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The story of mRNA vaccines at the messaging edge of genetics

I write this column sitting in Cambridge, UK, and only a mile away is The Eagle, where Watson and Crick (with some unthanked help from Rosalind Franklin) conjured the double helix structure of DNA and kickstarted the discipline of genetics. In The Gene: An Intimate History, Dr Siddhartha Mukherjee underlines its importance. “Three profoundly destabilizing ideas ricochet through the twentieth century,” he writes, “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. 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 DNA information to the protein factory. In 1961, French scientists Jacques Monod and François Jacob solved that puzzle by discovering mRNA, a specialised molecule that carried this source code of life, with the ‘m’ denoting its lowly status as a mere ‘messenger’.

If the covid pandemic is the greatest disruptor of our times, then mRNA vaccines are perhaps its greatest story. It is the story of fundamental, painstaking scientific research and struggle of 40 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 struck by the more glamorous DNA, and the repeated rejection by the body of synthetic RNA, the scientific establishment pooh-poohed her claim for decades. Kariko soldiered on, and in the early 2000s, she and her research partner Drew Weissman tweaked one of the nucleosides to sneak it past the cell’s innate defences. An impetuous group of postdocs, professors and venture capitalists noticed this, mangled the words ‘modified’ and ‘RNA’ and created a company called Moderna. Around the same time, another pair of RNA savants, Ugur Sahin and Ozlem Tureci, started 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 make 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.” That is what the mRNA wizards did in early 2020. On 11 January 2020, Chinese researchers published the genetic sequence of the ‘2019 novel coronavirus’. It took just 48 hours for Moderna to finalize the construct of its vaccine, and by February, it was shipped out for clinical trials.

That speed can be credited to the way mRNA vaccines work; it is like injecting a software code into our cells. The mRNA directs the cell to synthesize 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 into high gear, and start producing antibodies. Once this minute amount of injected mRNA is over, the cells stop making that protein, but the immune response persists—to seek and destroy the covid virus if it dares trespass again.

Thus, mRNA is an entirely different mechanism to build immunity; its story has just started. Scientists at Yale are close to a mRNA weapon against malaria. BioNTech is working on individualized proteins against particular tumours. 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 great scientific breakthrough, but, like so many of them, this ‘overnight’ success took 40 years to happen, sparked in the 70s by the ‘mRNA hustler’ Katalin Kariko.

Jaspreet Bindra is an author and chief tech whisperer at Findability Sciences

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