Weissman's 2005 discovery made mRNA safe to use as medicine

Person: Drew Weissman
Lived: b. 1959
Field: Immunology
From: American

The story

Efficient methods for making messenger RNA in the laboratory, without growing cells, were introduced in the 1980s, and many scientists hoped to use mRNA to instruct the body's cells to produce helpful proteins. But lab-made mRNA was unstable, hard to deliver and triggered inflammation, so enthusiasm for using it in medicine was limited. At the University of Pennsylvania, the Hungarian biochemist Katalin Karikó kept working on it despite repeated funding rejections, and in 1997 she began collaborating with Drew Weissman, an immunologist who had just arrived at Penn.

Weissman studied dendritic cells, which watch for invaders and set vaccine-induced immune responses in motion, and one of his main goals was an HIV vaccine. The pair showed that dendritic cells loaded with mRNA encoding an HIV protein could stimulate T-cell responses, but they also noticed that the lab-made mRNA itself switched the cells on, releasing inflammatory signals. In 2004 they reported that it contained double-stranded RNA contaminants that activate an immune sensor called TLR3.

The crucial clue came from comparison. RNA from mammalian cells, including transfer RNA, did not provoke the same reaction, and they knew that the bases in such RNA are frequently chemically modified. Testing variants of mRNA with altered bases, including pseudouridine, they found that the inflammatory response was almost abolished, and that modifications of uridine in particular stopped the dendritic cells from being activated. The key paper was turned down by Nature and Science before appearing in the journal Immunity in 2005, fifteen years before the COVID-19 pandemic.

In further studies published in 2008 and 2010, they showed that base-modified mRNA also produced much more protein, partly because it activated less of an enzyme, PKR, that shuts down protein production. Modified mRNA delivered to the spleens of mice made more protein and caused less immune activation. A later refinement, N1-methylpseudouridine, became the most common modified base in mRNA vaccines, including both COVID-19 vaccines approved in late 2020.

The Nobel committee called the 2005 finding a paradigm change in understanding how cells recognise different forms of mRNA, although the study received little attention when it first appeared. It removed a critical obstacle to mRNA medicine and became the foundation of vaccines given to hundreds of millions of people.