Analysis of molecular and cellular events is crucial in modern life sciences research, for a better understanding of (i) fundamental biological processes, (ii) the changes that characterise associated disease states, and (iii) the development of therapeutics. This research proposal brings together seven research areas, spanning the regulation of the immune and nervous systems, haemopoiesis, tissue development and regeneration and cell metabolism that share a common theme of wanting to utilise sensitive, quantitative and high throughput state-of-the-art instrumentation to analyse a range of cellular mechanisms. This instrument is the Mesoscale Discovery (MSD) SECTOR Imager (SI) 6000 which offers a sensitive, adaptable platform with which to measure several analytes in cell or cell-derived samples. The technology relies on the use of chemically tagged antibodies that recognize the analytes of choice. When bound to their target, the Abs emit light upon electrochemical stimulation which is measured and quantified. The main features provided by the instrument are: - the ability to accurately quantify activation of specific signals; - it facilitates detection of multiple signals simultaneously. - in situations where cell samples may be limiting, information on several different signalling molecules can be generated simultaneously. - the system allows for more rapid analysis, - provides platform for developing our own custom made assays for future applications.

Large-Area Electronics is a branch of electronics in which functionality is distributed over large-areas, much bigger than the dimensions of a typical circuit board. Recently, it has become possible to manufacture electronic devices and circuits using a solution-based approach in which a "palette" of functional "inks" is printed on flexible webs to create the multi-layered patterns required to build up devices. This approach is very different from the fabrication and assembly of conventional silicon-based electronics and offers the benefits of lower-cost manufacturing plants that can operate with reduced waste and power consumption, producing electronic systems in high volume with new form factors and features. Examples of "printed devices" include new kinds of photovoltaics, lighting, displays, sensing systems and intelligent objects. We use the term "large-area electronics" (LAE) rather than "printable electronics" because many electronic systems require both conventional and printed electronics, benefitting from the high performance of the conventional and the ability of the printable to create functionality over large-areas cost-effectively. Great progress has been made over the last 20 years in producing new printable functional materials with suitable performance and stability in operation but despite this promise, the emerging industry has been slow to take-off, due in part to (i) manufacturing scale-up being significantly more challenging than expected and (ii) the current inability to produce complete multifunctional electronic systems as required in several early markets, such as brand enhancement and intelligent packaging. Our proposed Centre for Innovative Manufacturing in Large-Area Electronics will tackle these challenges to support the emergence of a vibrant UK manufacturing industry in the sector. Our vision has four key elements: - to address the technical challenges of low-cost manufacturing of multi-functional LAE systems - to develop a long-term research programme in advanced manufacturing processes aimed at ongoing reduction in manufacturing cost and improvement in system performance. - to support the scale-up of technologies and processes developed in and with the Centre by UK manufacturing industry - to promote the adoption of LAE technologies by the wider UK electronics manufacturing industry Our Centre for Innovative Manufacturing brings together 4 UK academic Centres of Excellence in LAE at the University of Cambridge (Cambridge Integrated Knowledge Centre, CIKC), Imperial College London (Centre for Plastic Electronics, CPE), Swansea University (Welsh Centre for Printing and Coating, WCPC) and the University of Manchester (Organic Materials Innovation Centre, OMIC) to create a truly representative national centre with world-class expertise in design, development, fabrication and characterisation of a wide range of devices, materials and processes.

By 2025 targeted biological medicines, personalised and stratified, will transform the precision of healthcare prescription, improve patient care and quality of life. Novel manufacturing solutions have to be created if this is to happen. This is the unique challenge we shall tackle. The current "one-size-fits-all" approach to drug development is being challenged by the growing ability to target therapies to only those patients most likely to respond well (stratified medicines), and to even create therapies for each individual (personalised medicines). Over the last ten years our understanding of the nature of disease has been transformed by revolutionary advances in genetics and molecular biology. Increasingly, treatment with drugs that are targeted to specific biomarkers, will be given only to patient populations identified as having those biomarkers, using companion diagnostic or genetic screening tests; thus enabling stratified medicine. For some indications, engineered cell and gene therapies are offering the promise of truly personalised medicine, where the therapy itself is derived at least partly from the individual patient. In the future the need will be to supply many more drug products, each targeted to relatively small patient populations. Presently there is a lack of existing technology and infrastructure to do this, and current methods will be unsustainable. These and other emerging advanced therapies will have a critical role in a new era of precision targeted-medicines. All will have to be made economically for healthcare systems under extreme financial pressure. The implications for health and UK society well-being are profound There are already a small number of targeted therapies on the market including Herceptin for breast cancer patients with the HER2 receptor and engineered T-cell therapies for acute lymphoblastic leukaemia. A much greater number of targeted therapies will be developed in the next decade, with some addressing diseases for which there is not currently a cure. To cope, the industry will need to create smarter systems for production and supply to increasingly fragmented markets, and to learn from other sectors. Concepts will need to address specific challenges presented by complex products, of processes and facilities capable of manufacture at smaller scales, and supply chains with the agility to cope with fluctuating demands and high levels of uncertainty. Innovative bioprocessing modes, not currently feasible for large-scale manufacturing, could potentially replace traditional manufacturing routes for stratified medicines, while simultaneously reducing process development time. Pressure to reduce development costs and time, to improve manufacturing efficiency, and to control the costs of supply, will be significant and will likely become the differentiating factor for commercialisation. We will create the technologies, skill-sets and trained personnel needed to enable UK manufacturers to deliver the promise of advanced medical precision and patient screening. The Future Targeted Healthcare Manufacturing Hub and its research and translational spokes will network with industrial users to create and apply the necessary novel methods of process development and manufacture. Hub tools will transform supply chain economics for targeted healthcare, and novel manufacturing, formulation and control technologies for stratified and personalised medicines. The Hub will herald a shift in manufacturing practice, provide the engineering infrastructure needed for sustainable healthcare. The UK economy and Society Wellbeing will gain from enhanced international competitiveness.

Chiral amines are prevalent in natural products, which often display potent biological activity. Such chiral amine motifs are also frequently found in pharmaceutical drug compounds and chemical building blocks meaning that the development of environmentally benign and sustainable routes to produce these important motifs is extremely desirable. Nature synthesizes these complex and valuable molecules through the action of highly specialized enzymes. These natural catalysts enable an extremely efficient biosynthesis from simple starting materials, installing functional groups with exceptional levels of selectivity. Chemical catalysts are frequently designed to mimic the action of enzymes and are often capable of achieving impressive selectivity. However, unlike enzymes, processes involving these catalysts usually involve high temperatures, sub-optimal pH, organic solvent and complex purification methods. Enzymes called omega-transaminases (TAs) catalyze the conversion of commercially available or easily accessible starting materials to high-value amines. These biocatalysts require an additional donor molecule to provide the amine functional group. This donor is ultimately converted to a by-product and the desired amine product is formed. However, the reaction is freely reversible and unless this by-product is removed from the reaction, low yields of the desired amine will be isolated, as the enzyme will more readily catalyse the reverse reaction to regenerate starting materials. A number of elegant approaches have been reported which remove this ketone by-product and allow access to appreciable quantities of the chiral amine. These strategies include the addition of expensive enzymes or the use of extremely large quantities of the amine donor in combination with the technically challenging removal of ketone by-products. One such approach, which relies on an extensively modified TA, is currently used for the industrial synthesis of the antidiabetic drug compound, sitagliptin. However, the approach is far from efficient and the development of this heavily modified TA biocatalyst was enormously challenging, highlighting an immediate need for more sustainable strategies for performing these biotransformations and for developing suitable enzyme catalysts. This research will build upon recent work reported in our laboratory that describes arguably the most efficient approach to date for performing biotransformations involving TAs. The success of the approach is due to spontaneous precipitation of the by-product, which cannot regenerate starting materials. This polymer is also highly colored and has allowed the development of an effective high-throughput screening strategy that enables the rapid identification of active enzymes. Our focus now is to optimize the process further and make it more suitable for industrial application. Specifically, low cost amine donor molecules will be used that are spontaneously removed from the reaction in a similar way to our previously reported method. We will also apply a simple high-throughput screening strategy to assist in the genetic engineering of natural enzymes in order to increase the scope of the reactions that they can catalyze and make them suitable for industrial scale synthesis. The enzymes developed in this study will enable cost-effective, sustainable and environmentally neutral methods for the small/medium and industrial scale production of one of the most important compound classes.

It is now widely accepted that up to ten years are needed to take a drug from discovery to availability for general healthcare treatment. This means that only a limited time is available where a company is able to recover its very high investment costs in making a drug available via exclusivity in the market and via patents. The next generation drugs will be even more complex and difficult to manufacture. If these are going to be available at affordable costs via commercially viable processes then the speed of drug development has to be increased while ensuring robustness and safety in manufacture. The research in this proposal addresses the challenging transition from bench to large scale where the considerable changes in the way materials are handled can severely affect the properties and ways of manufacture of the drug. The research will combine novel approaches to scale down with automated robotic methods to acquire data at a very early stage of new drug development. Such data will be relatable to production at scale, a major deliverable of this programme. Computer-based bioprocess modelling methods will bring together this data with process design methods to explore rapidly the best options for the manufacture of a new biopharmaceutical. By this means those involved in new drug development will, even at the early discovery stage, be able to define the scale up challenges. The relatively small amounts of precious discovery material needed for such studies means they must be of low cost and that automation of the studies means they will be applicable rapidly to a wide range of drug candidates. Hence even though a substantial number of these candidates may ultimately fail clinical trials it will still be feasible to explore process scale up challenges as safety and efficency studies are proceeding. For those drugs which prove to be effective healthcare treatments it will be possible then to go much faster to full scale operation and hence recoup the high investment costs.As society moves towards posing even greater demands for effective long-term healthcare, such as personalised medicines, these radical solutions are needed to make it possible to provide the new treatments which are going to be increasingly demanding to manufature.