In 1989, when Katalin Karikó submitted her first grant application to develop messenger RNA-based gene therapy, she knew she had a game-changing technology in her hands. But the Hungarian biochemist, then a professor at the University of Pennsylvania, could only dream of using mRNA in humans. In theory an almost perfect platform to make drugs and vaccines, mRNA was stacked with practical problems that would keep it away from clinical use for decades.
Then, at the end of 2019, a strange new infectious disease appeared in Wuhan and spread quickly across the planet, changing the world and sending countries and companies racing for a medical treatment that would stop the pandemic’s illness and fatalities. mRNA has become one of the saviour technologies of the COVID era; now, that success is just the first step in a transformation in how we might recognise – and cure – everything from the flu to cancer.
The concept behind mRNA technology is strikingly simple. mRNA – which stands for messenger ribonucleic acid – is a single-stranded chain of nucleotides. In an organism, it acts as a messenger, a short-lived intermediary that communicates the information contained in our genes to the ribosomes. These are the cell’s protein factories, which read the code and translate it into a protein.
Special delivery: how mRNA technology works at a cellular level
1. Uptake by endocytosis
The liposome, or nanoparticle, is swallowed by the cell through endocytosis, the process by which cells absorb external material by engulfing it in a pouch – vacuole – of cell membrane called an endosome.
2. Endosomal escape
The endosome’s membrane breaks down, and the liposome is released inside the cell.
3. Release from carrier
The presence of enzymes inside the cell degrades the liposome. The mRNA strings are released and can travel to the protein-making ribosomes.
In the ribosomes, the mRNA strings are read and translated into antigens – pathogen proteins. The resulting antigens are exposed to the cell surface, where immune system cells recognise them as foreign, triggering an immune response that creates a memory for the antigen. If the real pathogen appears, immune cells recognise the same antigen and attack.
Scientists have learned to transcribe a genetic sequence from a string of DNA to a string of mRNA. A synthetic mRNA sequence with the right blueprint can be turned into a drug that, like a message in a bottle, delivers instructions into a cell to turn it into a literal bodyguard through its specialised resulting protein.
In a vaccine, the mRNA string encodes the recipe to make the antigen – a protein from the pathogen we want to protect ourselves from. Once the vaccine is inside the cells, the instructions are used to synthesise the antigen, which is exposed to the cell surface. Then, a subset of immune system cells recognises the antigen as foreign, triggering an immune response. This mechanism creates a memory for this antigen. Later, when the real pathogen is present, those cells recognise the same antigen and react rapidly and strongly against the infectious agent.
After the protein has been produced, the mRNA is degraded via physiological, metabolic pathways. “It’s a transient thing,” says Associate Professor Archa Fox, a molecular biologist and mRNA expert at the University of Western Australia. This desirable trait reduces the risk of unwanted side-effects by uncontrolled protein expression.
Two main issues had hindered the advance of the technology. “One was what we call a delivery problem,” says Fox. That same transience that makes mRNA desirable is also a problem: how to protect it from degradation during its journey throughout the body and into cells. In the late 1990s, researchers were able to pack the fragile messenger into shells of fat molecules called lipid nanoparticles, which had been studied for almost two decades as a possible delivery mechanism for anti-cancer drugs. The lipidic vehicle protects mRNA from thermal degradation and shields it from destructive enzymes while shunting it to the cell.
There was another major problem. The body strongly rejects RNA from outside sources, probably to avoid being hijacked by pathogens, and in early studies the mRNA often proved so toxic that it killed the lab animals it was tested on.
It took until 2005 for Karikó, who now oversees mRNA research at BioNTech, to discover that by adding pseudouridine into the mRNA she could fool the cell into thinking that the delivered mRNA was not a foreign invader. This breakthrough laid the foundations for the apparent overnight success of today’s mRNA COVID-19 vaccines.
For over three decades, researchers across the world had been working on mRNA therapeutics that can instruct the body to make its own drugs. With COVID, that platform has reached industrial scale, and offers opportunities for cures that have eluded answers thus far.
“It’s a flexible platform,” says Professor Thomas Preiss, a molecular biologist and mRNA expert at the Australian National University.
The most likely next step for mRNA is as a protection against influenza. Numerous biotech companies around the world have also turned their focus to research into mRNA vaccines against the many tropical infectious diseases we still don’t have protection for – and some think that personalised cancer vaccines could be the holy grail of mRNA tech.
This excerpt is republished online from Cosmos Magazine Issue 92, which went on sale on Thursday 2 September 2021.
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Originally published by Cosmos as Message in a bottle
Dr Manuela Callari is a Sydney-based freelance science writer who specialises in health and medical stories.
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