by Francesca Tomasi
figures by Jovana Andrejevic 

Right now, the world is eagerly awaiting clinical trial data for two candidate COVID-19 vaccines known as mRNA vaccines. mRNA stands for “messenger RNA,” referring to the molecule that the vaccine delivers to our bodies. Once the vaccine enters our cells, the mRNA tells them exactly how to build a piece of the SARS-CoV-2 virus. The vaccine itself cannot make us sick. But building this piece of virus and exposing our bodies to it allows our immune system to mount a response, thereby training our bodies to fight the real deal if we get infected by SARS-CoV-2.

But how do our cells actually do that? What is mRNA, and how does an mRNA vaccine tell our bodies what to make, and how to make it? Understanding how this works boils down to the fact that every single cell on Earth is a tiny, microscopic factory.

Cells are nature’s factories

Whether it’s a computer, a tablet, or a phone, the device on which you are reading this article was built in a factory. The factory works nonstop, whirring with machines that build and process items according to very specific instructions (Figure 1, left). Cells – the smallest functional units of any living organism – are tiny factories that build biological products, or molecules (Figure 1, right). 

Cells also need explicit instructions for building things: these are called genomes, the complete set of genetic material – DNA – stored within a cell. The human genome, for instance, contains tens of thousands of genes, each of which provides exact specifications for a biological product. While DNA is analogous to letters of the alphabet, a gene is the word that forms from stringing together these letters in a specific way. Together, genes compose the sentences that make up the genome’s instruction manual.

Cells contain machines that build proteins

In an electronics factory, a written instruction manual is not enough to tell a machine how to actually build a product. Written descriptions are turned into blueprints for manufacturing: a robot can directly interact with a blueprint to piece together an object. The same is true for living cells: our DNA instruction manual is turned into a blueprint called messenger RNA, or mRNA. The biological products made from these blueprints are called proteins, and they perform the structural, functional, and regulatory activities required to keep an organism alive. 

Just as complex electronics are built from a set of raw materials, the millions of proteins found in nature are made by piecing together different combinations of a set of building blocks known as amino acids. A protein forms when amino acids are linked together and fold into a specific shape based on their chemical properties. mRNA tells you which amino acid goes where. The biological machine that reads mRNA and pieces together amino acids is called a ribosome, and every cell has thousands (bacteria) to millions (some mammalian cells) of them. 

Ribosomes are universal, and essential for life 

Ribosomes churn out every single protein a cell needs to survive and are incredibly complicated machines. In fact, it took decades of research to figure out exactly how they work: the Nobel Prize in Chemistry was awarded in 2009 to three scientists (Venki Ramakrishnan, Thomas Steitz, and Ada Yonath) for their work on understanding the structure and function of the ribosome.

While we now know that ribosomes look slightly different in different organisms, all ribosomes perform a universal set of critical functions for building proteins. They all move along an mRNA blueprint, take an amino acid, and attach it to a growing chain of amino acids that ultimately becomes a protein. How does this work?

Ribosomes collect and link amino acids together

mRNA is a chain of chemicals called nucleotides, which a ribosome “reads” in groups of three: every set of 3 nucleotides (called a codon) contains the blueprint for a specific amino acid. A ribosome doing its job looks a bit like a Pacman making its way along a string of cookies: for every set of 3 mRNA nucleotides, the ribosome collects the corresponding amino acid and attaches it to a growing string of amino acids (Figure 2).

Ribosomes have essential support workers called transfer RNA (tRNA) that bring them the right amino acid each step of the way: when Pacman opens its mouth over an mRNA codon, tRNA enters the mouth, carrying the right amino acid with it (Figure 2).   

As the ribosome collects a new amino acid, it attaches this amino acid to the chain of amino acids it has just pieced together by performing a chemical reaction. As it moves farther along the mRNA, this chain grows (Figure 2). Once a ribosome has finished reading a blueprint, it releases a protein into the cell. That ribosome is then ready to repeat the process.

Viruses use our ribosomes to make their own proteins

The universal use of DNA, mRNA, and amino acids is what make it possible for viruses to exist. This is because a virus on its own is not a living organism. Instead, it is a blob of fats and proteins that enters the cells of other organisms and uses their factories to replicate. A virus also carries with it an instruction manual or blueprint, to tell a cell exactly how to build more of it.

The parts of a virus that our immune system sees (antigens) are typically whatever encapsulate the rest of the fats, proteins, and genetic material inside. In the case of SARS-CoV-2, one important surface molecule is called the spike protein, named for the fact that it physically juts out from the rest of the virus. The spike protein plays an essential role in SARS-CoV-2 binding to a host cell. It is considered a very important antigen that can be exploited for vaccine design. 

The idea behind vaccines is that exposing our bodies to some of these antigens mimics the virus enough for our bodies to mount an immune response, but without making us sick from the actual pathogen. Conventional vaccines have achieved this either by using inactivated viruses or engineering other harmless viruses to encode some of a pathogenic virus’s antigens in their blueprint.

Our understanding of ribosomes and how they build proteins (Figure 2) has enabled us to pursue an emerging vaccine technology that would bypass the need for producing large quantities of virus: mRNA vaccines. 

mRNA vaccines: a new way to give our cells a leg up against viruses?

Consider the spike protein in SARS-CoV-2: researchers can make mRNA that encodes the blueprint for this protein, and have developed ways to deliver this mRNA to our cells. Once it enters our cells, our ribosomes read it as just another blueprint in the factory, and they make the spike protein. Once spike proteins are produced, they are stuck on the surface of our cells to be recognized by our immune system. Engineering the right mRNA is our way of handing our cells the blueprints they need to protect themselves–and therefore our bodies–from a virus.

An mRNA vaccine adds a new level of simplicity to vaccine design because it bypasses the need to engineer viruses and requires less expensive materials to produce. Engineering entire viruses requires large-scale use of mammalian cell cultures and/or chicken eggs, while producing mRNA in large quantities can be done quickly and efficiently in a test tube. This means that, in theory, an mRNA vaccine could be made on a mass scale using fewer resources, and in less time. 

Our ribosomes know what to do, but we still have a lot to learn

A handful of companies are developing mRNA vaccines in the fight against COVID-19. At the time of writing this article, two vaccines have made it through preclinical trials and early-phase safety trials, and are now undergoing large-scale efficacy studies in tens of thousands of people. Several more are in early investigational studies.

We’ve never had an approved mRNA vaccine before, and because of this we still have a lot to learn. How do mRNA vaccines compare to more traditional technologies? Is the immune response caused by these vaccines strong enough to protect us from disease? How long does this protection last? Is the vaccine safe for pretty much everyone? The goal of efficacy trials is to give an experimental vaccine to thousands of volunteers and see how many become infected compared to participants who received a placebo. In the end, if a vaccine is found to be protective against SARS-CoV-2, drug-makers can seek regulatory approval to administer their vaccine in a given country.

For now, it’s safe to say our ribosomes know what they’re doing. And we’re doing our best to figure it out too.

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Francesca Tomasi is a fourth-year PhD candidate in Dr. Eric Rubin’s lab at the Harvard T. H. Chan School of Public Health, where she studies Mycobacterium tuberculosis ribosomes in the context of antibiotic development.

Jovana Andrejevic is a fifth-year Applied Physics Ph.D. student in the School of Engineering and Applied Sciences at Harvard University. 

Cover Image: “Catching the dance of antibiotics and ribosomes at room temperature” by SLAC National Accelerator Laboratory is licensed under CC BY-NC-SA 2.0

For More Information:

• To learn more about the SARS-CoV-2 spike protein, check out this article. 

• Track COVID-19 vaccines using this NY Times link. 

• Check out this book to learn how the structure of the ribosome was discovered

• Learn more about ribosomes and how they work, see the Khan Academy.