On October 2, 2023, The Nobel Assembly at the Karolinska Institutet awarded the 2023 Nobel Prize in Physiology or Medicine jointly to Katalin Karikó and Drew Weissman “for their discoveries concerning nucleoside base modifications that enabled the development of effective mRNA vaccines against COVID-19.” [Source: Nobel Prize Announcement]

The Nobel Prize in Physiology or Medicine is presented annually by the Nobel Assembly at the Karolinska Institutet for outstanding discoveries in physiology or medicine. It is one of five separate prizes established by Alfred Nobel’s 1895 will, awarded “to those who, during the preceding year, have conferred the greatest benefit to humankind” in the fields of Physics, Chemistry, Physiology or Medicine, Literature, and Peace.

The awarded discoveries by Karikó and Weissman were deemed critical for developing effective mRNA vaccines against COVID-19 during the pandemic that began in early 2020. Their work contributed to the unprecedented rate of vaccine development during one of the greatest threats to human health in modern times. Their groundbreaking findings fundamentally changed the understanding of how mRNA interacts with the immune system.

Katalin Karikó, a Hungarian biochemist, and Drew Weissman, an American immunologist, started their collaboration in the early 1990s while working at the University of Pennsylvania. They developed methods to use mRNA for therapy, leading to the discovery that dendritic cells recognize in vitro transcribed mRNA as a foreign substance, activating vaccine-induced immune responses. RNA contains four bases, abbreviated A, U, G, and C, corresponding to A, T, G, and C in DNA, the letters of the genetic code. Karikó and Weissman knew that nucleoside bases in RNA from mammalian cells are frequently chemically modified, while in vitro transcribed mRNA is 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, which they delivered to dendritic cells. Thus, they have found out that the inflammatory response was almost abolished when base modifications were included in the mRNA.

Karikó and Weissman’s key publications in 2005 were a paradigm shift, revealing that modifying the bases of mRNA reduced the inflammatory response. These findings, made fifteen years before the COVID-19 pandemic, became a stepping stone for the development of vaccines that saved millions of lives and allowed societies to return to normal conditions.

References/Key Publications:

  1. Karikó, K., Buckstein, M., Ni, H., & Weissman, D. (2005). Suppression of RNA Recognition by Toll-like Receptors: The impact of nucleoside modification and the evolutionary origin of RNA. Immunity, 23(2), 165–175.
  2. Karikó, K., Muramatsu, H., Welsh, F.A., Ludwig, J., Kato, H., Akira, S., & Weissman, D. (2008). Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol Ther, 16(10), 1833–1840.
  3. Anderson, B.R., Muramatsu, H., Nallagatla, S.R., Bevilacqua, P.C., Sansing, L.H., Weissman, D., & Karikó, K. (2010). Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation. Nucleic Acids Res., 38(17), 5884–5892.