Nottingham Molecular Pathology Node (NMPN) for Integrated Multi-platform Biomarker Research and Knowledge Transfer

The context of the research
There have been substantial recent investments in Stratified Medicine and Analytical Science by the MRC and EPSRC. A recent MRC Pathology Review has highlighted the need for a robust pathway and capability for the development and adoption of new diagnostic tests. Nottingham Molecular Pathology Node will provide the necessary path and capability to fill the needs identified by the MRC review.

Aims and objectives

To create an infrastructure to drive molecular diagnostic biomarker research down the development pathway utilizing molecular pathology/biobanking strengths and integrating computational/bioinformatics expertise
This initiative will bring together Nottingham's expertise in molecular pathology, East midlands Pathology (Empath) which is the largest clinical pathology service in Europe and has the largest repository of archival tissue in Europe, Nottingham Health Sciences Biobank which is the CRC UK National Biobank co-ordinating centre and Nottingham's Advanced data Analysis Centre (ADAC) which has strong computational expertise including bioinformatics, artificial neural networks, statistics and data interpretation skills for integrating knowledge from several platforms.

To use this infrastructure where Nottingham has existing translational research strengths
Our strategy will be to use the infrastructure to produce world-class innovative research and progress new biomarkers from discovery, down the development pathway into the clinic. Nottingham's major clinical research strengths are: (i) Respiratory and (ii) GI/liver diseases where we have critical mass, expertise, patient cohorts and infrastructure supported by MRC, NIHR, research charities, EU and industry funding.

To address areas of unmet clinical need
Chronic Obstructive Pulmonary Disease (COPD) affects over 1 million people in UK and kills 25,000/year. Idiopathic Pulmonary Fibrosis (IPF) is commoner than all leukaemias combined kills 50% within 3 years of diagnosis. Lymphangioleiomyomatosis (LAM) has no effective treatment and we host the UK centre. Cystic Fibrosis (CF), the commonest genetic disease and median age of death is 35-40 usually due to Pseudomonas infection. Hepatitis B/C affect more than 500,000 people in the UK. H. pylori affects 1 in 6 people in the UK and causes peptic ulceration and gastric cancer.

To use existing large patient cohorts to facilitate translation
Nottingham Respiratory Research Unit (NRRU) has well-phenotyped cohorts (n) including IPF (550), LAM (100), CF (400), and COPD (400). We contribute to national/international collaborations including IMI UBIOPRED, MRCMAP COPD, NIHR Respiratory TRP, MRC Rare Diseases Consortium, CRAFT Consortium. The NIHR Nottingham Digestive Disease Biomedical Research Unit (NDDBRU) hosts HCV Research UK, a national cohort (10,000) and clinical database/biorepository, and is a MRC Stratified Medicine Consortium STOP-HCV member. NDDBRU has non-alcoholic fatty liver disease (NAFLD; 300), compensated cirrhosis (200), Hepatitis B (200) and H.pylori cohorts.

To use the infrastructure to train the next generation of molecular pathologists
We will run high quality Master' levels programmes, short taught courses and summer training schools meeting NHS/industry needs for molecular pathologists in the genomic medicine era. NMPN will provide a platform for aligning ACL posts, PhDs and MSc projects.

Potential applications and benefits
Our approach will develop world leading translational molecular diagnostic capabilities in GI/liver and respiratory diseases. The work will lead to the development and clinical application of biomarkers/molecular diagnostics and computer modeling algorithms in several important infective, inflammatory and fibrotic diseases of the respiratory, GI systems and liver and will likely be applicable to diseases in other organ systems. It will benefit patients, scientists, industrial partners and the health and wealth of the nation.

NMPN brings together pathologists, molecular biologists, clinicians, computer scientists, the Nottingham Health Science Biobank (NHSB), Nottingham University Hospitals NHS Trust (NUH), Empath, Pharma/biotech companies and electronic engineering companies.
Co-localisation of expertise, an exceptional tissue repository with linked real-time stratified patient data and well-defined clinical cohorts are resources we aim to use to create a new and original infrastructure encompassing informatics, computational modelling and molecular pathology. This will allow (i) biomarker testing to reveal hidden disease strata (discovery push), (ii) testing clinically stratified patient cohorts to reveal discriminatory biomarkers (clinical pull) and (iii) robust biomarker validation enabling early clinical translation. NMPN models will integrate multi-platform data including DNA/RNA/Proteomic/Metabolomic profiles, digital image analysis, genomic profiling of pathogens as well as data from other sources (e.g. radiology) to provide clinical decision support.
Our models will be tested in infection/inflammation/fibrosis and repair - disease processes with variable outcomes and treatment responses and providing an ideal template for stratification. NMPN will focus on upper & lower gastrointestinal tract, liver and respiratory tract, which feature amongst Nottingham's major research strengths. Although developed for infection/inflammation/fibrosis the models will be transferable to other diseases and easily disseminated to other nodes.
We will work closely with industry and align with other nodes to transfer knowledge and ensure research is translated from bench-to-bedside. NMPN will provide in-depth training for PhD students, new Fellowships in Molecular Pathology, rotation of NHS clinical pathology trainees through the Node, and creation of a new Associate Professor post. We will deliver a distance-learning MSc course for the network and organise annual summer training schools.

Who will benefit?
1. Patients and the public
2. Respiratory and GI/Liver translational researchers
3. Discovery Scientists
4. The wider scientific community
5. Pharmaceutical and diagnostics companies
6. Other molecular pathology nodes
7. Government and policymakers

How will they benefit?
Patients and the public: This proposal is aimed at developing new molecular diagnostics/biomarkers for stratifying a number of important diseases with a view to allowing appropriate targeting with existing or novel therapies. This will help ensure that in future patients are treated with the right drug for their condition at the most appropriate time and there will be suitable biomarkers to evaluate the response to treatment. In the medium to long term this is likely to improve the quality of life and longevity of patients with a number of conditions, which currently have high morbidity and mortality. There is therefore a real possibility of a major impact on the nation's health.

Respiratory and GI/Liver researchers: The areas of disease we are researching are those that there is a real need to develop biomarkers of infection, biomarkers predicting decline and the appropriate point to intervene with different therapies. Our results are likely to have wide recognition within the respective scientific communities.

Discovery scientists: The node will provide a vehicle for the translation of excellent basic discovery research making sure that cutting edge discovery science is not wasted and is able to reap its full benefit.

The wider scientific community: Although our node will focus on respiratory, GI and liver diseases the platform created could be used to facilitate research in diseases in other organs as the techniques developed, knowledge of disease mechanisms and modeling algorithms developed may be applicable to a much wider range of infective, inflammatory and fibrotic diseases.

Pharmaceutical and diagnostics companies: Pharmaceutical companies interested in drug development will benefit from developing stratified models and companion diagnostic which indicate the phenotypes of patient that their products can best target. The route to market will be more rapid and the chance of test and drug adoption into routine clinical practice will be considerably enhanced.

Other molecular pathology nodes: The platforms, techniques and modeling algorithms we set up will be shared with other molecular pathology nodes in the network giving added value to their work. This is likely to be a twoway exchange of knowledge in an ongoing manner. By integrating the training components with training taking place in the other nodes we will ensure that the UK has one of the most comprehensive training structures for molecular pathology worldwide.

Government and policymakers: By setting up a series of molecular pathology nodes this initiative will give the UK an international lead and is increase its competitiveness as a marketplace for new molecular diagnostic and biomarker research. It will also improve flow from outside of the UK into the UK of trainees capitalizing on excellent training opportunities MSc and PhD's in molecular pathology. It is likely therefore to contribute to the nations wealth. It will provide data on new ways of stratifying the phenotypes of patients with disease which will be helpful to organisations such as NICE when developing guidelines for disease treatment and monitoring.