- Scientist Katalin Karikó struggled for years to convince colleagues that messenger RNA could have disease-fighting applications in humans.
- In 2005, she found a way to configure mRNA so that it slipped past the body’s natural defences – a discovery that paved for the way for the world’s first mRNA vaccines.
- The COVID-19 vaccines from both Pfizer-BioNTech and Moderna rely on this technology.
- Pfizer’s vaccine was authorised Friday for emergency use in the US.
- Visit Business Insider’s homepage for more stories.
When biochemist Katalin KarikÃ³ first entered the US with her husband and 2-year-old daughter, she had no cell phone or credit card.
“It was a one-way ticket,” she told Business Insider. “We didn’t know anybody.”
It was 1985. The family was moving from Hungary to Philadelphia, Pennsylvania, so KarikÃ³ could take a postdoctoral position at Temple University. They were only permitted to exchange $US100, but KarikÃ³ found a workaround: She hid extra cash â€” Â£900 British pounds â€” in her daughter’s teddy bear. The money had come from selling the family’s car on the black market.
In a way, KarikÃ³’s entire career has been based on this kind of clever solution. In 2005, she discovered a way to configure messenger RNA â€” a molecule that kickstarts the production of proteins â€” so that it slipped past the body’s natural defences, unannounced.
That paved the way for what has recently turned out to be one of modern science’s greatest achievements: the world’s first mRNA vaccines.
KarikÃ³, now 65, oversees mRNA protein replacement at BioNTech, a German biotech firm that developed a coronavirus vaccine in partnership with US pharma giant Pfizer. That vaccine has now been authorised in the UK, Canada, Bahrain, Saudi Arabia, and the US. KarikÃ³’s work also inspired the founding of Moderna, the US biotech company developing a competing coronavirus shot.
Both vaccines use mRNA to deliver a coded message to the body that triggers an immune response. And so far, both have been found to be highly effective at preventing COVID-19: Pfizer and BioNTech’s two-shot regimen was found to be 95% effective, while Moderna’s was shown to be 94.5% effective. Moderna’s vaccine could be approved in the US later this month.
Many scientists expect both vaccines’ efficacy rates to go down a bit once they get administered to the general public, but the results so far have been far better than most experts anticipated.
For KarikÃ³, though, the success came after a long fight.
‘Everybody rejected it’
KarikÃ³’s first mRNA-therapy grant application was rejected in 1990, a year after she joined the faculty at the University of Pennsylvania. Then came more rejections, one after another.
“I kept writing and improving the approach â€” better RNA, better delivery,” KarikÃ³ said. “I came up with applications and so on, tried to get to government funding, private funding from investors, but everybody rejected it.”
KarikÃ³ was demoted to an adjunct position in 1995. Around the same time, she was diagnosed with cancer. Her husband, meanwhile, was held up in Hungary due to a visa issue, and wound up staying away six months.
Still, KarikÃ³ kept pursuing her research.
Her studies of RNA built on the work of scientists at the University of Wisconsin and biotech company Vical Incorporated, who’d figured out how to manufacture mRNA so it would instruct living cells to make specific proteins. Those studies, conducted around 1990, laid the foundation for the future COVID-19 vaccines.
These new vaccines use a small piece of mRNA from the coronavirus genome to tell the body to produce the virus’ spike protein. That’s the part that helps the coronavirus attach to and invade cells, and it’s what the immune system targets in its response. So when the body detects the protein’s presence, it develops antibodies to neutralise it, resulting in protection against the virus.
Unlike more traditional shots, mRNA vaccines stimulate the production of killer T cells, which stop the coronavirus from replicating. The vaccines are also relatively easy and quick to produce, since they’re made in test tubes or tanks rather than cultivated in cells.
But in order to make a successful mRNA vaccine in the first place, KarikÃ³ had to overcome a major roadblock: the approach was triggering a dangerous immune response in mice.
A prize-worthy discovery
KarikÃ³ had found that when lab-made mRNA was injected on its own, the body would recognise it as a foreign invader and destroy it right away, before it could trigger the protein-making process. Studies in mice showed the process could even lead to an inflammatory response that would risk a patient’s health. So researchers had to trick the body into believing that lab-made mRNA didn’t pose a threat.
KarikÃ³ worked for years to find a solution. Her workdays usually started at 6:00 a.m., and she worked some weekends and holidays â€” even slept in the office occasionally.
“From outside, it seemed crazy, struggling, but I was happy in the lab,” she said. “My husband always, even today, says, ‘This is entertainment for you.’ I don’t say that I go to work. It is like play.”
At the same time, KarikÃ³ was raising a future Olympic athlete. Her daughter, Susan Francia, won gold medals on the US rowing team in 2008 and 2012. KarikÃ³’s post at UPenn enabled her to send Susan to college there for a quarter of the regular tuition.
“I said, ‘Never in my life could I afford that, so no matter what I have to stay on the job,'” KarikÃ³ said.
Then in 1997, KarikÃ³ met Drew Weissman, an immunologist who’d just joined the university. They got to chatting while sharing a photocopy machine, then began working together to address the mRNA immune-response problem.
The culprit turned out to be a single RNA building block, or nucleoside, called uridine. With a slight modification to that nucleoside, KarikÃ³ and Weissman were able to stop the dangerous reaction in mice.
When she realised it was working, KarikÃ³ said, “I just repeated my experiment because I thought I messed up.”
But it wasn’t a mistake â€” the pair published the finding in 2005. Some scientists now think that it’s worthy of a Nobel Prize.
“If anyone asks me whom to vote for some day down the line, I would put them front and centre,” Derrick Rossi, a professor at Harvard Medical School, told STAT and The Boston Globe. “That fundamental discovery is going to go into medicines that help the world.”
A novel delivery system
Even after KarikÃ³’s discovery, researchers still had to figure out how to stop the body from breaking down mRNA too quickly for it to be effective.
“There’s two parts that make mRNA a success,” Robert Langer, a biomedical engineering professor at the Massachusetts Institute of Technology and a co-founder of Moderna, told Business Insider. “Developing better mRNAs and then developing better ways to deliver it.”
Langer, too, faced pushback for discoveries that later proved key to mRNA vaccines. In 1976, he published a paper showing that when nucleic acids like DNA and RNA were encased in various polymers, the polymers would release the acids without triggering an inflammatory response.
The paper received widespread criticism. People didn’t believe the results.
“It was the first time anybody put nucleic acids into tiny particles and showed you could use them for delivery,” Langer said. “The reason why people were so upset and thought it was wrong â€” they felt, ‘How could a big molecule get out of a package?’ It’s like walking through a wall.”
The technology, as it turns out, paved the way for groundbreaking drug delivery methods like the ones used to send chemotherapy to a tumour site. Current mRNA coronavirus vaccines similarly use a lipid molecule to help mRNA cross the cell membrane.
“Over the years, that’s a lot of what I did is develop better and better drug delivery systems,” Langer said.
In 2010, Rossi and fellow Harvard Medical School professor Timothy Springer approached Langer about forming a company based on mRNA therapy, inspired by KarikÃ³ and Weissman’s work. Langer was in.
“I don’t know that it was rocket science to figure out that it would be a big deal,” he said.
The three scientists, along with cardiovascular scientist Kenneth Chien, co-founded Moderna â€” named after “modified RNA.”
“One of the big obstacles for all these things has been the delivery part,” Langer said. “That was the part I felt like I could make a difference in.”
A patent tug-of-war
KarikÃ³ and Weissman filed a patent for their work shortly after their research was published. When the patent was originally submitted, KarikÃ³’s name was listed second. But she fought to get first billing.
“I said, ‘No, it was my idea,'” she said. “I insisted â€” change it back.”
Her insistence was, perhaps, a reaction to sexism she’d faced earlier in her career. Once, KarikÃ³ said, she was asked for the name of her supervisor while running her own lab. She was referred to as “Mrs.” in an article in which her male colleagues were given the title “professor.” Another article confused her as a postdoc in Weissman’s lab.
“I don’t work in anybody’s lab,” KarikÃ³ said. “I created my own field.”
Armed with their patent, KarikÃ³ and Weissman formed an mRNA-based drug company called RNARx, but it didn’t get far off the ground. In 2010, the University of Pennsylvania sold the exclusive licence to KarikÃ³ and Weissman’s patent to Gary Dahl, the head of a lab supply company called Cellscript.
Shortly after, KarikÃ³ was approached by Flagship Pioneering, the venture capital company backing Moderna. It was also interested in her licence â€” but it was too late.
Without access to the patent, Moderna was tasked with finding its own modified nucleoside that could replicate KarikÃ³’s results. The company received a patent for that nucleoside, among others, in 2014.
As Langer put it: “All science is built on other science.”
The end of a decades-long journey
Competition in the mRNA field continued to grow. By 2013, Moderna’s research was gaining traction â€” the company received $US240 million from the UK drug company AstraZeneca to find, develop, and commercialize mRNA treatments for cardiometabolic diseases and cancer.
KarikÃ³ wanted a new way to enter the ring. After UPenn declined to promote her to a faculty role in 2013, she joined BioNTech as senior vice president. KarikÃ³ told Wired that UPenn faculty said they’d “concluded that I was not of faculty quality.”
“When I told them I was leaving, they laughed at me and said, ‘BioNTech doesn’t even have a website,'” she said.
That work required her to live in Germany, while her husband stayed in Philadelphia.
“I told him, ‘I’ll just go until the first person will be injected with modified RNA.’ Then I said, ‘You know, I want to see that person be cured,'” KarikÃ³ said. “Now I can come home.”
Indeed, the Pfizer-BioNTech injection is the first mRNA vaccine ever authorised. Moderna’s shot is poised to become the second. The company has never gotten a vaccine approved, though it had entered eight mRNA vaccines into clinical trials before the pandemic, including a flu vaccine.
“When people are saying, ‘There is no messenger RNA vaccine that’s ever been,’ it is very critical and very important to know that not because it failed,” KarikÃ³ said. “It just didn’t have time to be advanced by many people.”
Neither she nor Langer were surprised when two mRNA vaccines proved successful at preventing COVID-19.
“It followed the path of things that we’d already done before,” Langer said, adding, “it was a high likelihood that it would work, but there’s nothing like seeing the data.”
Like KarikÃ³, Langer sees this vaccine as the culmination of his life’s work.
“The other things I did were sort of the start of the journey,” he said. “This is, for me, close to the end where you actually see a human validation, that something that you’ve contributed to is going to really change the world.”
Yet even at a career high, both Langner and KarikÃ³ celebrated only modestly. After receiving the good news about Moderna’s vaccine trials, Langer said he spent his day like most others: talking to his students and Moderna employees on Zoom.
KarikÃ³ said she got the call about the Pfizer-BioNTech results the night before they were publicly announced. Afterward, she treated herself to a bag of chocolate-covered peanuts.
“I told my husband, I will eat the whole thing now,” she said.
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