Messenger RNA

On 25 April 1953, when Watson and Crick published their double helix structure, they solved one mystery but created another. DNA's elegant twisted ladder explained heredity's physical mechanism, but left a glaring gap: if DNA never leaves the nucleus, how does it instruct proteins being assembled in the cytoplasm? The genetic library was locked in the vault while the factory floor desperately needed its blueprints.

By 1958, Crick had articulated his "central dogma"—information flows from DNA to RNA to protein—but this was more prophecy than proof. The adjacent possible had assembled all the pieces: X-ray crystallography, density gradient centrifugation, radioactive isotope tracing, and the PaJaMo experiment showing a mysterious transient molecule they called simply "X."

On 15 April 1960—Good Friday—at King's College Cambridge, Sydney Brenner and Francis Crick were listening to François Jacob describe bacterial experiments when Brenner let out "a loud yelp." Jacob had mentioned that a gene appeared to create some fleeting RNA messenger. In that instant, the pieces converged: what if a disposable RNA copy ferried instructions from the nuclear archive to cytoplasmic assembly lines?

During summer 1960, in Matthew Meselson's Pasadena laboratory at Caltech, Brenner and Jacob infected bacteria with radioactively labeled phage and watched where the hot RNA went. After a tense month of fiddling with experimental conditions, they observed short-lived RNA molecules appearing at ribosomes precisely when new proteins were being made. In May 1961, two back-to-back papers in Nature characterized what Jacob and Jacques Monod christened "messenger RNA."

Yet mRNA's medical potential remained locked. The molecule was maddeningly fragile, degrading within minutes. When researchers injected synthetic mRNA into cells in the 1990s, the immune system attacked it as foreign. By 1995, the University of Pennsylvania demoted biochemist Katalin Karikó after repeated grant rejections.

In 2005, Karikó and Drew Weissman discovered that replacing uridine with pseudouridine rendered mRNA immunologically silent. By 2015, lipid nanoparticles could smuggle mRNA past cell membranes. When SARS-CoV-2's sequence emerged in January 2020, BioNTech and Moderna had the complete toolkit. By December 2020, both had vaccines demonstrating 95% efficacy. On 2 October 2023, Karikó and Weissman received the Nobel Prize.