How the World of mRNA was Changed by 2023 Nobel Laureates

Over the past two decades, advanced therapies have flooded the medicinal scene. Pharmaron’s expertise can accommodate a range of advanced therapy developments, with cell and gene therapy capabilities as well as mRNA therapeutics. For example, LC-MS capabilities to assess new lipid nanoparticle delivery systems and in-house process innovation for production. 

In light of the 2023 Nobel Prize in Physiology or Medicine, how did proof of concept from 2005 become vaccines that saved millions globally from COVID-19? And how is Pharmaron involved in mRNA’s past, present, and future?

In the late hours of October 1, 2023, most of us were preparing for the Monday morning ahead. For Dr. Katalin Karikó and Dr. Drew Weissman, the night was flush with anticipation as recognition of their decades of perseverance was just moments away. The following morning, October 2, the Nobel Prize in Physiology or Medicine was awarded to Drs. Karikó and Weissman “for their discoveries concerning nucleoside base modifications that enabled the development of effective mRNA vaccines against COVID-19”.¹

While an unprecedented surge of attention brought clinical mRNA research to scientific celebrity in 2019, Weissman and Karikó had already collaboratively published their breakthrough mRNA discovery 14 years prior in 2005.² So what does it take to earn a Nobel Prize? 

For decades after the conception of in vitro mRNA synthesis in 1969, scientists faced a major barrier in the translation of mRNA research for therapeutic use. In vitro synthesized mRNAs were wholly rejected by cells, inciting inflammatory reactions—our bodies were recognizing lab-grown mRNAs as foreign. This erased much of the hope surrounding mRNA therapeutic discovery. Karikó was unperturbed. Meanwhile, Weissmann, a physiologist at UPenn, was carrying out research with dendritic cells, which was perfect for a partnership with Karikó. It would be their chance meeting and fortuitous collaboration that yielded the monumental 2005 success entitled “Suppression of RNA Recognition by Toll-like Receptors: The impact of nucleoside modification and the evolutionary origin of RNA”.²

Toll-like receptors (TLRs) are a component of the innate immune system responsible for recognizing pathogens and orchestrating an immune response. It is now understood that these TLRs recognize and respond to different nucleic acids (the building blocks of DNA, RNA, mRNA, tRNA etc.) from pathogens and fully translated components. In 2000, just 5 years before the Nobel-earning discovery, a different team identified that synthetic DNA, when unmethylated, activates TLR9, instigating an immune response. Keen to investigate how cells were differentiating in vitro mRNA from mammalian derived, Karikó and Weiss narrowed in on a similar difference.

Inspired by the established knowledge surrounding DNA, the pair investigated the impact of post-translational processing modifications in RNA. Mandatory modifications include end capping and polyadenylation, but it is common for mRNA to be additionally chemically modified at internal points. Among these modifications are acetylation, sulfonation, methylation, lipidation, amidation and pseudouridylation—the key modification that facilitated the COVID-19 vaccine. Karikó and Weiss initially tested five total chemical isosteres including three of the four major building blocks of mRNA— A, U, G, and C. The original five were: m5C, m6A, m5u, s2U, and pseudouridine (m5C refers to methylation on the fifth carbon of cytosine, s2U to sulfonation of the second carbon of uracil).

The dendritic cells fed the modified synthetic mRNA, which demonstrated increased transcription and decreased intensities of inflammatory reaction proportional to the quantity and diversity of modifications.^2,5

These results are the foundation of the December 2020 COVID-19 mRNA vaccines. Along with two further landmark papers in 2008 and 2010 detailing the increased translational potential of modified mRNA and the precise effect of pseudouridylation respectively, Karikó and Weismann reignited the hope for mRNA therapeutics. ^5,6 While the research alone was and is still groundbreaking, the recognition is also situational. Their Nobel prize, like most, is a result of the research of many in their area and in others, one crucial contribution was optimization of the vaccine technology itself.

The mRNA vaccine technology was designed and executed— in record time— as an alternative to traditional viral-vectored vaccines that use a disarmed or weakened fragment of a virus to ‘teach’ the immune system. The traditional process has been enormously successful (notice we don’t hear too much about polio nowadays), but mass-producing and manually weakening viral components is time-consuming. The new method was imperative for the unprecedented 11-month turnaround seen in 2020. mRNA vaccines are governed by the same principles as traditional vaccines. However, because they deliver mRNA fragments encoding viral proteins instead of a full protein, the arduous task of translation (protein building) is left in the very competent and efficient ‘hands’ of our own cells. 

While the outside world slowly returns to normal, the world of mRNA remains invigorated by both the success of the COVID-19 vaccine and now the 2023 Nobel Prize. Pharmaron is experiencing this invigoration too. In 2021, the global scientific community rallied behind efforts to produce effective synthetic mRNA, but also effective methods of delivery. The Discovery Process Chemistry team at Pharmaron’s Beijing campus contributed to the “development of a safe and scalable process for the production of a high purity thiocarbamate based ionizable lipid as an excipient in mRNA encapsulating lipid nanoparticles (LNPs)”.⁷ In more recent years Pharmaron has continued to contribute in important ways. Whether it be the smaller-scale contribution to the development of SYS6006, a novel mRNA vaccine against SARS-Cov-2, or the £151 million investment in the soon-to-open Liverpool campus expansion focusing on gene therapies and vaccine development, Pharmaron makes essential contributions to the continuation of this year’s Nobel Prize discoveries.^8,9