How mRNA vaccines were made: Stalled progress and happy accidents
“I said, ‘I’m an RNA scientist. I can do anything with RNA,” Dr. Karikó recalls telling Dr. Weissman. He asked her: Could you make an HIV vaccine?
“Oh yeah, oh yeah, I can do it”, Dr. Karikó noted.
Until then, commercial vaccines carried modified viruses or virus fragments into the body to train the immune system to attack invading microbes. An mRNA vaccine would instead carry instructions – encoded in mRNA – that would allow cells in the body to pump out their own viral proteins. This approach, Dr. Weissman believed, would better mimic a real infection and elicit a more robust immune response than traditional vaccines.
It was a fringe idea that few scientists thought would work. A molecule as fragile as mRNA seemed an unlikely vaccine candidate. Grant reviewers were also unimpressed. His lab had to operate with start-up funds that the university gives new faculty members to get started.
At that time, it was easy to synthesize mRNA in the lab to code for any protein. Drs. Weissman and Karikó inserted mRNA molecules into human cells growing in Petri dishes and, as expected, the mRNA instructed the cells to make specific proteins. But when they injected mRNA into mice, the animals got sick.
“Their fur got ruffled, they hunched over, they stopped eating, they stopped running,” Dr. Weissman said. “No one knew why.”
For seven years, the duo studied how mRNA works. Countless experiments have failed. They wandered into one dead end after another. Their problem was that the immune system sees the mRNA as a piece of an invading pathogen and attacks it, sickening the animals while destroying the mRNA.
Eventually, they solved the mystery. The researchers found that the cells protected their own mRNA with a specific chemical modification. So the scientists tried to make the same change to mRNA made in the lab before injecting it into cells. It worked: the mRNA was taken up by the cells without causing an immune response.