Innovative Technologies for Stratified and Experimental Medicine

Lead Research Organisation: University of Cambridge
Department Name: Clinical School

Abstract

We aim to build scientific and computing infrastructure in the School of Clinical Medicine at the University of Cambridge that will allow us i) to develop new technologies for measuring and imaging molecules in humans, and ii) to apply these technologies directly and immediately to major research programmes for understanding and treatment of cancer, metabolic disorders, and many other therapeutic areas.

Our strategic vision is that many diseases, that are traditionally diagnosed and treated as if all patients with the same diagnosis were largely the same, will become increasingly stratified. We expect that advances in biomedical science will demonstrate that there are in fact many different genetic and molecular pathways to the same clinical diagnosis. This has potentially important implications for more precise targeting of treatment: more refined diagnostic stratification of patients could identify more exactly which patients were most likely to respond to specific treatments. To realise this vision, we propose to create three new high-tech facilities for clinical research in Cambridge; a Stratified Medicine Core Laboratory (SMCL), a Molecular Imaging Centre (MIC), and a High Performance Hub for Informatics (HPHI).

The SMCL will allow us to measure a large number of peptides and other molecules in blood or other tissue samples with enhanced accuracy and sensitivity. The SMCL will also provide new facilities for next generation sequencing of DNA so that genetic variants driving disease can be identified in individual patients with sufficient precision and reliability to optimize diagnostic stratification and to inform clinical management immediately.

The MIC will allow us to measure molecules by imaging of patients, rather than by lab analysis of tissue samples. The MIC will comprise a new whole body scanner that can simultaneously collect MRI and PET data, as well as new facilities for manufacturing and administering labeled molecules as imaging probes to patients. The new radiochemistry facilities in the MIC will allow us to produce a much larger range and volume of radioactively labeled molecules that can be detected by PET imaging. The MIC will also support the technological development of dynamic nuclear polarization (DNP). This is a radically innovative method of molecular imaging which could potentially allow us to detect labeled molecules by MRI and without exposing patients to the risks of radioactivity. We will also upgrade one of our existing MRI scanners and locate it closer to the main focus of experimental medicine research in Cambridge.

The HPHI will provide the computational resources required to store and analyse the very large volumes of data produced by the SMCL and the MIC. It is also crucially important that the results of clinically actionable molecular analysis and imaging can be linked to individual patient records. This is key to "pulling through" the benefits of new technology to deliver stratified medicine in clinical practice. It is also important that the "big data" generated by the SMCL and MIC can be shared with the wider scientific community including our research partners elsewhere in the UK. We therefore propose to invest in new facilities for data storage, computational analysis, secure and ethically approved linkage of research data to clinical records, and data sharing. This computational hub will be managed as part of the University of Cambridge's new high performance computing facility.

These infrastructural investments have been planned to create an integrated platform for molecular and genetic stratification of human disease. They will enhance the impact of internationally leading research groups already established in Cambridge and they are coordinated with major infrastructural programmes already funded by the University or other agencies. They will underpin a step change in our capacity to harness the potential of new technologies to deliver our strategic vision.

Technical Summary

The vision is to use the explanatory and predictive power of genetics, biomolecular assays, and molecular imaging, to refine diagnostic and therapeutic stratification of patients with cancer, metabolic, neuroscience, cardiovascular and musculoskeletal disorders. To do this, we are seeking capital investment in 3 coordinated and strategically important areas for innovative technology and stratified medicine in Cambridge:
1) Stratified Medicine Core Laboratory: will deliver high-throughput, clinically actionable, sensitive and precise measures of multiple pathophysiologically important biomolecules. The SMCL will use new mass spectrometry immuno-assays for a wide range of peptides; extended capacity for existing multiplex assays; and next generation sequencing for deep genotyping.
2) Molecular Imaging Centre: will pioneer clinical translation of new technologies, such as dynamic nuclear polarization imaging and simultaneous PET/MRI imaging of radioligand binding (PET) combined with MRI markers of local tissue structure and function. The MIC will provide pharmacy support for quality controlled production and administration of PET radioligands and hyperpolarized molecules for DPN imaging. It will also include some enhanced capacity for 3T MRI in stratified and experimental medicine, optical imaging of epithelial dysplasia and neoplasia, and cell tracking in regenerative medicine.
3) High Performance Hub for Informatics: will deliver storage, analysis, sharing, and NHS clinical linkage, for the large volumes of complex data that will be generated by the SMCL and the MIC. This integrative computational hub will link together the two key biomedical platforms and provide the principal University portal for clinical "pull through" of stratified medicine to and from individual patient records in the NHS.
These investments will leverage international research strengths in Cambridge and are aligned with major investments by Cambridge University Health Partners.

Planned Impact

No impact summary is required for applications to the Clinical Research Infrastructure call.

Publications

10 25 50
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Annus T (2016) The pattern of amyloid accumulation in the brains of adults with Down syndrome. in Alzheimer's & dementia : the journal of the Alzheimer's Association

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Bevan Jones WR (2016) [F]AV-1451 PET in behavioral variant frontotemporal dementia due to MAPT mutation. in Annals of clinical and translational neurology

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Bevan-Jones RW (2018) [F]AV-1451 binding is increased in frontotemporal dementia due to C9orf72 expansion. in Annals of clinical and translational neurology

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Bevan-Jones WR (2019) In vivo evidence for pre-symptomatic neuroinflammation in a MAPT mutation carrier. in Annals of clinical and translational neurology

 
Description BBSRC iCASE
Amount £105,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2018 
End 09/2022
 
Description BBSRC iCASE studentship partnered with MedImmune (Sam Galvin)
Amount £95,196 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2016 
End 09/2020
 
Description Dementia Platform UK
Amount £2,677,560 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2014 
End 03/2015
 
Description MRC MDU
Amount £1,500,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 04/2018 
End 03/2023
 
Description Medimmune grant
Amount £272,857 (GBP)
Organisation MedImmune 
Sector Private
Country United States
Start 06/2015 
End 08/2017
 
Description NIHR Cambridge Biomedical Research Centre
Amount £112,000,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 04/2017 
End 03/2022
 
Description PET++: Improving Localisation, Diagnosis and Quantification in Clinical and Medical PET Imaging with Randomised Optimisation
Amount £821,421 (GBP)
Funding ID EP/S026045/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 08/2019 
End 08/2022
 
Description GE MRC CRI PET/MRI 
Organisation GE Healthcare Limited
Country United Kingdom 
Sector Academic/University 
PI Contribution The University, as part of the MRC Dementia Platform UK, will enable access to the new PET/MRI system and will share expertise and software for advanced image acquisition with the GE team.
Collaborator Contribution GE have provided substantial cash contribution in the form of major discounts on list price of the PET/MRI system and related equipment, amounting to about 46% of list price. GE will additionally provide substantial in-kind support including: scientific and technical staff working on-site to help the University commissioning the new PET/MRI system and optimising its performance as part of the MRC Dementia Platform UK; PhD studentship; image analysis software; funds for start-up research projects on the new scanner.
Impact No outputs yet
Start Year 2015
 
Description LGC peptidomics 
Organisation LGC Ltd
Country Global 
Sector Private 
PI Contribution Supporting a BBSRC iCASE studentship
Collaborator Contribution Analysis and training
Impact One publication to date
Start Year 2017
 
Description Mercodia assay validation 
Organisation Mercodia AB
Country Sweden 
Sector Private 
PI Contribution Mass spec analysis to validate Mercodia's glucagon assay. Measurement of patient samples using glucagon and glicentin assays to establish the cause of assay cross reactivity
Collaborator Contribution Provision of assays and suggestions for protocol changes to remove cross-reactivity
Impact Mercodia published a white paper outlining the collaboration and how it has impacted on the use of the glucagon assay
Start Year 2018
 
Description Siemens MRC CRI SKYRA 
Organisation Siemens AG
Department Siemens Magnet Technology
Country United Kingdom 
Sector Private 
PI Contribution The University will provide access to Siemens to the 3T SKYRA system and will release prototype pulse sequences for MRI data acquisition.
Collaborator Contribution Siemens will commit technical and scientific staff to work alongside the University commissioning the new 3T SKYRA upgrade and optimising its performance.
Impact TBC
Start Year 2015
 
Description Siemens MRC CRI Skyra 
Organisation Siemens Healthcare
Country Germany 
Sector Private 
PI Contribution The University of Cambridge in general and the Wolfson Brain Imaging Centre in particular have long-standing research collaboration agreements with Siemens. The University provides access to equipment, software and clinical data in support of the collaborative partnership with Siemens.
Collaborator Contribution Siemens provided a substantial discount on the list price of SKYRA 3T upgrade.
Impact No outputs yet from SKYRA upgrade.
Start Year 2015
 
Description 13th annual Biomarkers Congress 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact An industrial congress bringing together a variety of industrial technologies for the measurement of biomarkers
Year(s) Of Engagement Activity 2018
 
Description Cambridgeshire Girlguiding Girls in STEM event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other audiences
Results and Impact Cambridgeshire Girlguiding Girls in STEM event
Year(s) Of Engagement Activity 2020
 
Description DG Poster at EASD study group 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact DG. Poster at Incretin Study Group: "Modelling human enteroendocrine cells using adult intestinal organoids"
Year(s) Of Engagement Activity 2019
 
Description FR. presentation at Danish Diabetes Academy Winter School for postdoctoral researchers, at Higuerõn Hotel in Malaga/Spain 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact "Incretins along the gut-pancreas-brain axis".
Year(s) Of Engagement Activity 2019
 
Description FR: Mercodia Diagnostics, Uppsala. Invited speaker 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Invited to talk to Mercodia about how our mass spec analysis methods complement their immunoassay development
Year(s) Of Engagement Activity 2019
 
Description Interactive presentation of MRC CRI funded MRI technology for general public 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Cambridge Brainfest was a major public engagement event organised by Cambridge Neuroscience, which attracted 3000 visitors to the Corn Exchange in central Cambridge for two days of interactive exhibitions, short talks and other events. There were multiple exhibits and talks which featured the high performance MRI equipment funded by this award.
Year(s) Of Engagement Activity 2017
URL https://www.neuroscience.cam.ac.uk/brainfest
 
Description PL. Talk at Incretin Study Group 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact PL. Talk at Incretin Study Group. "Peptidomics to study enteroendocrine cells after bariatric surgery"
Year(s) Of Engagement Activity 2019
 
Description REF Poster at SymBLS 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Size Exclusion Chromatography for Measuring Free and Antibody-bound Insulin in Hiratas Patients
Year(s) Of Engagement Activity 2019
 
Description REF. Poster at DMDG open meeting 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact "Size Exclusion Chromatography for Measuring Free and Antibody-bound Insulin in Hiratas Patients"
Year(s) Of Engagement Activity 2019
 
Description REF. Poster at EASD incretin study group 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact REF poster at EASD study group "A multiplex method for quantifying gut hormone peptides using Mass Spectrometry"
Year(s) Of Engagement Activity 2019
 
Description REF. Poster at REID Bioanalytical Forum 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Immunoassay vs Mass Spectrometry -Measuring insulin and insulin analogues in human plasma
Year(s) Of Engagement Activity 2019
 
Description RGK. American Society for Mass Spectrometry (ASMS) 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Waters user group meeting, presentation:
"LC-MS analysis of plasma from patients with insulin autoimmune syndrome"
Waters MS focused user meeting (Pharmaceutical track)
Outcome: Video of talk available on Waters website, video interview on Select Science website, as well as an in-lab video interview.
Year(s) Of Engagement Activity 2019
 
Description RGK. Poster at EASD incretin study group 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact "Development of a rapid extraction method for the analysis of gut peptide hormones by LC-MS/MS"
Year(s) Of Engagement Activity 2017
 
Description RGK. Poster at EASD incretin study group 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Poster at EASD incretin study group: "Proglucagon peptide analysis - will the real peptide please stand up!"
Year(s) Of Engagement Activity 2019
 
Description RGK. Reid Bioanalytical Forum 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact "LC-MS analysis of plasma from patients with insulin autoimmune syndrome"
Meeting focussing on broad bioanalytical approaches for wide range of analytes
Outcome: Video interview by Bionalaysis zone, available on their website
Year(s) Of Engagement Activity 2019
 
Description RGK. Waters UK and Ireland Clinical User Meeting 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Waters UK and Ireland Clinical User Meeting 2019
"LCMS Analysis of Proinsulin Derived Peptides"
Waters meeting for users of MS systems in clinical environments
Year(s) Of Engagement Activity 2019
 
Description SG. Poster at EASD incretin study group 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact SG. Poster at EASD study group. "Characterisation of novel gut-derived peptides in vivo and in vitro"
Year(s) Of Engagement Activity 2019
 
Description SG. Poster at EASD incretin study group 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact LC-MS based detection of insulin-like peptide 5 in primary colonic cultures
Year(s) Of Engagement Activity 2017
 
Description Tutor on the Drug Metabolism and Discussion Group (DMDG) large molecule bioanalysis course 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Industry/Business
Results and Impact Richard Kay was Tutor on the Drug Metabolism and Discussion Group (DMDG) large molecule bioanalysis course. A three day course held at Loughborough University, focussed on the dissemination of knowledge for developing bioanalytical methodologies for large molecule analytes.
Year(s) Of Engagement Activity 2017
 
Description Tutor on the Drug Metabolism and Discussion Group (DMDG) large molecule bioanalysis course 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Industry/Business
Results and Impact Richard Kay was Tutor on the Drug Metabolism and Discussion Group (DMDG) large molecule bioanalysis course. A three day course held at Loughborough University, focussed on the dissemination of knowledge for developing bioanalytical methodologies for large molecule analytes.
Year(s) Of Engagement Activity 2017