Integrating innovative technologies for genotyping and phenotyping in stratified medicine

Lead Research Organisation: University of Birmingham
Department Name: Immunity and Infection

Abstract

The mechanisms associated with how a disease develops and progresses, or response to a treatment, are not identical but are dependent on the human subject. The strategy defined as stratified medicine is based on grouping patients with distinct mechanisms of disease, or particular responses to treatments in order to identify and apply treatments that are effective for particular groups of patients. This provides the opportunity to rapidly define or alter patient management and treatments early, providing a maximum benefit to the patient. To achieve this, it is necessary to combine data on the chemical composition of cells and biofluids like urine, with data related to age, gender and other characteristics to provide information on how to diagnose a disease, to identify the correct treatment rapidly, and to monitor patients based on risk of relapse. The aim is this strategy is to deliver a system of monitoring and treatment which is tailored towards the individual patient.

We are proposing to build upon the world-leading clinical and research environment within Birmingham by creating a West Midlands Stratified Medicine Innovation & Translation Facility through major infrastructure investment, aligned to an ambitious research programme which will enhance our mechanistic knowledge as well as diagnostic and clinical capabilities. Research will particularly focus on immune-mediated inflammatory diseases (e.g. arthritis and liver disease) and blood cancers (e.g. leukaemia), which are increasing in prevalence in the UK, partly as a consequence of an aging population. Our interdisciplinary research programme will focus on the molecular study and characterisation of different cell types within each disease and the associated molecular changes in the patient. It will develop and test the integration of multiple diagnostic strands including methods called mass cytometry, metabolic phenotyping and single-cell genomics and functional genomics. We will obtain new insight into the mechanisms of how diseases develop and progress, and their responsiveness to treatment, with the aim to drive innovative discoveries into clinical practice through the establishment of stratified diagnostics and targeted therapies. This will not only build on local investments such as the £24m Institute for Translational Medicine (co-funded by government, along with our NHS partners University Hospitals Birmingham) and the new £4.1m Centre for Computational Biology, but also concurrent national investments in new technology such as CyTOF cell sorting and the recent MRC-NIHR National Phenome Centre, all of whom we are collaborating with to enable a step-change in national capabilities in stratified medicine research.

Technical Summary

Stratified medicine is applied to group patients based on specific disease phenotype, mechanism of onset or progression and response to treatment; these mechanisms are specific to individual patients and means a personalised approach to management throughout a patient journey is required to maximise patient survival and minimise healthcare costs. To develop novel stratified medicine approaches, we will integrate multiple clinical and molecular datasets for diagnosis and management of disease, with the aim of delivering a system of monitoring and treatment which is tailored towards the individual patient. These type of data integration must (i) inform research into disease causation and development, (ii) contribute to patient management and (iii) provide insights towards novel therapeutics. We are proposing to build upon the unique integrated clinical and research setting within Birmingham by creating a West Midlands Stratified Medicine Innovation & Translation Facility through major infrastructure investment, aligned to an ambitious research programme which will enhance our mechanistic knowledge as well as diagnostic and clinical capabilities. Research will particularly focus on immune-mediated inflammatory diseases and blood cancers, which are disciplines of great local strength. This will not only build on local investments such as the £24m Institute for Translational Medicine (co-funded by government, along with our NHS partners University Hospitals Birmingham) and the new £4.1m Centre for Computational Biology, but also concurrent national investments in new technology such as CyTOF cell sorting and the recent MRC-NIHR National Phenome Centre, all of whom we are collaborating with to enable a step-change in national capabilities in stratified medicine research.

Planned Impact

Stratified medicine is one of the cornerstones of MRC's ambitions to secure impact from medical research, and we believe that there are four key areas in which this proposal can offer significant value:

The primary area of impact is around HEALTH, building on outstanding clinically-focused programmes of research in Birmingham in blood cancers, chronic inflammatory disease (particularly rheumatology), liver disease and rare disease. Links with clinical services such as the West Midlands Regional Genetics Laboratory and Clinical Immunology Service are crucial to realizing benefit in these areas, as is the integration with extensive existing healthcare data through our collaborators such as University Hospitals Birmingham and Birmingham Children's Hospital through the Birmingham Health Partners strategic alliance. Through our clinical academic teams and our NHS partners we have excellent links to existing patient groups as well as clinicians themselves, and the development of the proposed facility within the new £24m Institute for Translational Medicine offers clear opportunities to continue to develop new collaborations and raise awareness of the potential of new approaches aligned to our three key aims: (i) inform research into disease pathogenesis and responsiveness to treatment, (ii) contribute to patient management, and (iii) provide insights towards novel therapeutics. Public engagement programmes will also be a key factor throughout the project lifecycle, supported both by the University and our BHP collaborators, including direct personal engagement as well as wider media communications in partnership with the funding bodies supporting this proposal.

With respect to ECONOMIC impact, we already have a proven track record in developing new diagnostics into robust routine clinical laboratory practice, commercialising these assays and disseminating them worldwide (thebindingsite.com, serascience.com), and we anticipate significant further commercial opportunitie through the research programme outlined here. Development of metabolomic capacity and provision is not only intended to engage with other research areas but also provide a service to industry partners involved in therapeutics, healthcare and nutrition. Note that the proposal already has strong buy-in from industry partners in terms of technology development and implementation, with £4.2m contributed from instrument suppliers (in-kind contributions over the next five years of £2.5m and discounts on instruments of £1.7m).

We will also have major ACADEMIC impacts, where as stated our programme of work will inform research into disease pathogenesis and responsiveness to treatment, building particularly on local excellence in immune-mediated inflammatory diseases and blood cancers. Through our academic conferences as well as our existing national programmes (e.g. NIHR BRU, MRC-ARUK Centre, ARUK Centre, NIHR TRP) we will disseminate our findings, and will continue to engage with the other academic teams applying to the present call for CyTOF instruments to realise added value on a national scale. The establishment of the West Midlands Regional Phenome Centre will also have international impact in the field, providing a lasting infrastructure to support the growing requirements of phenomics in the clinical and population health arena in the UK.

Finally, we will also strive to influence key POLICY impacts, working with our clinical partners as well as organisations such as the West Midlands Academic Health Sciences Network and the funding bodies themselves, particularly in the fields of blood cancer trials and chronic inflammatory disease, to ensure that the discoveries and outputs of our research help to inform policy at a local, national and international level in terms of proactive approaches to patient stratification and treatment.
 
Description CRUK Programme Grant
Amount £1,505,202 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2017 
End 03/2022
 
Description CRUK Project Grant
Amount £671,139 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2017 
End 09/2023
 
Description CRUK/14/033 STAR-TREC: Saving the rectum by watchful waiting or TransAnal microsurgery following (chemo)Radiotherapy versus Total mesorectal excision for early Rectal Cancer
Amount £122,893 (GBP)
Funding ID 19393 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2016 
End 07/2019
 
Description Cancer Research UK / Medical Research Council Stratified Medicine Consortium
Amount £5,000,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 04/2015 
End 03/2020
 
Description Characterisation of Chromatin Landscapes of Pre-leukaemic and Leukaemic Stem Cells in Core Binding Factor AML and their Response to Epigenetic Therapy
Amount £209,375 (GBP)
Funding ID MR/P019609/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 08/2017 
End 08/2020
 
Description Fellowship
Amount £1,004,344 (GBP)
Organisation Versus Arthritis 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2016 
End 08/2021
 
Description Finding therapeutic targets in FLT3-ITD AML using a systems biology approach
Amount £1,651,941 (GBP)
Funding ID MR/S021469/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2019 
End 02/2023
 
Description Investigating the role of protein hydroxylation in cancer
Amount £1,315,935 (GBP)
Funding ID 24552 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2017 
End 09/2023
 
Description Kennedy Trust for Rheumatology Research Programme Grant
Amount £7,010,630 (GBP)
Organisation The Kennedy Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2017 
End 05/2024
 
Description MECHANISTIC INSIGHTS INTO THE DEVELOPMENTAL-STAGE SPECIFIC ACTIVITY OF A UBIQUITOUSLY EXPRESSED TRANSCRIPTION FACTOR
Amount £662,125 (GBP)
Funding ID BB/M020800/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 12/2015 
End 01/2019
 
Description MICA: Stratification in COloRectal cancer: from biology to Treatment prediction: S-CORT
Amount £5,079,623 (GBP)
Funding ID MR/M016587/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 04/2015 
End 03/2021
 
Description MRC infrastructure
Amount £7,200,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2015 
End 01/2019
 
Description Mechanistic Insights Into Aberrant Transcriptional Programming In Acute Myeloid Leukaemia
Amount £1,543,859 (GBP)
Funding ID 15001 
Organisation Bloodwise 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2015 
End 12/2020
 
Description Molecular stratification of rectal cancer.
Amount £317,899 (GBP)
Funding ID 102732/Z/13/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2014 
End 04/2017
 
Description NIHR Biomedical Research Centre
Amount £12,120,962 (GBP)
Organisation Government of Catalonia 
Department Department of Health
Sector Public
Country Spain
Start 04/2017 
End 03/2022
 
Description Research Grant
Amount £281,683 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 10/2016 
End 03/2018
 
Description Research Grant
Amount £91,450 (GBP)
Organisation Ono Pharmaceutical 
Sector Private
Country Japan
Start 03/2017 
End 03/2018
 
Description STAR-TREC Phase 3: Saving the rectum by watchful waiting or TransAnal surgery following (chemo)Radiotherapy versus Total mesorectal excision for early Rectal Cance
Amount £1,067,800 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2019 
End 07/2027
 
Description System-wide analysis of transcriptional and chromatin reprogramming by EVI1 and RUNX1-EVI1 oncoproteins
Amount £213,834 (GBP)
Organisation The Kay Kendall Leukaemia Fund 
Sector Academic/University
Country United Kingdom
Start 06/2016 
End 11/2019
 
Description Target validation and proof of function: blocking Tenascin-C in an acute mouse model of Sjögrens Syndrome (PI - Francesca Barone)
Amount £57,323 (GBP)
Organisation Nascient ltd 
Sector Private
Country United Kingdom
Start 05/2017 
End 05/2018
 
Description Tender to apply metabolomics in research at the Defence Science and Technology Laboratories in the UK
Amount £80,000 (GBP)
Organisation Defence Science & Technology Laboratory (DSTL) 
Sector Public
Country United Kingdom
Start 10/2016 
End 09/2019
 
Description Understanding the molecular basis and consequences of chemoradiosensitivity in rectal cancer in order to improve therapy (MOL-RSRC)
Amount £1,505,202 (GBP)
Funding ID 23923 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2017 
End 03/2022
 
Description Collaboration with Amanda Drake 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution 1. Sample preparation, data acquisition and data analysis of mouse blood and tissue samples.
Collaborator Contribution 1. Provision of mouse blood and tissue samples.
Impact 1. One publication is in press.
Start Year 2016
 
Description Collaboration with Dr Colm Cunningham 
Organisation Trinity College Dublin
Country Ireland 
Sector Academic/University 
PI Contribution 1. Preparation, data acquisition and data analysis for metabolic phenotyping of mouse biofluids and tissues to investigate the metabolic impact of delerium
Collaborator Contribution 1. Provision of mouse biofluids and tissues to investigate the metabolic impact of delerium
Impact This collaboration is multi-disciplinary and involves analytical chemists, bioinformaticians and clinical researchers
Start Year 2016
 
Description Collaboration with Dr Georg Lietz 
Organisation Newcastle University
Country United Kingdom 
Sector Academic/University 
PI Contribution 1. Sample preparation, data acquisition and data analysis of pig urine and plasma for a pig model of hypervitamin A.
Collaborator Contribution 1. Provision of pig urine and plasma for a pig model of hypervitamin A.
Impact This is a multi-disciplinary collaboration involving analytical chemists, bioinformaticians and clinical scientists
Start Year 2017
 
Description Collaboration with Dr Nicholas Timpson 
Organisation University of Bristol
Country United Kingdom 
Sector Academic/University 
PI Contribution 1. Sample preparation, data acquisition and data analysis of human plasma
Collaborator Contribution 1. Provision of human plasma
Impact This is a multi-disciplinary collaboration between analytical chemists, bioinformaticians, epidemiologists and clinical scientists
Start Year 2016
 
Description Collaboration with Dr Oscar Yanes 
Organisation Rovira i Virgili University
Country Spain 
Sector Academic/University 
PI Contribution 1. Sample preparation, data acquisition and data analysis of human plasma samples.
Collaborator Contribution 1. Provision of human plasma samples.
Impact This is a multi-disciplinary collaboration between analytical chemists, bioinformaticians and clinicians
Start Year 2017
 
Description Collaboration with Laura Torchen 
Organisation Northwestern University
Country United States 
Sector Academic/University 
PI Contribution 1. Sample preparation, data acquisition and data analysis of human serum for the study of PCOS.
Collaborator Contribution 1. Provision of serum samples for metabolic phenotyping.
Impact This is a multi-disciplinary collaboration between analytical chemists, bioinformaticians and clinical scientists
Start Year 2016
 
Description Collaboration with Tharos Ltd 
Organisation Tharos Group
Country United Kingdom 
Sector Private 
PI Contribution 1. Two studies to analysis horse faeces to define metabolic differences between healthy horses and horses diagnosed with laminitis. 2. Sample preparation, data acquisition and data analysis of horse faeces.
Collaborator Contribution 1. Provision of horse faeces.
Impact This is a multi-disciplinary collaboration between analytical chemists, bioinformaticians and vets.
Start Year 2017
 
Description Collaboration with Thermo Fisher Scientific to develop new metabolomic assays and software for metabolic phenotyping 
Organisation Thermo Fisher Scientific
Country United States 
Sector Private 
PI Contribution 1. Development and validation and UPLC-MS assays for untargeted metabolomics. 2. Sharing of developed assays for distribution by Thermo Fisher Scientific. 3. Development of new metabolite annotation software. 4. Development of optimal approaches for the collection of MS/MS data in metabolic phenotyping.
Collaborator Contribution 1. Significant reduction in purchase costs of instruments (45% discount). 2. Early beta testing of new software and scientific instruments. 3. Priority engineer visits for scientific instruments.
Impact 1. Loan of a UPLC-MS instrument to the University of Birmingham to be applied for training courses and for assay development work. 2. This collaboration is multi-disciplinary and includes bioinformatics, analytical chemistry and clinical research.
Start Year 2013
 
Description Collaboration with Waters Ltd to apply new metabolomic assays for metabolic phenotyping 
Organisation Waters Corporation
Country United States 
Sector Private 
PI Contribution 1. Testing and application of standardised UPLC-MS assays for large-scale metabolic phenotyping with feedback
Collaborator Contribution 1. Provision of standardised UPLC-MS assays for metabolic phenotyping. 2. Provision of a UPLC-MS system for training courses.
Impact This is a multidisciplinary collaboration involving analytical chemists, bioinformaticians and clinical researchers
Start Year 2015
 
Description EMBL-EBI hosting of software developed 
Organisation EMBL European Bioinformatics Institute (EMBL - EBI)
Country United Kingdom 
Sector Academic/University 
PI Contribution My research team are developing a software for metabolite annotation of liquid chromatography-mass spectrometry datasets acquired applying metabolomic approaches. The research team is currently developing the software and will test and validate the software. Additional functions are being developed outside those defined in the grant proposal including new approaches to report confidence of accurate matching to metabolites.
Collaborator Contribution The EMBL-EBI team will host the software as a web-based and accessed tool for the metabolomics comunity as part of the MetaboLights data repository.
Impact The collaboration is multi-disciplinary (analytical chemistry, metabolomics, bioinformatics)
Start Year 2016
 
Description MRC stratified medicine alcoholic hepatitis 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaborative partnership funded by MRC lead by ICL
Collaborator Contribution research methods and analysis
Impact nil so far
Start Year 2017
 
Description University of Bonn 
Organisation University Hospital Bonn
Country Germany 
Sector Academic/University 
PI Contribution Visiting research fellow Philipp Lutz awarded 24 month fellowship to work in our laboratory on the role of NK cells in liver disease
Collaborator Contribution Philipp has generated new data during his stay with us that will from the basis of at least one high profile publication and also a future grant application
Impact Publications being prepared
Start Year 2015
 
Description University of Bonn 
Organisation University Hospital Bonn
Country Germany 
Sector Academic/University 
PI Contribution Visiting research fellow Philipp Lutz awarded 24 month fellowship to work in our laboratory on the role of NK cells in liver disease
Collaborator Contribution Philipp has generated new data during his stay with us that will from the basis of at least one high profile publication and also a future grant application
Impact Publications being prepared
Start Year 2015
 
Description Trustee PSC Support 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Trustee of patients support charity responsible for overseeing charity and organising meeting to share research advances
Year(s) Of Engagement Activity 2015,2016,2017
URL http://www.pscsupport.org.uk/?gclid=CjwKEAjwqZ7GBRC1srKSv9TV_iwSJADKTjaDl5WWgqCsixq9oG84SRlUY8FyF_2U...