Stockholm, Sweden · 2 October 2023 — The Nobel Assembly at Karolinska Institutet announced that the 2023 Nobel Prize in Physiology or Medicine has been awarded 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." The prize recognised foundational research conducted at the University of Pennsylvania in the early 2000s — work that was initially met with scepticism but ultimately transformed global vaccinology.
The laureates' discoveries fundamentally changed the understanding of how mRNA interacts with the human immune system and contributed to the unprecedented rate of vaccine development during one of the greatest threats to human health in modern times.
The Promise and Problem of mRNA
In cells, genetic information encoded in DNA is transferred to messenger RNA (mRNA), which serves as a template for protein production. During the 1980s, efficient methods for producing mRNA without cell culture — known as in vitro transcription — were introduced, accelerating molecular biology across multiple fields.
Researchers had long hoped to use mRNA for vaccine and therapeutic purposes. Unlike traditional vaccines that require large-scale cell culture to produce killed or weakened viruses, mRNA vaccines could theoretically be designed and manufactured rapidly. However, significant roadblocks stood in the way: in vitro transcribed mRNA was unstable, difficult to deliver, and triggered inflammatory reactions. Enthusiasm for clinical applications was initially limited.
A Fruitful Collaboration
Hungarian biochemist Katalin Karikó was devoted to developing methods to use mRNA for therapy. As an assistant professor at the University of Pennsylvania in the early 1990s, she persisted in her vision despite difficulties convincing research funders of its significance. A new colleague, immunologist Drew Weissman, was interested in dendritic cells — key players in immune surveillance and the activation of vaccine-induced immune responses. Their collaboration began focusing on how different RNA types interact with the immune system.
Karikó and Weissman noticed that dendritic cells recognise in vitro transcribed mRNA as a foreign substance, leading to activation and the release of inflammatory signalling molecules. They wondered why in vitro transcribed mRNA was recognised as foreign while mRNA from mammalian cells did not produce the same reaction.
The Breakthrough: Base Modifications
The researchers realised that bases in RNA from mammalian cells are frequently chemically modified, while in vitro transcribed mRNA is not. They hypothesised that the absence of altered bases could explain the unwanted inflammatory reaction.
To test this, they produced different variants of mRNA, each with unique chemical alterations in their bases, and delivered them to dendritic cells. The results were striking: the inflammatory response was almost abolished when base modifications were included in the mRNA.
From Discovery to Vaccine
In further studies published in 2008 and 2010, Karikó and Weissman demonstrated that mRNA generated with base modifications markedly increased protein production compared to unmodified mRNA, due to reduced activation of an enzyme that regulates protein production. By showing that base modifications both reduced inflammatory responses and increased protein production, they had eliminated the critical obstacles to clinical applications of mRNA.
Interest in mRNA technology began to accelerate. By 2010, several companies were working on the method, pursuing vaccines against Zika virus and MERS-CoV — the latter closely related to SARS-CoV-2. When the COVID-19 pandemic struck in early 2020, two base-modified mRNA vaccines encoding the SARS-CoV-2 surface protein were developed at record speed, reporting protective effects of around 95% and receiving regulatory approval by December 2020.
The Laureates
Katalin Karikó was born in 1955 in Szolnok, Hungary. She received her PhD from the University of Szeged in 1982 and conducted postdoctoral research at the Hungarian Academy of Sciences, Temple University, and the University of Health Science in Bethesda. In 1989, she was appointed Assistant Professor at the University of Pennsylvania, where she remained until 2013. She then became vice president and later senior vice president at BioNTech RNA Pharmaceuticals. Since 2021, she has been a Professor at Szeged University and an Adjunct Professor at the Perelman School of Medicine at the University of Pennsylvania.
Drew Weissman was born in 1959 in Lexington, Massachusetts. He received his MD and PhD from Boston University in 1987, completed clinical training at Beth Israel Deaconess Medical Center at Harvard Medical School, and performed postdoctoral research at the National Institutes of Health. In 1997, he established his research group at the Perelman School of Medicine at the University of Pennsylvania, where he is the Roberts Family Professor in Vaccine Research and Director of the Penn Institute for RNA Innovations.
The 2023 Nobel Science Season
The Medicine prize was the first of the 2023 science Nobels announced:
| Prize | Laureates | Citation |
|---|---|---|
| Physiology or Medicine | Katalin Karikó, Drew Weissman | Discoveries concerning nucleoside base modifications that enabled mRNA vaccines against COVID-19 |
| Physics | Pierre Agostini, Ferenc Krausz, Anne L'Huillier | Experimental methods that generate attosecond pulses of light for the study of electron dynamics in matter |
| Chemistry | Moungi G. Bawendi, Louis E. Brus, Alexei I. Ekimov | Discovery and synthesis of quantum dots |
The Physics prize honoured the development of attosecond light pulses — the shortest flashes ever created — which allow scientists to observe the movement of electrons within atoms. The Chemistry prize recognised the discovery and synthesis of quantum dots, nanoscale semiconductor particles now used in television displays, LED lighting, and biomedical imaging.
Looking Forward
The impressive flexibility and speed with which mRNA vaccines can be developed pave the way for using the platform against other infectious diseases. In the future, the technology may also be used to deliver therapeutic proteins and treat certain cancer types. The mRNA platform represents one of the most significant advances in vaccinology in decades, and its applications extend far beyond the pandemic that brought it to global prominence.
Sources
- Nobel Prize press release, Nobel Assembly at Karolinska Institutet, 2 October 2023 —
- Karikó K, Buckstein M, Ni H, Weissman D. Suppression of RNA Recognition by Toll-like Receptors. Immunity 23, 165–175 (2005)
- Karikó K et al. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector. Mol Ther 16, 1833–1840 (2008)
- Nobel Prize in Physics 2023 press release —
- Nobel Prize in Chemistry 2023 press release —
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