mRNA contains four different bases, abbreviated A, U, G, and C. The Nobel Laureates discovered that base-modified mRNA can be used to block activation of inflammatory reactions (secretion of signaling molecules) and increase protein production when mRNA is delivered to cells. © The Nobel Committee for Physiology or Medicine. Ill. Mattias Karlén
The Nobel Assembly at Karolinska Institutet has 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.”
In 2005, the two University of Pennsylvania researchers published a seminal paper on the use of modified bases in in vitro-transcribed mRNA that received little attention. Fifteen years later, amidst the worst public health crisis since the Spanish Flu, that basic research laid the foundation for two vaccines that would end up saving millions of lives.
The big breakthrough
After working with different forms of RNA throughout her Ph.D., postdoctoral work and early career, Karikó set up her own group at the University of Pennsylvania with full intentions to make the mRNA platform suitable for clinical use.
That same year, Drew Weissman, a physician scientist with an interest in basic immunology and vaccine development, joined the University from the NIH, where he was a part of Anthony Fauci’s group, investigating how HIV-1 interacts with target receptors on different types of immune cells.
With Weissman’s background in immunology and Karikó’s expertise in RNA biochemistry, the two complemented each other well and were quick to team up, focusing on how different RNA types interact with the immune system.
Their big breakthrough came when they noticed that dendritic cells recognize in vitro transcribed mRNA as a foreign substance thereby activating an inflammatory response. However, the same did not occur for mRNA from mammalian cells. Why the difference?
RNA contains four bases, abbreviated A, U, G, and C, corresponding to A, T, G, and C in DNA. Karikó and Weissman knew that 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. The results were stunning: The inflammatory response was almost abolished when base modifications were included in the mRNA.
This was a paradigm change in the overall understanding of how cells recognize and respond to different forms of mRNA—a profound discovery for the use of mRNA as therapy.
In further studies published in 2008 and 2010, Karikó and Weissman showed that the delivery of mRNA generated with base modifications markedly increased protein production compared with unmodified mRNA. The effect was due to the reduced activation of an enzyme that regulates protein production.
“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,” said The Nobel Assembly at Karolinska Institutet during the announcement earlier today.
COVID-19 and more
When the COVID-19 pandemic began, both BioNTech and Moderna chose to use mRNA with modified bases building on the discoveries by Karikó and Weissmann. With unprecedented funding and support from governments, organizations and industry, both the Pfizer/BioNTech’s and Moderna’s mRNA vaccines for SARS-CoV-2 were proven safe, effective and deployable in record time.
The development of both vaccines was thanks in part to decades of basic research and optimization of mRNA vaccines, including Karikó and Weissman’s modified bases discovery in 2005. For example, both SARS-CoV-2 mRNA vaccines had complete substitutions of uridine with N1-methylpseudouridine (m1ψ) to avoid unwanted inflammatory responses, to ramp up protein translation, and to enable higher mRNA amounts to be used in each vaccine dose.
Since the approval of the first mRNA vaccine for SARS-CoV-2, more than 13 billion COVID-19 vaccine doses have been given globally. The availability of the vaccines saved millions of lives and prevented severe disease in many more.
Additionally, the success of the COVID-19 vaccines gave great promise to mRNA vaccines for other diseases, including different kinds of cancers, Lyme disease, HIV and more. It is likely that at least some of these varying mRNA applications will have different requirements for modified bases. Luckily, given Karikó and Weissmann’s basic research, scientists already know how to do that.
Information provided by Press release. NobelPrize.org. Nobel Prize Outreach AB 2023. Mon. 2 Oct 2023. <https://www.nobelprize.org/prizes/medicine/2023/press-release/>