The story of mRNA vaccines at the messaging edge of genetics

“Three profoundly destabilizing ideas ricochet through the twentieth century,” writes Dr Siddhartha Mukherjee, in his ‘The Gene: An Intimate History’, “trisecting it into three unequal parts: the atom, the byte, the gene.” These three are the fundamental units of matter, information, and life, and while a lot has been written about the transformational power of the first two, it is the third one, the gene, which promises to transform our lives the most. I write this column sitting in Cambridge, and only a mile away is The Eagle, where Watson and Crick (with some unthanked help from Rosalind Franklin) conjured up the double helix structure of the DNA, and kickstarted the discipline of genetics. DNA solved one of the greatest puzzles in biology, it was the code or information to produce the building blocks of life – proteins. However, its discovery gave birth to a fresh puzzle: DNA lives in the cell nucleus, but proteins are created in the cytoplasm, a totally different part of the cell. There had to be something that somehow carried the DNA information to the protein factory. In 1961, French scientists Jacques Monod and François Jacob solved that puzzle by discovering the now-famous mRNA, a specialised molecule that carried this source code of life, with them denoting its lowly status as the ‘messenger’. If the pandemic is the greatest disruptor of our times, the mRNA vaccine is perhaps its greatest story. It is the story of fundamental, painstaking scientific research and struggle of forty years, which blossomed into a planet-saving vaccine when its time came. The story starts in 1978, when Hungarian scientist Katalin Kariko first proposed that synthetic or manufactured RNA could actually do something useful. Star stuck by the more glamorous DNA, and the repeated rejection by the body of synthetic RNA, the scientific establishment poohpoohed her claim for decades, pulling back her grant and demoting her. Kariko soldiered on, and only in the early 2000s, she and her research partner Drew Weissman tweaked one of the nucleosides to sneak it past the cell’s innate formidable defences. An impetuous group of postdocs, professors and VCs noticed this, mangled the words ‘modified’ and ‘RNA’ and created a company called Moderna. Almost simultaneously, another pair of RNA savants, Ugur Sahin and Ozlem Tureci, founded a company to develop mRNA-based treatments for cancer, and called it BioNTech. As Adam Maida writes in The Atlantic, “the dream of mRNA persevered in part because its core principle was tantalizingly simple, even beautiful: The world’s most powerful drug factory might be inside all of us. People rely on proteins for just about every bodily function; mRNA tells our cells which proteins to make. With human-edited mRNA, we could theoretically commandeer our cellular machinery to make just about any protein under the sun.” You could manufacture molecules to repair organs or direct blood flow, or you could commandeer your cells “to cook up an off-menu protein which our immune system would learn to identify as an invader and destroy.” And that is what the mRNA wizards did in early 2020. On January 11, 2020, Chinese researchers published the genetic sequence of the ‘2019 novel coronavirus’. It took just 48 hours for Moderna to finalise the construct of the vaccine, and by February it was shipped out for clinical trial.
This blinding speed is because of the way mRNA vaccine works; it is like injecting a software code into our cells. The mRNA directs the cell to synthesise a protein, in this case the spike protein of the coronavirus, and the protein factory in the cell mass produces it. Our cells, in turn, kick their immune system in to high gear, and start producing antibodies to it. Once this minute amount of injected mRNA is over, the cells stop making that protein, but the immune response still persists – to seek and destroy the COVID virus if it dares trespass again. Thus, the mRNA is an entirely different mechanism to build immunity, and its story will not end when the pandemic recedes; in fact, its story has just started. Scientists at Yale are close to an mRNA weapon against malaria, the world’s most destructive disease. BioNTech is working to create on-demand, individualised proteins against particular tumours, in a new way to fight cancer. Multiple sclerosis and other auto-immune diseases are also being targeted with tailored mRNA therapies. This is the beauty of this ‘genetic software code’; as Tureci says, “…mRNA can be broadly transformational. In principle, everything you can do with protein can be substituted by mRNA.”. It is a tremendous scientific breakthrough, but like so many of them, this ‘overnight’ success took forty years to happen, sparked in the seventies by the ‘mRNA hustler’, Katalin Kariko, who made it all possible.

(This article was first published as an OpEd in Mint on June 10, 2021)