDO-mRNA with pseudouridine” (with supplier name for these components). Also, samples/source of the “whatever proteins.”
These samples are needed to develop and validate analytical tests to authenticate the claims made here. Thanks.
Reply
Greg Spinolae
| #
PseudoUridine is not Uracil.
PSEUDO-RNA (ie. a pretend RNA containing PseudoUridine instead of Uracil) has not been demonstrated anywhere to instruct the same way as ACTUAL RNA.
QED – The RNA instruction set is corrupted.
Catabolic enzymes have evolved to breakdown ACTUAL RNA.
The catabolism of PSEUDO-RNA has not been demonstrated.
[Indeed; there is evidence that there may be little or even NO catabolism of this pseudo-RNA]
It is not for sceptics to prove new medicines don’t work.
It is for producers to prove that they DO.
Reply
nils-ola holtze
| #
A protein’s function is determined by its structure. Since they use both pseudouridin and replace some codons with synonymous codons it changes folding- structure-function. Synonymous codons code for the same amino acid but have a different occupation time in the ribosomes which causes different angles between the amino acids. How could anyone know what the final protein looks like and thus its function in our bodies? According to Levinthals paradox there are more than 10 to the power of 600 different ways this protein could Impossible to know beforehand.
Reply
Saeed Qureshi
| #
@ “Since they use both PSEUDOURIDIN and replace SOME CODONS with SYNONYMOUS CODONS it changes FOLDING- STRUCTURE-FUNCTION. Synonymous codons code for the SAME AMINO ACID BUT HAVE A DIFFERENT OCCUPATION TIME in the RIBOSOMES which causes DIFFERENT ANGLES between the AMINO ACIDS.”
With due respect, this is what I am looking for (THE CHEMISTRY/EXPERIMENTAL PART); who and where has this been done for mRNA for the SARS-COV-2 virus? Please provide references and sources of such named substances. Please, help. Thanks.
Reply
nils-ola holtze
| #
Hi Saeed.
I wrote this article some months ago. You will find some good references under sources. I’m happy I did it then because its getting more and more difficult to find good stuff on internet
https://newsvoice.se/2023/08/levinthals-paradox-gene-splicing/
Hope you find it useful.
Reply
MattH
| #
Hi Nils-Ola.
The monkey would wear out an infinite number of typewriters in failure if the hypothetical impossibilities could be tested.
Reply
nils-ola holtze
| #
Interesting question Matt. The increase in incidence of many autoimmune diseases has been blamed on covid. Could not possible be the vaccine? A possible mechanism beside cross reaction, could be the phenomenon of protein induced NETosis that is known to cause a plethora of different diseases if overstimulated.
Reply
Saeed Qureshi
| #
Thanks for your response.
Your response (the cited publication) is an extended version of your comment above. Sorry, it is not a response to my question. I am asking for the chemistry aspect of methods/experiments to support your view, which is missing.
In the publication, you are describing the biology of evolution (ref. Darwin, random mutation, etc.), not the chemistry or experimental method details, particularly the COVID-19 virus or mRNA vaccine.
It appears that you are also questioning the virology narrative – i.e., not having answers to so many open questions.
Reply
nils-ola holtze
| #
Thank you Saeed, for the clarifying answer
English is not my first language so maybe I misunderstood. First, I must congratulate your ability to read so fast, many references! It has never been done because it’s impossible to predetermine the structure of a protein this size. The question should be asked the manufacturer, but they can’t answer. We are not injected with a copy of the mRNA sequence to the spike-protein, but with a sequence to an unknown protein. You need very advanced technique to determine a 3D structure of an existing protein. And then a lot of time to figure out reactions and interactions in vivo, different temperatures and ph often changes the structure/function complicating things.
In many ways the companies tried to buy something that is not for sale i.e., time. If you inject people with something, you need time to determine what it does in the body. I hope this answers your question.
Reply
MattH
| #
Hi Nils.
Has there been an identified increase in the occurrence of Graves’ Disease and Hashimoto’s since the usage of the mRNA injections.
Thank you.
Matt
Saeed Qureshi
| #
Thanks again for your response.
“I hope this answers your question.” I am sorry, it does not.
That is why I am asking. Where is the evidence (chemistry/science) showing that there is a specific mRNA, its protein (like s-protein)? It is nowhere.
To me, it is like the “virus”. They make all kinds of claims about it, but it (virus) is nowhere to be found.
Anyway, thanks for responding.