Karikó and Weissmann started working together on possible chemical modifications to make a synthetic mRNA molecule more stable and less likely to set off a cell’s alarm mechanisms. They were particularly interested in dendritic cells, which play a crucial role in initiating and regulating an immune response. For mRNA to be useful as a therapeutic, it would need to be translated into protein for long enough to generate an immune response to that protein. Suspicious cells are much too quick to shut down protein production from unadorned RNA. If you try the brute force approach of chucking in a large amount of mRNA you run the risk of generating a serious inflammatory reaction.

In a landmark publication, cited by the Nobel Assembly, Karikó, Weissmann and colleagues showed the effects of different modifications of RNA – m5C, m6A, m5U, s2U and pseudouridine – on dendritic cell activation. A model mRNA with pseudouridine (or otherwise modified U) wasn’t recognised as dangerous by dendritic cell receptors. In the way of these things, the paper didn’t end up in one of the top three scientific journals (Nature, Science or Cell). The New York Times reported that ‘the study was eventually accepted by a niche publication called Immunity,’ a cause of some hilarity for immunologists who would on the whole be delighted to publish there.

The best example of a landmark paper being published in a truly niche journal was the discovery that led to our understanding of which cells produce antibodies. We now call them B cells, the B standing for bursa of Fabricius. This is an organ, situated at the wrong end of birds, that mammals lack: we produce B cells from our bone marrow. In a 1956 article entitled ‘The Bursa of Fabricius and Antibody Production’, Bruce Glick, Timothy Chang and George Jaap described the phenomenon whereby bursectomised chickens failed to raise an antibody response. Science rejected their paper and it was eventually published in Poultry Science – not a journal that many immunologists keep abreast of.

Karikó and Weissman followed up their finding published in Immunity with papers describing the role and utility of pseudouridine in Molecular Therapy and showed the importance of mRNA purification in Nucleic Acids Research: solid, unflashy stuff, also in time cited by the Nobel Assembly. But Karikó was demoted and then let go by her university: not productive enough, didn’t win enough big grants. We shouldn’t care where science is published – the whole business of scientific publishing is increasingly silly and in the end a scientific paper stands or falls on its merits – but we do care because careers depend on it.

https://www.lrb.co.uk/blog/2023/october/bursectomised-chickens-and-other-breakthroughs