(2021).īack then, however, few researchers were thinking about mRNA as a medical product - not least because there was not yet a way to manufacture the genetic material in a laboratory. These experiments themselves built on years of work with liposomes and with mRNA both were discovered in the 1960s (see ‘The history of mRNA vaccines’). The liposomes packaged and protected the mRNA and then fused with cell membranes to deliver the genetic material into cells. As far back as 1978, scientists had used fatty membrane structures called liposomes to transport mRNA into mouse 3 and human 4 cells to induce protein expression. Malone’s experiments didn’t come out of the blue.
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“It’s a long series of steps,” says Paul Krieg, a developmental biologist at the University of Arizona in Tucson, who made his own contribution in the mid-1980s, “and you never know what’s going to be useful”.
The story illuminates the way that many scientific discoveries become life-changing innovations: with decades of dead ends, rejections and battles over potential profits, but also generosity, curiosity and dogged persistence against scepticism and doubt.
In reality, the path to mRNA vaccines drew on the work of hundreds of researchers over more than 30 years. But formal prizes restricted to only a few scientists will fail to recognize the many contributors to mRNA’s medical development. The debate over who deserves credit for pioneering the technology is heating up as awards start rolling out - and the speculation is getting more intense in advance of the Nobel prize announcements next month. “I’ve been written out of history,” he told Nature. Still, Malone, who calls himself the “inventor of mRNA vaccines”, thinks his work hasn’t been given enough credit. Today’s mRNA jabs have innovations that were invented years after Malone’s time in the lab, including chemically modified RNA and different types of fat bubble to ferry them into cells (see ‘Inside an mRNA COVID vaccine’). Dozens of academic labs and companies worked on the idea, struggling with finding the right formula of fats and nucleic acids - the building blocks of mRNA vaccines. For many years after Malone’s experiments, which themselves had drawn on the work of other researchers, mRNA was seen as too unstable and expensive to be used as a drug or a vaccine. Global sales of these are expected to top US$50 billion in 2021 alone.īut the path to success was not direct. Those experiments were a stepping stone towards two of the most important and profitable vaccines in history: the mRNA-based COVID-19 vaccines given to hundreds of millions of people around the world. It was the first time anyone had used fatty droplets to ease mRNA’s passage into a living organism. Later that year, Malone’s experiments showed that frog embryos absorbed such mRNA 2. Another member of the Salk lab signed the notes, too, for posterity. If cells could create proteins from mRNA delivered into them, he wrote on 11 January 1988, it might be possible to “treat RNA as a drug”. Realizing that this discovery might have far-reaching potential in medicine, Malone, a graduate student at the Salk Institute for Biological Studies in La Jolla, California, later jotted down some notes, which he signed and dated. Human cells bathed in this genetic gumbo absorbed the mRNA, and began producing proteins from it 1. He mixed strands of messenger RNA with droplets of fat, to create a kind of molecular stew.
In late 1987, Robert Malone performed a landmark experiment. The RNA sequence used in the COVID-19 vaccine developed by Pfizer and BioNTech (Ψ is a modified form of the uridine nucleotide, U).