Without mRNA, your genetic code would be nothing more than a string of chemicals, and the proteins it codes for would never get made; in short, your body wouldn’t—couldn’t—exist.
Every cell in your body contains a copy of your genome—that vast DNA information repository often referred to as the blueprint of life. While the phrase may be oversimplistic, it captures an important truth about what the genome is: a genetic instruction manual for the synthesis of proteins whose myriad functions provide the foundation of life.
Almost every biological event and process in your body depends on proteins, and human disease is often the result of a breakdown in the proper functioning of one or more proteins. In between DNA and protein, however, is a third class of biomolecules: messenger RNAs (mRNA). These ancient molecules effectively translate the information stored in the DNA of your genome to temporary templates that your cells use to manufacture specific proteins.
Isolated in 1961 by Sydney Brenner, Francis Crick, Francois Jacob, and Jacob Monod eight years after the discovery of the DNA double helix, mRNA may seem at first glance to have an unglamorous intermediary role, but its functions are central to multicellular life, encoding the more than 20,000 proteins that keep your body working. Without mRNA, your genetic code would be nothing more than a string of chemicals, and the proteins it codes for would never get made. In short, your body wouldn’t—couldn’t—exist.
The transient and programmable nature of mRNA confers broader therapeutic utility than nearly all other classes of known drugs.
This well-known biomolecule has generated considerable interest over the past few years. Specifically, mRNA has emerged as the foundation for a potential class of medicines that direct cells to make proteins designed to fight or prevent disease. mRNA drugs will function very differently from small-molecule drugs (like many of the best-known pharmaceuticals) and biologic drugs (like recombinant proteins and monoclonal antibodies). This is important because of the many limitations of these more established drug classes. The molecules of recombinant-protein drugs, for example, are mostly large, and their degree of instability typically makes direct protein delivery impractical. Gene therapy aims to resolve some of these challenges by delivering viral nucleic acids that encode therapeutic proteins into cells. But current gene therapies come with many potential risks, including unwanted immune system reaction, the targeting of the wrong cells, and the possibility of causing cancer through genomic incorporation. And because gene therapies incorporate into the genome, their effects may be permanent.
What if you could make mRNA into a drug?
Two overarching factors have hindered the clinical progression of mRNA therapeutics: first, the instability and immunogenicity of mRNA produced outside cells, and second, the lack of sufficiently effective and selective delivery systems to drive protein expression in diseased cells.
Moderna, a company originated by Flagship Pioneering, is focused on the idea that messenger RNA can be reengineered into a versatile set of drugs and vaccines. Tackling mRNA stability, immunogenicity, and delivery, the Moderna team first found that one of mRNA’s four chemical building blocks—called uridine—can be replaced with a slightly modified nucleoside called pseudouridine. Remarkably, your immune system can’t identify mRNAs containing this modification, but your cells’ natural protein production machinery can. The result is that your cells recognize these synthetic mRNAs as if your body had produced them, so they can persistently generate therapeutic proteins without activating your immune system. Moderna has gone on to expand the scope of nucleoside modifications and identify effective vehicles for delivering therapeutic quantities of mRNA to diseased cells.
The company uses mRNA to teach a person’s cells to make whatever is needed to treat or prevent disease—cancer-fighting cytokines, virus-extinguishing antibodies, heart-mending growth factors, waste-devouring enzymes. The transient and programmable nature of mRNA confers broader therapeutic utility than nearly any other class of known drugs.
The importance of mRNA as a unique class of programmable medicines cannot be overstated. This is underscored by the COVID-19 pandemic (SARS-CoV-2, coronavirus) that, in a matter of months, killed more than a million people and infected tens of millions more. Recognizing signs of the virus early in 2020, Moderna conceptualized and initiated early testing for a mRNA vaccine against COVID-19. Less than a year later, data showed Moderna’s COVID-19 vaccine candidate is 94.5% effective in the first interim analysis of its 30,000 patient Phase 3 study.
As mRNA is proving highly effective at instructing the body to fight the deadly coronavirus, the implications for treating other diseases are profound. mRNA medicines can go inside cells to direct protein production, something not possible with many other drugs. They could replace a missing protein or deliver a cancer-fighting peptide. And because of their programmability, different mRNA medicines can be made by simply swapping out one therapeutic gene for another. With these capabilities, mRNA drugs have the potential to treat or prevent diseases that today are untreatable—and thus the ability to usher in a new era of human health.
This explainer was updated on November 18, 2020.
Messenger RNA Timeline
Discovery of mRNA
Discovery of interferon induction by mRNA
First in vitro translation of isolated mRNA
Development of liposome-mediated mRNA delivery
In vitro transcription of mRNA
Demonstration that naked mRNA injected into mice is translated
Vasopressin mRNA injected to rat brain corrects disease
First vaccinations with mRNAs encoding cancer antigens
First anti-tumor T cell response after injection of mRNA in vivo
Initiation of first clinical trial with mRNA using ex vivo transfected dendritic cells
Discovery that nucleoside-modified RNA is non-immunogenic
First human cancer immunotherapy using direct injection of mRNA
iPSC generation with mRNA
Nucleoside-modified mRNA corrects disease in preclinical study
Moderna doses first subject in a clinical trial with mRNA investigational medicine
First reports of mRNA-LNP formulation for in vivo vaccines against the Zika virus
Moderna announces dosing of 755 subjects across 10 potential mRNA medicines to treat cancers, influenza, Chikungunya, and respiratory syncytial virus, among other disorders and diseases
Moderna meets its primary efficacy endpoint in the first interim analysis of its COVID-19 vaccine candidate in its Phase 3 study
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