G protein-coupled receptors are trans-plasma membrane proteins that allow the transfer of information encoded by hormones and neurotransmitters into cells and tissues of the body and, by so doing, act to control physiological responses. They are both the largest group of such signal transducers and have proved to be the most useful in acting as the molecular targets for new medicines. Despite this, many GPCRs have not yet been targeted in this way because we currently know too little about their specific roles in the body and the potential usefulness or consequences of promoting or blocking their actions. The receptor GPR84 is a good example of this. It is known to be expressed by a range of key immune cell subtypes and also that its levels can be increased dramatically in such cells in many situations associated with inflammation. Moreover, it is known that levels of GPR84 on immune cells in the blood can be a useful indicator of the likely effectiveness of treatment of the lower gut inflammatory condition ulcerative colitis. There are also suggestions that either stimulating or blocking GPR84 might be useful approaches to treat conditions ranging from neuropathic pain to atherosclerosis. However, to date none of these suggestions have really been addressed in a substantive way. In very large part this reflects that until very recently no tool compounds have been available to block the action of GPR84 and, although it is known than certain fatty acids can activate GPR84 it requires very high concentrations that are probably not present normally in the circulating blood to do so. This suggests that activation of GPR84 may be produced by ligands other than fatty acids and it is also known that a molecule we generate in the body after eating broccoli and related vegetables is able to activate GPR84. We plan a comprehensive approach to understand the biological functions of this receptor that will employ each of novel chemical ligands that we have identified and characterised, and each of computational, structural and molecular biology-based studies designed to understand how such ligands activate or block the receptor. These will inform how such information can be used to develop ligands that are even more effective. We will also develop and use mice which either lack expression of GPR84 or in which we will replace the mouse version of GPR84 with the equivalent human receptor. Following initial characterisation we will use these mouse lines to study the capacity of activators and blockers of GPR84 to prevent or modify features of disease phenotypes. These studies will determine the likely potential to translate the outcomes from this programme of work to predict whether regulation of the activity of GPR84 may be useful in efforts to develop novel treatments for diseases in humans.

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.

Chemical biology research spearheads the development of novel molecular tools and technologies to study molecular interactions and address life sciences challenges. The impact of these technologies and understanding they unlock is transformative, supporting innovation across the UK economy, in sectors such as healthcare & med-tech, personal care, agri-science, and bio-tech; with a combined annual turnover > £100bn. It further supports the UK knowledge economy by kick-starting a new wave of disruptive SMEs. With the world population predicted to increase in both number and age, pressing demands are being made upon UK plc. This is leading to the industrialisation of the life sciences with Chemical Biology led molecular tools and technologies being dovetailed with "Industry 4.0" advances in additive manufacturing, machine learning and automation. Chemical Biology will therefore play a pivotal role in innovation R&D pipelines, enabling biological and biomedical research to advance more rapidly towards product development and end-user application, e.g. novel diagnostics and drugs to tackle disease; sensors and agro-chemicals/technologies for crop protection; improved formulations in the personal care sector; and increased understanding of nutrient impact on long-term health through advances in molecular measurement technologies. In parallel these advances will benefit the UK instrumentation science sector. There is a therefore a pressing need for a new type of PhD graduate able to embrace this industrial revolution of the life sciences, combining the creation of the next generation of molecular tools and technologies with industry 4.0 technologies. The Centre for Doctoral Training (CDT) in Chemical Biology: Innovation for the Life Sciences will directly address this skills shortage, by training ~80 PhD students, providing them with the skills to operate seamlessly across the physical/mathematical sciences and life sciences and capitalize upon and drive breakthroughs at the human-machine interface. Graduates will emerge armed with an in-depth understanding of product development pipelines acquired through first-hand experience of multi-disciplinary translational research and early stage commercialisation. This will enable them to become leaders of technology innovation in academia, industry and healthcare. To achieve this the CDT is working closely with industry and SMEs to develop new frameworks for training, collaboration and translation within a cohort-based programme, where no student is an island and diversity and equality are promoted at all levels. The PhD students will be supported by one of the largest Chemical Biology communities in the world, the Institute of Chemical Biology at Imperial College London, which brings together over >135 research groups and industry partners. They will also benefit from new innovation habitats designed to unlock student creativity, promote new lean and open innovation models, stimulating knowledge transfer and industry partner engagement, and kick-start their own companies. This training and research ecosystem will be a catalyst for new state of the art technology development, with each research project at the physical/mathematical and life sciences interface driving the development of new molecular technologies, addressing life science bottlenecks and transforming the path of the life sciences towards industry 4.0. The new bespoke innovative training programme will fuse exciting professional/transferable skills courses with world-class translational research, e.g. including a micro-MBA, science communication training at the BBC, industry placements, ideation and commercialisation competitions, hands-on prototyping, and will also provide a framework for responsible research with students being trained on ethical, societal, ecological and economical aspects of their projects. This will take place through a 1-year master course that seamlessly connects with a 3-year PhD research project.

Efficient synthesis remains a bottleneck in the drug discovery process. Access to novel biologically active molecules to treat diseases continues to be a major bottleneck in the pharmaceutical industry, costing many lives and many £millions per year in healthcare investment and loss in productivity. In 2016, the Pharmaceutical Industry's estimated annual global spend on research and development (R&D) was over $157 billion. At a national level, the pharmaceutical sector accounted for almost half of the UK's 2016 £16.5bn R&D expenditure, with £700 million invested in pre-clinical small molecule synthesis, and 995 pharmaceutical related enterprises (big pharma, SMEs, biotech & CROs) employing around 23,000 personnel in UK R&D. The impact of this sector and its output on the nation's productivity is indisputable and worthy of investment in new approaches and technologies to fuel further innovation and development. With an increasing focus on precision medicine and genetic understanding of disease there will be to a dramatic increase in the number of potent and highly selective molecular targets; identifying genetically informed targets could double success rates in clinical development (Nat. Gen. 2015, 47, 856). However, despite tremendous advances in chemical research, we still cannot prepare all the molecules of potential interest for drug development due to cost constraints and tight commercial timelines. By way of example, Merck quote that 55% of the time, a benchmarked catalytic reaction fails to deliver the desired product; this statistic will be representative across pharma and will apply to many comparable processes. If more than half of the cornerstone reactions we attempt fail, then we face considerable challenges that will demand a radical and innovative a step change in synthesis. Such a paradigm shift in synthesis logic will need to be driven by a new generation of highly skilled academic and industry researchers who can combine innovative chemical synthesis and technological advances with fluency in the current revolution in data-driven science, machine learning methods and artificial intelligence. Synthetic chemists with such a set of skills do not exist anywhere in the world, yet the worldwide demand for individuals with the ability to work across these disciplines is increasing rapidly, and will be uniquely addressed by this proposed CDT. By training the next generation of researchers to tackle problems in synthetic chemistry using digital molecular technologies, we will create a unique, highly skilled research workforce that will address these challenges and place UK academic and industrial sectors at the frontier of molecule building science. The aspiration of next-generation chemical synthesis should be to prepare any molecule of interest without being limited by the synthetic methodologies and preparation technologies we have relied on to date. Synthetic chemists with the necessary set of such skills and exposure to the new technologies, required to innovate beyond the current limitations and deliver the paradigm shift needed to meet future biomedical challenges, are lacking in both academia and industry. To meet these challenges, the University of Cambridge proposes to establish a Centre of Doctoral Training in Automated Chemical Synthesis Enabled by Digital Molecular Technologies to recruit, train and develop the next generation of researchers to innovate and lead chemical synthesis of the future.

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.