The story of mRNA: How a once-dismissed idea became a leading technology in the Covid vaccine race

It is a story that began three decades ago, with a little-known scientist who refused to quit...

Before messenger RNA was a multibillion-dollar idea, it was a scientific backwater. And for the Hungarian-born scientist behind a key mRNA discovery, it was a career dead-end.

Katalin Karikó spent the 1990s collecting rejections. Her work, attempting to harness the power of mRNA to fight disease, was too far-fetched for government grants, corporate funding, and even support from her own colleagues.

...It all made sense on paper. In the natural world, the body relies on millions of tiny proteins to keep itself alive and healthy, and it uses mRNA to tell cells which proteins to make. If you could design your own mRNA, you could, in theory, hijack that process and create any protein you might desire — antibodies to vaccinate against infection, enzymes to reverse a rare disease, or growth agents to mend damaged heart tissue.

In 1990, researchers at the University of Wisconsin managed to make it work in mice. Karikó wanted to go further.

“Every night I was working: grant, grant, grant,” Karikó remembered, referring to her efforts to obtain funding. “And it came back always no, no, no.”

By 1995, after six years on the faculty at the University of Pennsylvania, Karikó got demoted. She had been on the path to full professorship, but with no money coming in to support her work on mRNA, her bosses saw no point in pressing on.

She was back to the lower rungs of the scientific academy.

“Usually, at that point, people just say goodbye and leave because it’s so horrible,” Karikó said.

...In time, those better experiments came together. After a decade of trial and error, Karikó and her longtime collaborator at Penn — Drew Weissman, an immunologist with a medical degree and Ph.D. from Boston University — discovered a remedy for mRNA’s Achilles’ heel.

...“That was a key discovery,” said Norbert Pardi, an assistant professor of medicine at Penn and frequent collaborator. “Karikó and Weissman figured out that if you incorporate modified nucleosides into mRNA, you can kill two birds with one stone.”

...Derrick Rossi, a 39-year-old postdoctoral fellow in stem cell biology at Stanford University in 2005 when he read the first paper. Not only did he recognize it as groundbreaking, he now says Karikó and Weissman deserve the Nobel Prize in chemistry.

“If anyone asks me whom to vote for some day down the line, I would put them front and center,” he said. “That fundamental discovery is going to go into medicines that help the world.”



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mRNA vaccines: an idea more than 30 years in the making

When Katalin Karikó, Ph.D., came to the United States from Hungary in 1985, she brought with her a passionate determination to work on mRNA. Messenger RNA is fundamental to life: sets of blueprints, spelled out using four nucleotide “letters,” for building every protein in every life form on Earth. Karikó’s big idea was to produce proteins at will by injecting mRNA into cells, but her experiments did not work for a long time. Lack of success forced her to rely on one senior scientist after another to support her work, while she made only meager wages.

In 1998, Karikó partnered with Drew Weissman, M.D., Ph.D., at the University of Pennsylvania. Weissman was interested in developing an HIV vaccine based on mRNA. After many failures, Karikó and Weissman learned that natural mRNAs use small amounts of slightly modified nucleotides, in addition to the four standard nucleotides. When the scientists inserted the modified nucleotides into the mRNAs they were using in their research, they began to find that these modified mRNAs produced proteins efficiently without causing undesirable side effects. They began to publish their findings, starting in 2005. By the time the coronavirus that causes COVID-19 showed up in 2020, Karikó and Weissman were already working on an influenza vaccine based on their mRNA technology.

2. Visionary companies fueled the drive toward mRNA vaccines