The single most posed question regarding mRNA technology is this. Can the technology be used to alter our DNA and can the messenger RNA employed by new vaccines gain access to the host’s DNA? The manufacturers assure us it can not. The issue is hugely complex, not as well understood as most would have you believe and there are still questions that both science and the vaccine manufacturers need to address.
New emerging research raises important questions and could also potentially affect our understanding of the coronaviruses. To really understand the content of this article, a little refresher course in basic biology is required for reference. I’ve tried to keep it as simple as possible and we are going to take a few side roads to arrive at the conclusion. Stay with us as we examine the most studied viruses in the world, discover how they’ve mastered the art of subterfuge, and examine our efforts to stay one step ahead.
A human cell
Although there are many different cells within our bodies, for simplicity we’ll look at a generalized cell structure. A cell consists of three parts: the cell membrane, the nucleus, and, between the two, the cytoplasm. Within the cytoplasm lie intricate arrangements of fine fibers and hundreds or even thousands of minuscule but distinct structures called organelles.
The vaccine manufacturers are at pains to point out that the mRNA they use in their vaccines bypasses our DNA (your DNA is encased within your cell in the nucleus, the purple and deep blue bit in the image below). Vaccine mRNA is delivered directly to the cytoplasm of a cell (the light blue section below), in effect, replicating our cell’s DNA-based processes of making(transcribing) RNA within the nucleus of the cell. Our DNA also releases any messenger RNA it creates into the cytoplasm.
According to the manufacturers, their mRNA can not be reintegrated into the nucleus and DNA of our cells. in other words, their mRNA cannot cross the nuclear membrane. Everything is restricted to the cytoplasm, as with the coronaviruses, on which their vaccines are molded. Is their explanation consistent with emerging science?
If you’re still having trouble visualizing cell layout, have a quick look at this article that breaks down cell structure to its basic levels.
The wonders of the viral world
To truly appreciate the complexity and subtle beauty of life and nature, and to appreciate the limitations of our understanding, examine the humble virus and its life cycle. We are toddlers in a new world, just learning to read and the limits of our knowledge are reflected by our vulnerability.
Certain viruses are capable of hijacking our DNA. In fact, it is such a common occurrence, that a small portion of every person’s DNA is comprised of bits of viral code. We carry with us a history book of our ancestor’s brushes with viruses. The human genome is replete with endogenous retroviruses (HERVs, also known as retrotransposons) that have entered the human germline at various times in the evolutionary past and now occupy 8.3% of our genome.
The HIV virus is perhaps best known for exploiting this mechanism, commandeering our DNA, from where it then orchestrates its attacks. It’s one of the reasons HIV has been so difficult to combat. This is a typical trait of the family of viruses known as retroviruses.
What’s the main difference between these viruses and your standard-issue, run-of-the-mill virus? Two key processes that differentiate retroviruses from standard viruses are reverse transcription and genome integration. Remember we learned earlier that transcription is simply another name in cell biology for ‘making’, so reverse transcription simply means reverse or backward making. Genome integration refers to the ability of these viruses to invade and commander our bodies’ DNA via their RNA, incorporating their genetic material into ours.
Without becoming too technical, retroviruses are a type of virus in the viral family called Retroviridae. They use RNA as their genetic material and are named after a special enzyme that’s a vital part of their life cycle, namely reverse transcriptase. Simply put, this enzyme allows retrovirus RNA access to the nucleus of our cells.
You might wonder why we’re headed down this route, as coronaviruses arent classified as retroviruses, but rather RNA viruses. RNA viruses typically invade a cell and conduct their business in the cytoplasm, where they replicate without accessing our DNA. So why the retrovirus thing? Read on, all will be revealed.
Retroviruses are capable of insane amounts of cellular and genetic engineering, processes so intricate and delicate that you cannot but be left in awe at their complexity and ingenuity. Their ingenious design is not apparent until you understand the complex engineering they can undertake to hijack our cells and reprogram our DNA for their own use. For science, these viruses pose a massive headache and it can take decades to develop mechanisms to combat them.
An important part of the retroviral war is the virus’s ability to hide within our cells without being “active”. These stowaways are referred to as latent reservoirs. infected individuals appear completely healthy. You can even pass all the tests science can throw at you and the stowaways will remain undetected. Viruses can also employ another trick to evade the body’s defenses, hiding in plain sight where the body’s natural immune system doesn’t look, so-called “immunoprivileged sites”.
Dormancy can last weeks, months, or years, ensuring the virus survives. In some instances, as with the Ebola virus, and EVD, individuals who test negative for the virus or who are asymptomatic, are in fact contaminated with latent reservoirs of the Ebola virus and can act as vectors for new outbreaks. Coronaviruses are capable of this little trick as well. For instance, in a study, infected men were found to have traces of the SARS-CoV2 virus in their semen, two to three days after recovery. Semen is the perfect hiding place for a virus and it’s one of the places Ebola chooses.
The testes, along with the eyes, placenta, fetus, and central nervous system, are considered to be “immunoprivileged sites”, which means they are protected from severe inflammation associated with an immune response. This is probably an evolutionary adaptation that protects vital structures. Immune cells are prevented from interacting with cells in the testes and the brain by means of blood-tissue barriers(BTB).
These “immunoprivileged sites” are, in effect, safe zones where viruses may be protected from the host’s immune response, if, and only if, the viruses are able to penetrate the BTB. We know SARS.CoV2 is capable of penetrating these barriers, but don’t as yet understand how it achieves this. This is evidenced by infected cells in the central nervous system. You can read a more detailed explanation of the impact of coronavirus on the brain here.
Let’s examine the mechanism viruses use to pull off their stowaway act, as this involves, amongst other tricks, reverse transcription and this, as we’ll discuss later, may have relevance to the mRNA vaccines. Then we can examine the real reason we’re here, data released in a preprint from Harvard and MIT, entitled SARS-CoV-2 RNA reverse-transcribed and integrated into the human genome.
The viral magic trick called reverse transcription
Sciencemag first published a reference to the study above in December of 2020 in an article entitled “The coronavirus may sometimes slip its genetic material into human chromosomes — but what does that mean?”. Perhaps the best way to understand how this process works is to examine HIV, one of the most studied and best understood retroviruses on the planet. I also chose HIV as it is not subject to the flurry of conflicting information that surrounds the coronavirus.
You can skip over this, but understanding the processes these viruses use is key to understanding emerging and existing questions relating to mRNA technology.
HIV is called a retrovirus because it works in a back-to-front way. Unlike other viruses, retroviruses store their genetic information using RNA instead of DNA, meaning they need to ‘find’ DNA when they enter a human cell in order to make new copies of themselves. To achieve this, they need to access the nucleus of the cell to get at the DNA it contains. To make this easier to understand we need to examine the structure of HIV to understand what happens. Here’s a graphic to help you visualize how this works.
- HIV specifically targets CD4 cells, the body’s principal defenders against infection, using them to make copies of the virus.
Inside the virus envelope is a layer called the matrix. The core of the virus, or nucleus, is held in the capsid, a cone-shaped structure in the center of the virion. The capsid contains two enzymes essential for HIV replication, the reverse transcriptase and integrase molecules. It also contains two strands of RNA — which hold HIV’s genetic material. HIV’s RNA is made up of nine genes that contain all the instructions to make new viruses.
I’m going to skip over the virus’s attachment and fusing to the cell and focus on what happens after attachment. You can find a more detailed explanation of the HIV life cycle here.
Reverse transcription and Integration
When HIV RNA enters the cell it must be `reverse transcribed` into proviral DNA before it can be integrated into the DNA of the host cell. HIV uses its reverse transcriptase enzyme to convert RNA into proviral DNA inside the cell.
After HIV RNA is converted into DNA, HIV’s integrase enzyme attaches itself to the end of the proviral DNA strands and it is passed through the wall of the cell nucleus. Once the proviral DNA enters the cell nucleus, it binds to the host DNA and then the HIV DNA strand is inserted into the host cell DNA.
After the proviral DNA is integrated into the DNA of the host cell, HIV remains dormant within the cellular DNA. This stage is called latency and the cell is described as ‘latently infected’. It can be difficult to detect these latently infected cells even when using the most sensitive tests.
Transcription and Translation, the final phase
The cell will now produce HIV RNA (remember, DNA produces RNA) if it receives a signal to become active. Our CD4 cells become activated if they encounter an infectious agent. When the cell becomes active, HIV uses the host enzyme RNA polymerase to make messenger RNA. This messenger RNA provides the instructions for making new viral proteins in long chains.
The long chains of HIV proteins are cut into smaller chains by HIV’s protease enzyme and are assembled into a new copy of the virus inside the cytoplasm of the infected cell. The new copy of the virus then exits its host and sets off in search of another CD4 cell to infect.
Is the SARS-CoV2 virus capable of accessing the nucleus of an infected cell?
To answer this, let’s start by examining existing literature for older coronaviruses, notably SARS and MERS. What does the scientific literature say about the ability of these viruses to access our DNA?
The problem we immediately encounter here is the scarcity of research. A lot of the outbreaks for these viruses were small, affecting sample sizes, geographical locations posed challenges in terms of collecting reliable data, and the duration of often isolated and contained outbreaks was brief. Unlike Covid, there was no widespread testing of populations, so even something as simple as suggested mortality rates are skewed for these viruses, as scientists were unable to account for asymptomatic and mild infections in the broader populations.
Now would be the perfect time to underscore the rationale for widespread testing. We can not truly assess the impact of a virus on a population unless we can develop a cohesive data set for a large majority of the group. Say you‘ve’ an island of a hundred thousand people, 1000 are hospitalized and 100 die. Can you claim a ten percent mortality rate for the virus? Absolutely not. Can you ascertain if asymptomatic carriers are transmitting the virus or how long they act as reservoirs? Absolutely not.
While you can argue that a percentage of this data may be compromised as a result of human error, it remains essential. Testing, as widespread as possible, is critical to forming a proper understanding of any virus and highlighting areas of concern. It’s how investigative research has arrived at the report below. Discrepancies are showing up in PCR tests that cannot be explained away with historical research.
The Preprint
When you have eliminated the impossible, whatever remains, however improbable, must be the truth.
Sir Arthur Conan Doyle’s Sherlock Holmes
Sir Arthur Conan Doyle’s fictitious crime solver, Sherlock Holmes would have felt very much at home in a modern virology setting but may have frowned on the profession’s proclivity for forcing data to conform to accepted models, rather than examining alternate solutions, however improbable. Researchers at MIT and Harvard have uncovered evidence of segments of SARS-CoV2’s genetic material mixed in with ours. They’ve come up with a hypothesis to explain these bits of viral code, backed by in vitro experiments.
You can access the preprint in the NIH National Library of Medicine, and I have referenced large portions of it below. The paper, “SARS-CoV-2 RNA reverse-transcribed and integrated into the human genome” is already contentious, simply by its title alone. It’s the scientific version of covid research clickbait and the question we need to ask is does it hold up under scrutiny? Below is the paper’s abstract and I have highlighted portions in bold.
Prolonged SARS-CoV-2 RNA shedding and recurrence of PCR-positive tests have been widely reported in patients after recovery, yet these patients most commonly are non-infectious. Here we investigated the possibility that SARS-CoV-2 RNAs can be reverse-transcribed and integrated into the human genome and that transcription of the integrated sequences might account for PCR-positive tests. In support of this hypothesis, we found chimeric transcripts consisting of viral fused to cellular sequences in published data sets of SARS-CoV-2 infected cultured cells and primary cells of patients, consistent with the transcription of viral sequences integrated into the genome. To experimentally corroborate the possibility of viral retro-integration, we describe evidence that SARS-CoV-2 RNAs can be reverse transcribed in human cells by reverse transcriptase (RT) from LINE-1 elements or by HIV-1 RT, and that these DNA sequences can be integrated into the cell genome and subsequently be transcribed. Human endogenous LINE-1 expression was induced upon SARS-CoV-2 infection or by cytokine exposure in cultured cells, suggesting a molecular mechanism for SARS-CoV-2 retro-integration in patients. This novel feature of SARS-CoV-2 infection may explain why patients can continue to produce viral RNA after recovery and suggests a new aspect of RNA virus replication.
To test whether SARS-CoV-2’s RNA genome could integrate into the DNA of our chromosomes, the researchers added the gene for reverse transcriptase (RT), an enzyme that converts RNA into DNA, to human cells and cultured the engineered cells with SARS-CoV-2. In one experiment, the researchers used an RT gene from HIV. They also provided RT using human DNA sequences known as LINE-1 elements, which are remnants of ancient retroviral infections and make up about 17% of the human genome. Cells making either form of the enzyme led to some chunks of SARS-CoV-2 RNA being converted to DNA and integrated into human chromosomes.
This was consistent with the findings of fragmented viral material from the PCQR tests in the general population.
You can begin to see why this paper and research could be viewed as contentious and why it’s been met with resistance. It not only challenges our current understanding of RNA viruses, suggesting the viruses may possess a broader skillset than previously imagined, it also potentially raises new questions relating to the use of mRNA vaccines. If the vaccine mRNA is modeled on a portion of the virus, and the virus is capable, under certain circumstances of reverse transcription, what then of claims by mRNA vaccines that their products cannot contaminate our DNA?
It’s important at this point, to explain that mRNA vaccines don’t reproduce the entire virus in your cytoplasm, they merely create a copy of the spike protein attached to the virus which helps it bind with our own cells. Reproducing a portion of the virus minimizes risk and allows our body the opportunity to mount an early defense against the spike protein when we encounter the SARS-CoV2 virus in the wild. Of equal importance is the length of time for which the vaccine RNA stays viable in the cytoplasm, and we’ll examine this issue towards the end of the article.
What prompted this research?
What prompted these researchers to investigate whether viral RNA could become hardwired into our genomic DNA? Their motive had nothing to do with mRNA vaccines. They were simply puzzled by the growing number of people who were testing positive for COVID-19 by PCR long after the infection was gone. It was known that these people were not reinfected, so where was the viral genetic material the PCQR tests were identifying coming from?
The authors sought to answer how a PCR test is able to detect segments of viral RNA when the virus is presumably no longer present in a person’s body. They hypothesized that somehow segments of the viral RNA were being copied into DNA and then integrated permanently into the DNA of somatic cells. This would allow these cells to continuously churn out pieces of viral RNA that would be detected in a PCR test, even though no active infection existed.
Through their experiments, they did not find full-length viral RNA integrated into genomic DNA; rather, they found smaller segments of the viral DNA, mostly representing the nucleocapsid (N) protein of the virus, although other viral segments were found integrated into human DNA at a lower frequency. It is important to note that the authors emphasize their results don’t imply that SARS-CoV-2 establishes permanent genetic residence in human cells to keep pumping out new copies, as HIV does.
How has the scientific community reacted?
“This is a very interesting molecular analysis and speculation with supportive data provided. I do not think it is a complete story to be certain … but as is, I like it and my guess is it will be right.” — Robert Galeo, Head of the Institute of Human Virology
“Impressive and unexpected. Because it is all pieces of the coronaviral genome, it can’t lead to infectious RNA or DNA and therefore it is probably biologically a dead end. It is also not clear if, in people, the cells that harbor the reverse transcripts stay around for a long time or they die. The work raises a lot of interesting questions.” — David Baltimore, a virologist at the California Institute of Technology who won the Nobel Prize for his role in discovering RT
“LINE-1 elements in the human genome rarely are active. It is not clear what the activity would be in different primary cell types that are infected by SARS-CoV-2.” — Zandrea Ambrose, a retrovirologist at the University of Pittsburgh
“I’m not yet convinced but it’s believable, solid evidence shows that LINE-1 RT can allow viral material to integrate in people. The evidence of SARS-CoV-2 sequences in people should be more solid, and the in vitro experiments conducted by Jaenisch’s team lack controls I would have liked to have seen. All in all, I doubt that the phenomenon has much biological relevance, despite the authors’ speculation.” — John Coffin, Retrovirologist at Tufts University
What has the paper established
1) Segments of SARS-CoV-2 Viral RNA can become integrated into human genomic DNA.
2) This newly acquired viral sequence is not silent, meaning that these genetically modified regions of genomic DNA may be transcriptionally active (DNA is being converted back into RNA). Note the paper does not confirm this, merely indicates it, their FISH data is not conclusive and more study is required.
3) Segments of SARS-CoV-2 viral RNA retro-integrated into human genomic DNA in cell culture. This retro-integration into genomic DNA of COVID-19 patients is also implied indirectly from the detection of chimeric RNA transcripts in cells derived from COVID-19 patients. Although their RNAseq data suggest that genomic alteration is taking place in COVID-19 patients, the point needs to be proven conclusively. This is a gap that needs to be closed in the research. The in vitro data in human cell lines, however, is air-tight.
4) This viral retro-integration of RNA into DNA can be induced by endogenous LINE-1 retrotransposons, which produce an active reverse transcriptase (RT) that converts RNA into DNA. (All humans have multiple copies of LINE-1 retrotransposons residing in their genome.). The frequency of retro-integration of viral RNA into DNA is positively correlated with LINE-1 expression levels in the cell.
5) These LINE-1 retrotransposons can be activated by viral infection with SARS-CoV-2, or cytokine exposure to cells, and this increases the probability of retro-integration.
What questions can we now ask?
The author of this paper is well respected and considered brilliant by his peers. There can be no doubt about the authenticity of the research and although the paper has not yet been subjected to peer review, another consequence of the pandemic, it certainly will be. It is our hope that the results from the research act to spur on further research to eliminate or conclusively show the validity of the suggested mechanisms, both in -vivo and in-vitro.
It’s well known that in-vivo results don’t always translate when the experiment is transferred to a living host, therefore it’s essential we continue the research to its logical conclusion. The paper raises a number of issues, possibilities that we don’t as yet have conclusive answers to. The mere fact we now have to ask these questions would suggest caution moving forward until we have conclusively addressed potential concerns.
1. Can RNA from an RNA virus, SARS-CoV2, reach our DNA?
It would almost certainly seem so. Whether in one piece or in genetics bits, the virus appears to be finding its way into our DNA. PCR tests are finding the viral genetic material when they shouldn’t. If the mechanism the paper describes is responsible, that is cause for concern. There may prove to be other mechanisms involved we don’t as yet understand, perhaps involving immunoprivileged sites. More research is required.
2. If viral RNA can find its way into our DNA, can the same hold true for synthetic RNA?
It is a possibility that we cannot conclusively rule out, particularly given the fact that synthetic RNA has been engineered to be more resilient and produce more proteins than its less chemically stable natural version. This makes the cell more alert to the presence of synthetic RNA and offers the cell more time to address the foreign body chemically. In other words, the likelihood of whatever processes the natural RNA is subjected to being expressed on the synthetic version, increases exponentially.
3. Can I infect anyone with this genetic material?
The obvious answer to this is no. This is not the same way in which the HIV virus we learned about earlier operates. These are fragments of RNA, so think of it like a computer program. If you cut the program into sections, those individual pieces may or may not be able to run on their own, but they cannot perform the original function of the program. The paper does not suggest you would become infectious to others.
The statement above does not mean that you would be unable to transmit these segments to other people, simply that the recipient won’t be able to develop covid from the fragments.
4. Do I need to be worried about this?
Absolutely not. This paper simply explores and deepens our understanding of viruses and reminds us that we are still learning about many aspects of a virus’s life cycle. Viruses are as unique and gifted as we are and each possesses its own toolbox of tricks to ensure its survival. Remember as you sit and read this, an 8th of your body is made of bits of viral genetic code. We’ve done just fine up to now as a species co-existing with viruses and there may very well be a selective advantage to us as a species to incorporate bits of viral genetic material into our own genome. We are still learning and as technology advances, so does our understanding of this infinitely complex system.
5. So where does this leave mRNA vaccines?
mRNA covid vaccines are proving in the short term to be safer and less likely to elicit allergic responses than the more traditional covid vaccines. They also appear efficacious against new strains and can be reverse engineered to address emerging strains far more rapidly than conventional vaccines. The technology is fantastic and holds huge promise for the future of medicine. Do we know what the long-term consequences, if any, will be to us from the use of the mRNA vaccine? No. That’s the honest answer.
It’s too early into the life cycle of this technology to know for sure and we lack detailed long-term evaluations of the impacts on our bodies. The urgency of the pandemic has robbed us of the opportunity to subject these vaccines to rigorous long-term scrutiny (all the covid vaccines, not merely the mRNA vaccines) but let’s not forget, that without the pandemic, we would not have made this leap in technology, perhaps not for another five or six years, perhaps longer.
So in answer to the question, is there any chance these vaccines could have their RNA incorporated into our DNA, the answer, for now, would have to be this.
We cannot emphatically rule out the possibility and nature says ‘never say never’. It’s one of the reasons we need to proceed with as much caution as possible and Medika strongly supports an individual’s right to choice in the matter of vaccination. Educate yourself and then choose, but understand that in terms of risk, if you are in an at-risk category for covid, the mRNA and other vaccines are a no-brainer. Get vaccinated.
Compare the risk of death with an almost negligible, unquantified possibility of genetic absorption that may, or may not be deleterious to your health. Then roll up that sleeve and thank your nurse.
