Research in the U.S.
Katalin Karikó moved to the USA with her family in 1985. She and her husband were able to smuggle in dollars exchanged on the black market sewn into their daughter’s teddy bear, and they sold everything they owned to buy their one-way tickets. They had to start a whole new life. Scholarship opportunities awaited in Spain, France, and England, but the U.S. employment contract was the most promising. Karikó was supported by her family in everything: she spent most of her time in the laboratory, obsessively conducting research or just busy reviewing the literature. She continued her work at the Department of Biochemistry, Temple University, Philadelphia, PA, in the laboratory of Robert Suhadolnik, an expert on modified nucleosides. As a continuation of her research in Szeged, attempts were made to design and introduce into cells antiviral synthetic oligonucleotides by modifying nucleosides. Some of their developments even reached the phase of clinical trials, however, techniques of cell delivery were not sufficiently advanced at the time. Karikó then worked briefly at Bethesda, MD, research center northeast of Washington D.C. It was here that she became acquainted with interferons and immersed herself in molecular biology. This work involved a multi-hour commute between Bethesda and Philadelphia.
But armed with the experience gained at this time, she continued her work at the University of Pennsylvania from 1989 (Cardiovascular Division, Department of Medicine, School of Medicine). It was here that she decided that she wanted to make mRNA suitable for therapeutic purposes. Since mRNA is an unstable molecule, and at that time the problem of its delivery and synthesis into the cell had only just been solved, not many people gave it a chance. So much so, that although she wrote many applications, one after the other, all of them were rejected. She was demoted in 1995, unable to obtain a full professorship. Despite all these difficulties, she persisted with her chosen topic, although sometimes considering a change. The main topic of research in the cardiology department of the university was the delivery of urokinase receptor into cells using synthetic mRNA and lipofectin as a mode of delivery. The method proved to be successful in cell cultures, and post-translational modifications were also present in the finished, functional protein – a result that filled her with confidence.
When Karikó continued her work in neurosurgery from 1998 with immunologist Drew Weissman (Weissman Lab, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania), their research focused on vaccine development for the HIV virus. Weissman first tried DNA, but switched to mRNA on Karikó’s advice. At that time, they could not yet know how long and fruitful their cooperation would be. In contrast to previous work, they focused on immune cells (human dendritic cells) and soon discovered that the introduced synthetic mRNA unfortunately induced an immune response (2000).
Others might have been deterred by this result, but Katalin Karikó tried with renewed vigor to find a solution. Subsequently, her research focused on what caused this phenomenon and how to avoid an unwanted immune response. The main objectives of her research were to investigate the therapeutic possibilities of mRNA and the interactions between synthetic mRNAs and the immune system, and later to investigate the role of RNA-binding immune receptors (some of the Toll-like receptors).
The effect of various natural RNA isolates on immune cells was also studied. Unexpectedly, it was found that the least immunogenic was the transfer RNA (tRNA) molecule. The reason for this was thought to be discovered in that it contained a large number of modified nucleosides. It was known that more than 100 modifications were possible, but at that time the enzymes that generated them had not been identified, and only a few modified nucleosides were available for synthesis. Modified nucleosides that did not occur in nature were not used, based on the previous negative experience of other researchers. Of the 10 types of molecules available on the market at the time, only 5 could be incorporated into the synthetic mRNA molecule. Fortunately, it was found that 4 modifications of the uridine base made the molecule non-immunogenic (2005). In 2008, it also became clear that, of the 4 types of modified uridine, the incorporation of pseudouridine into the mRNA molecule resulted in the production of large amounts of protein. These discoveries provided a real breakthrough. Since 2006, Karikó and Weissman have been successful at applying for funding from the American National Institute of Health (NIH). Although only few noticed their results for a while, two companies were founded to use this technology, BioNTech and Moderna, in 2008 and 2010, respectively. Karikó and Weissman also founded a company in 2005, called RNARx, but they could not obtain the patent rights for themselves. These were owned by the University of Pennsylvania and then also purchased by Moderna and BioNTech through CellScript LLC. In 2011, another graduate of the University of Szeged, biologist Norbert Pardi joined Katalin Karikó's research group. By 2012, an in vivo animal experiment also demonstrated that the procedure did not elicit an immune response and produced a functional protein. In 2013, BioNTech, Europe's largest privately owned biotechnology company, offered Katalin Karikó a position as vice president (and that of senior vice president in 2019). She joined the company together with her colleague Hiromi Muramatsu, with whom she had previously conducted extensive work in the laboratory. They sought to work with a company that had a clinical program and already produced mRNA for therapeutic purposes. Eventually, the company’s modified mRNA program was launched by them. Meanwhile, Norbert Pardi took over the management of the Philadelphia lab from Kariko.
By 2017, the first, anti-Zika vaccine containing modified mRNA encapsulated in lipid nanoparticles was developed in collaboration with Norbert Pardi. And the COVID-19 pandemic in 2020 brought Karikó world fame in connection with the development of the vaccine jointly developed by BioNTech and Pfizer.