Edinburgh-St Andrews Consortium for Molecular Pathology, Informatics and Genome Sciences

The human genome project and the technological advances that accompanied it, including the recent advent of the "thousand dollar genome" have opened up new possibilities in medicine, including the opportunities for more precise, molecular diagnoses and personalised treatment based on genome information. The technologies are now at a stage where, with appropriate validation and optimisation, they will soon be moved into routine clinical care to accelerate disease diagnosis and improve patient outcomes. However, to introduce this "step-change" in diagnostics and pathology successfully into the clinic, will require the coordinated action of expertise from multiple fields, including the physical sciences, and training of modern-style pathologists to be familiar with multiple advanced technologies.
The Edinburgh-St Andrews Molecular Pathology Node will integrate the proven strengths of the Universities of Edinburgh and St Andrews in molecular pathology and diagnostics (training, development and clinical implementation), image analysis of complex phenotypes and computing, with the breadth of genome medicine and genome sciences experience available within the Universities and NHS Lothian. These strengths include institutes and centres with substantial existing MRC, EPSRC and charitable investment including the MRC Human Genetics Unit, MRC Farr Institute, CRUK Cancer Centre and EPSRC-funded supercomputer and optical imaging facilities.

The main aims of the Node will be: (1) training a new generation of molecular pathologists capable of handling modern genome-analysis-aided approaches to diagnosis and treatment of human disease; (2) developing new tests and clinical applications utilizing the advantages of novel technologies; (3) creation of new algorithms, standard operating procedures, data flow schemes and advanced statistical and computational methods that will directly facilitate analysis of the vast and complex data generated by genomics and imaging methods, to implement these new molecular pathology approaches in the clinic. We will focus on areas of clinical need where we believe genome-based assays will most rapidly enter the clinic, particularly the genetic diagnosis of acutely ill children and babies, genetic diagnosis in fetuses with congenital malformations, inherited subtypes of common diseases in adults, and the diagnosis and monitoring of patients with cancer through development of "liquid biopsies" from cell-free DNA in circulating blood.

A significant part of the proposed work will be done by practicing clinicians and diagnosticians in the framework of a purpose-designed Masters Research Programme in Molecular Pathology, to which experts in many fields will contribute, including those in the UK National External Quality Assurance Scheme (UK NEQAS) for Molecular Genetics and Pathology, which is based at the Royal Infirmary in Edinburgh. Together with our world-leading partners from the biotechnology and pharmaceutical industry, we will develop and integrate these genome and imaging-based methods to implement new diagnostic methods in healthcare and to produce and sustain a generation of "genomically-skilled" pathologists who will be leaders in the introduction of these methods into routine practice for the next generation of doctors and scientists.

The Edinburgh-St Andrews Molecular Pathology Node will integrate proven strengths in molecular pathology, (training, development and clinical implementation), image analysis of complex phenotypes, informatics and genomics to build expertise, quality assurance and capacity in 21st century molecular diagnostics. Drawing on additional strengths in the MRC Human Genetics Unit, MRC Farr Institute, CRUK Cancer Centre, EPSRC-funded supercomputer facilities and industrial collaborations, we will establish a Masters by Research in Molecular Pathology, and thus train a new generation of scientists who will develop new assays, algorithms and standards for genome and epigenome analysis and interpretation for clinical use. We will implement state-of-the-art genome technologies to mainstream molecular diagnosis of Mendelian diseases in adult medicine and establish rapid genetic diagnosis of acutely ill children and neonates. We will develop "liquid biopsies" for managing cancer via genetic and epigenetic analyses of tumours and cell-free circulating DNA and will use state-of-the art digital imaging, image analysis and spectroscopy of tumours to provide more precise diagnoses and predictive stratification for patient management. The leads for this proposal all work at the interface of academia and the NHS and, by defining diagnostic standards in collaboration with the UK National External Quality Assurance Scheme (UK NEQAS) for Molecular Pathology and Genetics, hosted in Edinburgh by NHS Lothian, can ensure that these innovations are translated rapidly to clinical practice in the NHS. The Node's activities will be dovetailed with industry at every stage: technology development, assay design and implementation, data interpretation and clinical validation. The new Molecular Pathology Masters programme will produce and sustain a generation of new academic pathologists and help create a virtual Centre for Molecular Pathology as a basis for a substantive MRC Centre in the longer term.

Through the clinical, academic and public engagement activities of the PI and co-Investigators, there has already been significant public, industrial and healthcare interest in the proposed activities of this Node.

Following the "Clinical Genomes Scotland" meeting in Edinburgh in October 2014, organised by Aitman, Porteous and Hastie, the Clinical Genetics Forum of Scotland held a number of meetings, culminating in the recommendation to the Scottish Chief Medical Officer (CMO) for the funding of 750 clinical genome sequences per year. Detailed discussions with the CMO have now led to provision for £1 million for clinical sequencing of Scottish genomes. This funding is part of an overall package of £10 million, to be jointly provided by the MRC and Scottish government, contingent on successful peer review of a single Scottish application for this funding (submitted February 2015, Aitman co-PI). If awarded, this funding will have a major impact on genome activities in Scotland and across the UK.

The public sector has also shown considerable interest in the genome and pathology activities of this grouping of researchers. For example, the PI has been invited by Genetic Alliance and Rare Diseases UK to speak at their annual reception at the Scottish Parliament in February 2015. Public events are planned by co-I Morris as part of the public engagement activities of the Scottish Farr Institute.

The proposed Node has also received considerable interest from local, national and international industry. The globally leading genome sequence company, Illumina, is one of our formal partners and will share early access protocols and software and has allocated a half-time postdoctoral scientist to work with us in their development labs. The leading multinational pharmaceutical company, Biogen Idec, has sponsored three Masters studentships and indicated its keenness to collaborate with us on genome-based disease stratification projects. Other companies, including Nucana, Definiens, Qunitiles and Aridhia have indicated they will collaborate with the Node, once established, on clinical trials of genome-based assays.

Overall, the training of 18 Pathologists as Masters students on our MSc by Research, who will be versed in the most up-to-date genome and computational technologies in their applications to healthcare, will create a step-change in training of academic pathologists. We anticipate that some of our graduates will be the leaders in development of molecular diagnostics for the next generation of clinicians and healthcare scientists.