Thread by @eh_den

COPTIGATE - THE SUMMARY EDITION!
(thread)

Highlights from my writing on the topic of codon optimization, for those who have never heard about it before (or for those who wish to share it with others).

#COptiGate

Before you bombard experts (e.g. @RWMaloneMD) with endless requests to comment on the validity of what I write, please read this thread, then go to the previous threads (links below), and see the references I use.
There is MUCH MORE INFORMATION in my previous threads!

#COptiGate

1) Inconsequential (“silent”) mutations are known as synonymous mutation.
2) Synonymous mutations contribute to cellular processes which are determining protein structure and function.
3) Synonymous mutations influence protein folding.

#COptiGate

4) Protein misfolding has been linked with neurodegeneration in Alzheimer and Parkinson disease, and many other pathologies.
5) Protein misfolding resulting in intracellular PAO accumulation is sufficient to cause cardiomyocyte death and heart failure.

#COpgiGate

6) For example, these misfolded proteins, known as PRIONS, cause a number of rare brain disorders, such as kuru, bovine spongiform encephalopathy (“mad cow” disease), and Creutzfeldt-Jakob disease.

#COptiGate

brainfacts.org/archives/2010/…

7) The last decade has seen an exponential increase in published research on the topic of synonymous mutations.
8) Most studies that linked synonymous mutations to diseases focused on a single (or very few) nucleotide* substitutions.
*nucleotide - genetic letter.

#COptiGate

9) codon optimization creates a large-scale alteration of the gene sequence.
10) Up until recently, codon optimization technology was only used for research and in the manufacturing of therapeutic proteins.

#COptiGate

11) SARS_CoV_2, as well as all its variants/mutations are called wild type (WT), which describes their original form (in nature).
12) Pfizer, Moderna, AstraZeneca, Janssen etc. all use codon optimization, on top of other elements; their products do not generate WT.

#COptiGate

13) There is a lack of understanding on the difference between proteins synthesized using codon optimization compared to those which did not pass a codon optimization process.
14) Using the codon optimization technology gives multiple advantages to the manufacturers.

#COptiGate

15) HOWEVER, Codon optimized proteins carry potential risks as their modified nucleotide sequences may have unpredictable effects on the structure and function of proteins.

#COptiGate

16) For example, codon optimization can achieve efficiency in creating large amounts of the required protein (eg spike), but doing so at the expense of the accuracy of the protein being manufactured, resulting in generating unknown proteins due to errors/misreading.

#COptiGate

17) Another example: codon optimization might change the shape of the protein, which in result will lead the immune system to be trained to detect a wrong pathogen thus greatly reducing its ability to stop the pathogen, in our case SARS_CoV_2 and its mutants.

#COptiGate

18) It is therefore necessary to have well qualified methods that are fit-for-purpose and can be used to evaluate the risk of codon optimization during drug development and manufacture. The regulators did not have such framework in place.

#COptiGate

19) Prior to COVID19, the use of gene therapy was extremely limited, so even though regulatory agencies were well aware of the need for methods and processes, the limited use and the long review process deemed sufficient to identify codon optimization side effects.

#COptiGate

20) Because in 2020 the WHO has declared COVID19 as a pandemic, and since governments across the world followed happily by implementing emergency regulations, the medical regulators had been instructed to get vaccines approved as fast as possible.

#COptiGate

21) All the gene therapies which were introduced as vaccines to the SARS_CoV_2 virus and it's variants went via a fast-track process such as the FDA's Emergency Use Authorization (EUA)

#COptiGate

22) The use of the fast-track approval process created a gap where the assumption that codon optimization side effects will be able to be identified as part of the review process, as there was no regulatory process to review risks related to codon optimization.

#COptiGate

23) HOWEVER, since the fast-track process has been chosen, the risks which were usually being measured as part of the normal process were not measured.
24) The codon optimization related risks are not even required to be measured in the FDA's BLA for Pfizer vaccine.

#COptiGate

25) The fact manufacturers use a technology which they are fully aware of is problematic, and the fact regulators are fully aware of it but do not even have a process to review it, tells you everything you need to know about the validation process and it's value.

#COptiGate

26) Not measuring a risk does not make it go away, just makes it become invisible.
27) The only one who takes the risk is YOU, because all the countries in the world have signed a full indemnity to manufacturers and anyone who administers their products (#PrizerLeak).

#COptiGate

28) The purpose of the #COptiGate threads was to help people realize the risks related to codon optimization, which no one seems to have bothered to tell them that they exist.
29) The silence of the scientific community and media on the matter is a huge disgrace.

#COptiGate

30) One's education does not make them a scientist. One's position of power (government or academia) does not make them trustworthy. PLEASE, STOP TRUSTING "AUTHORITIES". It is YOUR health, it is YOUR safety, it is YOUR life.

YOU HAVE THE RIGHT TO QUESTION EVERYTHING!

#COptiGate

THREADS TO READ # 1

COPTIGATE - THE WORST DESIGN FLAW IN HUMAN HISTORY THAT IS IMPACTING YOUR HEALTH.

(use "Show replies" multiple times to expand)

#COptiGate

https://twitter.com/eh_den/status/1426885632140394499

THREADS TO READ # 2

COPTIGATE - 3D CHESS EDITION

(use "Show replies" multiple times to expand)

#COptiGate

https://twitter.com/eh_den/status/1428102982839721992

THREADS TO READ # 3

REVERSE ENGINEERING: WHAT DO WE KNOW ABOUT THE GENETIC CODE WITHIN THE PFIZER VACCINE?

(use "Show replies" multiple times to expand)

#COptiGate

https://twitter.com/eh_den/status/1431674294606651393

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https://twitter.com/eh_den/status/1430868765378498562

Antibody-dependent Enhancement (ADE) & Codon Optimization:

31) ADE: antibodies generated as a result of the vaccine response recognize and bind to SARS_CoV_2 virus, but they are unable to prevent infection, because they were trained badly.

#COptiGate

https://twitter.com/eh_den/status/1431674426685370368

32) Not only the S-2P design of the spike protein generated by Moderna, Pfizer and Janssen is faulty, introducing codon optimization on top of that might lead to errors in the RBD domain on the generate spike protein can further increase the risk of ADE.

#COptiGate

33) The reason for the S-2P prefusion design was "to provoke stronger immune response...but it can also means the spike protein lingers in the plasma membrane bound to ACE2 receptors because of impaired fusion capabilities"
dpbh.nv.gov/uploadedFiles/…
#COptiGate

34) HOWEVER, as the Salk institute has shown, if the spike protein is binding to ACE2 it disrupts the ACE2’s molecular signaling to mitochondria, causing the mitochondria to become damaged and fragmented.

salk.edu/news-release/t…

#COptiGate

35) Antibody production against S-2P spike bind with soluble /plasma ACE-2 (shedding) can cause:
coryzal symptoms; shortness of breath; abnormal liver function; LOST OF TASTE; Lymphopenia; Renal failure; ARDS; Kawasaki; myocarditis; and stoke.

frontiersin.org/articles/10.33…

#COptiGate

Source:
"Effects of codon optimization on coagulation factor IX translation and structure: Implications for protein and gene therapies" (Aikaterini Alexaki et al., 2019)
#COptiGate