The global need for complex biological medicines such as cancer treatments and vaccines continues to grow. However the capability to manufacture high quality products at scale remains challenging with existing technology. Improvements to production capabilities and demand for products based on viral vectors and liposomes have resulted in exacerbated purification issues downstream, leading to performance and lifespan compromises of biomanufacturing unit operations such as filtration and chromatography. Solutions are required in order purify ever increasingly concentrated process streams in an efficient and cost-effective manner to meet growing demand for bio-therapeutics. The research proposed here utilises cutting-edge 3D imaging, analysis and digital design approaches in order to produce novel bioseparation materials that have clear advantages over existing purification technology. Applying methodology established at UCL structures can be designed, fabricated through 3D printing, analysed and improved through a design cycle. Pall Biotech, a leading international bioprocess vendor and applications expert, will provide secondment opportunities that will enable access to industrial experts and industrially relevant materials for this research in order to perform commercially applicable case studies.

Most of the world's population is now living in cities and travelling more. As a result we are more likely to come into contact with infections that we would not have been exposed to just a few decades ago due to interactions with more people. The environment plays an important role in the transmission of some infections and it is possible to reduce the transmission of such disease by better filtration of water and air. Some filtration systems are currently used which physically stop pathogens such as bacteria. However these systems cannot stop virus particles, are expensive, require frequent maintenance and careful disposal. The aim of this project is to design one air and one water filter which will actively kill bacteria and viruses, thereby reducing their numbers in the environment. These filters will require less maintenance and be inexpensive to produce. During the project, we will first test the antimicrobial effect of a variety of nanoparticles. These will then be modified chemically so that they can be incorporated into materials that are suitable for water and air filtration. The filters containing the antimicrobial nanoparticles will be produced using a new EPSRC funded spinning technology developed at UCL. Once we have produced the antimicrobial filtration materials, we will test their ability to kill viruses in air and bacteria in water. We will test filters with different concentrations of antimicrobial nanoparticles and with different depths. We will also make sure that the filters are effective at flow rates that are used in the real world. The antimicrobial filters will be of most interest to the healthcare industry in the first instance, but they will also be relevant to busy public buildings (such as schools and care homes) and transport vehicles (such as airplanes). Furthermore, the filters will be capable of oxidising non-biological materials, like tar and pollution particulates and will improve air quality in a range of indoor environments. During the project we will be collaborating with industrial partners (including Pall Corporation, the world's biggest filtration company) and clinicians to ensure that we produce a viable product. At the end of the project, the technology will be validated and ready for scale-up production and we plan to apply for further funding for a collaborative project with industry in order to do this.

The engineering paradigm of measure, model, manipulate and manufacture underpins the design of products, processes and structures with reliable, predictable performance. The design process requires a detailed knowledge of what the interacting components are, how they interact and the forces (rules) that govern those interactions. This is why it was possible to send a man to the moon in 1969 (i.e. to predict functional performance based on known physical interactions) but not to cure cancer (unpredictability deriving from complex, unknown components and interactions). Accordingly, as we enter a new age of biological engineering, the extent to which it will be possible to engineer complex biological systems for human benefit will ultimately depend upon the extent of our knowledge of those systems - the rules that govern how the complex biological system functions - or malfunctions in the case of disease. To engineer any biological system effectively we need a basic blueprint - knowledge (or design principles) that helps us to understand specifically how that organism is functionally equipped. For biological engineers this primary information is an organism's complete DNA sequence (it's genome). For simple organisms such as bacteria the genome is relatively simple - only about 6000 genes (functional genetic units) in Escherichia coli for example. In human cells there are over 30,000 genes and a large amount of 'non-coding' DNA involved in regulation of these genes. Using microbial genome sequence information, bioengineers can for the first time truly engage in the engineering design process. New ways of measuring and modelling the complexity of simple bacterial systems have emerged (this is 'systems biology') which enables us to (genetically) manipulate cells and manufacture novel products and processes using new tools (this is 'synthetic biology'). Importantly, bioengineers can now predict the functional capability of simple bacteria growing in vitro using computer models. Similar approaches are now being developed for inherently more complex mammalian cells. This project is designed to provide a much needed genomic resource for academic and industrial bioscientists and bioengineers in the UK concerned with the production of a new generation of recombinant DNA derived medicines made by made by genetically engineered cells in culture - biopharmaceuticals. Biopharmaceuticals are proving to be revolutionary treatments for many serious diseases such as rheumatoid arthritis and a range of cancers. We want to determine the genome sequence of an extremely important type of 'cell factory' that is used to make these bio-medicines; the Chinese hamster ovary (CHO) cell. Most (60-70%) biophamaceuticals are currently made by genetically engineered CHO cells in culture as well as the vast majority of those in development. However, despite the huge industrial and scientific importance of this cell type, we still do not have the CHO cell's genome sequence: The fundamental informatic resource necessary to utilise new systems and synthetic biology tools to understand and engineer the function of this cell factory. To address this problem we have formed a consortium of the UK's leading academic groups involved in research into CHO cell based manufacturing systems based at the Universities of Kent, Manchester and Sheffield, and four key industrial partners involved in biopharmaceutical manufacturing in the UK. In this project we will utilise the most advanced DNA sequencing technology available to rapidly sequence, assemble and annotate the CHO cell genome. We will establish a network to disseminate this information and to determine how we might most effectively harness this resource for future engineering strategies to improve CHO-cell based production processes. This project is necessary for, and will lead to, cutting-edge applied research underpinning new biopharmaceutical manufacturing technology.

The chemical and pharmaceutical industries are currently reliant on petrochemical derived intermediates for the synthesis of a wide range of valuable chemicals, materials and medicines. Decreasing petrochemical reserves, and concerns over increasing cost and greenhouse gas emissions, are now driving the search for renewable and environmentally friendly sources of these critically needed compounds. This project aims to establish a range of new manufacturing technologies for efficient conversion of biomass in agricultural waste streams into sustainable sources of these valuable chemical intermediates. The UK Committee on Climate Change (2018) has highlighted the importance of the efficient use of agricultural biomass in tackling climate change. The work undertaken in this project will contribute to this effort and help the UK government achieve its stated target of 'net-zero emissions' by 2050. The new approaches will be exemplified using UK-sourced Sugar Beet Pulp (SBP) a renewable resource in which the UK is self-sufficient. Over 8 million tonnes of sugar beet is grown annually in the UK on over 3500 farms concentrated in East Anglia and the East Midlands. After harvest, the beet is transported to a small number of advanced biorefineries to extract the main product; the sucrose we find in table sugar. SBP is the lignocellulosic material left after sucrose extraction. Currently it is dried (requiring energy input) and then sold as a low-value animal feed. SBP is primarily composed of two, naturally occurring, biological polymers; cellulose and pectin. Efficient utilisation of this biomass waste stream demands that applications are found for both of these. This work will establish the use of the cellulose nanofibres for making antimicrobial coatings and 3D-printed scaffolds (in which cells can be cultured for tissue engineering and regenerative medicine applications). The pectin will be broken down into its two main components: L-arabinose and D-galacturonic acid. The L-arabinose can be used directly as a low-calorie sweetener to combat the growing problem of obesity. The D-galacturonic acid will be modified in order to allow formation of biodegradable polymers which have a wide range of applications. This new ability to convert SBP into a range of useful food, chemical and healthcare products is expected to bring significant social, economic and environmental benefits. In conducting this research we will adopt a holistic approach to the design of integrated biorefineries in which these new technologies will be implemented. Computer-based modelling tools will be used to assess the efficiency of raw material, water and energy utilisation. Techno-Economic Analysis (TEA) and Life Cycle Analysis (LCA) approaches will be employed to identify the most cost-effective and environmentally benign product and process combinations for potential commercialisation. The results will be widely disseminated to facilitate public engagement with the research and ethical evaluation. In this way the work will support the UK in its transition to a low-carbon, bio-based circular economy.

The UK government recognises that 'our economy is driven by high levels of skills and creativity' and has prioritised investment in skills as a means to recovery rapidly from the current economic downturn (HM Government: New Industry, New Jobs, 2009). Bioprocessing skills underpin the controlled culture of cells and microorganisms and the design of safe, environmentally friendly and cost-effective bio-manufacturing processes. Such skills are generic and are increasingly being applied in the chemical, pharmaceutical and regenerative medicine sectors. Recent reports, however, highlight specific skills shortages that constrain the UK's capacity to capitalise on opportunities for wealth and job creation in these areas. They emphasise the need for bioprocessing skills related to the application of 'mathematical skills... to biological sciences', in core bioprocess operations such as 'fermentation' and 'downstream processing' and, for many engineering graduates 'inadequate practical experience'. UK companies have reported specific problems in 'finding creative people to work in fermentation and downstream processing' (ABPI: Sustaining the Skills Pipeline, 2005 & 2008) and in finding individuals capable of addressing 'challenges that arise with scaling-up production using biological materials' (Industrial Biotechnology Innovation and Growth Team report: Maximising UK Opportunities from Industrial Biotechnology, 2009). Bioprocessing skills are also scarce internationally. Many UK companies have noted 'the difficulties experienced in recruiting post-graduates and graduates conversant with bioprocessing skills is widespread and is further exaggerated by the pull from overseas (Bioscience Innovation and Growth Team report: Bioscience 2015, 2003 & 2009 update). The EPSRC Industrial Doctorate Centre (IDC) in Bioprocess Engineering Leadership has a successful track record of equipping graduate scientists and engineers with the bioprocessing skills needed by UK industry. It will deliver a 'whole bioprocess' training theme based around fermentation and downstream processing skills which will benefit from access to a superbly equipped £25M bioprocess pilot plant. The programme is designed to accelerate graduates into doctoral research and to build a multidisciplinary research cohort. Many of the advanced bioprocessing modules will be delivered via our MBI Training Programme which benefits from input by some 70 industry experts annually (www.ucl.ac.uk/biochemeng/industry/mbi). Research projects will be carried out in collaboration with many of the leading UK chemical and pharmaceutical companies. The IDC will also play an important role supporting research activities within biotechnology-based small to medium size enterprises (SMEs). The need for the IDC is evidenced by the fact that the vast majority of EngD graduates progress to relevant bioindustry careers upon graduation. This proposal will enable the IDC to train the next generation of bioindustry leaders capable of exploiting rapid progress in the underpinning biological sciences. Advances in Synthetic Biology in particular now enable the rational design of biological systems to utilise sustainable sources of raw materials and for improved manufacturing efficiency. These will lead to benefits in the production of chemicals and biofuels, in the synthesis of chemical and biological pharmaceuticals and in the culture of cells for therapy. The next generation of IDC graduates will also possess a better understand of the global context in which UK companies must now operate. This will be achieved by providing each EngD researcher with international placement opportunities and new training pathways either in bioprocess enterprise and innovation or in manufacturing excellence. In this way we will provide the best UK science and engineering graduates with internationally leading research and training opportunities and so contribute to the future success of the UK bioprocess industries.