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Human Health, Innovation

Messenger RNA: Using an Ancient Molecule to Teach Cells New Skills

3-D illustration of a single strand of ribonucleic acid. Credit: nobeastsofierce for Shutterstock

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. And while this phrase may be oversimplistic, it does capture 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. Proteins are the workhorses of the body.

Almost every biological event and process in your body depends on them, 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. Discovered 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 “middleman” role—but in reality its role is central to multicellular life. Indeed, mRNAs encode 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 would function very differently from small-molecule drugs (like many of the best-known pharmaceuticals) and traditional 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, tend to be 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.

Using mRNA as a drug opens up a breadth of opportunities to treat and prevent disease. mRNA medicines can go inside cells to direct protein production, something not possible with other drugs. This new class of medicines could replace a missing protein or deliver a cancer-fighting peptide. And because of its programmability, different medicines can be made by simply swapping out one therapeutic gene for another. mRNA drugs have the potential to treat or prevent diseases that today are untreatable—and thus the potential to improve human health and lives around the world.

Messenger RNA Timeline

1961

Discovery of mRNA

1963

Discovery of interferon induction by mRNA

1969

First in vitro translation of isolated mRNA

1978

Development of liposome-mediated mRNA delivery

1984

In vitro transcription of mRNA

1990

Demonstration that naked mRNA injected into mice is translated

1992

Vasopressin mRNA injected to rat brain corrects disease

1995

First vaccinations with mRNAs encoding cancer antigens

1999

First anti-tumor T cell response after injection of mRNA in vivo

2001

Initiation of first clinical trial with mRNA using ex vivo transfected dendritic cells

2005

Discovery that nucleoside-modified RNA is non-immunogenic

2009

First human cancer immunotherapy using direct injection of mRNA

2010

iPSC generation with mRNA

2011

Nucleoside-modified mRNA corrects disease in preclinical study

2015

Moderna doses first subject in a clinical trial with mRNA investigational medicine

2017

First reports of mRNA-LNP formulation for in vivo vaccines against the Zika virus

2018

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

Story By

Nicholas Plugis

Nicholas Plugis joined Flagship Pioneering as an associate after completing the firm's Fellows Program. At Flagship, Nicholas conducts explorations to discover unexplored biological mechanisms and new biotechnologies. As part of a team of entrepreneu...

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