Integrating innovative technologies for genotyping and phenotyping in stratified medicine

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.

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.

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 opportunities 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.