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.

Point-of-care testing has been identified as a key element in the international strategy for combating antimicrobial resistance but really it is a key element in all areas of medical practice. At present many of the diagnostic methods which we use do not give the desired instantaneous feedback and are relatively expensive to use. This is particularly an issue in the third world. Our ultimate vision is to produce a paper or plastic strip, a bit like a liquid crystal thermometer, that will provide a specific color-change when it detects a particular bacterial toxin or other disease 'marker'. Test strips that can be used at the point of care, which are cheap and disposable and which do not require a source of power. These will be based on phospholipid (biomembrane-like) coated liquid crystal droplets. The intrinsic amplification properties and the remarkable sensitivity of liquid crystal droplets to bacterial toxins have already been demonstrated but there are a number significant problems that need to be overcome before this promise can be translated into a practicable system. Making use of the unique combination of skills and experience that exists at Leeds, this is what we aim to do. In particular we will develop systems for controlled production of uniform suspensions of droplets of the desired size, to achieve control over the alignment of the liquid crystal at the phopholipid interface, to develop methods for addressing bulk samples rather than (as has been the case so far) individual droplets, to find ways of 'packaging' the droplets either in gels or on surfaces, and to undertake a series of demonstrations of the response and selectivity of these droplets to series of increasingly difficult and demanding test systems mostly based around significant bacterial toxins. This exciting multidisciplinary approach that uses liquid crystals in a new way will both enhance our fundamental scientific understanding of liquid crystals, biomembranes and biomolecule interactions, and potentially provide a new way of diagnosing significant healthcare problems.

Gestational diabetes (too much sugar in the blood in pregnancy) and pregnancy hypertensive disorders (high blood pressure that occurs in pregnancy, and which can lead to fits in the mother and death in the baby) cause significant maternal and neonatal mortality and morbidity in low and middle income countries and there is no systematic approach to prevention. The estimated global prevalence of gestational diabetes is 16%, with higher rates in in South Asia and Africa [1]. Gestational diabetes increases the incidence of the adverse outcomes of caesarean section, pregnancy induced hypertensive disease, excessive birthweight, birth injury, future obesity and future diabetes: untreated, it contributes to a cycle which promotes obesity and diabetes in future generations[2]. Pregnancy hypertensive disorders account for 17.3% of maternal deaths in low socio-economic countries, and are the second commonest cause of maternal death after haemorrhage[3]. In resource rich countries, testing for gestational diabetes is undertaken in women at high risk, together with treatment of those affected and regular self-monitoring of blood sugar levels. Such an approach is inappropriate in resource poor settings due to the high cost of testing and blood sugar monitoring, and the lack of availability of blood sugar monitoring kits. However, measurement of maternal body mass index (weight and height) cheaply and effectively identifies a high-risk group for both gestational diabetes and pregnancy hypertensive disorders. Additionally, one of the treatments (metformin) for gestational diabetes is relatively cheap, widely available, and safe, regardless of blood sugar levels [4-6]. Recent in vitro and clinical data suggest that metformin might reduce the incidence and severity of pregnancy hypertensive disorders [6-8]. We propose that metformin could be a pragmatic approach to preventing gestational diabetes and pregnancy hypertensive disorders in obese pregnant women in resource poor settings. This is a feasibility study of a clinical trial to determine whether metformin is effective in preventing gestational diabetes and pregnancy hypertensive disorders in women at high risk of both conditions. In this feasibility study, we will find out if it is possible for us to do a full trial, how big such a trial would be, and how expensive it would be. We will ask obese pregnant women in participating sites in Malawi and Zambia to take either metformin or matching placebo tablets. We will see how many women wish to participate, how many take the treatment, and what effect the treatment has. We will also be able to see how common gestational diabetes and pregnancy hypertensive disorders are in this population. Although this feasibility study is too small to answer the question "Is routine administration of metformin a pragmatic approach to preventing gestational diabetes and pregnancy hypertensive disorders in obese pregnant women in resource poor settings" it will facilitate a larger (and likely more expensive study) to be able to do so. Our group of clinicians, researchers and policy makers in Malawi, Zambia and the UK has the necessary expertise to carry out both the feasibility study and a further substantive study, and we are well placed to be able to translate the results of the research into clinical practice. References 1. International Diabetes Federation (IDF) IDF Diabetes Atlas, 7th Edition, 2015. 2. NICE, Diabetes in pregnancy. NICE guideline 2015. 3. Global Burden of Disease Maternal Mortality and Morbidity Collaborators, Lancet, 2016. 388: p. 1775-1812. 4. Balsells, M., et al., BMJ, 2015. 350: p. h102. 5. Chiswick, C., et al., Lancet Diabetes Endocrinol, 2015. 3: p. 778-86. 6. Syngelaki, A., et al., N Engl J Med, 2016. 374: p. 434-43. 7. Brownfoot, F.C., et al., Am J Obstet Gynecol, 2016. 214: p. 356 e1-356 e15. 8. Romero, R., et al., Am J Obstet Gynecol, 2017. 217: p. 282-302

This project aims to develop two recent discoveries from the St Andrews laboratory. Project 1: The first project develops from a recent syntheses of 1,2,3,4- and 1,2,4,5-tetrafluorocyclohexanes. Importantly the stereochemistry of the molecules has all of the fluorines on the same face of the cyclohexanes. We find that this makes these cyclohexanes very polar. TWhen cyclohexane adopts a chair conformation, then there are always two diaxial C-F bonds. This polarity renders these compounds crystalline solids, and NMR experiments reveal that the two faces are highly polarised. So the project aims now to incorporate this motif into more meaningful structures. We think that the all-syn tetrafluorocyclohexane motif can have wide ranging roles in developing performance molecules for pharmaceuticals and agrochemicals research. However in this project we will use liquid crystals as a background to explore their properties. Many liquid crystalline molecules that are used in modern displays for personal computers, smart phones and iPads etc contain fluorine atoms. This is because the C-F bond is polar, but it has low viscosity, and thus it can orientate and cycle very rapidly in changing electric fields. The all-syn tetraflurocyclohexane motifs appear to have exactly the correct caharacteristics for a particular class of LC's known as -ve dieletric anisotropic LC's. These are molecules where the dipole is orientated perpendicular to the molecular axis. The project requires that we develop chemistry around a phenyl derivative of the 1,2,4,5-tetrafluorocyclohexane. We plan to carry out a diversity of chemistry on this motif, and also to improve synthetic protocols. We want also to explore synthesis routes to other derivatives of the tetrafluorocyclohexane ring system eg. carboxylic acid and amine motifs we feel will be extremely attractive for medicinal chemistry research. One of the leading research companies and global suppliers of perfomance LC's, Merck in Darmstadt, Germany, have agreed to support the project by evaluating candidate compounds as LC's and they will assist in providing facilities to scale up the synthesis of these motifs. This aspect of the project will be successful if we can demonstrate a practical application of the all-syn tetrafluorocyclohexane and illustrate to the wider community its potential in the development of performance organic molecules. Project 2. The second project was stimulated by a new reaction carried out in the laboratory, which recognised that if an acetylenethioether is treated with an HF source, it generates a fluoroviny thioether (RS(F)=CH2). More significantly we find that the fluorovinyl thioether is a relatively stable entity. There is hardly any literature on this motif and in this research we want to explore its potential in the early stage design of enzyme inhibitors (fragment approach). We have recognised that the motif approximates the steric and electronic profile of an enol of a thioester. Thioester enols/ates are important intermediates in enzymology, eg. enzymes that process acetyl-CoA such citrate and malate synthase, acetyl-CoA carboxylase, and enoyl reductases of fatty acid biosynthesis are attractive. Therefore we want to assess if the fluorovinyl thioether moiety will be recognised and bind to these enzyme active sites by co-crystallisation X-ray studies. This requires that we synthesise appropriate motifs that represent truncated pantetheinyl moieties carrying the RS(F)=CH2 motif. These compounds will be co-crystallised with enzymes over-expressed in E. coli. In discussions with Syngenta they have suggested we explore such ligands for enoyl reductase, a target relevant to the agrochemical sector. A successful outcome will show that this motif binds to these enzyme active sites (by X-ray crystallography), and provides a starting poing for fragment based inhibitor development. The programme will introduce this motif to the wider research community.