How do mammalian cells handle mRNA therapeutics: Optimising the molecular basis of manufacture

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The use of mRNA to generate vaccines against COVID-19 has cemented the potential for nucleic acids to develop approaches to prevent viral infection and to have wider applications in the treatment of life-threatening cancers (Nature [2021] 589: 189-191; The Lancet [2022] 23: e450-e458). To maximise the potential of mRNA (and other nucleic acid-based therapeutics) we need to understand more about their delivery into cells, intracellular handling/stability and the processes that link cellular localisation to effective expression. We also need to determine if findings are generic to cell types or if processes can be optimised for specific cell types and status. This provides the overall aim for your project. The specific objectives of your project will require you to (i) generate a panel of mRNA products (ii) examine the uptake, processing and expression within a panel of cultured mammalian cells, (iii) screen host cell phenotype in response to the extent of product expression, (iv) use machine learning methods to understand changes in metabolic pathways upon uptake of mRNA products by mammalian cells and (v) test hypotheses derived by engineering specific cellular functionalities. In achieving these objectives you will master a wide range of analytical, cellular and molecular techniques, including fluorescence microscopy, high resolution mass spectrometry assays, omics data interrogation, chemometrics methods, data interpretation and cellular and process engineering. Working with the Centre for Process Innovation (CPI) RNA Centre of Excellence (https://www.uk-cpi.com/about/national-centres/rna-centre-of-excellence) we will be part of a wider vision to innovate design and manufacture of RNA vaccines and therapeutics.