Rejection to Triumph: Katalin Karikó

It is by no means a surprise that Katalin Karikó and her colleague, Drew Weissman, were awarded the 2023 Nobel Prize in Physiology or Medicine on October 2, 2023. Their discoveries concerning nucleoside base modifications were a scientific breakthrough, pioneering the profound development of COVID-19 vaccines. Karikó’s incredible journey from impoverished beginnings in Hungary to making discoveries integral to vaccine development is a testament to her success. 

Karikó’s story begins at the University of Szeged in Hungary, where she pursued her Bachelor of Science in biology and Ph.D. in biochemistry, completing her doctoral studies in 1982. Karikó continued her academic and research career by undertaking postdoctoral research at the Institute of Biochemistry of the Biological Research Centre in Hungary, where, despite great adversity, she conducted research and began exploring the therapeutic potential of mRNA—the transfer site of genetic information encoded in DNA that is used as a template for protein production. Trouble struck Karikó’s research during this time. With the sweep of communism, Hungary faced resource constraints, particularly in scientific fields. Funding for research and access to equipment and materials were often limited, making it challenging for young scientists like Karikó to conduct research. Karikó also faced gender discrimination as she fought to make a name for herself in a male-dominated field. 

Much skepticism accompanied Karikó’s decision to explore the therapeutic potential of mRNA. In the 1980s, in vitro transcription—an efficient method for producing mRNA without cell removal—was introduced. This method recreates the cellular mechanism of the DNA to RNA transcription process in a test tube, then uses radioactively labeled nucleotides to make the resulting RNA strand radioactive. These features allow it to serve as a probe in further tests. This allowed for increased use of mRNAs, which are vital in the human body because they instruct cells to produce antigen molecules, which then stimulates the production of antibody proteins that fight disease. This decisive step of in vitro transcription initially accelerated the development of molecular biology applications in several fields, including mRNA technologies, but roadblocks lay ahead. mRNA was considered unstable and challenging to deliver, as it required the development of sophisticated carrier lipid systems to encapsulate it. The mRNA gave rise to inflammatory reactions within the cells, and the body's natural defense mechanisms quickly degraded the synthetic mRNA. Thus, enthusiasm for developing the mRNA technology for clinical purposes was limited among clinicians. 

However, these obstacles did not discourage Karikó, who was devoted to developing methods to use mRNA for therapy. In doing so, Karikó emigrated to the U.S. in 1985 to take a postdoctoral position at Temple University in Philadelphia. She eventually became a research assistant professor at the University of Pennsylvania, but she was demoted in 1995 because she never got a National Institutes of Health grant for her mRNA research. This was once again the result of the heavy skepticism around her research. Yet she persisted, and a few years after this setback, in 1998, she met immunologist Weissman, and the two conversed about mRNA. Their conversation intrigued Weissman, who then asked Karikó to work in his lab. Weissman was initially interested in dendritic cells, which have essential functions in immune surveillance and the activation of vaccine-induced immune responses. Spurred by new ideas from Karikó, a fruitful collaboration between the two began, focusing on how different RNA types interact with the immune system. 

Karikó and Weissman noticed that dendritic cells recognize in vitro transcribed mRNA as a foreign substance, which leads to their activation and the release of inflammatory signaling molecules. In contrast, the in vitro transcribed mRNA was recognized as foreign from mammalian cells and did not give rise to the same reaction. Karikó and Weissman knew that bases in RNA from mammalian cells were frequently chemically modified, while in vitro transcribed mRNA were not. They wondered if the absence of altered bases in the in vitro transcribed RNA could explain the unwanted inflammatory reaction. To investigate this, they produced different variants of mRNA, each with unique chemical alterations in their bases. These RNAs were then delivered to dendritic cells, and the results were striking: the inflammatory response was almost abolished when base modifications were included in the mRNA. This signaled a massive change in human understanding of how cells recognize and respond to different forms of mRNA. Karikó and Weissman adapted this in further studies published in 2008 and 2010, in which they showed that the delivery of mRNA generated with base modifications markedly increased protein production when compared to unmodified mRNA. The effect was due to the reduced activation of an enzyme that regulates protein production. Thus, these invented modified mRNA technologies were proven to be successful in producing proteins inside the human body that fight pathogens, and they were then used in Pfizer-BioNTech and Moderna's vaccines to prevent COVID-19 infection.

The groundbreaking research of Karikó has undeniably reshaped the landscape of mRNA-based therapeutics and opened the doors to an exceptional era of medical innovation. Her pioneering work in developing mRNA vaccines, notably the COVID-19 vaccine, has not only changed our ability to combat infectious diseases but has also offered promising possibilities for treating a wide array of formerly untreatable conditions, including some cancers and genetic disorders. Karikó’s dedication and perseverance in scientific exploration have demonstrated the profound impact that a single individual can have on the world of medicine. Her findings with Weissman make them deserving holders of the Nobel Prize.