Humans have massively altered flows of nitrogen on our planet, leading to both benefits for food production and multiple threats to the environment. There are few places on Earth more affected than South Asia, with levels of nitrogen pollution rapidly increasing. The result is a web of interlinked problems, as nitrogen losses from agriculture and from fossil fuel combustion cause air and water pollution. This damages human health, threatens biodiversity of forests and rivers, and leads to coastal and marine pollution that exacerbates the effects of climate change, such as by predisposing reefs to coral bleaching. Altogether, it is clear that nitrogen pollution is something we should be taking very seriously. The amazing thing is that so few people have heard of the problem. Everyone knows about climate change and carbon footprints, but how many people are aware that nitrogen pollution is just as significant? One reason for this is that scientists and policy makers have traditionally specialised. Different experts have focused on different parts of the nitrogen story, and few have the expertise to see how all the issues fit together. This challenge is taken up by a major new research hub established under the UK Global Challenge Research Fund. The "GCRF South Asian Nitrogen Hub" is a partnership that brings together 32 leading research organisations with project engagement partners from the UK and South Asia. All eight countries of the South Asia Co-operative Environment Programme (SACEP) are included. The hub includes research on how to improve nitrogen management in agriculture, saving money on fertilizers and making better use of manure, urine and natural nitrogen fixation processes. It highlights options for more profitable and cleaner farming for India, Pakistan, Bangladesh, Nepal, Afghanistan, Sri Lanka, Bhutan and the Maldives. At the same time, the hub considers how nitrogen pollution could be turned back to fertilizer, for example by capturing nitrogen oxide gas from factories and converting it into nitrate. The fact that all the SACEP countries are included is really important. It means that lessons can be shared on good experiences as well as on whether there are cultural, economic and environmental differences that prevent better management practices from being adopted. It is also important from the perspective of international diplomacy, and provides an example to demonstrate how working together on a common problem is in everyone's interest. It puts the focus on future cooperation for a healthier planet, rather than on the past. The South Asian case provides for some exciting scientific, social, cultural and economic research challenges. The first is simply to get all the researchers talking together and understanding each other. There are dozens of languages in South Asia, matching the challenge met when different research disciplines come together. This is where developing a shared language around nitrogen can really help. There are lots of nitrogen forms ranging from unreactive atmospheric nitrogen (N2), to the air pollutants ammonia (NH3) and nitrogen dioxide (NO2), to nitrate (NO3-) which contaminates watercourses, and nitrous oxide (N2O) which is a greenhouse gas. The impacts of each of these are being studied to provide a better understanding of how they all fit together. The result is an approach that aims to give a much more coherent picture of the nitrogen cycle in South Asia: What is stopping us from taking action, and what can be done about it. One of the big expectations is that the economic value of nitrogen will help. India alone spends around £6 billion per year subsidising fertilizer supply. It means that South Asian governments are strongly motivated to use nitrogen better. At which point research from the South Asian hub can provide guidance on where they might start.

Formulation engineering is concerned with the manufacture and use of microstructured materials, whose usefulness depends on their microstructure. For example, the taste, texture and shine of chocolate depends on the cocoa butter being in the right crystal form - when chocolate is heated and cooled its microstructure changes to the unsightly and less edible 'bloomed' form. Formulated products are widespread, and include foods, pharmaceuticals, paints, catalysts, structured ceramics, thin films, cosmetics, detergents and agrochemicals, with a total value of £180 bn per year. In all of these, material formulation and microstructure control the physical and chemical properties that are essential to the product function. The research issues that affect different industry sectors are common: the need is to understand the processing that results in optimal nano- to micro structure and thus product effect. Products are mostly complex soft materials; structured solids, soft solids or structured liquids, with highly process-dependent properties. The CDT fits into Priority Theme 2 of the EPSRC call: Design and Manufacture of Complex Soft Material Products. The vision for the CDT is to be a world-leading provider of research and training addressing the manufacture of formulated products. The UK is internationally-leading in formulation, with many research and manufacturing sites of national and multinational companies, but the subject is interdisciplinary and thus is not taught in many first degree courses. A CDT is thus needed to support this industry sector and to develop future leaders in formation engineering. The existing CDT in Formulation Engineering has received to date > £6.5 million in industry cash, has graduated >75 students and has 46 currently registered. The CDT has led the field; the new National Formulation Centre at CPI was created in 2016, and we work closely with them. The strategy of the new Centre has been co-created with industry: the CDT will develop interdisciplinary research projects in the sustainable manufacture of the next generation of formulated products, with focus in two areas (i) Manufacturing and Manufacturability of New Materials for New Markets 'M4', generating understanding to create sustainable routes to formulated products, and (ii) 'Towards 4.0rmulation': using modern data handling and manufacturing methods ('Industry 4.0') in formulation. We have more than 25 letters from companies offering studentships and >£9 million of support. The research of the Centre will be carried out in collaboration with a range of industry partners: our strategy is to work with companies that are are world-leading in a number of areas; foods (PepsiCo, Mondelez, Unilever), HPC (P+G, Unilever), fine chemicals (Johnson Matthey, Innospec), pharma (AstraZeneca, Bristol Myers Squibb) and aerospace (Rolls-Royce). This structure maximises the synergy possible through working with non-competing groups. We will carry out at least 50 collaborative projects with industry, most of which will be EngD projects in which students are embedded within industrial companies, and return to the University for training courses. This gives excellent training to the students in industrial research; in addition to carrying out a research project of industrial value, students gain experience of industry, present their work at internal and external meetings and receive training in responsible research methods and in the interdisciplinary science and engineering that underpin this critical industry sector.

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.

The United Nations University in Tokyo has estimated that an average 2 g silicon chip utilizes 1.6 kg of fossil fuels, 73 g of chemicals and 32 kg of water. This kind of waste is unprecedented in heavy manufacturing. For example, in car manufacturing the ratio of finished goods to waste is roughly equal. This is primarily because the nanomanufacturing technology used thus far is a layer-by-layer additive and subtractive process. As dimensions become increasingly small, the additive layers are increasingly smaller. Hence more subtractive waste is generated (as efficiencies are not one-to-one with further size scaling). Innovations thus far in nanomanufacturing have focused mostly on reducing feature sizes, which have now reached remarkably small dimensions, where further scaling will not deliver increased performance. This opens up the possibility of updating existing electronics, as functionality rather than scaling (or the feature size node) is the main driver. Meanwhile in academia, considerable research into self-assembly of nanoscale particles has also been of interest. With the renewal of this fellowship, I intend to advance developments during the last four years, not only within my group, but worldwide, towards integration of two or more additive nanomanufacturing processes to create functional devices. This research is supported substantially by industrial partners, to the tune of £339,700, underlining the significance of the research in industry.

The lifETIME CDT will focus on the development of non-animal technologies (NATs) for use in drug development, toxicology and regenerative medicine. The industrial life sciences sector accounts for 22% of all business R&D spend and generates £64B turnover within the UK with growth expected at 10% pa over the next decade. Analysis from multiple sources [1,2] have highlighted the limitations imposed on the sector by skills shortages, particularly in the engineering and physical sciences area. Our success in attracting pay-in partners to invest in training of the skills to deliver next-generation drug development, toxicology and regenerative medicine (advanced therapeutic medicine product, ATMP) solutions in the form of NATs demonstrates UK need in this growth area. The CDT is timely as it is not just the science that needs to be developed, but the whole NAT ecosystem - science, manufacture, regulation, policy and communication. Thus, the CDT model of producing a connected community of skilled field leaders is required to facilitate UK economic growth in the sector. Our stakeholder partners and industry club have agreed to help us deliver the training needed to achieve our goals. Their willingness, again, demonstrates the need for our graduates in the sector. This CDT's training will address all aspects of priority area 7 - 'Engineering for the Bioeconomy'. Specifically, we will: (1) Deliver training that is developed in collaboration with and is relevant to industry. - We align to the needs of the sector by working with our industrial partners from the biomaterials, cell manufacture, contract research organisation and Pharma sectors. (2) Facilitate multidisciplinary engineering and physical sciences training to enable students to exploit the emerging opportunities. - We build in multidisciplinarity through our supervisor pool who have backgrounds ranging from bioengineering, cell engineering, on-chip technology, physics, electronic engineering, -omic technologies, life sciences, clinical sciences, regenerative medicine and manufacturing; the cohort community will share this multidisciplinarity. Each student will have a physical science, a biomedical science and a stakeholder supervisor, again reinforcing multidisciplinarity. (3) Address key challenges associated with medicines manufacturing. - We will address medicines manufacturing challenges through stakeholder involvement from Pharma and CROs active in drug screening including Astra Zeneca, Charles River Laboratories, Cyprotex, LGC, Nissan Chemical, Reprocell, Sygnature Discovery and Tianjin. (4) Embed creative approaches to product scale-up and process development. - We will embed these approaches through close working with partners including the Centre for Process Innovation, the Cell and Gene Therapy Catapult and industrial partners delivering NATs to the marketplace e.g. Cytochroma, InSphero and OxSyBio. (5) Ensure students develop an understanding of responsible research and innovation (RRI), data issues, health economics, regulatory issues, and user-engagement strategies. - To ensure students develop an understanding of RRI, data issues, economics, regulatory issues and user-engagement strategies we have developed our professional skills training with the Entrepreneur Business School to deliver economics and entrepreneurship, use of TERRAIN for RRI, links to NC3Rs, SNBTS and MHRA to help with regulation training and involvement of the stakeholder partners as a whole to help with user-engagement. The statistics produced by Pharma, UKRI and industry, along with our stakeholder willingness to engage with the CDT provides ample proof of need in the sector for highly skilled graduates. Our training has been tailored to deliver these graduates and build an inclusive, cohesive community with well-developed science, professional and RRI skills. [1] https://goo.gl/qNMTTD [2] https://goo.gl/J9u9eQ