In this prologue to our Spotlight series focusing on mRNA biotechnology, we take a look at the history of mRNA research.
Approval of the mRNA based COVID vaccines from Moderna and Pfizer has shone a spotlight on mRNA technology. The speed of these approvals has led some people to assume that mRNA vaccine technology is new. However, while it is true that we have only recently begun to be able to harness the potential of mRNA, in fact the story of its discovery and the research and development into its use as a vaccine is a long one which began back in the 1960s.
mRNA was discovered in 1961. Given mRNA’s importance in the process by which our genetic information is translated into proteins, the possibility of harnessing this process and using mRNA e.g. as a therapy to treat genetic diseases has long been considered. However, it wasn’t until the 1990s that research on mRNA therapies began to gain momentum, and even then the field of synthetic mRNA research encountered many difficulties and scientific scepticism.
On paper, the idea of using mRNA as a vaccine or therapy makes sense. If you could design and synthesize mRNA (i.e. synthetic mRNA), you could use it to prompt cells in the body to produce any protein you could think of. In principle this has broad reaching implications. For example, this process could be used as a protein replacement therapy to treat genetic diseases caused by the body’s inability to produce a particular protein (such as is the case in various metabolic disorders). Or, it could be used as a vaccine, prompting cells to make an antigen which would be recognised by our immune systems (as is the case with the SARS-COV-2 spike protein and the mRNA COVID vaccines).
However, there have been two major roadblocks with synthetic mRNA. Firstly, mRNA is much less stable than DNA and it breaks down quickly in the body. Delivering mRNA to the right place in the right cells has therefore proved difficult as it is often destroyed in the process. Another difficulty that scientists have grappled with is that once synthetic mRNA has been delivered into the body it can trigger an excessive immune response with serious consequences for patients.
Given these difficulties, for a long time synthetic mRNA research did not receive as much attention relative to other research areas such as gene therapy and gene editing. However, some researchers persevered. In particular, a Hungarian born scientist at the University of Pennsylvania, Katalin Karikó, continued to try and solve the issues with mRNA delivery and immune response.
In the mid-2000s, after more than a decade of work and several set-backs, this perseverance paid off as Katalin Karikó and her collaborator at Penn, Drew Weisman, discovered a way to alter mRNA so that it would not itself trigger the immune system by modifying some of the mRNA nucleosides. The initial difficulties of delivery of the mRNA into the body without being broken down has also been solved. Several delivery systems have now been developed for mRNA including lipids, lipid-like materials, polymers and protein derivatives. One of the most commonly used delivery systems is lipid nanoparticles (LNPs) into which mRNA is packaged.Both the Pfizer / BioNTech and Moderna COVID Vaccines use LNPs which enable the mRNA to be delivered intact to where they are needed in the body.
These breakthroughs spurred renewed interest in the potential of mRNA, including from individuals who would go on to later found Moderna in the US and BioNTech in Germany. Both Moderna and BioNTech have gone on to take licences of the mRNA technology developed by Karikó and Weissman at Penn. Such has been the importance of their work that this month Karikó and Weissman have been awarded the 2022 Breakthrough Prize in Life Sciences (renowned as the “Oscars of Science”) which comes with a $3 million prize pot. There have also been calls for the pair to be awarded a Nobel Prize for their work on mRNA. To bring the story full circle, Karikó is currently serving as Senior Vice President at BioNTech, overseeing its mRNA programme.
There are many exciting potential applications for mRNA. We have examined the most promising ones in our article “Spotlight on mRNA: what is mRNA and what can it be used for?”
Both the Pfizer/BioNTech and Moderna vaccines were initially approved for use in the UK under an Emergency Use Authorisation and in the United States under an Emergency Use Authorisation. The Pfizer/BioNTech vaccine received full approval in the United States in August 2021
 Cobb, M. Who discovered messenger RNA? Curr. Biol. 25, R526–R532 (2015). doi: https://doi.org/10.1016/j.cub.2015.05.032
 Maria Cristina Valsecchi, Rare diseases the next target for mRNA therapies, Nature Italy, 09 May 2021. doi: https://doi.org/10.1038/d43978-021-00058-x
 Hou, X., Zaks, T., Langer, R. et al. Lipid nanoparticles for mRNA delivery. Nat Rev Mater (2021). https://doi.org/10.1038/s41578-021-00358-0
 Pardi, N., Hogan, M., Porter, F. et al. mRNA vaccines — a new era in vaccinology. Nat Rev Drug Discov 17, 261–279 (2018). https://doi.org/10.1038/nrd.2017.243