Ion Beam Analysis for the 2020's and Beyond: An Integration of Elemental Mapping and 'omics'

The vision of this Fellowship proposal is to provide a unique capacity internationally, where proteins, metabolites and trace elements can be imaged and co-located at the sub-micron scale, under ambient pressure. This is not available using any other technique and will provide significant benefits to researchers in industry and academia studying the fluxes of metabolites, proteins and other biomarkers in tissues and cells. The Fellowship will develop a new emerging world leader and provide training to a team of researchers in this new field.

The vision will be achieved by developing a novel toolbox for molecular speciation, to be used alongside ion beam analysis (IBA). The Fellowship will tackle this challenge with three interconnecting work packages, each investigating a different approach to augmenting the molecular speciation that can be provided alongside or with IBA techniques. These approaches can be summarised as follows: 1. Multimodal mass spectrometry and ion beam trace element imaging; 2. Microscale (point) protein and metabolite characterisation alongside ion beam trace element imaging; 3. Multiplexed ion beam imaging of biomolecules and proteins using antibody-lanthanide tags.

This will provide a step change in the UK's capability in the characterisation of biological materials. This proposal will enhance the >£10M investment that EPSRC has recently made in renewing the UK National Ion Beam Centre (UKNIBC) contract and investment in associated equipment (EP/P001440/1; EP/I036516/1), ensure continuing provision of cutting-edge capability in the UK and provide enhanced capabilities at the UKNIBC. It will also ensure the primary benefits go to the needs of UK industry and academia and support the development of applications across RCUK priority areas, with significant economic and societal benefits.

Impact summary

This Fellowship is aims to bring together physicists, chemists and bio-scientists to support the ambition and dissemination of high resolution protein, metabolite and trace element imaging of bio-samples in their native state. The impact of the facility will therefore be broad and spans the RCUK priority areas of Healthcare Technologies, Tissue Engineering, Animal Health, Combating AMR, Bioenergy, Food, Nutrition and Health, Healthy Ageing Across the Life Course, 3Rs in Animal Research and Synthetic Biology. In formulating this proposal, £50M RCUK grants have been identified and the grant holders have been invited to join the Applications Steering Group to maintain an operational focus during the course of the project and to help achieve impact.

The Synthetic Biology Roadmap for UK highlights a recent assessment performed by BCC Research. It predicts an increase of one order of magnitude in a period of five years. In 2016 the market was worth $10.8 bn and will continue growing. In synthetic biology, sub-cellular mass spectrometry and elemental mapping will provide a deeper understanding of metabolic profiles within microbial systems to address biotechnological challenges - for example the use of microbial communities to make methane. Another goal of synthetic biology is the design and construction of biological systems capable of performing logic computations, that is, to integrate environmental signals to produce desired outputs. A better understanding of trace element, metabolite and protein fluxes within cells, provided by the proposed equipment is currently unavailable and will give insight into how cells allocate their resources. This will support efforts in tissue engineering as well as the creation of genetic circuits, with potential for huge economic growth in the UK.

In infectious disease research, sub-cellular mass spectrometry and elemental mapping is key to better understanding of the host-pathogen interaction. This is imperative for gaining a better understanding of the mechanisms of antimicrobial resistance. Additionally, bovine TB, caused by Mycobacterium bovis, is the biggest threat to the livestock industry in GB. Its incidence in cattle herds has steadily risen since the mid-1980s and the current control regime costs the taxpayer around £100 million a year. Sub-cellular elemental and molecular analysis will provide key information on the disease progression and will assist with strategies for developing vaccines. Therefore the results will be of interest to vaccine manufacturers and have a significant economic and societal impact.

Radiation biology is a field which underpins new developments in particle therapy for cancer, with numerous new commercial and NHS centres being developed across the UK, and hundreds internationally. Sampling individual organelles will reveal for the first time changes organelle-to-organelle metal, metabolite and protein distribution within single cells before and after irradiation. This type of information is not currently available, and will provide important information on how to predict radio-sensitivity of cells and therefore optimise radiotherapy treatments.

In general, the toolbox will have impact across RCUK areas as it provides a broad paradigm that can be applied across research areas.