Ultra-sensitive Mass spectrometry for Precision Medicine

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Over the past decade, we have witnessed a revolution in cellular and developmental biology. The advent of cheap and rapid nucleotide sequencing approaches has enabled us to quantify RNA from minute samples with single-cell and spatial resolution on a routine basis. Unbiased scRNAseq has given us unprecedented insight into how cellular heterogeneity and changes within underpin most biological processes. Nevertheless, mRNA expression is just one aspect of the cellular state, and it may not be the most informative in terms of function because the relationship between biomolecules DNA, mRNA and protein, is nonlinear when quantified. The abundance of proteins, the molecules through which genes exercise their function, is dependent on the balance between production and destruction, or translation and degradation. Neither process is linearly dependent on mRNA abundance, explaining the absence of correlation. Thus, to identify the state of the cellular proteome we cannot rely on mRNA abundances as a proxy, we must directly quantify the proteins. The field of clinical mass spectrometry-based proteomics has to date not been able to generate biological insights anywhere close to what sequencing approaches have been able to do. However, many of the limitations that have hampered the progress of mass spectrometry have recently been overcome and we propose to establish such capability in Edinburgh for MRC-funded colleagues and a broad network of collaborators. We propose to install a state-of-the-art mass spectrometer with an associated liquid chromatography separation. The system will be installed in the internationally recognised Institute of Genetics and Cancer (IGC) Mass Spectrometry Facility at the University of Edinburgh. The system will be used by a consortium of investigators from the IGC, the Centre for Inflammation Research (CIR) and Centre for Regenerative Medicine (CRM) Edinburgh to investigate cellular and disease heterogeneity in human diseases. The work we are doing will shed light on how protein dynamics are regulated during cancer, inflammation and in other cellular stress and disease contexts. Importantly, we wish to interrogate how proteome changes shape the response of the patient to challenges during normal physiology and disease.