The Washington Post - USA (2021-10-26)

TUESDAY, OCTOBER 26 , 2021. THE WASHINGTON POST EZ EE E5

AMANDA ANDRADE-RHOADES FOR THE WASHINGTON POST

Laying the groundwork to fight the pandemic

These features are part of a series about the vaccine vanguard, scientists who helped create coronavirus vaccines. B arney Graham, the architect of the spike protein found in most of the vaccines, h olds a model of a respiratory syncytial virus p rotein in his home office in Rockville, Md. Read more about him at wapo.st/barney_graham_vaccine.

“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?’ ”
It was still relatively early in
Kariko’s decades-long quest to
turn basic biology into medicine.
The idea that fired her imagina-
tion that day in 1993 would turn
out to be a detour on an obscure
personal journey filled with awe-
inspiring ideas, careful experi-
ments, successes that went large-
ly unnoticed and the repeated
sting of rejection.
Then, the coronavirus pan-
demic 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 dedica-
tion, 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 constella-
tion of researchers, crisscrossing
scientific disciplines and stretch-
ing back more than half a cen-
tury, will get a mention. But
Kariko and an immunologist
named Drew Weissman whom
she met at a p hotocopier 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 sci-
entist 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 con-
vincing 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 enthusi-
asm 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 be-
come the object of pop culture
fascination, appearing on Time
magazine’s list of influential peo-
ple of the year and in People
magazine. Scholars who study
innovation discuss how her story
reveals blind spots in the scientif-
ic 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 near-
ly every major award in science
and medicine, and both are con-
sidered contenders for a future
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 hus-
band to fix or saved Hungarian
pickle jars to store the ingredi-
ents for her experiments — these
were essential. She wasn’t work-
ing for anyone else’s idea of suc-
cess. 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 a m
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 butch-
er, 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 fierce-
ly 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 lipo-
somes, bubbles that could be
used to encapsulate genetic ma-
terial. 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

KARIKO FROM E1

for their experiment. The investi- gator 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 some- thing? You make it,” Kariko said. She met her husband, Bela Francia, at a d isco 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 post- doctoral position at Temple Uni- versity in Philadelphia. The family bought one-way tickets and sold their car, smug- gling 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 s leeping 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 cardiolo- gist 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 therapeu- tic 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 chil- dren. 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 P hD 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,” Bar- nathan 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 f elt bad, because it was clear she was so bright and had such good ideas.”

Kariko is blasé about the strug- gle 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 hang- ing 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 distinc- tive 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 disap- pointing. “Experiments never err, your expectations do,” Kariko likes to say, paraphrasing Leonar- do da Vinci. David Langer began working with her in Barnathan’s lab while he was a medical student. He was impressed by Kariko’s compul- sive 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 cer- ebrovascular spasm, a complica- tion 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 l ab 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 technol- ogies. 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 scien-

tific collaboration. One of Kariko’s gifts as a scientist, her colleagues say, is her ability to design and execute thoughtful experiments, includ- ing thinking hard about the con- trols. 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 v accine 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 re- placing 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 strug- gled to find investors. As biotech interest began to heat up outside their lab, the pair kept working on the science. Nor- bert 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 materi- al 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 Kar- iko 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 investi- gator. 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, look- ing 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, good- bye,’ ” 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 Moder- na 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 foot- note: Her daughter is a two-time Olympic gold-medal rower. Then, at a c ertain 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. [email protected]

For Katalin Kariko, a dream decades in the making

“She knows she’s

brilliant, and she

doesn’t suffer fools....

Kate does nothing for

money. The reality is,

she is doing the best

science she can do.” David Langer

COURTESY OF KATALIN KARIKO For more than two decades, Drew Weissman and Katalin Kariko worked shoulder-to-shoulder at the lab bench to turn messenger RNA, the genetic instruction books that tell cells how to build proteins, into medicine.

The Washington Post - USA (2021-10-26)

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