SPECIAL REPORT The story of mRNA: How a once-dismissed idea became a leading technology in the Covid vaccine race
By DAMIAN GARDE — STAT @damiangarde and JONATHAN SALTZMAN — BOSTON GLOBENOVEMBER 10, 2020
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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.
The problem, she knew, was that synthetic RNA was notoriously vulnerable to the body’s natural defenses, meaning it would likely be destroyed before reaching its target cells. And, worse, the resulting biological havoc might stir up an immune response that could make the therapy a health risk for some patients.
It was a real obstacle, and still may be, but Karikó was convinced it was one she could work around. Few shared her confidence.
“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.
There’s no opportune time for demotion, but 1995 had already been uncommonly difficult. Karikó had recently endured a cancer scare, and her husband was stuck in Hungary sorting out a visa issue. Now the work to which she’d devoted countless hours was slipping through her fingers.
“I thought of going somewhere else, or doing something else,” Karikó said. “I also thought maybe I’m not good enough, not smart enough. I tried to imagine: Everything is here, and I just have to do better experiments.”
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.
The stumbling block, as Karikó’s many grant rejections pointed out, was that injecting synthetic mRNA typically led to that vexing immune response; the body sensed a chemical intruder, and went to war. The solution, Karikó and Weissman discovered, was the biological equivalent of swapping out a tire.
Every strand of mRNA is made up of four molecular building blocks called nucleosides. But in its altered, synthetic form, one of those building blocks, like a misaligned wheel on a car, was throwing everything off by signaling the immune system. So Karikó and Weissman simply subbed it out for a slightly tweaked version, creating a hybrid mRNA that could sneak its way into cells without alerting the body’s defenses.
“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.”
That discovery, described in a series of scientific papers starting in 2005, largely flew under the radar at first, said Weissman, but it offered absolution to the mRNA researchers who had kept the faith during the technology’s lean years. And it was the starter pistol for the vaccine sprint to come.
And even though the studies by Karikó and Weissman went unnoticed by some, they caught the attention of two key scientists — one in the United States, another abroad — who would later help found Moderna and Pfizer’s future partner, BioNTech.
Derrick Rossi, a native of Toronto who rooted for the Maple Leafs and sported a soul patch, was 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.”
But Rossi didn’t have vaccines on his mind when he set out to build on their findings in 2007 as a new assistant professor at Harvard Medical School running his own lab.
He wondered whether modified messenger RNA might hold the key to obtaining something else researchers desperately wanted: a new source of embryonic stem cells.
In a feat of biological alchemy, embryonic stem cells can turn into any type of cell in the body. That gives them the potential to treat a dizzying array of conditions, from Parkinson’s disease to spinal cord injuries.
But using those cells for research had created an ethical firestorm because they are harvested from discarded embryos.
Rossi thought he might be able to sidestep the controversy. He would use modified messenger molecules to reprogram adult cells so that they acted like embryonic stem cells.
He asked a postdoctoral fellow in his lab to explore the idea. In 2009, after more than a year of work, the postdoc waved Rossi over to a microscope. Rossi peered through the lens and saw something extraordinary: a plate full of the very cells he had hoped to create.
Rossi excitedly informed his colleague Timothy Springer, another professor at Harvard Medical School and a biotech entrepreneur. Recognizing the commercial potential, Springer contacted Robert Langer, the prolific inventor and biomedical engineering professor at the Massachusetts Institute of Technology.
On a May afternoon in 2010, Rossi and Springer visited Langer at his laboratory in Cambridge. What happened at the two-hour meeting and in the days that followed has become the stuff of legend — and an ego-bruising squabble.
Langer is a towering figure in biotechnology and an expert on drug-delivery technology. At least 400 drug and medical device companies have licensed his patents. His office walls display many of his 250 major awards, including the Charles Stark Draper Prize, considered the equivalent of the Nobel Prize for engineers.
As he listened to Rossi describe his use of modified mRNA, Langer recalled, he realized the young professor had discovered something far bigger than a novel way to create stem cells. Cloaking mRNA so it could slip into cells to produce proteins had a staggering number of applications, Langer thought, and might even save millions of lives.
“I think you can do a lot better than that,” Langer recalled telling Rossi, referring to stem cells. “I think you could make new drugs, new vaccines — everything.”
Langer could barely contain his excitement when he got home to his wife.
“This could be the most successful company in history,” he remembered telling her, even though no company existed yet.
Three days later Rossi made another presentation, to the leaders of Flagship Ventures. Founded and run by Noubar Afeyan, a swaggering entrepreneur, the Cambridge venture capital firm has created dozens of biotech startups. Afeyan had the same enthusiastic reaction as Langer, saying in a 2015 article in Nature that Rossi’s innovation “was intriguing instantaneously.”
Within several months, Rossi, Langer, Afeyan, and another physician-researcher at Harvard formed the firm Moderna — a new word combining modified and RNA.
Springer was the first investor to pledge money, Rossi said. In a 2012 Moderna news release, Afeyan said the firm’s “promise rivals that of the earliest biotechnology companies over 30 years ago — adding an entirely new drug category to the pharmaceutical arsenal.”
But although Moderna has made each of the founders hundreds of millions of dollars — even before the company had produced a single product — Rossi’s account is marked by bitterness. In interviews with the Globe in October, he accused Langer and Afeyan of propagating a condescending myth that he didn’t understand his discovery’s full potential until they pointed it out to him.
“It’s total malarkey,” said Rossi, who ended his affiliation with Moderna in 2014. “I’m embarrassed for them. Everybody in the know actually just shakes their heads.”
Rossi said that the slide decks he used in his presentation to Flagship noted that his discovery could lead to new medicines. “That’s the thing Noubar has used to turn Flagship into a big company, and he says it was totally his idea,” Rossi said.
Afeyan, the chair of Moderna, recently credited Rossi with advancing the work of the Penn scientists. But, he said, that only spurred Afeyan and Langer “to ask the question, ‘Could you think of a code molecule that helps you make anything you want within the body?’”
Langer, for his part, told STAT and the Globe that Rossi “made an important finding” but had focused almost entirely “on the stem cell thing.”
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