On 2nd October 2023 the Nobel Prize in Physiology or Medicine 2023 was announced as jointly awarded to Drs Katalin Karikó and Drew Weissman. The prize celebrates their “discoveries concerning nucleoside base modifications that enabled the development of effective mRNA vaccines against COVID-19″. Head of the Nobel Prize committee, Thomas Perlmann commented that “the work had a major impact on society during the recent pandemic”.
Nobel-worthy research
Karikó and Weissman reportedly met by “chance” while photocopying papers in the late 1990s. By this time, Hungarian biochemist Karikó had been “devoted” to developing therapeutic uses for mRNA. In the face of funding “difficulties” she and Weissman began a “fruitful collaboration” with a focus on how different RNA types engage with the immune system.
They established that dendritic cells recognise in vitro transcribed mRNA as a “foreign substance”, triggering activation and the release of inflammatory-signalling molecules. From here, they realised that “critical properties” must distinguish different types of mRNA, as they observed that the in vitro transcribed mRNA was picked up as “foreign” but mRNA from mammalian cells did not provoke such a reaction.
To investigate if the absence of altered bases in in vitro transcribed RNA could explain the inflammatory reaction, they produced different variants of mRNA, with unique chemical alterations in their bases. These were delivered to dendritic cells and produced “striking” responses. The inflammatory response was “almost abolished” when base modifications were included in the mRNA.
This result is described by the Nobel Prize statement as a “paradigm change” in our understanding of how cells recognise and respond to mRNA. Published in 2005, the “key discovery” was further illuminated in later studies, which revealed that the delivery of mRNA generated with base modifications “markedly increased protein production” in comparison with unmodified mRNA. This was due to the reduced activation of a protein production regulator enzyme.
“Through their discoveries that base modifications both reduced inflammatory responses and increased protein production, Karikó and Weissman had eliminated critical obstacles on the way to clinical applications of mRNA.”
Applications during the COVID-19 crisis
The University of Pennsylvania’s Penn Today suggests that the “true value of the pair’s lab work” was “revealed in the most timely of ways” during the COVID-19 pandemic. The companies that used Karikó and Weissman’s technology were able to build “highly effective” vaccines. The University’s President, Liz Magill, commented that the pair are “brilliant researchers” who “represent the epitome of scientific inspiration and determination”.
“Day after day, Dr Weissman, Dr Karikó, and their teams worked tirelessly to unlock the power of mRNA as a therapeutic platform, not knowing the way in which their work could serve to meet a big challenge.”
However, for Magill, the “greatest inspiration of all” is the promise that they will “not stop here”, representing “truest devotion to their field”.
Congratulations to Karikó and Weissman; we at The World Vaccine Congress look forward to your future success.
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