The 2023 Nobel Prize in Physiology or Medicine goes to Katalin Karikó and Drew Weissman for their mRNA work which lead to the rapid development of vaccines against the COVID-19 pandemic. There is no mistaking the intent of the Nobel committee in this award to specifically recognize the contribution of mRNA vaccines. They open their press release with a discussion of vaccines and the pandemic.
The Science
Messenger RNA (mRNA) was discovered in 1961 at the Institut Pasteur in Paris. It was known that DNA (deoxyribonucleic acid) contains the genetic information of inheritance, which consists of genes that code for specific proteins. The DNA resides inside the nucleus of each cell, and yet protein is manufactured outside the nucleus. mRNA was discovered as the messenger – an mRNA molecule is made as a copy of a DNA gene (transcription), travels to outside the nucleus and then directs the assembly of a specific sequence of amino acids into a protein (translation). This process is known as the central dogma of molecular biology.
In the 1980s it was discovered how to manufacture mRNA outside of living cells – in vitro. This created the potential for using mRNA as a therapeutic tool. However, in vitro mRNA was not very stable and caused inflammatory reactions when injected into mammals. For this reason many researchers thought its therapeutic potential would be limited, even a dead end.
This is where Katalin Karikó and Drew Weissman come in. They began a collaboration into figuring out what was different between natural (in vivo) mRNA and in vitro mRNA. They discovered that in vivo mRNA has chemically modified bases compared to the in vitro version. Apparently a step was missing in the creation of in vitro mRNA.
RNA has four bases like DNA, but slightly different. DNA has the famous ATGC bases – adenine, thymine, guanine, and cytosine. They form the four-letter genetic code of DNA. RNA, rather has an AUGC code – with uracil replacing thymine. These bases are molecules that can be chemically modified.
The breakthrough for Karikó and Weissman came from research they did with various modifications of the RNA bases. They focused on the inflammatory reaction that in vitro RNA was provoking, which seemed to occur through stimulation of dendritic cells in the immune system. They found that a particular modification of the mRNA bases essentially shut down the inflammatory response of the dendritic cells. Their results were published in 2005.
They further found that the modified mRNA was more stable and significantly increased the translation into proteins. The modified bases, they found, also shut down a regulatory enzyme that decreased protein translation. These later findings were published in 2008 and 2010.
Their work revived interest in mRNA as a potential therapeutic tool. Moderna, one of the companies who eventually manufactured an mRNA vaccine, was founded in 2010, to capitalize on the work of Karikó and Weissman.
mRNA Vaccines
The science of in vitro mRNA is certainly important and impactful work, opening up a powerful new therapeutic tool for modern medicine. But it seems clear that Karikó and Weissman also partly owe their Nobels to the fact that the technology their research created met the moment with the COVID-19 pandemic.
The timing was perfect. Their research lead to the development of mRNA vaccine technology, initially working on Zika and MERS-CoV. But when the pandemic hit, the mRNA vaccine technology was ready, and was able to show its true potential.
mRNA vaccine work by injecting the code for a spike protein from the COVID virus (SARS-CoV-2) into the subject. The mRNA is taken up by the muscle cells where it is translated into the spike protein and released into the blood. This provokes an immune response against the protein, priming the body for later exposure to the full live virus.
One big advantage of this approach is that nothing has to be cultured. Vaccines made from modified or inactivated viruses require culturing of the virus in cells, which is a slow process. Meanwhile, we have the ability to mass produce in vitro mRNA once we know the genetic sequence, which is something we can now also do very quickly.
In vitro mRNA for these reasons is a fantastic vaccine platform. We encountered a novel virus, rapidly sequenced its genetic code, manufactured mRNA for its proteins, which were then modified and packaged in a delivery system. The pandemic hit in early 2020, and by December we had approval for two mRNA-based vaccines, which were rapidly mass-produced and distributed. Vaccines based on other platforms were also developed, but the mRNA vaccines were quicker and appear to be more effective. This is the kind of rapid-response technology we need for future pandemics.
The technology is also not done. Researchers are working on self-replicating mRNA, which I wrote about recently. This allows for the injection of a much smaller amount of mRNA which then replicates itself, providing a longer stimulation of the immune system and potentially greater immunity or reduced need for booster shots. This technology is still in development but showing promise.
There are also potential applications for mRNA technology beyond vaccines including immunotherapies, protein replacement therapies, and genome engineering.
The work of Karikó and Weissman was a critical fulcrum between the development of in vitro mRNA and therapeutic applications.
