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. Irrespective of the ingenuity of the synthetic chemist, the complexity of synthetic endeavours means that they are often the pinch point in the development of a new product or the advance of new molecular science. In addition, synthesis can no longer rely on intensive use of human, material, and time resources, and creative solutions to ways of making molecules faster, more efficiently, using less energy, and avoiding rare to toxic metals are urgently needed. Recent developments in digital chemistry (eg reaction technology and automation, data collection & analysis, machine learning & artificial intelligence, computation & molecular design, and the use of virtual reality) now make possible a fundamental change in the way molecular targets are identified and synthesis is carried out. The chemical and pharmaceutical discoveries which underpin a major sector of the UK's economy are almost entirely dependent on synthesis, and our industrial partners see an urgent need for a new generation of employees who combine cutting-edge chemical synthesis expertise with the state-of-the-art digital skills that are set to revolutionise the field. We therefore propose a CDT that will train students to carry out world-leading chemical synthesis at the University of Bristol, the UK's top institution for chemistry research (REF2021), with their creativity and productivity being enhanced by an initial 8-month Digital Chemistry (DC) training focus that un-derpins a subsequent 3 1/4 year PhD project. The training will be delivered in the form of a set of modules that embody key aspects of DC such automation, algorithm-driven optimisation, photochemistry, electrochemistry and flow chemistry supported by training in the techniques of machine learning and data analysis. These activities will be applied to current synthetic challenges in two short immersive 'mini-projects' in research labs and will feed into a PhD research project in an area of synthetic chemistry that is underpinned by the application of digital chemistry methods. The focus of the CDT aligns with Bristol's global reputation in chemical synthesis and computation, and in its current investment in digital chemistry as a strategic research direction. Bristol Chemistry has enviable success in spinout companies, and alongside ongoing training in professional development skills we aim to cultivate an entrepreneurial ethos by partnering with local start-up partners to provide immersive workshops, placements, network links and mentorship to nurture future spin-outs by CDT students. We will build on lessons learnt from delivering previous successful CDTs in Chemical Synthesis, and we will continue to develop our recruitment, training & research opportunities in line with best practice for Equity, Diversity & Inclusion, applying more widely lessons from the evolution that has allowed the diversity of our applicant team to be reflected in the ~50/50 M:F and ~25% minority ethnic composition of our management committee. Our evolved CDT will build on our unrivalled depth of experience to train diverse cohorts of creative and entrepreneurial experts in chemical synthesis, skilled in modern aspects of technology & data science. Our graduates will be uniquely prepared as research pioneers in the ever-changing scientific and industrial landscape of the chemical sciences that continue to underpin this country's prosperity.

Harnessing the immune system to treat cancer has revolutionised survival outcomes for many patients. Immune checkpoint inhibitor therapies which unleash the brakes from immune cells to kill cancer cells, have become standard of care for many cancer subtypes. The success of existing, emerging and future immunotherapies and their routine use in the NHS is dependent on the appropriate tools, data and technology to rationalise their use and manage their side effects. Nevertheless, almost no biomarkers today can effectively distinguish responders from non-responders, predict toxicity, or guide treatment choices. Moreover, existing datasets lack standardization, suffer from sampling biases, and fail to integrate 'multi-omics' data with clinical information. Our platform, MANIFEST, leverages existing and also novel scalable methodologies to provide deep profiling of each patient receiving immunotherapy and will deliver on multimodal data integration and modelling. We represent a diverse group of UK-wide experts in cancer research and clinical care comprising 6 major NHS trusts, 14 academic institutes and universities, and with strong upfront top-up investment (>£ 12 million) from industry partners (namely IMU Biosciences, Guardant Health, Natera, Roche-imCORE, Roche-Sequencing, M:M Bio and Microbiotica; among others). To demonstrate the utility of the MANIFEST platform, we will deliver exemplar projects encompassing multiple tumour types (melanoma, renal cell carcinoma, bladder cancer and triple negative breast cancer), where prediction of treatment outcomes and toxicities to both standard of care and emerging immunotherapies remains a significant unmet need. Specifically, we have access to pre-existing longitudinal samples of >3,000 patients across 10 reported studies (RAMPART, MITRE, PRISM, EXACT, CAPTURE, PaVeMenT, ALEXANDRA, neoTRIP, ABACUS and ABACUS-2). In parallel, we will utilise existing governance at partner NHS sites for prospective sample collection (blood, stool and tumour) and processing. With a tiered approach, we aim to profile patient and tumour samples at scale (~3,000 patients over 3 years). We will implement standard of care diagnostic workflows for high-volume biomarker discovery (Tier 1). We reserve in-depth profiling, through Tiers 2 and 3 participation, to further characterise tumours including discovery-focused techniques, such as high-dimensional peripheral immune profiling, liquid biopsy (cfDNA, immune methylation profiling), and spatial image-profiling approaches coupled with molecular profiling (WES, bulk&long-read RNAseq, TCR&BCRseq). Finally, for selected patients, we will apply our expertise in Representative Sequencing (RepSeq), a novel tumour sampling methodology which overcomes pervasive sampling bias in solid tumours; and pre-clinical modelling through patient-derived tumour fragments (PDTFs) for drug sensitivity screening. Finally, we will deploy a team of 12 experts in artificial intelligence and machine learning to deliver on multimodal data acquisition and integration in our in-house Trusted Research Environment (TRE). We are also excited to be teaming up with the National Pathology Imaging Co-operative (NPIC) and Genomics England (GEL) to synergise efforts in translating discoveries for patient benefit.