Too much, too little or poor quality sleep is associated with several human diseases, in particular metabolic disorders such as obesity and Type 2 diabetes. For example, individuals who sleep < 6 hours per night have a 75% increased risk of obesity. Another aspect of sleep patterns is our individual circadian rhythm - the 24 hour cycle of changes in hormones, body temperature and most body systems which regulate our feelings of wakefulness and sleepiness. Disrupting our circadian rhythms is strongly associated with disease. For example, shift-workers have a >40% increased risk of heart disease. While these associations are strong and robust, the nature of these associations means that we can't say whether sleep patterns are causing disease, whether the diseases affect sleep patterns or if something else associated with both (for example, socioeconomic status) explains the association. One way of addressing the causal direction is to use genetics - because an individual's genetics doesn't change over their lifetime we can use genetic variants as causal "anchors". A now widely-used technique called Mendelian Randomisation uses genetic variants associated with a trait of interest (e.g. chronotype) to allow us to test whether it causes an increased risk of disease (e.g. obesity) or vice versa. Identifying genetic variants associated with normal variation in sleep patterns will also provide new insights in the biology of sleep and circadian rhythms and provide new targets for therapeutics to treat sleep disorders. In this proposal we first aim to identify genetic variants associated with sleep patterns. We will do this by initially testing >20,000,000 genetic variants in 480,000 individuals from the UK Biobank study against traits such as sleep duration, sleep efficiency and measures of circadian rhythms. We will determine these sleep variables for each individual using both self-reported and activity-monitor based estimates of sleep. Using accelerometer derived estimates of sleep will be important because there may be reporting inaccuracies from self-reported measures. In UK Biobank self-reported measures of sleep duration, sleep efficiency and chronotype will be available in all 500,000 individuals and we will be able to validate the associations in a subset of 100,000 individuals with activity monitor data. We will replicate the associations identified from UK Biobank using data from >200,000 including international studies such as 23andMe, the CHARGE and chronogen consortia. This replication stage is important to ensure the genetic associations are robust. We will use the associated genetic variants signals in two ways. First, we will provide biological insights at each of the individual variants using a range of in silico approaches to gain insights into individual genes important in sleep and circadian rhythms. We will look for connections across association signals to highlight pathways, biological systems and tissues that are important in these phenotypes. Second, we will perform Mendelian Randomisation analyses to test the causal direction of the epidemiological association between sleep patterns and metabolic disease. We will use robustly associated variants and test whether they are associated with BMI, Type 2 diabetes and heart disease from independent very large-scale genome-wide association results. We will also perform the reverse analyses and test whether robustly associated BMI and Type 2 diabetes variants are associated with sleep patterns. We will use the latest Mendelian Randomisation techniques such as Egger's regression to overcome potential biases. This work will lead to important new insights into the biology of sleep and circadian rhythms and help determine the causal nature of the association between metabolic disease and disrupted sleep.

The manufacture of chemicals makes a major contribution to the UK's economy; £10 bn p.a. in the chemicals and £9bn in the pharmaceuticals sectors alone. The recent report of the Chemistry Growth Strategy Group states that 'By 2030, the UK chemical industry will have further reinforced its position as the country's leading manufacturing exporter and enabled the chemistry-using industries to increase their Gross Value Added contribution to the UK economy by 50%' with "smart manufacturing" as one of three priorities in realising their vision. Our proposal aims to contribute to this smart manufacturing by transforming the way in which continuous photochemistry can be applied to commercial chemical manufacture. There is considerable current academic interest in new photochemical reactions for organic synthesis but how they might be used industrially is usually ignored. Nevertheless the potential of photochemistry in manufacturing is widely recognized if only it could be made scalable and efficient. Traditionally the pharmaceutical and fine chemicals industries have used batch reactors for manufacture, which are difficult to adapt effectively for photochemistry. Therefore, this proposal focuses on continuous reactors which not only permit innovation in design to overcome technical limitations of current photoreactors but also provide a direct route to increased throughput via scale up or scale out. We will tackle some of the technical and engineering issues inherent in conventional photoreactors. These engineering problems include getting light efficiently into the reactors, build-up of opaque material on transparent surfaces key safety issues, particularly in reactions involving oxidation, as well as cost issues related to low efficiency of many light sources and difficulties of scale up. Our project proposes to create new engineering approaches to continuous photochemical manufacture of chemicals, which could transform chemical processes and cost. Our proposal addresses key technical/scientific barriers frustrating current commercial use of photochemistry and promises cheaper products in the pharmaceutical, agrochemical and fine chemicals sectors. Our team consists of three investigators with a proven track record of taking chemical processes from laboratory to commercial plant. Between us, we have the expertise needed for success; namely, in photochemistry, continuous organic reactions, manufacturing, mechanical and chemical engineering and process monitoring.

Our vision is to use continuous photochemistry and electrochemistry to transform how fine chemicals, agrochemicals and pharmaceuticals are manufactured in the UK. We aim to minimize the amount of chemicals, solvents and processing steps needed to construct complex molecules. We will achieve this by exploiting light and/or electricity to promote more specific chemical transformations and cleaner processes. By linking continuous photochemistry and electro-chemistry with thermal flow chemistry and environmentally acceptable solvents, we will create a toolkit with the power to transform all aspects of chemical synthesis from initial discovery through to chemical manufacturing of high-value molecules. The objective is to increase efficiency in terms of both atoms and energy, resulting in lower cost, low waste, low solvent footprints and shorter manufacturing routes. Historically photo- and electro-chemistry have been under-utilised in academia and industry because they are perceived to be complicated to use, difficult to scale up and engineer into viable processes despite their obvious environmental, energy and cost benefits. We will combine the strategies and the skills needed to overcome these barriers and will open up new areas of science, and deliver a step-change (i) providing routes to novel molecular architectures, hard to reach or even inaccessible by conventional methodologies, (ii) eliminating many toxic reagents by rendering them unnecessary, (iii) minimizing solvent usage, (iv) promoting new methodologies for synthetic route planning. Our proposal is supported by 21 industrial partners covering a broad range of sectors of the chemistry-using industries who are offering £1.23M in-kind support. Therefore, we will study a broad range of reactions to provide a clear understanding of the most effective areas for applying our techniques; we will evaluate strategies for altering the underlying photophysics and kinetics so as to accelerate the efficiency of promising reactions; we will transform our current designs of photochemical and electrochemical reactors, with a combination of engineering, modelling and new fabrication techniques to maximize their efficiency and to provide clear opportunities for scale-up; we will exploit on-line analytics to accelerate the optimisation of continuous photochemical and electrochemical reactions; we will design and build a new generation of reactors for new applications; we will identify the most effective strategies for linking our reactors into integrated multi-step continuous processes with minimized waste; we will demonstrate this integration on at least one synthesis of a representative pharmaceutical target molecule on a larger scale; we will apply a robust series of sustainability metrics to benchmark our approaches against current manufacturing.