What is the Scientific Foundation of mRNA Technology?

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What is the Scientific Foundation of mRNA Technology?

This year’s Nobel Prize in Physiology or Medicine has been awarded for the crucial mRNA base modification technology used in the development of COVID-19 mRNA vaccines.

The buzz around awarding the Nobel Prize for mRNA technology had been growing since 2021, but the highest acclaim didn’t materialize during that year.

What is the Scientific Foundation of mRNA Technology?

It was an unexpected turn of events in the same year that allowed us to quickly witness a surge in high-quality analytical articles following the awarding of the Nobel Prize to mRNA technology. This article was originally written in 2021, prior to the Nobel Prize announcement, and has been slightly updated to reflect the developments over the past two years.

To be precise, this Nobel Prize is attributed to the mRNA modification technology, which is a vital component of mRNA vaccines today.

However, both mRNA vaccines and the broader mRNA technology rely on several scientific foundations.

Since the emergence of misinformation about mRNA vaccines altering genes or claims that the inventors of mRNA vaccines warned against their own technology, it’s essential to review the scientific underpinnings of mRNA vaccines to debunk these unfounded notions.

The Theoretical Foundation of mRNA Technology

The foundation of mRNA vaccines rests on the concept of introducing mRNA to express a gene artificially.

This concept is based on our understanding of the central dogma of genetics, which describes the flow of genetic information. In the context of the human body, genetic information resides in DNA, such as the genetic code for collagen in our skin.

The structural information for collagen is encoded in DNA, but DNA does not directly translate into proteins. Instead, it goes through an intermediate step involving RNA.

Among the various types of RNA, mRNA carries the genetic information from DNA and serves as a template for protein synthesis. In essence, mRNA acts as the messenger while other types of RNA (tRNA, rRNA) are responsible for the actual protein production – think of mRNA as the courier of information while others are the workers.

With the central dogma of genetics in mind, consider the possibility of introducing DNA or RNA to express a protein. For instance, some medical aesthetics advertisements tout the injection of collagen and how it can enhance one’s appearance. If we apply the central dogma, we can introduce DNA and RNA carrying the collagen gene into cells and allow the cells to use these introduced genes as templates to produce collagen. This is akin to teaching someone to fish rather than simply giving them a fish.

The concept of using mRNA to express genes is the foundation of mRNA vaccines. This idea has significant merit for a couple of reasons. Firstly, it is theoretically feasible based on genetic principles, and secondly, there are advantages to using mRNA to express genes in certain scenarios.

Using DNA as the carrier for gene expression in the human body can be quite complex. Striking a balance between long-term and short-term gene expression is often challenging. In gene therapy, the ideal scenario is to permanently fix the disease-causing gene to provide a one-time, lifelong solution. However, the reality is much more intricate. Contrary to some misconceptions, consuming genetically modified food, for example, doesn’t transform a person into a genetically modified organism.

The human body doesn’t directly absorb DNA fragments; they must be delivered into the body’s cells via a carrier, often using viral vectors. This raises safety concerns related to the carrier itself. In summary, the process is exceptionally complex, and sometimes, the introduction of foreign genes may result in diminishing expression over time.

Additionally, certain carriers may lead to long-term problems, such as incorrect integration into the human genome, which can be extremely dangerous and, in extreme cases, lead to cellular transformation and cancer.

In contrast, mRNA operates in the cell’s cytoplasm, distinct from DNA, which resides in the cell nucleus. This distinction means that mRNA does not pose any risk to the human genome. Furthermore, the route taken by mRNA to enter cells is shorter, and mRNA itself is inherently unstable in certain scenarios, mitigating the risk of long-lasting effects.

In summary, introducing foreign genes for expression using mRNA has a theoretical foundation in genetics, is theoretically viable, and has real-world applications in specific contexts.

Challenges and Breakthroughs

While theoretically viable and in demand, making mRNA technology a reality presented its own set of challenges. Scientists struggled with a fundamental issue – the strong immunogenicity of RNA molecules.

This is consistent with the laws of nature: many viruses use RNA as their genetic material, and the immune system has evolved to be highly vigilant against RNA. Although human cells use mRNA to express genes, when faced with free-floating RNA molecules, the immediate response of the human body is to consider them as potential viruses and destroy them. When introducing foreign mRNA into animals or humans, a strong immune response would often break down the mRNA molecules. This not only prevented gene expression but also led to severe side effects due to the intense immune reaction.

It’s important to note that the term “strong immunogenicity” here refers to the stimulation of the innate immune system. Modern mRNA vaccines also exhibit immunogenicity, but they are designed to work in a way that stimulates the innate immune system appropriately, leading to the subsequent activation of the adaptive immune system and the development of a robust immune memory. In contrast, the earlier mRNA approaches failed to progress beyond the innate immune response. In the context of COVID-19 vaccines, this would be akin to receiving a vaccine that causes a high fever but fails to generate any antibodies, as the vaccine is rapidly degraded.

Due to this reason, the application of mRNA technology stagnated for a long time, and many scientists considered it hopeless. This skepticism was not unfounded because the problem mRNA technology needed to address was how to deceive the human immune system, and it wasn’t a simple case of petty thievery – it was more like trying to pull off a grand heist.

The emergence of RNA modification technology was a crucial turning point that made mRNA technology a reality. This RNA modification technology, developed by the two Nobel laureates of 2023, Katalin Karikó and Drew Weissman, received widespread recognition after the success of the mRNA COVID-19 vaccines.

Karikó’s journey was particularly challenging, marked by grant rejections and nearly losing her job. While her story now seems legendary, it’s essential to recognize that her setbacks were closely tied to the inherent difficulties of mRNA technology itself. For instance, when applying for research funding, other scientists had already attempted to use mRNA as a carrier to express genes and deliver drugs, but as mentioned earlier, human cells weren’t cooperating – they were “cutting off heads” of mRNA molecules. Naturally, grant reviewers had to question whether such projects were worthwhile.

Moreover, Karikó, as a scientist, did not merely replicate previous mRNA synthesis and delivery methods, thinking that would lead to success. She recognized the shortcomings of previous approaches and understood that mRNA’s potent immunogenicity needed to be addressed for introducing foreign genes to work. Therefore, her collaboration with Drew Weissman shifted the focus of mRNA delivery technology research toward reducing the immune-stimulating properties of mRNA molecules. In 2005, they discovered that by chemically modifying uridine (U) in mRNA to a pseudo-uridine, the mRNA molecule would no longer provoke a strong immune response from immune cells.

This discovery is what we now know as mRNA modification technology, a technique used by Moderna and BioNTech in their COVID-19 vaccines. In the past, not everyone believed that mRNA modification was necessary. For instance, another German company, CureVac, thought that reducing the number of uridine molecules could solve the problem, and Translate Bio, which was later acquired by Sanofi, optimized mRNA through other structural changes (capping). They all believed that these methods could address the immunogenicity issue of mRNA. However, the widespread success of mRNA vaccines has proven the effectiveness and feasibility of mRNA modification, making it the mainstream approach for mRNA drug delivery.

Apart from overcoming the immunogenicity issue, the success of mRNA technology relies on various other scientific breakthroughs. For example, figuring out how to efficiently deliver mRNA molecules into the human body is crucial. Directly injecting mRNA into the body results in low efficiency, and if the mRNA is not taken up by human cells, it won’t be effective. This is where the breakthrough in lipid nanoparticle encapsulation technology comes into play. It involves using lipid molecules to encapsulate mRNA, forming nano-sized particles. Some vaccine conspiracy theories exploit the term “nanoparticles,” but in reality, it’s just a measure of size.

With mRNA modification and lipid nanoparticle carriers, the development of mRNA vaccines was not without its challenges. Both BioNTech and Moderna initially focused on mRNA technology for drug delivery in other diseases, and they didn’t make significant progress. Even in vaccine development, Moderna’s previous attempt at a broad-spectrum flu vaccine resulted in lower immune responses in humans compared to results obtained in animal models, slowing down progress. The breakthrough with the COVID-19 vaccines is due in part to the specific characteristics of the SARS-CoV-2 virus, recent advancements in vaccine design, and the efforts of recent years.

In Conclusion

It’s evident that scientific breakthroughs like mRNA vaccines or mRNA technology are not the work of one or two individuals, nor are they simple scientific technologies. They are the result of numerous scientific advancements coming together to achieve success.

It’s also important to acknowledge that, in addition to mRNA vaccines, adenovirus vector vaccines, and recombinant protein vaccines for COVID-19 have shown promising efficacy. This reflects the presence of many excellent vaccine technology platforms today, which are the cumulative result of countless incremental technological breakthroughs over the years. Most of these breakthroughs may never feature in discussions about Nobel Prizes and the like, but they make substantial contributions to the entire human society.

What is the Scientific Foundation of mRNA Technology?

References:

https://www.nature.com/articles/nrd.2017.243

https://www.nature.com/articles/d41586-021-02483-w

(source:internet, reference only)

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