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.

Chemical Synthesis (CS) is an area upon which much of modern society relies as it enables the customized fabrication of products that are the ubiquitous materials of life and society. These include new drugs and medicines, new materials and polymers, nanomaterials, and a vast range of fine and effect chemicals on which the texture and quality of our lives depend. Without future core developments in the chemical sciences, UK plc and societal progress will stall and be left behind in a ferociously competitive modern world. We now plan to train a new generation of world-class PhD students so that the UK chemical industry can maintain its competitive position in the world as a place for highly innovative and creative research. One of the hardest aspects of CS is mastery of the vast 'synthetic tool box' of techniques required to become a professional chemist. The perfect chemist would be akin to highly skilled F1 mechanic with a state of the art toolbox and the ability to design and engineer from scratch - a molecular mechanic if you like. However in reality a student is often focussed too narrowly towards a particular area of synthesis and as a result can end up with a budget toolkit and a limited range of experience. We wish to explore CS by adopting a new 'Holistic' research approach that will be integrated with a revolutionary e-learning framework in a way that has not been previously articulated in the field of Chemistry. Instead of a traditional 'one PI - one-student - one idea' programme, we wish to bring together a group of internationally renowned chemists from organic, inorganic, physical and theoretical backgrounds to pool their skills in order to design from the ground up new and useful solutions for chemical synthesis. Our Research Opportunities Group (ROG) at Bristol does exactly this by bringing together staff from across and outside the chemistry discipline to discuss potential research areas in a Brainstorming format customized to our needs. We have found that this has been highly effective and has led to new research that simply would not have blossomed in a traditional approach. We now wish to instill our ROG philosophy and modus operandi into our students. Our aim is to get these students to think about their research as a collective rather than as isolated individuals working in separate research groups. The benefits of this will be enormous, not least in that they will all play an active role in the design of each-others projects as well as being exposed to a pool of supervisory experience of great breadth and experience. Key to the training experience will be the design and implementation of a revolutionary e-learning resource called the postgraduate Dynamic Laboratory Manual (pgDLM). The pgDLM will allow students to carry out a virtual version of an essential, often complex, experimental technique before experiencing it in the laboratory thus gaining a much deeper understanding of an experiment before they carry it out for real . By creating a pgDLM with an evolving library of online techniques we will not only enable students to embrace new techniques confidently but also simultaneously establish a valuable resource which will be made available to all practitioners of CS in both academe and industry. Industry will play a key role in defining the focus and contemporary relevance of the csDTC and will be broadly represented on a Steering Group. These external advisors will play an active role in project selection, assessment and will participate in the training programme. By producing the right product and working closely with industrial partners from the outset, the csDTC will be well positioned to leverage external support to sustain the Centre beyond the EPSRC funding period. Through this vision we aim to produce a new generation of industrial and academic leaders and, by delivering this goal, secure Bristol as a premier centre for Chemical Synthesis.

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.

The Hub will create a seamless link between science and applications by building on our established knowledge exchange activities in quantum technologies. We will transform science into technology by developing new products, demonstrating their applications and advantages, and establishing a strong user base in diverse sectors. Our overarching ambition is to deliver a wide range of quantum sensors to underpin many new commercial applications. Our key objective is to ensure that the Hub's outputs will have been picked up by companies, or industry-led TSB projects, by the end of the funding period. The Hub will comprise: a strong fabrication component; quantum scientists with a demonstrated ability to combine scientific excellence with technological delivery; leading engineers with the broad collective expertise and connections required to develop and use new quantum sensors. We have identified, and actively involved, industry enablers to build a supply chain for quantum sensor technology. As well as direct physics connections to industry, the engineers provide strong links to relevant industrial users, thus providing information on industrial needs and enabling rapid prototype deployment in the field. To establish a coherent national collaborative effort, the Hub will include a UK network on quantum sensors and metrology, which will also exploit the connections that Prof Bongs and all Hub members have forged in Europe, the US and Asia. This inter-linkage ensures capture of the most advanced developments in quantum technology around the world for exploitation by the UK. Quantum sensors and metrology, plus some devices in quantum communication, are the only areas where laboratory prototypes have already proven superior to their best classical counterparts. This sets the stage, credibly, for rapid and disruptive applications emerging from the Hub. The selection of prototypes will be driven by commercial pull, i.e. each prototype project within the Hub must demonstrate, from the outset, industry or practitioner engagement from our engineering and/or industrial collaborators. We have strong industry support across several disciplines with the structures in place actively to manage technology and knowledge transfer to the industry sector. Particular roles are played by NPL and e2V. We will closely collaborate with NPL as metrology end-user on clock, magnetometer and potentially Watt balance developments with a lecturer-level Birmingham-NPL fellow contributed by Birmingham University and our PRDAs spending ~17 man-years in addition to 3-5 PhD students on these joint projects in the Advanced Metrology Laboratory/incubator space. E2v have a unique industrial manufacturing/R&D facility co-located within the School of Physics and Astronomy at Nottingham that has already catalysed the expansion of their activities into the Quantum Technology domain. Public Engagement conveying the Hub's breakthroughs will be a high priority - for example annually at the Royal Society Summer Exhibitions. In addition to cohort-training of 80 PhD students working within the Hub, the Hub will contribute to the training of ~500 PhD students via electronically-shared lectures (many already running within the e-learning graduate schools MPAGS, MEGS, SEPNET and SUPA) across the institutions within the Hub. The Hub will create an internationally-leading centre of excellence with major impact in the area of quantum sensors and metrology. To widen the impact of the Hub and ensure long-term sustainability, we will actively pursue European and other international collaborative funding for both underlying fundamental research and the technology development.

Lung diseases such as Asthma and Chronic Obstructive Pulmonary Disease affect one in five people in the UK and kill someone every 5 minutes. The number of patients with these lung diseases was increasing in the NHS even before COVID-19. We are also learning about serious long-term effects of COVID-19 that will add to the existing burden on the NHS. There have been huge advances in technologies that allow scientists to see inside the lungs and measure what we breathe out. While this information has taught us quite a lot, it is still very difficult to combine different sources of information and turn it into new or improved treatments. Getting that useful information out of large amounts of medical test results requires sophisticated physics-based mathematical and statistical models run on powerful computers - a combination of techniques called data-driven biophysical multiscale modelling. The ability to develop those kinds of models will allow us to better understand how diseases start and how they progress. Our BIOREME network will support new research that uses these techniques to mimic biological and mechanical processes that occur throughout the lung. Using the information from thousands of lung tests, the idea is then to get these models to mimic real diseased lungs. In order to improve and build trust in these models, some of our projects will be focused on comparing their outputs to results from other lung tests. Medical scientists can then use such models to test what might happen in a particular type of lung disease, and to investigate possible responses to new treatments before testing these in patients. Most importantly, this will lead to the design of new drugs and improved trials for new treatments. The first step will be to get medics, imaging experts and mathematicians together with industry and patient group representatives to decide on which specific research areas to prioritise, where this form of modelling will make the most difference. This NetworkPlus award will then allow us to organise multiple events, in different formats, designed to help researchers to collaborate, and to come up with the best initial projects to help achieve our goals. We will then help the researchers to develop these into larger projects that will attract funding from other sources and continue the research into the future. Even after this funding runs out, BIOREME will provide a lively forum for lung researchers to continue solving problems using these advanced computational tools. Finally, BIOREME will support outreach activities to engage and educate communities and young people in the role that mathematics can play in medicine and healthcare, and to inspire a new generation of respiratory scientists from diverse backgrounds.