Katalin Karikó
Katalin Karikó has always gotten where she’s wanted to go. At age 13, she ventured solo across Hungary from the small town where she grew up, Kisújszállás, to a selective science summer camp, navigating train changes along the way. Then she set off on foot, asking people along the way for directions. The next year, she again traveled on her own—this time to a national contest in Budapest. An adult was supposed to be waiting for her on the other end, and she hoped he’d be there.
She arrived. She thrived. She won third place in the country-wide biology competition.
Because the family did not have a telephone, her parents learned that the trip had gone smoothly only after she returned a week later. Until she was ten years old, they all lived in a one-room cottage with no running water and spotty electricity.
Karikó’s willingness to brave unknown territory has benefited the planet’s entire population. By figuring out how to create messenger RNA (mRNA) that human bodies can exploit and tolerate, she laid the bedrock for SARS-CoV-2 vaccines that have saved millions of lives. Her foundational work also promises to help individuals with an astounding array of other maladies. Throughout her career, she has triumphed over a plethora of technical, scientific, and professional challenges.
Although the physical environment of Karikó’s childhood was simple, her parents valued richness of the mind. Neither one had gone to high school, but her father played violin and could multiply two-digit numbers in his head. Her mother brought a radio and a record player into the family home. School work was a priority for Karikó and her sister.
After her dad lost his long-held position as a butcher because he participated in the 1956 Hungarian uprising, he did odd jobs until he was hired in a pub. “I could see that he was always coming up with a solution,” she says.
Science interested young Karikó. She watched the birth of a calf and marveled that a whole animal had fit inside the cow. She noticed that a shimmering blue feather turned gray when she ran her finger over it. Plants, especially, fascinated her.
At the University of Szeged, in Hungary, in the mid 1970s, the medical potential of mRNA captured her imagination. These molecules could, in principle, provide templates for any missing or defective protein. Unlike DNA, mRNA would not cause mutations by inserting into chromosomes and it would disappear—like a drug—rather than take up permanent residence in people’s cells.
Many practical barriers stood between this therapeutic fantasy and its realization. Scientists would need to make mRNAs of interest in test tubes, a feat that did not become feasible until 1984. They also needed to deliver the molecules to cells within animals. To accomplish this task, the mRNA required packaging to protect it from destructive enzymes en route. But a transport vessel alone would not solve the problem, as the cargo had to traverse the cell’s oily lipid bilayer, which repels mRNAs.
As an undergraduate, Karikó began tackling the delivery step. She wrapped DNA—a close relative of mRNA—inside lipid sacs called liposomes. When she required the starting material for this chemical sheathe, she had to spend about a week extracting essential ingredients from brains that her supervisor obtained from the slaughterhouse. During her Ph.D., she learned how to manipulate RNA. After graduation, she continued the project as a postdoctoral fellow, but funding dried up. In 1985, she left the lab—and the country—to pursue her scientific objective.
She, her husband, Béla Francia, and their toddler daughter, Susan, departed for Philadelphia, where she had secured a position at Temple University. Karikó sewed the family’s nest egg—proceeds from the sale of their car—into a teddy bear. Because Hungary limited exportable foreign cash, smuggling it out was the best option.
She spent three years there, and then moved to the Uniformed Services University of Health Sciences in Bethesda to learn molecular biology, where she got wind of a new product, lipofectin, a lipid that could carry nucleic acids into cells. Using it seemed a lot easier than making those liposomes in Hungary.
She needed an academic title to obtain a green card and she wanted to get back to her family, who had stayed put while she slept on friends’ floors in Bethesda during the week, so she applied for positions in the Philadelphia area. This search brought her to Elliot Barnathan, a cardiologist who was setting up his lab at the University of Pennsylvania. In 1989, he hired her as a research assistant professor, a non-tenured faculty position.
They aimed to devise an mRNA-based strategy to combat heart disease. Using lipofectin, the duo delivered to human cells in petri dishes an mRNA whose product fosters breakdown of blood clots. They made significant strides, obtaining copious amounts of functional protein.
By this time, other researchers had produced non-mammalian proteins in rodents by injecting the animals with mRNAs. Still, scientists’ enthusiasm floundered. mRNA instability presented an insurmountable hurdle, the thinking went, and although additional packaging materials were emerging, each one came with drawbacks.
Karikó bucked conventional wisdom and persevered. She wrote grant after grant; each one was rejected. Reviewers may have questioned whether a basic-science investigator in a clinical department could succeed on projects that large and experienced mRNA groups didn’t dare try. Institutional support faltered, in part because some local colleagues could not handle her unapologetic focus on robust inquiry rather than politics. At one presentation, she questioned whether the biological “signal” that her colleague showed exceeded background levels. She was asked not to attend those meetings anymore.
Barnathan paid her salary and tried to protect her from people who didn’t understand her value system or her science, but his influence had limits. In 1995, her position was revoked because she had timed out on the research assistant professorship without gaining promotion. She could stay if she would accept a demotion. Progress was percolating, and she decided to stick around.
Then Barnathan left Penn, and David Langer, a former medical student whom Karikó had trained and was now a resident, persuaded the chair of his department—Neurosurgery—to hire her. Langer believed in Karikó and he wanted to keep collaborating with her.
Karikó tenaciously absorbed information and sought opportunities that might further her quest. In 1997, she met Drew Weissman, a new faculty member, who wanted to create an HIV vaccine. She offered to make him mRNA that encoded his HIV protein of choice.
When they delivered this mRNA to dendritic cells, sentinels of the immune system, grown in culture dishes, it supported generous production of the HIV protein. Unfortunately, the mRNA also sparked potent immunostimulatory signals. This behavior rendered the system inappropriate for therapeutic use because unintended inflammation can cause serious harm. Some of these effects interfere with vaccine applications as well, although the investigators did not know that at the time. Fortunately for both ventures, Karikó was committed to developing mRNA as a protein-replacement tool, so she resolved to circumvent the unacceptable immunoreactivity.
As the researchers attempted to ferret out features of the mRNAs that mobilized the immune response, they noticed that a particular type of RNA was immunologically quiet. Intrigued, Karikó realized that this molecule contains large numbers of so-called modified nucleosides—RNA building blocks that differ in subtle chemical ways from their normal counterparts. By substituting modified versions for their conventional cousins, she and Weissman found that certain replacements generated mRNAs that don’t provoke the immunological blast. Supplanting uridine with its pseudouridine analog was especially effective.
In 2005, they published these breakthrough results and waited for the conference invitations to roll in, but none came. They marched onward, and the data sparkled even brighter. Cells that carried pseudouridine-containing mRNA produced more protein than those that carried unmodified mRNA. This property as well as the lack of immunoreactivity held up in mice. The team reported these findings in 2008.
The following year, Karikó asked to be reinstated as a research assistant professor. She was told that she was “not faculty quality,” she says.
In the meantime, one scientist had grasped the significance of the modified mRNAs. Derrick Rossi, then at Harvard Medical School, deployed the agents to convert fully developed mammalian cells into embryonic stem cells. This high-profile result, published in 2010, awakened biologists and helped launch the company Moderna.
Although the pseudouridine trick slashed inflammation, residual levels remained. Karikó and Weissman’s team figured out how to separate mRNA from the contaminants that spurred this unwelcome response. They then assessed whether the methodology would support manufacture of a physiologically relevant protein in animals. They injected mice with mRNA that encodes erythropoietin, a hormone that is administered to treat some forms of anemia. Quantities of the substance rose in the rodents’ blood and so did red blood cell counts, the researchers reported in 2012. They demonstrated similarly promising results in monkeys, all without inducing the problematic immune reaction.
In 2013, Karikó joined BioNTech to work on protein-replacement therapies. She and Weissman—now separated by the Atlantic Ocean—continued to improve the modified mRNA-based strategy. Crucially, they sought a packaging system devoid of downsides—toxicity, lability, or other characteristics that would compromise use in humans. Many labs were developing candidate substances, and the team tested each one. Using so-called lipid nanoparticles, Karikó and Weissman’s group produced a promising vaccine against Zika virus that conferred rapid and lasting immunity in mice and monkeys.
When the SARS-CoV2 pandemic hit in 2020, the technology was ready. BioNTech/Pfizer and Moderna made safe and powerful vaccines with unprecedented speed. To date, hundreds of millions of people across the globe have received these life-saving interventions.
Karikó’s relentless allegiance to her goal prompted a medical revolution. Researchers are exploiting modified mRNAs to develop vaccines for manifold microbial scourges, and they are harnessing the molecules to treat a range of afflictions, including cancers, infectious diseases, autoimmune disorders, heart failure, and inherited illnesses. Katalin Karikó and her dream of mRNA-based remedies have arrived.
Authored by Evelyn Strauss, Ph.D.