Original article (in Croatian) was published on 04/08/2021
A professor from Stanford announced the development of a “superhero DNA vaccine” and caused confusion by calling the mRNA vaccine against Covid-19 genomic.
A haughty professor from Stanford University, Euan Ashley, recently announced the so-called “superhero DNA vaccine” development within just ten years.
Thanks to the rapid development of several types of technologies, these vaccines, according to Ashley, will rewrite or repair bad genes, following the example of the genetic code of “superhumans”. An example are some Olympic athletes, who have unusually elevated hemoglobin levels, which allows them more oxygen in the body and greater endurance. Superhumans include people who do not feel pain and people with the least chance of getting Alzheimer’s and other diseases.
In interviews and reports on this bombastic breakthrough in medicine, mRNA vaccines are also mentioned, i.e., the similarity of DNA superhero vaccines with those in the production of Pfizer or Moderna against Covid. Following this, Faktograf received the following inquiry:
Hello Faktografci! I have one VERY IMPORTANT question for you. The future of the human race literally depends on this. The question is: IS IT POSSIBLE TO ALTER HUMAN DNA WITH COVID MRNA VACCINES? While answering this, please keep in mind the latest news from Stanford University in which scientists announced that they had invented a DNA-modifying vaccine and said that their system was identical to the system used by Pfizer. Please reply, thanks [sic]
The vaccine has not (yet) been invented
To begin with, professor Euan Ashley did not say that he invented the vaccine in question.
“Ashley believes the vaccine could begin testing as early as 2026, and that it could be available for use in 10 to 15 years”, the Daily Mail reported, after talking to him in late June.
The Daily Mail also quotes the following sentence:
“The technology is similar to that used by Pfizer to create its mRNA vaccine against Covid-19”.
mRNA does not alter DNA
It does not state which technologies or “system” it is based on. But before we address that part of the query, it should be noted that the answer to the question of whether mRNA vaccines against Covid-19 alter human DNA, which we have written about many times [1, 2, 3, 4, 5, 6], is still – No. Injected mRNA acts directly on ribosomes, organelles to which DNA issues orders for protein production via mRNA. It does not enter the cell nucleus, where human DNA is located, nor alter it.
Genomic medicine is a discipline that is just entering the scene and uses unique information about the genetics of patients for the purpose of clinical care, it is stated in the Health Desk of the technological non-profit organization Meedan, which gathers public health experts. Gene editing is being investigated for the treatment of rare genetic disorders, and the goal is to change the genetic code of patients through “revision, removal or replacement of a mutated gene”.
“For example, using gene therapy, medical scientists can work to insert a healthy, non-mutated version of a gene to overpower the effect of the mutated gene. They can also work on removing a mutated gene. Examples of diseases that can be treated with this technology are cystic fibrosis, Duchenne muscular dystrophy and hemoglobinopathies. Another potential clinical application of this process would be the treatment of HIV and some types of cancer,” doctor Christine Mutaganzwa, a member of the Health Desk’s team of experts, told Faktograf.
All these treatments are still being investigated. Many of them are still in the earliest stages of scientific examination. They also note that some challenges will have to be overcome before the potential for gene editing can be translated into effective treatment.
“False claims on the internet suggest that mRNA vaccines against COVID-19 may be using genomic medicine to alter our DNA. There is no evidence that mRNA vaccines inject any gene editing technology into the body. Once key immune-fighting instructions are delivered to our immune system, our bodies immediately destroy the mRNA vaccines, leaving no lasting mark on them. Vaccines never enter the nucleus of human cells, where DNA is stored,” says Mutaganzwa.
Technology development
The advancement of several different technologies was a prerequisite for discussing the development of a “vaccine” that could intervene in the genome. From Ashley’s texts, interviews, as well as posts on social media, it is clear that part of his enthusiasm is based on the recent success of the company owned by Nobel laureate Jennifer Doudna, a biochemist from Berkeley, California.
Her team was able to permanently stop the abnormal production of transthyretin protein (TTR) in the liver with gene therapy, in patients whose condition was caused by gene mutations. Until then, the accumulation of TTR and its consequent disease, (familial) amyloidosis, detrimental to the work of the heart and peripheral nervous system, was treated by suppressing the work of problematic genes. The tool was an interfering RNA (siRNA). But siRNA only interfered with mRNA to deliver a message to the ribosome about protein production, which required repeating the process and exposing it to overexposure to drugs such as glucocorticoids and antihistamines. In addition, it did not stop, but only slowed the disease.
Genome editing based therapy, developed by Doudna’s team, “knocked out” the controversial gene, as Ashley writes, with spectacular results:
Among the six patients tested, a 52% decrease in transthyretin protein was observed in the lower dose group (therapies) and a staggering 87% for the higher dose group.
Doudna was awarded the Nobel Prize in Chemistry last year for a discovery related to gene editing with CRISPR-Cas9 technology. As Marko Mocibob, assistant professor at the Faculty of Science (Ideje.hr) explained, Doudna and her colleagues recognized and showed in 2012 that the Cas9 protein can be used to cleave DNA at a specific, targeted place in a living cell and thus initiated tectonic changes in the field of genetic engineering whose scale is yet to be foreseen.
A milestone in at least two common technologies
Ashley did not answer our question, but we consulted with Mocibob about the parallels that are drawn between the mRNA of the vaccine and the announced genetic modification of the vaccine. We have located at least two technologies that connect them. One of them is the decades-long development of a lipid nanoparticle (LNP), which serves as a carrier of the mRNA molecule to cellular plasma and is mentioned in the description of Ashley’s “superhero vaccine” (StudyFinds).
The second is the current speed of genome sequencing.
In his text for The European (where Ashely also refers to an interview for the Daily Mail), he calls the mRNA vaccine against Covid and the hypothetical “superhero” “genomic”, which he explains in more detail in an interview with The Scotsman:
“Genetic sequencing was the core technology in our fight against Covid-19. All the diagnostic tests we have are based at some level on the knowledge of the SARS-CoV-2 genome. Also, all vaccines approved so far are genomic vaccines, based on virus sequences. Sequencing also allows us to track the virus and its evolution to new variants around the world”, he says. He often states that sequencing the first genome took three billion dollars, ten years and involved the work of scientists from ten states, and now this is being done for several hundred dollars.
The wrong term
From this, it is clear that it would be impossible to create this vaccine without (fast) genome sequencing, and not because it is the same mechanism of gene modification therapy. Mocibob tells us that he finds Ashley’s use of the term “genomic vaccine” in this context strange, for several reasons.
“Such a term could be used conditionally for vaccines that change the genome, but even then the use of the term ‘genomic vaccine’ would be creative and not entirely correct, because we cannot ‘vaccinate’ the genome. But let us put aside certain linguistic freedom. In mRNA-based vaccines (BioNTech/Pfizer, NIH/Moderna), we cannot talk about ‘genomic vaccines’ because they do not change the genome, either temporarily or permanently, or contain the genome – but only one gene for the S-protein. I wouldn’t even call them genetic vaccines, because it doesn’t say much about them and the mechanism of its action, and because I don’t see the need for excessive use of the term gene/genetic/genomic, which often has a negative connotation, such as ‘nuclear’ or ‘synthetic’, explains Mocibob, emphasizing that Ashley, after all, is talking primarily about gene therapy, not vaccination.
As for lipid nanoparticles, Mocibob states that they can and are used in gene therapy as carriers (vectors) for the introduction of RNA, DNA and CRISPR/Cas9 components into cells for the purpose of genome editing, i.e., genetic engineering of somatic cells.
A ship to cruise the microcosmos
The mRNA molecules, just like those used to generate genes – sgRNA, or RNA guide – are so large and sensitive that they must have lipid armor or a “spaceship” to travel through the microcosm of the human body, loaded with various patrols. Otherwise, the mRNA would not survive the immune cells, the enzymes that would break it down, or the passage through the cell membrane to the ribosome.
“Scientists used a delivery method using tiny fat globules called lipid nanoparticles. They can help safely transport mRNA into the body, without degrading mRNA. Covid-19 mRNA vaccines use lipid nanoparticles to deliver vaccine formulas to target cells. It is likely that any future ‘superhero’ vaccine produced using genomic medicine will also use a fat-enveloped mRNA delivery method. For now, this is a theoretical idea”, our interlocutors at the Health Desk state.
That’s why the lipid shuttle is also mentioned in the description of Ashley’s superhero vaccine.
To ensure that gene regulators reach the right organs safely and are not destroyed by the body’s immune system, they are transmitted by targeting inactivated viruses or packaged in lipids (fat particles) sent to the exact destination. The lipid technique is used by Pfizer-BioNTech to package its Covid-19 vaccine.
From the fat sphere to the magic ball
Chemical & Engineering News magazine published a long history of lipid nanoparticles (shown HERE) on the market launch of the Covid-19 mRNA vaccine. It is 60 to 100 nanometers in diameter, which is one hundredth the size of the average human cell. It is also called the unsung hero of mRNA technology, and then Ashley promises gene therapy, although it received its first approval in 2018 as a carrier of the siRNA molecule.
The story began in the 1980s when scientists experimented with delivering dangerous drugs to tumor cells via liposomes – fat spheres. By packaging the drugs in the cavity of the liposomal capsule, an attempt was made to avoid contact between the toxic components of the drug and the rest of the organism. One of the scientists who worked on liposomes was Pieter Cullis, now a professor of molecular biology and biochemistry at the Canadian University of British Columbia.
Appetites have grown over time to the idea of introducing mRNA into cells, i.e., targeted therapies by delivering orders to cellular factories to create the desired protein. But the delivery of mRNA was far more complicated than the delivery of drugs to a tumor cell because it is a much larger molecule.
Since the 1980s, numerous lipid nanoparticles have been constructed and tested in this way. But in addition to making it difficult to get the ingredients, for decades, these nanoparticles failed when tested on animals or humans. Either the components would be toxic, or the delivery of mRNA, after success in cell cultures in the petri dish, would fail when carried into the cell of a living organism.
Four ingredients
The lipid nanoparticle has only four ingredients. One is cholesterol, and the remaining three are abbreviated in the Pfizer vaccine declaration for complicated chemical compounds, which we have already mentioned in the context of the composition of the vaccine: ALC-0315 and ALC-0159 and DSPC.
ALC-0315 stands for Ionizable Cationic Lipid, which was synthesized by Pieter Cullis in the late 1990s. As he explained, permanently positively charged lipids are toxic and tear cell membranes. Cullis was able to synthesize a positively charged lipid in an acidic environment, which is neutral when found in the blood. The positive charges of this lipid bind to the negatively charged mRNA backbone and release it only when they are in an acidic environment. Such an environment is found in the endosome, a structure on the cell membrane, which is a kind of reception and distribution center for the introduction of substances into the cell. Only when the cell “eats” the nanoparticle, together with the mRNA, in this way – the lipid changes its charge, the nanoparticle changes shape and the mRNA is released. Nanoparticle residues are broken down and excreted from the body.
But even after the synthesis of this lipid, the particle was still toxic for years. This was explained by the third ingredient: pegylated lipid. It is abbreviated in the Pfizer vaccine as ALC-0159, a lipid that, among other things, helps stabilize the particle and protects it from the immune system. ALC-0159 contains polyethylene glycol (PEG), an ingredient used in toothpaste, medications, shampoos and other products such as a thickener, moisture carrier and solvent. It can cause a severe allergic reaction in some people. For years, its problem was that it protects against external influences “too well”, that is, it did not allow degradation at the necessary time, as well as the release of mRNA.
There is also a phospholipid (DSPC), which in addition to cholesterol is responsible for the structure of the particle.
The development of the lipid nanoparticle has achieved efficiency in entering the organism’s cell, which makes it safe to use. And because of the conditional approval for mRNA vaccines, the LNP ingredient synthesis industry has also flourished.
How far are we from “superhero vaccines”?
Genetic engineering existed before CRISPR Cas9, but it was not as effective. Combined with really fast genome sequencing, by programming CRISPR-Cas9 molecules and successful synthesis of its carriers, it is not difficult to imagine replacing “broken” genes with the right ones. However, some do not fully believe in Ashley’s deadlines (IFLScience). Mocibob considers the claims mentioned in the articles from the Daily Mail and The European to be very speculative and not feasible
“The problem with any gene therapy is to achieve a high degree of gene replacement in a large number or most of the cells of the affected tissue or organ, and that will not change so quickly. This means that gene therapy is far from a ‘universal solution’ even for diseases in which the genetic component is the main component of the disease. For example, if you have a defective gene that causes a cardiac problem, that defective gene is present in 100% of heart cells. In this case, for gene therapy to work, it should be sufficient to replace the defective gene in a low percentage of cells. This is unlikely to be met and is applicable to many diseases”, says Mocibob.
An ideal target
But the problems don’t stop there. Ashley himself states that the disease that Doudna solved with gene therapy is an ideal target, i.e., the “lowest hanging fruit”. Mocibob points out that when paralleling Alzheimer’s disease and transthyretin amyloidosis, wrong parallels are drawn.
“Although both diseases belong to amyloidosis, which means that they are a consequence or marked by pathological accumulations of amyloid, these two diseases are unrelated. Alzheimer’s is characterized by the accumulation of amyloid beta (Aβ) plaques, which form in the brain, in brain tissue. In other words – they would have to apply the ‘vaccine’ or gene therapy directly to the brain, due to the blood-brain barrier. “In the article published in NEJM, the target organ for genome editing is the liver, which is much more ‘accessible’ for therapeutic intervention”, he states.
He also notes that the introduction or alteration of genes to the genes of top athletes or Olympians will not necessarily turn “ordinary people” into superhumans. Although top athletes certainly have some genetic predispositions, years of hard work and training are responsible for their results. According to Mocibob, the approach of gene modification to “supergenes” is dubious in terms of therapeutic strategy.
“The introduction of such genes into a diseased heart, lung or muscle does not guarantee transformation into a ‘superheart’, as it is very likely that these genes had to be present from the beginning, perhaps even from the fetal period to enable development into a ‘superorgan’ or into an organ that has above-average characteristics, accompanied with training and through appropriate stimulation by physical activity”, concludes Mocibob.
To conclude this topic, we can use the words of doctor Mutaganzwe: “The latest technologies in molecular biology, modern gene editing enzymes, have given scientists the ability to manipulate the genome, thus allowing biological research into potentially life-saving treatments. These technologies are not used in the development or production of COVID-19 vaccines”.