Glycans or sugars have a huge impact on biological processes in all domains of life. Most medically important drugs are glyco-modified and vaccines often target the sugars on the surface of disease-causing pathogens. Hence, glycans play a key role in both biology and biotechnology. Optimising the expression and addition of sugars to proteins through glycoengineering offers an important avenue to creating lower cost, more effective vaccines, developing better therapies and diagnostics, and generating tools to more efficiently study health and disease. Glycans are difficult to study and manufacture and are considered the 'dark matter of biology'. This requires a new approach, and the advancement of Engineering Biology through our GlycoCell consortium is both timely and appropriate. GlycoCell builds on our glycotechnology and Engineering Biology expertise and previous successes with a vision to scale and deploy a 'GlycoForge' facility as a UK national asset. The GlycoForge combines high-throughput automation, elegant experiment design, and advanced mathematical methods to rapidly engineer cells to make new glycans. GlycoCell will develop and integrate cutting-edge technologies, train the current and next generations of researchers, attract industry, and drive value-adding translation with the wider research community. GlycoCell's targets will include bacterial and viral vaccines, as well as therapeutic proteins for treatment of other diseases. Vaccines are the most effective way to prevent infections and proven to reduce antimicrobial usage. The most successful vaccines against bacteria are glycoconjugates (glycans linked to proteins), which provide robust, lasting immunity in all age groups. Current glycoconjugate vaccine manufacture is costly and precludes use in resource poor settings or in veterinary medicine. We will efficiently produce novel vaccines. We will target the human pathogen Group A streptococci and animal pathogen Streptococcus uberis. We will test the limits of the GlycoForges with the efficient expression of 100 glycan variants of Streptococcus pneumoniae and a novel Coxiella vaccine that has an as yet unresolved glycan structure. We will undertake a simulated pandemic 'pressure test' to deliver a 100-day rapid epidemic response that will be important for UK preparedness. These vaccines will be produced in parallel in bespoke E. coli and Bacillus cells which have multiple advantages for vaccine development and manufacture. For therapeutic proteins, the glycan structure can dictate pharmacokinetics, protein turnover, and function. Most therapeutic glycoproteins are manufactured in mammalian hosts to match human glycan structures. These are costly to culture, challenging healthcare budgets and limiting patient access to therapies. We will use the GlycoForge to further develop bacteria and yeast cells to produce human-relevant glycans as novel therapeutics. This will include engineering Saccharomyces yeast cells able to mimic the glycosylation patterns of fungal pathogens, producing novel anti-fungal drugs. Pichia yeast cells will be used to produce novel viral vaccines including HIV and papilloma virus. This work will be supported by a world-leading facilities for analysis of glycans. Training and development of the current and next generations of researchers across the UK and beyond will be central to GlycoCell and will be deeply integrated into all activities. A training program in engineering biology led by both academics and industrial partners will occur over 5 years. GlycoCell will be led by an experienced management team and will be steered by an International Advisory Group to secure our vision to produce novel glycan-based medicines and to guide succession planning.

Synthetic Biology is the engineering of biology. In this spirit, this Fellowship aims at combining control engineering methodology and expertise with synthetic biology current know-how to solve important real-world problems of high industrial and societal importance. Anticipated high-impact applications of synthetic biology range from cell-based diagnostics and therapies for treating human diseases, to efficiently transforming feedstocks into fuels or biochemicals, to biosensing, bioremediation or production of advanced biomaterials. Central to tackling these problems is the development of in-cell automatic feedback control mechanisms ensuring robust functionality and performance of engineered cells that need to operate under uncertain and changing environments. The availability of methods for designing and implementing feedback control mechanisms that yield improved robustness, efficiency and performance is one of the key factors behind the tremendous advances in engineering fields such as transportation, industrial production and energy. As in these and other engineering disciplines, systems and control engineering will accelerate the development of high-impact synthetic biology applications of societal, commercial and industrial importance. In particular, through this Fellowship, I propose a comprehensive engineering approach to push forward the robustness frontier in synthetic biology towards reliable cell-based biotechnology and biomedicine. This ambitious goal requires: (1) the development of feedback mechanisms to reduce the footprint of engineered metabolic pathways on their cell "chassis", (2) the development of system-level feedback mechanisms to robustly and efficiently manage one or more synthetic devices in the context of whole-cell fitness, and (3) the development of synthetic cell-based systems designed to restore and maintain the extra-cellular concentration of some biomolecules within tight homeostatic bounds. These three aspects define three work packages in my Fellowship. Each work package on its own tackles important synthetic biology challenges for real-world applications, while their combination in WP4 aims towards robust cell-based biotechnology and biomedicine. The corresponding work packages are: *WP1*: Automatic management of fluxes for robust and efficient metabolic pathways (through genetic-metabolic feedback control) *WP2*: Automatic management of cellular burden for robust and efficient whole-cell behaviour (through host-circuit feedback control) *WP3*: Automatic management of extra-cellular concentrations for robust homeostatic regulation of environmental conditions (through cell-environment feedback control) *WP4*: System integration and combination of the feedback control mechanisms developed in WP 1-3 The first two work packages address device robustness to cellular context, while the third addresses robust adaptation to and control of changing environmental conditions. WP4 will use and further develop the systems and control engineering framework developed in WP 1-3 to explore the synergistic combination of the proposed feedback control mechanisms. By providing systematic engineering solutions that endow engineered biosystems with robust functionalities, we will enable the enhancement of existing biotechnological processes and the reliable development of industrial applications to improve health and quality of life. Through the above, this Fellowship will foster strong and long-lasting economic and societal impact in the UK and globally and promote knowledge-based UK leadership.

Synthetic Biology is the underpinning discipline for advances in the UK bioeconomy, a sector currently worth ~£200Bn GVA globally. It is a technology base that is revolutionising methods of working in the biotechnology sector and has been the subject of important Government Roadmaps and supported by significant UKRI investments through the Synthetic Biology for Growth programme. This is now leading to a vibrant translational landscape with many start-ups taking advantage of the rapidly evolving technology landscape and traditional industries seeking to embed new working practices. We have sought evidence from key industry leaders within the emerging technology space and received a clear and consistent response that there is a significant deficit of suitably trained PhDs that can bridge the gap between biological understanding and data science. Our vision is a CDT with an integrative training programme that covers experimentation, coding, data science and entrepreneurship applied to the design, realisation and optimisation of novel biological systems for diverse applications: BioDesign Engineers. It directly addresses the priority area 'Engineering for the Bioeconomy' and has the potential to underpin growth across many sectors of the bioeconomy including pharmaceutical, healthcare, chemical, energy, and food. This CDT will bring together three world-leading academic institutions, Imperial College London (Imperial), University of Manchester (UoM) and University College London (UCL) with a wide portfolio of industrial partners to create an integrated approach to training the next generation of visionary BioDesign Engineers. Our CDT will focus on providing an optimal training environment together with a rigorous interdisciplinary program of cohort-based training and research, so that students are equipped to address complex questions at the cutting edge of the field. It will provide the highly-skilled workforce required by this emerging industry and establish a network of future UK Bioindustry leaders. The joint location of the CDT in London and Manchester will provide a strong dynamic link between the SE England biotech cluster and the Northern Powerhouse. Our vision, which brings together a BioDesign perspective with Engineering expertise, can only be delivered by an outstanding and proven grouping of internationally renowned researchers. We have a supervisor pool of 66 world class researchers that span the associated disciplines and have a demonstrated commitment to interdisciplinary research and training. Furthermore, students will work directly with the London and Manchester DNA Foundries, embedding the next generation bioscience technologies and automation in their training and working practices. Cohort training will be delivered through a common first year MRes at Imperial College London, with students following a 3-month taught programme and a 9-month research project at one of the 3 participating institutions. Cohort and industry stakeholder engagement will be ensured through bespoke training and CDT activities that will take place every 6 months during the entire 4-year span of the programme and include multi-year group hackathons, training in responsible research and innovation, PhD research symposia, industry research days, and entrepreneurial skills training. Through this ambitious cohort-based training, we will deliver PhD-level BioDesign Engineers that can bridge the gap between rigorous engineering, efficient model-based design, in-depth cellular and biomolecular knowledge, high throughput automation and data science for the realisation and exploitation of engineered biological systems. This unique cohort-based training platform will create the next generation of visionaries and leaders needed to accelerate growth of the UK bioeconomy.

The Covid-19 pandemic continues to take a huge toll - an estimated 6.3m people have died including 178,000 in the UK. Globally 1.6bn students have missed school, 250m people will be pushed into extreme poverty and economic losses are estimated at £12tr. History shows that epidemic and pandemic threats constantly emerge, whilst SARS-CoV-2 continues to mutate as it becomes endemic. It is clear that major losses could be prevented by sustained domestic investment in public health. Work undertaken within Vax-Hub1 on responsive technologies and accelerated quality control methods enabled rapid development and manufacture of the ChAdOx1 vectored vaccine against SARS-CoV-2 (licensed for emergency use in December 2020 via a non-profit partnership with AstraZeneca). Over 2.9bn doses have now been released in 180 countries. The UK had a leading role during the pandemic and the proposed Hub builds on this success to advance novel research on a broader range of technologies. Working closely with stakeholders, Vax-Hub will enable the UK to be better prepared for the next pandemic. This investment into The Future Vaccine Manufacturing Hub will enable our vision to make the UK the global centre for vaccine discovery, development and manufacture. The Vaccine Manufacturing Hub brings together a world-class multidisciplinary team with decades of cumulative experience in all aspects of vaccine design and manufacturing research. This Hub will bring academia, industry, not-for-profit organizations and policy makers together to propose radical change in vaccine development and manufacturing technologies, building on a technological innovation culture. The Hub will enhance future vaccine manufacturing through (i) de-risked manufacture of new vaccines by strategically innovating for a selected range of the most promising platform technologies (established and novel/disruptive); (ii) developing manufacturing options that improve the product quality and so immunogenicity; (iii) streamlined manufacturing process development with novel responsive solutions and advanced digitalisation strategies; (iii) a focus on enhancing stability and needle-free administration routes so they become a reality within the lifetime of the Hub. The proposed Hub would be the natural location for early-stage research before projects are transferred to a GMP manufacturing facility. The work focuses on development of improved vaccine platforms which can be flexible enough to be used for multiple product manufacture. These improved vaccine technologies are used as case studies to test rapid and responsive development tools to create a whole process mimicking vaccine manufacture, which could be easily and quickly deployed in case of epidemic/pandemic scenario. Finally the research focuses on standard and novel adjuvants to make mucosal delivery a reality, thus allowing alternative route to injection for mass administration. The Hub will establish the UK as the global centre for end-to-end vaccine research and manufacture. Additionally, vaccines should be considered a national security priority, as it is evident that diseases do not respect international boundaries, thus this work into capacity building and rapid response is a significant advantage. The impact of this Hub will be felt internationally, as the UK reaffirms its leadership in Global Health and works to ensure that the outputs of this Hub reach the global community and the most vulnerable, especially children.

Chemical biology is spearheading the development & translation of novel molecular tools and technologies to study biology and develop biomedical understanding. Dovetailing these platforms with industry 4.0/5.0 breakthroughs in automation & robotics, artificial intelligence & machine learning, the CDT will unlock the Lab of the Future paradigm. This will redefine the state of the art with respect to making, measuring, modelling & manipulating molecular interactions in biological systems, leading to novel R&D workflows, promoting efficient design-test cycles and driving sustainability. These molecular technologies will (i) enable biological & medical research, (ii) revolutionise understanding of disease & (iii) create novel diagnostics, drugs & therapies, focusing increasingly on individual patient outcomes. They will also impact the agri-tech sector which faces huge demand to increase productivity by unlocking strategies to e.g. track agrochemicals in plants/soil, understand modes of action & drive precision farming. Similarly, advances in personal care industrial processes are critically dependent on development of molecular technologies to gain insight into structured product design. The application of novel molecular tools/technologies, Lab of the Future strategies & their commercialisation through the instrumentation science sector is thus critical to the UK economy, supporting >4,500 healthcare, personal care, agri-science & biotech companies. This will transform (i) therapeutic, agrochemical & personal care product discovery (ii) med-tech/biotech/healthcare instrumentation R&D pipelines & (iii) stimulate creation of SMEs. Working closely with civic partners including Hammersmith & Fulham Council and the NHS, the CDT's talent & research pipeline will act as a growth engine for one of the most rapidly expanding Life Science ecosystems in Europe, the White City Innovation District. Given the importance of Chemical Biology to UK plc there is great demand but short supply of Chemical Biology PhD graduates able to match the pace of innovation across the physical/life science interface, at a time when industry & health sectors need these skills to accelerate productivity. The CDT in Chemical Biology: Empowering UK BioTech innovation with its unique 5 year programme: 1 year MRes + 3 year PhD + 1 year ELEVATE Fellowship directly addresses this skills gap by training a new generation of career-ready graduates, able to embrace the Lab of the Future concept and unlock its potential by fusing innovative molecular tools & tech with industry 4.0 & 5.0 advances to study molecular interactions & develop applications in the life science, agriscience & personal care sectors. CDT students will benefit from a research and training programme created with >100 industry/external stakeholders designed to meet future employer's needs. Our cohort-based programme with EDI at its heart, will allow students to contextualise their work within wider CDT activities & find novel solutions to their research, supported by one of the world's largest Chemical Biology communities: the Institute of Chemical Biology (>165) research groups. Students will be trained in multidisciplinary blue skies/translational research, lean innovation, scale fast/fail fast approaches, creating scientists able to understand molecular technologies, sustainable product design, early-stage commercialisation, & industry's pace of change. To support this, our training includes Future Lab & HackEDU courses (prototyping training), a drug screening programme, Biz-Catalyst (entrepreneurial training), InnovaLab (SME accelerator), a Data Science course, Human Centred Design, Science Communication (with BBC) & Bioethics/RRI/Sustainability/Policy courses. Following PhD completion, students can enter the ELEVATE fellowship programme, bridging the gap between PhD & industry/academia, offering training, personalised workplace opportunities & enable students to kickstart new companies.