2.1 Unmet Clinical Need Bronchiectasis (BE) is a progressive respiratory (lung) disease characterised by cough, mucus and severe, recurrent bacterial chest infections with high rates of ill health, time off work and marked reductions in health-related quality-of-life. In almost half of cases, the cause of bronchiectasis is unknown (idiopathic) and treatment in these patients remains "best guess" or symptom driven. Bronchiectasis presents a huge challenge to patients and doctors because no effective treatment is available. Both the world's first national guidelines (authored by coapplicants of this proposal) and Cochrane "best evidence" review of Bronchiectasis confirms this situation, reporting that small single-centre studies with ill-defined patient groups have hampered the few attempts to study clinical interventions /drug trials, rendering them of unproven use. Previously the MRC sponsored UK trials in Bronchiectasis in the 1950s: Since then major developments have been sorely lacking. This partly reflects a feeling that BE is rare. However recent evidence is against this: In the UK and the US healthcare demands due to BE and mortality rates are increasing with 70,000+ hospital admissions in the UK 2011. Based on projections from US health insurance claims there are 100,000 US patients. We have limited UK data on how common this bronchiectasis is: Experts have however estimated 30-60,000 patients are affected in the UK but recent research suggests over 100,000 are affected. Whilst the small case series reported so far demonstrate that "unknown cause" (idiopathic) and post-infectious bronchiectasis are the leading causes, bronchiectasis can also complicate common lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) or immune problems e.g. Rheumatoid arthritis. Cystic Fibrosis is an inherited (genetic) form of bronchiectasis which like COPD associated bronchiectasis has different outcomes, microbiology and management needs from Bronchiectasis. Cystic fibrosis is rare (10,000 cases in the UK) yet has made significant gains through multicentre working and coordinating research. To date no large studies of the genetic causes of idiopathic bronchiectasis have been conducted as this requires large numbers of patients beyond that a single centre can provide. There is currently no registry of well characterised patients with Bronchiectasis anywhere outside the US. The US national registry was commenced recently and has 1200 patients that differ to UK patients. There is an urgent need to build a large cohort of UK patients with Bronchiectasis in which large enough studies can be undertaken; adding in a biobank is a key additional strength. Brief description of the Cohort and Partnership The cohort will comprise 3500 symptomatic adult patients with a High Resolution CT scans demonstrating bronchiectasis. Patients will be characterised on the basis of clinical history, clinical examination and detailed investigations that are already part of routine clinical care with yearly reviews. A DNA biobank (from a blood sample) will be collected and will form a world's first in bronchiectasis providing a unique resource allowing future genetic studies to identify underlying genetic causes & new targets for treatment. The partnership links 9 recruiting centres with established clinics & track records in Bronchiectasis research spread across the UK that have never had funding to work together. Additionally ground-breaking scientific partners with expertise in relevant areas will for the first time allow comprehensive mapping of the knowledge gaps. Future research will be able to use the strength of the assembled cohort; we can deliver a programme of clinical trials that address fundamental issues. We will therefore tackle three major unmet needs 1) Lack of expertise in the area, 2) Lack of a clinical evidence base 3) Basic science- attracting skilled scientists to work in the area.

At the forefront of global pharmaceutical research is the development of "intelligent" medicines which are effective, affordable and safe, for diseases that are poorly treated (for example, cancer, infections, cardiovascular disease and neurodegeneration). The ideal medicine could be taken by a variety of means (pill, injection or inhaler), but should only act on diseased tissue at a 'specific' site in the body. However, the ability to direct a drug to particular desired locations in the body is still a major scientific challenge. Drugs can easily be degraded en route to their target leading to quickly decreasing drug levels. Higher levels of medication do not circumvent this problem due to potentially increased side effects or toxicity. Some drugs can simply not be delivered to their target due to barriers within the body: the ability to reach specific disease sites while leaving healthy cells intact would mean not only better therapeutic outcomes, but better qualities of life for patients and carers. Benefits through better formulation and targeting will be very apparent for those diseases that are increasing in ageing populations, such as cancer, which is predicted to affect (directly or indirectly) 1 in 3 in the European population by 2020. For these and other devastating diseases new therapeutic regimens are urgently needed. Research into Advanced Therapeutics requires not just scientific innovation but also a changed training paradigm for the scientists involved. Many advanced therapeutic formulations are inherently in the 'nano' size range i.e. larger than conventional drugs such as ibuprofen and paracetamol, but smaller than human cells, and thus spanning the traditional domains of chemistry, biology and medicine. Developing the science of these emergent nanomedicines towards clinical products requires a new generation of researchers trained across multiple scientific disciplines. The Centre for Doctoral Training we propose builds on our existing close partnerships with leading industry and academic institutions world-wide to offer training in the diverse and challenging disciplines underlying pharmaceutical science. The proposed Centre will combine expertise in analytical and medicinal chemistry, with materials science, engineering, biology and industrial pharmaceutics, to equip researchers with the skills they need to develop the next generation of pharmaceutical products. Accordingly, the CDT offers wider benefits to society as researchers trained in the Centre will be attractive to the chemicals, engineering and materials sectors as well as healthcare and medicine. Within the proposed CDT we aim to continue our broad-based training approach, such that researchers will have innovation and entrepreneurial skills, so vital for the developing industry sector. This focus on translational and business skills helped a team from Nottingham in the existing CDT to be winners of the NanoCom business competition in 2012. Ultimately, improvements in the industry and practice of therapeutics combined with enhanced academy / industry pathways to translation offer many future advantages, not just to the science, industry and medical base, but to patients, carers and society as a whole.

It is now clear that biological functions or diseases arise from complex interactive networks operating on many different scales. The translational work needed to transform promising new drugs and therapies into commercial products will increasingly require predictive mathematical and computational modelling at the systems level. The Systems Approaches to Biomedical Science (SABS) Centre aims to meet this demand by training a new generation of responsive research leaders with the ability to generate and apply novel physical and mathematical techniques to solve research problems of relevance to the pharmaceutical, biomedical, biotechnology and related sectors. SABS will address these industry-relevant scientific questions from the real world, and explore them through genuine academic-industrial collaborations. SABS will provide training and research across a wide range of areas, including the design and testing of new chemical and biological entities, modelling biological systems, and robust analysis of complex datasets. Such cross-disciplinary work will introduce students to cutting edge organic chemistry, chemoinformatics, chemical and synthetic biology, biophysics, advanced computational simulation, bioinformatics, data mining, statistical analysis, physical and structural study of biomolecules, and mathematical modelling. Over the last 4 years the SABS team have created a wide network of contacts within Oxford and across industry. SABS will continue to work closely with its partner companies (AstraZeneca, Diamond Light Source, e-Therapeutics, Evotec, GE Healthcare, GlaxoSmithKline, Hoffmann LaRoche, InhibOx, Lilly UK, Microsoft, Novartis, Pfizer, Structural Genomics Consortium and UCB), and with 14+ departments across the University. Every SABS student will be co-supervised and co-funded by industry and will be fully exposed to the industrial context of their research in both the taught programme, and in their industry-based research projects. They will develop skills in project management, strategic planning, leadership, team working, commercial awareness, and problem solving all of which will be required to translate innovations in basic and medical science into commercial product development. SABS will continue to use its ground-breaking and, currently, unique Open Innovation IP agreement, which allows all participants in the SABS consortium to see the results of all research projects. Participating companies regard it as a trail-blazing model for the future of industry-academia collaboration, because it simplifies inter-company research collaboration within the consortium and improves the existing business process for innovation and academic collaborations. From an academic perspective, it allows the students to participate in impactful industrial research whilst still gaining the benefits of research discussion with their peer cohort. Oxford University has made substantial investments both in infrastructure for graduate training and all research areas associated with SABS. It actively promotes interdisciplinary research with external collaborators, and is currently investing heavily in the new Target Discovery and Big Data institutes. SABS has demonstrated very strong user pull, and an ability to recruit new companies; three organisations are currently in the process of joining. In this new bid the companies have doubled their cash contribution per student to £30k, and will also cover all associated research and travel costs (currently averaging £8k per student); a clear commitment to the continuation of the SABS centre. Our minimum cohort size of 14 means industry will make a minimum cash contribution to student funding of £2.1m and a further £560k to research costs.

Modern society is reliant on chemical synthesis for the discovery, development and generation of a wide range of essential products. These include advanced materials and polymers, bulk fine chemicals and fertilizers, and most importantly products that impact on human health and food security such as medicines, drugs, and agrochemicals. Future developments in these areas are benficial for society as a whole and also for a wide range of UK industries. To date it has been common practice for the chemical industry to recruit synthetic chemists after PhD/postdoctoral training and then augment their synthetic knowledge with specific industrial training. Due to the changing nature of the chemical and pharmaceutical industry it is recognized that synthetic chemists require an early understanding of the major challenges and methodologies of biology and medicine. The concept of our SBM CDT arose from the need to address this skills gap without compromising training in chemical synthesis. We have designed a training programme focused on EPSRC priorities to produce internationally outstanding doctoral scientists fluent in cutting edge synthesis, and its application to problems in biology and medicine. To achieve this, we have formed a genuinely integrated public-private partnership for doctoral training whereby we combine the knowledge and expertise of industrialists into our programme for both training and research. We have forged partnerships with 11 global industrial partners (GSK, UCB, Vertex, Evotec, Eisai, AstraZeneca, Syngenta, Novartis, Takeda, Sumitomo and Pfizer) and a government agency (DSTL), which have offered: (i) financial support (£4.6M cash and £2.4M in-kind); (ii) contributions to taught courses; (iii) research placements; and (iv) management assistance. Our training partners are global leaders in the pharmaceutical and agrochemical industries and are committed to the discovery, development and manufacture of medicines and agrochemicals for the improvement of human health. To fully exploit the opportunities offered by commercial partners, the SBM Centre will adopt an IP-free model to allow completely unfettered exchange of information, know-how and specific expertise between students and supervisors on different projects and across different industrial companies; this would not be possible under existing studentship arrangements. This free exchange of research data and ideas will generate highly trained and well-balanced researchers capable of world-leading research output, and importantly will enable students to benefit from networks between academic and industrial scientists. This will also facilitate interactions between different industrial and government groups, leading to links between pharmaceutical and agrochemical scientists (for example). The one supervisor - one student model, typical of current studentship programmes, is unable to address significant and long-term training and research topics that require a critical mass of multidisciplinary researchers; consequently we propose that substantive research projects will also be cohort-driven. We envisage that this CDT will have a number of training and research foci ('Project Fields') in which synthesis is the unifying core discipline, to enable our public-private partnership to tackle major problems at the chemistry-biology-medicine interface. Our focused research fields are: New Synthetic Methods, 3D Templates for "Lead-Like" Compounds, Functional Probes for Epigenetics, Next Generation Anti-Infectives, Natural Product Chemistry and Tools for Neuroscience. This doctoral training programme will employ a uniquely integrated academic-industrial training model, producing graduates capable of addressing major challenges in the pharmaceutical/agrochemical industries who will ultimately make a major impact on UK science.

Clinical pharmacologists are physicians and scientists whose focus is developing and understanding existing and new drug therapies; they work in a variety of settings in academia, the NHS, industry and government. In the clinical setting, they work directly with patients, participate in trials, and investigate how patients respond to drugs, including why certain patients develop side effects to drugs. The total number of academic clinical pharmacologists trained in the UK is small, and there is an imperative to continue to train more clinical pharmacologists and other specialists with expertise in clinical pharmacology who can work between academia, healthcare and industry. In 2010, the Government recognised that the provision of high quality-care and better interaction with Industry requires clinicians to be familiar with the relevant practices in clinical pharmacology. The universities of Liverpool and Manchester, in collaboration with industry partners, were awarded funding from the MRC to address this unmet need in clinical pharmacology: The North West England MRC Clinical Research Training Fellowship Programme in Clinical Pharmacology and Therapeutics. This programme has allowed 13 clinical fellows (high flying trainee doctors), rigorously selected from across all medical specialties e.g. dermatology, rheumatology, paediatrics etc., to study for PhDs on a variety of clinical pharmacology related research topics such as drug safety and stratified medicine - matching the right drug to the right patient. In addition to their research work the fellows received without walls training with industry and modular training in key aspects of clinical pharmacology. The programme has been a tremendous success with 56 scientific journal publications, 21 conference presentations, 13 prizes and interactions with 61 NHS Trusts. All fellows will also get a PhD. We now wish to renew the scheme with the MRC and with 4 industry partners - Lilly, Novartis, Roche and UCB Pharma, to appoint 13 more fellows. The previous successful format and structure will be retained as will joint leadership from the two universities. Refinements to the programme include: increasing the number of industry partners thereby allowing us to cover more therapeutic areas including cancer; lengthening of the recruitment process to give potential fellows, their supervisors and industry representatives more time to develop research projects with strong alignment; identification of a lead industry partner for each fellow from the beginning of the programme to develop a partnership from the outset; ensuring, where possible, that fellows can spend up to one year with the industry partner at their site(s) performing different aspects of their project. These changes will enhance fellows' training with industry, and also increase the input provided by industry in individual projects. There will be very strong patient and public engagement (as in the current scheme) with involvement of patients in the planning of research proposals, a number of public lectures and involvement of fellows at events such as the Manchester Science Spectacular. The Fellowship Programme will go some way to producing academics with expertise in clinical pharmacology and helping to optimise the safe, targeted prescribing of existing drugs and the development of new therapies for human disease.