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Could GC content of mRNA vaccines affect cancer through potential G-quadruplexes?

Could GC content of mRNA vaccines affect cancer through potential G-quadruplexes?

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Warning: if you are an individual with a predisposition to experience anxiety, you might consider not reading this content to avoid feeling discomfort that reading this material could cause. This content discusses hypothetical scenarios only based on molecular information observed at the research level. If you or your loved one has been vaccinated with mRNA vaccines, you could find this content distressing despite its theoretical nature. Please proceed at your own discretion.


Unnatural twists leading to unintended consequences

In this post, we will summarize an unusual theory of how the mRNA vaccines could inadvertently be contributing to cancer development because the genetic sequence of the vaccinal mRNA was significantly altered from that what is actually found in SARS-CoV-2 virus.

Before we go on, we want to stress that this is only a proposed theory of the potential mechanism for promoting cancer development that currently has not been clinically investigated and thus is without evidence. The authors of the discussed article are sounding an alarm of concern of a potential problem and we collectively need to decide if it is worth paying attention to or not.

But the proposed molecular mechanism is quite unusual and fascinating, and a topic we have never yet breached in the pages of our blog: the formation of specific three-dimensional structures by the RNA called G-quadruplexes.

And a good point worth stressing is that by studying such possibilities we could increase vigilance to determine if such unintended consequences do take place. Such knowledge could improve the designs of future interventions at the molecular level. It also points to a broader awareness of how enormously complex the outcomes might be when science chooses to engage in biological interventions. The systems we are playing with are just astoundingly complex, and it is simply impossible to think of all the variables, even if we already have the requisite knowledge to be aware of what these variables might be. It shows how easily biological complexity can paint a confusing picture that obscures reality.

Image of Merogenomics article quote on why science cannot answer all questions

Before we get started, let us point out that the brainchild of this amazing theory came from a team that we previously covered when discussing COVID-19 mRNA vaccines leading to the production of exosomes and consequent interferon cytokine disturbance. This group has likely assembled the most complete understanding of the potential molecular dangers of mRNA vaccines, and have recently been rewarded by having their summary published in a peer reviewed journal. Currently, their publication stands as the most cogent look at the potential problems with mRNA vaccines that could have been overlooked in the mad rush to deal with the pandemic health crisis.

That said, to begin, let us provide some basic background on what makes up the genetic material we will be discussing.


Why a genetic sequence’s content matters

Recall that genetic material is made up of four chemicals (nucleotides) and it is the arrangement of these chemicals that define how information is stored. In the DNA these four chemicals are abbreviated as A, C, G and T and in RNA they are A, C, G and U (the T and U nucleotides are nearly identical to one another.) The vaccine’s man-made mRNA sequence (that codes for the spike protein) is not exactly identical to the natural RNA sequence of the actual spike protein found in the SARS-CoV-2 virus, though. The sequence has been artificially manipulated to enrich it with more G and C nucleotides. By the way, this can happen without mutating (or changing) the protein being produced because of the built-in redundance of the genetic coding that is used for the production of proteins. In nature, there is often more than one way to define which particular amino acid “building block” will be used in a protein’s production. But there can be many consequences to such manipulations of the genetic code, including the potential to enhance the production amount of the protein.

With that in mind, a study has determined that the RNA coding for the spike protein in SARS-CoV-2 has 36% of its code comprised of G and C nucleotides, whereas the Pfizer spike protein’s mRNA is made up of 53% G and C nucleotides and in the Moderna vaccine mRNA that number is 61%.

Image of Merogenomics article quote on GC content of vaccines vs spike gene

This enriched GC content in mRNAs can lead to consequences. How? Well, remember that basically these genetic materials are complimentary: the nucleotide C interacts with nucleotide G, while A can interact with either T or U nucleotides. As a result, an RNA sequence with complimentary arrangements of nucleotides near one another can actually lead to self-interactions and create three-dimensional structures as opposed to just being present in a linear form. One such 3-D feature is created when there is a series of G nucleotides in a row (in either DNA or RNA) and it is called a G-quadruplex formation. The G nucleotides start to make electrostatic interactions with one another and form a mini tower that protrudes like a mound on an otherwise smooth surface of a linear genetic code.

Consequently, it has been proposed that the artificial sequences in the experimental mRNA vaccines (remember: they are enriched in G and C nucleotides) are more likely to develop such G-quadruplex formations. This fact alone has dramatic implications, as G-quadruplexes in RNAs can easily impact the regulation of gene usage (how genes are used is referred to as gene expression)!

Is it here where we may find the Achilles’ heel that might accidentally promote cancer development? Let’s dive into that.


Why 3D structures of genetic material matters

G-quadruplex forming sequences are found across the entire human genome, and their distribution appears non-random. For example, they are found in telomeres (specialized structures protecting the degradation of genetic material at its ends), or in the promoter regions of numerous genes which are genetic regions that indicate where the genetic material is to be engaged by machinery that will use the code to produce the mRNA templates. mRNAs, of course, are themselves the blueprints used to generate proteins inside our cells. Notably, some of these promoters containing such G-quadruplexes are oncogenes, ie. genes that produce proteins that can be involved in promoting the development of cancer. But in total, approximately half of all the genes in the human genome are predicted to form G-quadruplexes.

Normally, to use our DNA code to generate mRNA, the double-stranded form of DNA has to be unwound to expose a single-stranded form that can then be used as a template by copying machinery to make the RNA. But since G-quadruplex structures are extra stable, their presence can inhibit the use of genes.

The stabilizing nature of the G-quadruplexes has been recognized as a potential target for medications that could ensure their presence in the promoter regions of oncogenes to silence the use of oncogenes that would otherwise promote cancer development. In other words, stabilization of G-quadruplexes is a possible option for cancer therapy.

Image of Merogenomics article quote on alternative cancer treatment using G quadruplexes

And that is the just first layer of how these structures could be influencing biology. To understand why the presence of G-quadruplexes in the vaccine mRNA could be problematic to cellular biology and trigger the development towards a cancerous state, we have to introduce two more layers. First, the G-quadruplexes, due to their specific three-dimensional shape, can also interact with specific cellular proteins. And second, mRNA can also be regulated by interacting with other tiny RNA molecules called microRNAs (abbreviated as miRNA). miRNAs are a fine-tuning mechanism of how genes are to be used (they fine tune the gene expression). A protein’s interaction with the genetic material will influence how much mRNA might be produced, and specifically miRNA binding to mRNA can influence how much that mRNA will be used as the template to produce new proteins of interest to the cell. Typically, the binding of miRNAs will repress the use of mRNA as a template for protein production.

So not only can the G-quadruplexes influence the fine balance between when the DNA is available to provide one of its single strands for the production of mRNAs, but they are also involved in a fine balance of interacting with regulatory proteins as well as the regulatory miRNAs. As everything in biology, if that balance is perturbed, serious problems can arise. For example, the reduction of available proteins or miRNAs can lead to serious problems such as cardiovascular diseases, neurodegeneration or cancer development.

Which finally brings us back to the vaccine mRNAs and their potential to generate their own G-quadruplexes at higher percentages.


Why manipulating mRNA vaccine genetic content might have been a problem

Recall that we mentioned the mRNA vaccines have been manipulated to have more GC nucleotides content than would be found in the same genetic material of the actual SARS-CoV-2 virus. This has been developed for numerous reasons such as achieving the stability of mRNA and the enhanced use of the mRNA template to produce the desired product inside the vaccine infected cells, in this case, the spike protein.

This enhanced GC nucleotide content is suspected to lead to an enhanced number of G-quadruplexes (19 in Moderna vaccine and 9 in Pfizer in comparison to 4 found in SARS-CoV-2 spike gene sequence). Considering that vaccination introduces an enormous amount of such mRNAs, vaccination potentially could result in sudden shift in how many G-quadruplexes are found inside a cell for interaction with proteins (including proteins that can unwind G-quadruplexes) or miRNAs (can bind the site of G-quadruplexes once unwound). In other words, vaccine mRNAs could act as decoys, sequestering these valuable molecular products for interaction with vaccine mRNA rather than their designated cellular targets. Which would mean that vaccine mRNAs, if entering the target cells with significant quantity could shift the balance of how the cell performs its normal functions, and affect how many and which proteins are produced by the cells. Instead of these proteins or miRNAs interacting with G-quadruplexes found naturally inside the cells, they would be busy interacting with the vaccine mRNA G-quadruplexes instead.

It is this sudden imbalance in available G-quadruplexes that could be a contributing factor to the inadvertent activation of oncogenes and promotion of cancer development.

We have brought up this concept of sequestering proteins away by foreign genetic material before in one of our videos (below). There we discussed a paper’s untested hypothesis based on modeling which posited how SARS-CoV-2 itself could possibly be negatively impacting the availability of RNA binding proteins by binding to these proteins directly, and preventing their interaction with cellular RNAs and leading to DNA damage of infected cells.

Remember that these sequence dependent, potential molecular impacts have not yet been experimentally found to be confirmed or denied. These biological questions still await a resolution.


p53 protein, king of cancer suppression

The authors of the G-quadruplexes paper then invested some energy discussing an example of how the dysregulation of two specific miRNAs could be a potential driver of cancer development. However, there is as yet absolutely no evidence that these molecular effects actually take place in cells that took up the vaccinal mRNA. This was for illustrative purposes – as an example of why there is a need for the proper analysis of these molecular events involving novel mRNA vaccine technology.

The example that they choose to focus on is the p53 protein, along with its upstream regulator, the p16 protein and they probably selected this combo for a good reason.

p53 is considered the master regulator of a network of genes involved in tumor suppression. The importance of p53 cannot be understated. More than half of all cancers will have mutations in a p53 protein. And those cancers that do not have mutations in p53, will have destructive mutations in proteins regulating p53. Thus, along with p16, these proteins participate in pathways that are perhaps affected in all cancers. So, we are talking about some big heavyweights here.

The role of p53 is super important, so it makes sense that cancer cell would want to have it destroyed if it wants to divide uncontrollably. p53 helps prevent the development of tumors by stopping cells with mutated or damaged DNA from dividing, a control guard that no cancer cell wants. p53 achieves that because it is a transcription factor, which means a protein that selects specific genes to be copied into mRNA which are then used as blueprints for protein production. Thus p53 as a transcription factor can influence the cell’s response by stimulating specific set of genes. There are literally hundreds of different transcription factors, since the regulation of our enormous genome is not trivial, but p53 is the most studied transcription factor ever.

Image of Merogenomics article quote on p53 role in cancer

This should not come as a surprise if p53 mutations are found in the majority of all cancers, right?

Because miRNAs play a role in how levels of p53 can be regulated, the authors insinuate that if such important miRNAs were to be dysregulated in their function due to presence of G-quadruplexes imposed by vaccine mRNAs, we could be encountering enhanced cancer development in some unfortunate recipients of these vaccines. But we stress once again, there is no direct evidence of this taking place as of right now.

But let us define how miRNAs are involved in this super important molecular system as this is still a fairly new discovery (and why the connection between the dysregulation of such miRNAs and cancer post vaccination might not have been at all apparent to the developers of these vaccines).

First, let's go back to p16 which is known to positively regulate the levels of p53 protein. But until recently it was not understood how this is achieved. It was known that p16 supports preservation of p53 by preventing the destruction of p53. p53 levels are controlled and down regulated by Mouse double minute 2 homolog (MDM2) protein. With so many words in the name of this gene, sometimes you wish names were more catchy. Like Mouse logshome double minute 2 is even more memorable. But alas, it is the MDM2 that is a negative regulator of p53. MDM2 is a protein that attaches another small protein called ubiquitin to p53, and any protein that has been ubiquitinated is destined for destruction. Therefore MDM2 leads to reduction levels of p53 by promoting its degradation. p16 in turn is a negative regulator of MDM2. In other words, p16 is an inhibitor of a protein that is an inhibitor of p53, and that is how p16 helps to keep p53 in existence. Until recently, there was a missing link of how p16 actually inhibits MDM2.

It turns out that this important process is achieved through miRNAs.

p16 controls the development and use of many molecules including miRNAs. These include two special miRNAs called miR-141 and mIR-146b-5p. These two miRNAs can bind to MDM2 mRNA and therefore prevent the use of the MDM2 mRNA blueprint for the production of the MDM2 protein.

Accordingly, when cells are not under stress, p16 is able to keep stable levels of p53 protein. If p16 were to disappear, miRNAs levels controlling MDM2 would disappear, and p53 becomes vulnerable to MDM2-initiated degradation.

Therefore, any threat to proper levels of miRNAs controlling MDM2 runs the risk of leading to reduced levels of p53, and loss of adequate tumor suppression activities. The importance of MDM2 and its regulation also cannot be understated. The MDM2 protein is overexpressed in many cancers as well, and high MDM2 levels are associated with poor cancer prognosis. Because MDM2 supresses p53 - which is a tumor suppressor - MDM2 is in itself an oncoprotein, a protein with a potential to promote cancer development.

The intimation of the authors seems to be that we better hope that mRNA vaccines with their own G-quadruplexes to seduce interaction with host cell miRNAs do not perturb the available miRNAs to such abnormal levels that we actually lose the ability to properly control cellular functions. Not having proper control over cellular behaviour, such as allowing a cell to divide with damaged DNA, is what can lead to cancer development.

And if you thought this level of mechanism of control sounds complex already, get ready. It can get much more complex because the web of interactions between so many different molecules can get very large, very fast. For example, a single miRNA can simultaneously affect production levels of many protein targets in one go. Another example of added complexity - p53 is a positive regulator of MDM2! This means, that p53 is responsible for boosting MDM2 levels that are responsible for shutting down its own existence. This sort of looks like p53 is on a suicide mission that is held in check by p16. While p16 maintains p53, p53 maintains properly functioning cells.

The whole idea comes down to this: is the amount of vaccinal mRNA G-quadruplexes enough to affect the molecular stability of cells harbouring the vaccine? At the moment we simply do not know. Perhaps it may, or possibly it is simply not enough of a shift to disrupt the balance when one considers that the human genome could have up to 700 thousand of these G-quadruplexes. Nevertheless, in a review of different potential negative molecular outcomes as a consequence of mRNA vaccines, Merogenomics found the concept of G-quadruplexes very fascinating in the least, while clearly hoping that the future will show there is no merit to this hypothesis.


This article has been produced by Merogenomics Inc. and edited by Jason Chouinard, B.Sc. Reproduction and reuse of any portion of this content requires Merogenomics Inc. permission and source acknowledgment. It is your responsibility to obtain additional permissions from the third party owners that might be cited by Merogenomics Inc. Merogenomics Inc. disclaims any responsibility for any use you make of content owned by third parties without their permission.


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