Proposal for a Fast Scanning Mass Spectrometer capable of Data Independent Acquisition for proteomics

Lead Research Organisation: The Francis Crick Institute
Department Name: Research


The Crick is a partnership between the Medical Research Council, Cancer Research UK, the Wellcome Trust and three leading universities: UCL (University College London), Imperial College London and King's College London. The Crick aspires to be one of the world's leading medical research institutes. The Crick achieves operational and research efficiencies and economies-of-scale through centralised facilities and functions, known as Science Operations, that provide all researchers at the Crick, irrespective of affiliation, with access to cutting-edge equipment, animals for research and laboratory enabling functions such as the Proteomics Science Technology Platform which houses cutting-edge mass spectrometry equipment. This technology can be used to investigate many aspects of proteins such as the quantification of protein expression, the discovery and characterisation of post-translational modifications and structural properties such as shape and solvent accessibility. This proposal is for a fast-scanning mass spectrometer capable of performing Data Independent Acquisition (DIA). The unprecedented scan speed, mass resolution and chromatographic stability that this system offers will enable studies that require high sensitivity, high throughput and high performance of label free peptide and protein quantification.

Technical Summary

The Crick aspires to be one of the world's leading medical research institutes. It achieves research efficiencies through centralised facilities and functions such as the Proteomics Scientific Technology Platform (STP). A BBSRC-funded fast scanning Mass Spectrometer in the Proteomics STP and made available to 100+ research groups at the Crick, and their collaborators. This application is being made by ten Crick Group Leaders with Dr Bram Snijders, Head of the Proteomics STP and is lead by Prof Sir Peter Ratcliffe. These diverse projects (illustrative of the breadth of research at the Crick), are united by the need for a fast scanning mass spectrometer with Data Independent Acquisition (DIA) capability.

-Peter Ratcliffe: Discovery of novel substrates of 2-oxoglutarate-dependent oxygenases
-Katrin Rittinger: Developing new chemical tools for studying the ubiquitin system. A cysteine reactive fragment screening platform capable of identifying targets in live cells or extracts
-Jesper Svejstrup: Prolyl isomerisation in transcriptional control
-Simon Boulton: Understanding DNA replication fork reversal
-Luiz Pedro de Carvalho: Quantitative proteomics of 60 mycobacterial species in response to different environmental perturbations
-Pontus Skoglund: Paleoproteomics
-Julian Downward: Dynamics of the c-RAF interactome
-Kathy Niakan: Profiling the proteome of the developing human pre-implantation embryo
-Dominique Bonnet: Maturation and differentiation of haematopoietic stem cells
-Ilaria Malanchi: Cellular heterogeneity in the tissue microenvironment

Planned Impact

The Crick aspires to be one of the world's leading medical research institutes. Its multidisciplinary approach, an emphasis on practical application of research and its links with academia, industry and the public sector will speed up the translation of discoveries made in the laboratory into treatments for disease. We fully expect outcomes from the Data Independent Acquisition (DIA) capable fast scanning mass spectrometer and its use by researchers across the Crick to have a pathway to impact through academic, economic and societal impacts.
Academic impact:
- Publication via various media including papers and conference presentations;
- Knowledge transfer and education, especially with respect to PhD students and early-career researchers / post-doctoral research associates.
Economic and societal impact:
- The Crick, its founding partners (the Medical Research Council, Cancer Research UK, the Wellcome Trust, UCL (University College London), Imperial College London and King's College London), and legacy research institutes at Mill Hill (MRC), Lincoln's Inn Fields and Clare Hall (CRUK) all have strong track records for converting research and discoveries into economic and societal benefit;
- The Crick organisation includes well-funded and specific groups responsible for Translation, Clinical Research, Public Engagement and Education; thus, we are confident that research outcomes from the BBSRC funded fast scanning mass spectrometer will convert into economic and societal benefits. It is worth emphasising that the mass spectrometer will be housed in the Crick's Proteomics STP, and hence be available to 100+ Crick research groups as well as our collaborators in partner institutions, such that the pathways to impact are many and varied.


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Description During 2022 we have continually improved our competitive profiling workflow using the cysteine reactive probe iodoacetamide desthiobiotin to probe the engagement of reactive fragments with the cysteinome. We have developed a 96-well plate platform combining Streamlined Cysteine Activity-Based Protein Profiling (SLC-ABPP), SP4 sample preparation, label free peptide quantification, rapid chromatographic gradients on an Evosep One and data independent acquisition (DIA) on a Bruker timsTOF Pro 2 to profile cysteine reactive fragments in both live cells and lysates. Our key goal here is expansion of the ligandable proteome.
Exploitation Route The data collected will be used as a data repository for the scientific community.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology