Don't Kill the Messenger:
How mRNA went from a Scientific Breakthrough to Public Debate

You can think of DNA like an online cookbook full of “recipes”, or genes. There are about 20,000 recipes in the cookbook but not all recipes are being cooked at the same time. That is to say, just because a gene exists in the genome, doesn’t necessarily mean that it is getting expressed all of the time. Changes in environment can call for a specific gene to be expressed and suppressed in different contexts. For example, melatonin-related genes are expressed or “turned on” more strongly in the evening to help regulate sleep and suppressed during the day. 

When we think of the central dogma, we think of protein production. But only ~1-2% (~20,000 genes) of the human genome is what we call protein-coding. The majority of your genome is actually made up of non-coding genes.

When a protein-coding gene is “turned on”, it gets transcribed into RNA, which is like printing a copy of a recipe from your online cookbook. Your ribosomes will then translate that RNA and build the corresponding protein, or use the printed copy of your recipe to cook the actual dish. Once the protein is built, the RNA naturally degrades and its components are recycled.

Types of RNA

Not all RNA serves the same purpose. There are multiple subtypes, each named for their role. For simplicity, we will only discuss the “core team” of RNA for protein production: mRNA, rRNA, and tRNA. 

• mRNA (messenger RNA): The copy of a gene that carries instructions from DNA.
  
  

• rRNA (ribosomal RNA): The structural RNA that makes up ribosomes.
  
  

• tRNA (transfer RNA): The adaptor that “reads” mRNA three bases at a time and brings in the corresponding amino acids to build proteins (Figure 2).

A majority of your non-coding genes are those for rRNA and tRNA, as well as others we are not going to discuss. But mRNA is the central player in protein synthesis, providing the direct message that tells the cell which proteins to make.

Structurally, RNA differs from DNA in a few ways:

• Similar to DNA, RNA is made up of a combination of 4 nucleic acids, but instead of thymine, RNA contains uracil (DNA: ATGC, RNA: AUGC).
  
  

• RNA is single-stranded, though some types (like tRNA) fold into shapes.
  
  

• RNA contains a ribose sugar (with one more oxygen atom than DNA’s deoxyribose).

(DNA = deoxyribonucleic acid; RNA = ribonucleic acid)

mRNA is fed through your ribosomes made of rRNA where tRNA reads the mRNA strand, 3 nucleic acids at a time. tRNA then attaches the nucleic-trio-corresponding amino acid to the building protein (Figure 2). mRNA is simply a linear strand of nucleotides that serves as a recipe for protein synthesis. Since the discovery of mRNA’s function, it has been at the center of modern biology and resulted in entire fields of research that revolve around it. 

Why Scientists Study mRNA

For various reasons, studying proteins directly is wildly difficult and expensive. You can read more about this challenge in a previous GGR article. By contrast, mRNA is easier to measure and still tells us which genes are active in a cell at a given moment. Because mRNA reveals what the cell is “doing,” (what recipes are being cooked at a given moment) it has become a powerful tool across biology, from basic research to applied medicine.

Methods like RNA-sequencing have the ability to profile all mRNAs in a sample to study transcriptional activity, scientists can measure mRNA expression in diseased states. You can even track expression patterns during physical processes like embryo development to see which genes drive cell differentiation. In neuroscience, researchers have shown mRNA changes in neurons during learning and memory formation that are associated with Arc mRNA expression. 

From Research to Therapy

mRNA’s simplicity has inspired scientists to design synthetic versions for therapeutic use. If you can provide the recipe, the cell can make the protein. Protein replacement therapies have used this technique to express missing proteins in genetic disorders. Another application, and probably the reason you were curious to read this article, mRNA is studied in immunology. Building on decades of research in synthetic biology, we can use mRNA to design vaccines for things like COVID-19, flu, and cancer. 

A Brief History of Vaccines
The term “vaccine” comes from the Latin term for cow, vacca. The famous story of how vaccines originated comes from an experiment Edward Jenner performed in 1796. After learning that people with cowpox were immune to smallpox, he used material from a milkmaid’s cowpox sore to inoculate a young boy, James. After a short period of side effects, he fully recovered. A few months later, Edward tested James resistance by then inoculating him with material from a smallpox sore. James remained perfectly healthy and is considered the first person vaccinated for smallpox. 

For over 200 years, vaccines have been made using protein-based methods. The piece of protein from a pathogen that your body’s cells will pick up and “present” to your immune system is called an antigen. Antigen-presentation to your immune system is how your body knows to tailor its defenses and build memory to fend off future attacks with ease. Vaccines attempt to provide a low dose of antigen as a means of priming your immune system without being exposed to the pathogen directly. 

There are vaccines that use a weakened, attenuated, version of the full pathogen, which can give strong and long-lasting immunity but is risky for immunocompromised individuals. Some vaccines use inactivated versions or small pieces of the pathogen, which are much safer but produce weaker immunity and will require booster shots. Which brings us to mRNA…

Why mRNA Vaccines?

While it may sound intuitive to consider mRNA as a possible avenue for designing vaccines, for decades, mRNA vaccines were considered too unstable and inflammatory. Recent breakthroughs (2000 - 2010) have unlocked their use:

• Chemical Modification of mRNA

Injected mRNA would degrade in minutes and cause damaging inflammatory responses. Researchers found that replacing some of the basic building blocks of RNA resolved these issues. This work awarded them the 2023 Nobel Prize in Physiology and Medicine. 

• mRNA Delivery Systems

The mRNA molecule cannot cross cell-membranes on its own. So researchers found a way to package it into lipid nanoparticles that act as a delivery system to get mRNA into your cells efficiently. 

• Sequencing and Bioinformatics Advances

Nowadays, the cost and speed of genome sequencing has become almost trivial. You can get the full genetic sequence of a pathogen within days, increasing the speed at which scientists can design and optimize the mRNA sequence they want to present to your immune system. 

• Antigen Design Strategies

With the ability of structural biology to build these synthetic molecules, researchers are able to incorporate all of these factors into the synthetic design of the molecule. mRNA vaccines allowed direct, fast expression of these engineered antigens without having to produce and purify proteins. (like the spike protein from the coronavirus)

Once stability, delivery system, and sequencing techniques were optimized, mRNA vaccines became the optimal choice for a path forward. 

For diseases that have struggled to have effective specificity in their treatments, designing vaccines with mRNA opens new opportunities for explorations. mRNA vaccines allow a speedy response to an outbreak, accommodate the safety concerns that come with using live or weakened viruses, have incredible flexibility to be designed to your desired sequence, and are easily scalable as they don’t require a host system like cells or cultures to be produced.

Sounds pretty remarkable. So then why are mRNA vaccines growing concern in the eyes of the public?

mRNA Controversy
Despite the groundbreaking science, public perception was shaped by the COVID-19 pandemic. Before 2020, no mRNA vaccine had been approved for human use. The emergency rollout of Pfizer and Moderna vaccines was seen as rushed, raising concerns about safety and long-term effects.

Between a raging virus and what felt like a quick fix solution, the public was rightfully nervous. This anxiety was only fueled by the politicization of the pandemic; the mRNA vaccine became a symbol in debates about freedom, mandates, and misinformation, causing the distrust of scientific institutions. 

Compounding the issue, many people misunderstood what mRNA does. It’s hard to trust something that you don’t fully understand. Some believed it could alter DNA or be used for “tracking”. Due to their invasive nature, conspiracy theories spread much faster than scientific explanations. mRNA went from being a basic biology term to a political buzzword almost overnight. So even though mRNA does not alter DNA, nor does it even enter the area of a cell that contains DNA (the nucleus), the fear was already instilled into the public perception. 

Don’t Kill the Messenger

Unfortunately, the backlash also influenced federal research funding, where grants studying Covid-19 and mRNA vaccines were some of the first to get cut. However, what is most concerning is that they are not only cutting grants mentioning “mRNA vaccine” but all grants with the term “mRNA” have been pulled into question. This overcompensation highlights a deeper problem in the system, which is that the decision-makers controlling research funding often lack a clear understanding of the science itself. And maybe that’s the real issue at hand… the gap in science communication.  

Regardless of personal view on vaccines, it’s worth returning to the basics: 

mRNA is simply a messenger; a linear strand of nucleotides that serves as a recipe for protein synthesis. 

Understanding that simple truth helps strip away the baggage and see mRNA for what it is: one of the most fundamental molecules in biology.