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

Lead Research Organisation: University of Surrey
Department Name: Chemistry

Abstract

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.

Planned Impact

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 fo 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.

Publications

10 25 50
 
Description We have shown that ion beam analysis can be used in conjunction with mass spectrometry imaging and we are developing experimental workflows. We have been using transnational access, provided through an EU project to attract new users to test applications in biosciences.
Exploitation Route It may be used to understand the interaction between trace elements and organic molecules in any system
Sectors Aerospace, Defence and Marine,Energy,Environment,Healthcare,Culture, Heritage, Museums and Collections,Pharmaceuticals and Medical Biotechnology,Security and Diplomacy

 
Description International Comittee for Particle Induced X Ray Emission
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
 
Description Lecture at Kings College London on Fellowship as part of toxicology module
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Improved knowledge of researchers on toxicology course at Kings College London
 
Description Royal Society of Chemistry Analytical Division
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact I have been working with the Royal Society of Chemistry as a member of the Analytical Division. I have been helping to organise the Analytical Research Forum for 2020. We are also exploring how we can train more researchers in our field and create awareness from school age upwards.
 
Description AstraZeneca 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution We have been developing a mass spectrometry method using DAPNe for the spatially resolved detection of drugs in tissue
Collaborator Contribution AZ have provided tissue mimetic samples, dosed with olanzapine, ternafenadine and other drugs as a model sample to explore the capabilities of DAPNe for tissue imaging
Impact Abstracts submitted to ASMS; presented at PIXE 2016 in Croatia; IBA 2017 in Shanghai.
Start Year 2016
 
Description Dstl 
Organisation Defence Science & Technology Laboratory (DSTL)
Country United Kingdom 
Sector Public 
PI Contribution We have been developing new mass spectrometry methods for the rapid screening of explosive residues
Collaborator Contribution Dstl have allowed Patrick Sears (Principal Scientist) to work in our laboratory with us to advise on best practise for explosive detection (common adduct signals, solvent systems etc)
Impact Innovate UK funding from the IRC ; 2 manuscripts in preparation
Start Year 2016
 
Description GSK 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution We are trialling new ion beam analysis methods and ion beam analysis with mass spectrometry imaging on samples provided by GSK. We have also brought our DAPNE system to GSK to work together on localised tissue extractions
Collaborator Contribution contribution by GSK is the provision of tissue samples from animals dosed with various different drugs, training in MALDI imaging, training in single cell extraction and cell culturing
Impact training of PHD and post doctoral students in the fellowship team new potential service offerings for the ion beam centre
Start Year 2019
 
Description Public Health England 
Organisation Public Health England
Department Public Health England Porton Down
Country United Kingdom 
Sector Public 
PI Contribution We are using ion beam techniques and mass spectrometry imaging to locate Au labelled drugs relative to other markers in tissue samples
Collaborator Contribution partners are providing sectioned tissues
Impact Studying au labelled drugs in marmoset tissues.
Start Year 2019
 
Description RBI 
Organisation Ruder Boskovic Institute
Country Croatia 
Sector Public 
PI Contribution We are seeking to explore the relation between drugs and their metabolites in fingerprints for drug testing and toxicology purposes and have been using DAPNe for this
Collaborator Contribution RBI have given beam time to understand more about how chemical imaging of drugs and metabolites
Impact student trained in Croatia in imaging analysis
Start Year 2018
 
Description Rutgers 
Organisation Rutgers University
Country United States 
Sector Academic/University 
PI Contribution We are carrying out multimodal imaging of TB granulomas provided by the team at Rutgers to explore trace element and molecular profiling
Collaborator Contribution The partners are providing sectioned tissues, prepared under different methods to fix and treat the samples to explore sample compatibility
Impact We are establishing appropriate sample handling strategies for multimodal imaging using ion beams and mass spectroemtry
Start Year 2019
 
Description University of Birmingham 
Organisation University of Birmingham
Department School of Biosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Use of FAIMS -MS for explosive detection and use of DAPNe for spatially resolved proteomics
Collaborator Contribution training on FAIMS MS at Bristol ; provision of samples and expertise of RA at Surrey
Impact postdoc has applied for follow on funding to explore this work further. this is a multidisciplinary project, requiring the collaboration of physicists, engineers, chemists and bioscientists
Start Year 2017
 
Description Appearance on BBC Crimewatch Roadshow 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Appearance on BBC Crimewatch roadshow, showcasing mass spectrometry methodology used for fingerprint analysis at crime scenes
Year(s) Of Engagement Activity 2020
 
Description Hampshire Science Group and Three Counties Science Group talks 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Talk to general public at Hampshire Science Group and another talk at 3 Counties Science Group. Increased knowledge of these groups on ion beam analysis and mass spectrometry. have been asked to give further talks
Year(s) Of Engagement Activity 2018
 
Description International Mass Spectrometry Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Purpose of the activity was to provide a lecture on ion beam and mass spectrometry imaging. The impact was questions and discussion after the talk. I have since had a number of enquiries from researchers who are interested to come to Surrey to work in our team
Year(s) Of Engagement Activity 2020
 
Description Portsmouth physical society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact 20 pupils attended the talk and this sparked questions and a discussion afterwards. I was also asked to give a lecture in November to the University of Third Age from one of the audience members.
Year(s) Of Engagement Activity 2018
 
Description Training event at international Atomic Energy Agency 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact This will take place in June in Italy and we will train forensic experts to use ion beam analysis techniques
Year(s) Of Engagement Activity 2019
 
Description school visit boxgrove school 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact workshop for children at Boxgrove primary school (100 children in year 2). School reported that students were inspired by the work we are doing
Year(s) Of Engagement Activity 2018