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.

Synthesis, the science of making molecules, is central to human wellbeing through its ability to produce new molecules for use as medicines and materials. Every new drug, whether an antibiotic or a cancer treatment, is based on a molecular structure designed and built using the techniques of synthesis. Synthesis is a complex activity, in which bonds between atoms are formed in a carefully choreographed way, and training to a doctoral level is needed to produce scientists with this expertise. Our proposed CDT is tailored towards training the highly creative, technologically skilled scientists essential to the pharmaceutical, biotech, agrochemical and materials sectors, and to many related areas of science which depend on novel molecules. Irrespective of the ingenuity of the synthetic chemist, synthesis is often the limiting step in the development of a new product or the advance of new molecular science. This hurdle has been overcome in some areas by automation (e.g. peptides and DNA), but the operational complexity of a typical synthetic route in, say, medicinal chemistry has hampered the wider use of the technology. Recent developments in the fields of automation, machine learning (ML), virtual reality (VR) and artificial intelligence (AI) now make possible a fundamental change in the way molecules are designed and made, and we propose in this CDT to engineer a revolution in the way that newly trained researchers approach synthetic chemistry, creating a new generation of pioneering innovators. Making use of Bristol's extensive array of automated synthetic equipment, flow reactors, peptide synthesisers, and ML Retrosynthesis Tool, students will learn and appreciate this cutting-edge technology-driven program, its potential and its limitations. Bristol has outstanding facilities, equipment and expertise to deliver this training. At its core will be a state-of-the-art research experience in our world-leading research groups, which will form the majority of the 4-year CDT training period. For the 8 months prior to choosing their project, students with complete a unique, multifaceted Technology & Automation Training Experience (TATE). They will gain hands-on experience in advanced techniques in synthesis, automation, modelling and virtual reality. In conjunction with our Dynamic Laboratory Manual (DLM), the students will also expand their experience and confidence with interactive, virtual versions of essential experimental techniques, using simulations, videos, tutorials and quizzes to allow them to learn from mistakes quickly, effectively and safely before entering the lab. In parallel, they will develop their teamworking, leadership and thinking skills through brainstorming and problemsolving sessions, some of them led by our industrial partners. Brainstorming involves the students generating ideas on outline proposals which they then present to the project leaders in a lively and engaging interactive feedback session, which invariably sees new and student-driven ideas emerge. By allowing students to become fully engaged with the projects and staff, brainstorming ensures that students take ownership of a PhD proposal from the start and develop early on a creative and collaborative atmosphere towards problem solving. TATE also provides a formal assessment mechanism, allow the students to make a fully informed choice of PhD project, and engages them in the use of the key innovative techniques of automation, machine learning and virtual reality that they will build on during their projects. We will integrate into our CDT direct interaction and training from entrepreneurs who themselves have taken scientific ideas from the lab into the market. By combining our expertise in synthesis training with new training platforms in automation, ML/AI/VR and entrepreneurship this new CDT will produce graduates better able to navigate the fast-changing chemical landscape.

Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at https://www.ukri.org/apply-for-funding/how-we-fund-studentships/. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.

The incidence of allergic disease has increased alarmingly in recent decades, nowhere more so than in the UK, where rates are now among the highest in the world. These conditions range from mild hayfever to life-threatening severe asthma or anaphylaxis, and include allergic rhinitis, atopic dermatitis and food allergies. All of these conditions involve reactions to otherwise innocuous substances in the environment, and all involve a particular type of antibody known as IgE. We have studied this antibody over many years, and understand much about how it differs from other types of antibody such as the protective IgG antibodies. All antibodies play two important roles: they recognize and bind - usually, in the case of IgG - to foreign invaders such as bacteria or viruses using one part of the antibody molecule, and then bind via another part to "receptor" molecules on cells that become activated to destroy the foreign material. But IgE has the remarkable property of binding so tightly to the cells that once bound it almost never comes off within the lifetime of the cell. This means that when an allergen such as pollen, or peanut, or house dust mite, gets into the body (through airway, gut or skin) and binds to the IgE antibodies, they can activate the cells immediately to deliver a powerful, inflammatory response. The cells are effectively "sensitized" to react to the allergen. IgE can be targeted to alleviate allergic conditions, and an "anti-IgE" antibody therapy, called omalizumab (XolairTM), may be prescribed for certain patients with severe asthma. It works by binding to IgE molecules and blocking them from binding to the cell receptors, thus preventing sensitization; however, IgE already receptor-bound, the "pathogenic" IgE, is unaffected. It now appears that Xolair at extremely high levels, well above those reached therapeutically, can actually bind to receptor-bound IgE and actively remove it. This is a remarkable discovery, and one that would have profound implications for anti-allergy therapy if it could be understood and harnessed. We believe that the key to understanding this phenomenon lies in the unique flexibility of the IgE antibody. Our previous studies have revealed, quite unexpectedly, that the receptor-binding part of the IgE molecule can adopt several different shapes, and indeed can communicate signals from one part of the molecule to another through subtle changes in shape. This phenomenon - called allostery ("other shape") - is what we want to explore in detail using a technique that can probe these changes and this communication at the atomic level. If we can understand how binding to one part of the IgE molecule (which is accessible when IgE is bound on the cell) can release it at another site (where it binds to the receptor), then we can begin to develop a much more effective therapeutic agent for allergic disease. However, the benefits may go well beyond allergic disease. The molecular processes of health and disease ubiquitously involve interactions between different proteins, and many of these interactions, like the IgE/receptor interaction, are very tight. Targeting these protein/protein interactions is traditionally considered to be difficult, but an understanding of allostery could open up new possibilities for intervening in a range of diverse medical conditions. We are collaborating in this project with the pharmaceutical company UCB with whom we have been working for several years. They are providing protein materials for the analysis, and their interest in understanding the IgE/receptor system, publishing the results, and applying this knowledge to other protein/protein interactions will ensure the rapid dissemination and commercial translation of the results of this study.

Over 75% of disease-involved proteins cannot be readily targeted by conventional chemical biology approaches. New approaches are needed to increase the scope of molecular medicine. Cryptic binding pockets, i.e. pockets that transiently form in a folded protein, but are not apparent in the crystal structure of the unliganded apo-form, offer outstanding opportunities to target proteins otherwise deemed 'undruggable' and are thus of considerable interest in academia and the pharmaceutical industry. Unfortunately, not only they are notoriously difficult to identify, but also the molecular mechanism by which they form is still debated. The aim of this collaborative project is to address the knowledge gaps and develop an efficient computational platform based on atomistic molecular simulations to systematically detect druggable cryptic pockets in targets of biopharmaceutical interest. The platform will build on our successful experience in developing and applying enhanced-sampling simulation algorithms to molecular recognition, and will be extensively tested on validated drug targets harbouring cryptic sites. The computational results will be further validated on novel targets by a combination of experiments in collaboration with an industrial partner (UCB).