JENKINTOWN, Pa. — Nearly three decades ago, Katalin Kariko called her husband and 10-year-old daughter into her home office in the Philadelphia suburbs to share a thrilling new scientific idea.
A one-way ticket. A cash-stuffed teddy bear. A dream decades in the making.
For Katalin Kariko, a life in full: Awe-inspiring ideas, careful experiments, unnoticed successes and the repeated sting of rejection
October 1, 2021 at 7:00 a.m. EDT
Kariko’s fascination with messenger RNA had already stretched more than a decade, and she thought that day that she had figured how out how to overcome one big hurdle to turning basic biology into a technology with huge medical potential. Messenger RNA was notoriously unstable, and she had thought of a way to stop it from getting chewed up and torn apart. Normally, it began to degrade at the ends, so she would make it into a circle.
“She was so excited, and we didn’t know, to be honest, what was happening or what she was explaining, but we sensed her enthusiasm, so we were excited, too,” her daughter, Zsuzsanna “Susan” Francia, recalled. “We’d be nodding along, and we were like, ‘Oh my gosh, fantastic,’ and after a little while, we’d be like, ‘When are we eating dinner?’ ”
This article is part of a series about the vaccine vanguard, the scientists who helped create coronavirus vaccines. Read about Drew Weissman and Barney Graham.
It was still relatively early in Kariko’s decades-long quest to turn basic biology into medicine. The idea that fired her imagination that day in 1993 would turn out to be a detour on an obscure personal journey filled with awe-inspiring ideas, careful experiments, successes that went largely unnoticed and the repeated sting of rejection.
Then, the coronavirus pandemic catapulted the questions Kariko had chipped away at on the margins of molecular biology to the red-hot center of science and medicine. Her fierce dedication, once seen as quixotic, was recognized as visionary. Her work undergirds coronavirus vaccines from Pfizer and German partner BioNTech, and Moderna.
The vaccine effort is far bigger than any one scientist’s dream. When the credits roll, a constellation of researchers, crisscrossing scientific disciplines and stretching back more than half a century, will get a mention. But Kariko and an immunologist named Drew Weissman whom she met at a photocopier nearly 25 years ago, will be two of the stars.
“I think she should be given credit for saving the world,” said Jean Bennett, a gene-therapy scientist at Penn who occupied the lab bench next to Kariko when they were starting their careers. Her ideas were “so ahead of her time, she had a hard time convincing people that they would actually work. They seemed too science fiction-y to people and too challenging.”
Kariko failed, repeatedly, to win the grants that would help give her scientific independence. It might have been easier to temper her impatient enthusiasm and direct her efforts toward more mainstream topics. But with tenacious, almost fanatical energy, she simply worked harder — arriving at the lab at 6 a.m. on weekdays and working nearly every weekend.
Recently, Kariko, 66, has become the object of pop culture fascination, appearing on Time magazine’s list of influential people of the year and in People magazine. Scholars who study innovation discuss how her story reveals blind spots in the scientific reward system — a tendency to shower support on incremental, predictable successes and not the ideas that are so risky and out of the box that they look impossible.
During the past few months, as if making up for lost time, she and Weissman have scooped up nearly ever major award in science and medicine, and both are considered contenders for the Nobel Prize.
Kariko looks at the setbacks differently. The years without money, fame or prestige, and the times she brought broken-down lab equipment home for her husband to fix or saved Hungarian pickle jars to store the ingredients for her experiments — these were essential. She wasn’t working for anyone else’s idea of success. She was working for herself.
Kariko remembers when, years ago, a colleague told another scientist, “Kati works for me.”
She spun on him.
“I don’t work for you. Do you think that Saturday, Sunday, I am here for you?” Kariko asked. “I am here for me. I am here to learn more and understand.”
‘Hooked on the science’
Kariko grew up in a two-room adobe house with a reed roof in the small village of Kisujszallas in Hungary. Her father was a butcher, her mother a bookkeeper. There was no running water. No television or refrigerator.
They had a garden. They had pigs. Kariko watched a neighbor’s cow give birth. She went on excursions to a nearby forest and remembers being curious about birds, plants, nature.
And she was good — and fiercely competitive — at science. By eighth grade, she ranked third-best in the country in biology.
As an undergraduate at the University of Szeged, she worked at the Biological Research Center in a laboratory focused on liposomes, bubbles that could be used to encapsulate genetic material. Hungary was behind the Iron Curtain, where it wasn’t easy to order laboratory ingredients. So the scientists looked up how to purify the phospholipids needed for their experiment. The investigator who ran the lab rode his bike to the slaughterhouse to pick up a cow brain so they could make their own phospholipids.
“This is the way I learned science, always, that there is no problem. You cannot buy something? You make it,” Kariko said.
She met her husband, Bela Francia, at a disco held as part of an annual biology celebration. He was 17, she 22. They married three years later. In graduate school in 1978, she started working with RNA. She wrote and defended her PhD thesis while pregnant.
In 1985, the lab where Kariko worked lost its funding. She looked for an opportunity in the United States, settling on a postdoctoral position at Temple University in Philadelphia.
The family bought one-way tickets and sold their car, smuggling the money inside a big brown teddy bear with red-rimmed eyes. A seam runs down its back, where Kariko performed the surgery. She keeps it in her daughter’s childhood room to this day.
Kariko worked at Temple for three years. Then, she got a job in Bethesda, Md., living there most of the week. She would read science papers until the library closed at 11 p.m., then stay at a friend’s apartment or simply spread a sleeping bag out on the office floor. At 6 a.m., she would start her experiments and go for a run.
In 1989, Kariko got a job at Penn’s medical school, a junior position that had the word “professor” in the title but was off the prestigious and secure tenure track. She would need grants or colleagues with extra funding to support her work.
She worked first with cardiologist Elliot Barnathan. Together, they showed messenger RNA could trigger human cells to pump out a complicated protein on demand. It was a proof of concept that opened the door to an array of medical applications.
After new blood vessels are stitched into patients for heart bypass surgery, about 10 percent will close during the first year, mostly because of blood clots. Barnathan and Kariko wanted to pretreat the blood vessels, by flushing through them messenger RNA that encoded therapeutic proteins. They hoped it would reduce the risk of a dangerous clot after surgery.
Bennett, the gene-therapy scientist, joined Penn a few years after Kariko and occupied a neighboring lab bench. Bennett had enough money to hire a laboratory technician but not enough to buy equipment.
Kariko recognized her plight, Bennett said, bequeathing an old refrigerator, “my first precious piece of equipment.” The fridge remains in Bennett’s lab, even though it has broken several times.
There weren’t many tenured female faculty then, and the ones Bennett knew did not have children. When Bennett asked one if she would take a vacation that year, the scientist said during the last week of August, she planned to leave at 5 p.m. and play golf every evening.
“I realized: This is tough. I don’t know if I can do this. But we both decided to put on the jets,” Bennett said. “We ran a hand-to-mouth campaign, but we were both so hooked on the science.”
As a PhD in a clinical department run by physicians with medical degrees who saw patients, Kariko was a “second-class citizen,” Barnathan said.
“At some point, there was not an interest in having her get promoted — and, in fact, she talks about it as being demoted,” Barnathan said. “It released her from the idea she had to do this stuff to climb the promotion scale. She could focus on her science. But in reality, I felt bad, because it was clear she was so bright and had such good ideas.”
Kariko is blasé about the struggle to balance family life with professional struggles. She often says Susan learned to get up, get dressed and take care of herself. She tears up a little remembering how little money they had.
Susan remembers her childhood differently. It’s true, she never saw her parents relax. Spring break meant a week hanging out in her mom’s lab because there was no money for a vacation. But there was a close-knit joy to their family — and deep pride in one another’s work.
Francia remodeled their house after his workday ended and built much of their furniture. Kariko was busy with work but found time to cook Hungarian food and bake chocolate cakes from scratch. Susan would do her homework, then hear the distinctive rattle of her mother pouring peanut M&Ms into a dish. She would run downstairs, and they would take a break.
Kariko was obsessed with messenger RNA, but colleagues say she also knew not to fall too deeply in love with any specific outcome and to learn from the data — even when it was disappointing. “Experiments never err, your expectations do,” Kariko likes to say, paraphrasing Leonardo da Vinci.
David Langer began working with her in Barnathan’s lab while he was a medical student. He was impressed by Kariko’s compulsive energy. She would spend a long day at work and then show up the next morning with a stack of new scientific papers, already highlighted, for him to catch up on.
Later, when he was in his neurosurgery residency, he learned Kariko was about to lose her lab. He pleaded with the neurosurgery department chair to take her on because he wanted to keep learning from her.
Together, Langer and Kariko worked on the idea of delivering messenger RNA to the blood vessels of the brain. It was a potential therapy for people suffering cerebrovascular spasm, a complication after certain types of stroke, when blood vessels spasm and trigger secondary strokes. The messenger RNA would deliver the code for an enzyme that synthesized nitric oxide, helping to dilate blood vessels and reduce the risk of death.
Langer respected Kariko but also saw how her inability — or unwillingness — to navigate the system worked against her. The fact she was an immigrant who spoke with an accent, that she was a woman in science may have made it easier for her to be overlooked. But more than that — she didn’t play the game.
He recalled Kariko standing up at a lab meeting and making a pointed, but accurate, critique of data being presented by a well-funded professor.
She was asked not to come back, he recalled.
“She knows she’s brilliant, and she doesn’t suffer fools,” Langer said. “And the reality of American research, which continues today, is pursuit of money is high on the list. Kate’s kind of the opposite. Kate does nothing for money. The reality is, she is doing the best science she can do and she has zero political savvy about how to navigate this world.”
‘How did I miss that?’
In the late 1990s, Kariko met a reserved immunologist named Drew Weissman who wanted to create an HIV vaccine and was considering different technologies. She told him about messenger RNA, touting its vast potential.
She offered to make messenger RNA for one of Weissman’s experiments.
“I make the RNA, that is what I’m doing. I’m good at it,” she told him.
When Weissman tested it in specialized immune cells he was interested in, he found the messenger RNA triggered an inflammatory response — a blow for Kariko.
“I was so sad,” she said. “How did I miss that?”
Solving that problem would be the beginning of what would become a world-changing scientific collaboration.
One of Kariko’s gifts as a scientist, her colleagues say, is her ability to design and execute thoughtful experiments, including thinking hard about the controls. A control can seem like an afterthought — a comparison run in parallel to ensure the results are really linked to whatever the scientist was testing. In a vaccine trial, the control is the group of people who receive a placebo shot.
In Kariko’s experiments with her lab-generated messenger RNA, she used as a control a naturally occurring kind of RNA, called transfer RNA. It did not trigger an inflammatory response. It was a clue.
Kariko and Weissman tried modifying their messenger RNA chemically to mimic the transfer RNA. They discovered that replacing a single letter of its four-letter alphabet could stop the messenger RNA from activating the immune system and increase tremendously the amount of protein cells produced.
They published their findings and patented the work in 2005. A year later, Kariko and Weissman founded a company called RNARx to commercialize this modified RNA. They won a small-business grant from the National Institutes of Health with the idea messenger RNA could be used to treat anemia.
The idea was ahead of its time. Two biotechnology companies — BioNTech in Mainz, Germany, and Moderna in Cambridge, Mass. — would recognize the potential even as RNARx struggled to find investors.
As biotech interest began to heat up outside their lab, the pair kept working on the science. Norbert Pardi, a scientist who grew up in Kariko’s small village in Hungary — whose grandfather worked in the butcher shop with Kariko’s father — had been meeting with Kariko every summer since he was in college. He came to Penn to work with Kariko and Weissman after he earned his PhD.
They had solved one problem — the immune reaction caused by messenger RNA — but still faced a different one. How would they get this incredibly fragile material into the body? Pardi worked on that.
Kariko taught him everything she knew about RNA. Typically, as scientists move through their career, their labs get larger and they spend less time running their own experiments. But Kariko didn’t have that success, and she also loved, and was unusually talented at, the benchwork.
“Kati taught me a lot, everything, about RNA,” Pardi said.
In 2013, Kariko retired from Penn as a senior research investigator. Her academic career looked nothing like a traditional success. But Kariko wasn’t done. She wanted her work to reach patients. She joined BioNTech, then a little-known start-up that had never created an approved medical product. She would live in Mainz, Germany, for 10 months out of the year.
“I could sit here and see the grass growing,” Kariko said, looking out on her wooded backyard in the Philadelphia suburbs. “And then I decided to go to Germany, to a biotech company that didn’t have a website, leaving my husband and my family behind. What the hell am I doing? For one week, every night, I cried myself to sleep.”
‘Watch the news today’
For months during the pandemic, Kariko would drop her daughter cryptic hints.
“Watch the news today,” she would tell Susan, who now works in the biotechnology industry. “Tomorrow, as soon as you wake up, Google search: BioNTech.”
“I think she hung up on me afterward: ‘I must go now, goodbye,’ ” Susan recalled.
Susan got married last year, and during the wedding prep, she would try to tell her mother about the dress she had chosen. But her mother would interrupt to talk about the coronavirus vaccine. The Pfizer-BioNTech and Moderna vaccines both depend on the modified RNA that Kariko and Weissman discovered.
For years, the family joke has been that Kariko is introduced at meetings with an important footnote: Her daughter is a two-time Olympic gold-medal rower. Then, at a certain point, over the last year and a half, things changed. A persistent Hungarian fan kept messaging Susan about getting an autographed picture.
She politely reminded him she had sent a picture already.
No, he said — he wanted an autographed photo of her mother.
Alice Crites contributed to this report.
Editing by Stephen Smith. Photo editing by Bronwen Latimer. Design by Tara McCarty. Copy editing by Melissa Ngo.