The vision for Edinburgh's Centre for Mammalian Synthetic Biology (SynthSys-Mammalian) is to pioneer the development of the underpinning tools and technologies needed to implement engineering principles and realise the full potential of synthetic biology in mammalian systems. We have an ambitious plan to build in-house expertise in cell engineering tool generation, whole-cell modelling, computer-assisted design and construction of DNA and high-throughput phenotyping to enable synthetic biology in mammalian systems for multiple applications. In this way we will not only advance basic understanding of mammalian biology but also generate tools and technologies for near-term commercial exploitation in areas such as the pharmaceutical and drug testing industries, biosensing cell lines sensing disease biomarkers for diagnositics, novel therapeutics, production of protein based drugs e.g. antibodies and also programming stem cell development and differentiation for regenerative medicine applications. In parallel we will develop and implement new understanding of the social and economic impact of this far-reaching technology to ensure its benefits to society.

Aerosol science, the study of airborne particles from the nanometre to the millimetre scale, has been increasingly in the public consciousness in recent years, particularly due to the role played by aerosols in the transmission of COVID-19. Vaccines and medications for treating lung and systemic diseases can be delivered by aerosol inhalation, and aerosols are widely used in agricultural and consumer products. Aerosols are a key mediator of poor air quality and respiratory and cardiac health outcomes. Improving human health depends on insights from aerosol science on emission sources and transport, supported by standardised metrology. Similar challenges exist for understanding climate, with aerosol radiative forcing remaining uncertain. Furthermore, aerosol routes to the engineering and manufacture of new materials can provide greener, more sustainable alternatives to conventional approaches and offer routes to new high-performance materials that can sequester carbon dioxide. The physical science underpinning the diverse areas in which aerosols play a role is rarely taught at undergraduate level and the training of postgraduate research students (PGRs) has been fragmentary. This is a consequence of the challenges of fostering the intellectual agility demanded of a multidisciplinary subject in the context of any single academic discipline. To begin to address these challenges, we established the EPSRC Centre for Doctoral Training in Aerosol Science in 2019 (CDT2019). CDT2019 has trained 92 PGRs with 40% undertaking industry co-funded research projects, leveraged £7.9M from partners and universities based on an EPSRC investment of £6.9M, and broadened access to our unique training environment to over 400 partner employees and aligned students. CDT2019 revealed strong industrial and governmental demand for researchers in aerosol science. Our vision for CDT2024 is to deliver a CDT that 'meets user needs' and expands the reach and impact of our training and research in the cross-cutting EPSRC theme of Physical and Mathematical Sciences, specifically in areas where aerosol science is key. The Centre brings together an academic team from the Universities of Bristol (the hub), Bath, Birmingham, Cambridge, Hertfordshire, Manchester, Surrey and Imperial College London spanning science, engineering, medical, and health faculties. We will assemble a multidisciplinary team of supervisors with expertise in chemistry, physics, chemical and mechanical engineering, life and medical sciences, and environmental sciences, providing the broad perspective necessary to equip PGRs to address the challenges in aerosol science that fall at the boundaries between these disciplines. To meet user needs, we will devise and adopt an innovative Open CDT model. We will build on our collaboration of institutions and 80 industrial, public and third sector partners, working with affiliated academics and learned societies to widen global access to our training and catalyse transformative research, establishing the CDT as the leading global centre for excellence in aerosol science. Broadly, we will: (1) Train over 90 PGRs in the physical science of aerosols equipping 5 cohorts of graduates with the professional agility to tackle the technical challenges our partners are addressing; (2) Provide opportunities for Continuing Professional Development for partner employees, including a PhD by work-based, part-time study; (3) Deliver research for end-users through partner-funded PhDs with collaborating academics, accelerating knowledge exchange through PGR placements in partner workplaces; (4) Support the growth of an international network of partners working in aerosol science through focus meetings, conferences and training. Partners and academics will work together to deliver training to our cohorts, including in the areas of responsible innovation, entrepreneurship, policy, regulation, environmental sustainability and equality, diversity and inclusion.

DRIVE-Health will train a minimum of 85 PhD health data scientists and engineers with the skills to deliver data-driven, personalised, sustainable healthcare for 2027 and beyond. Co-created with the NHS Trusts, healthcare providers, patients, healthtech, pharma, charities and health data stakeholders in the UK and internationally, it will build on the successes of its King's College London seed-funded and industry-leveraged pilot. Led by an established team, further growing the network of funding partners and collaborators built over the past four years, it will leverage an additional £1.45 of investment from King's and partners for every £1 invested by EPSRC. A CDT in data driven health is needed to deliver the EPSRC Priority for Transforming Health and Healthcare, EPSRC Health Technologies Strategy, and on challenges laid out in the UK Government's 2022 Plan for Digital Health and Social Care envisaging lifelong, joined-up health and care records, digitally-supported diagnoses and therapies, increasing access to NHS services through digital channels, and scaling up digital health self-help. This ambition is made possible by the increasing availability of real-world routine healthcare data (e.g. electronic health care record, prescriptions, scans) and non-healthcare sources (e.g. environmental, retail, insurance, consumer wearable devices) and the extraordinary advances in computational power and methods required to process it, which includes significant innovations in health informatics, data capture and curation, knowledge representation, machine learning and analytics. However, for these technological and data advances to deliver their full potential, we need to think imaginatively about how to re-engineer the processes, systems, and organisations that currently underpin the delivery of healthcare. We need to address challenges including transformation of the quality, speed and scale of multidisciplinary collaborations, and trusted systems that will facilitate adoption by people. This will require a new generation of scientists and engineers who combine technical knowledge with an understanding of how to design effective solutions and how to work with patients and professionals to deliver transformational change. DRIVE-Health's unique cohort-based doctoral research and training ecosystem, embedded across partner organisations, will equip students with specialist skills in five scientific themes co-produced with our partners and current students: (T1) Sustainable Healthcare Data Systems Engineering investigates methods and frameworks for developing scalable, integrated and secure data-driven software systems (T2) Multimodal Patient Data Streams will enable the vision of a highly heterogeneous data environment where device data from wearables, patient-generated content and structured/unstructured information from electronic health records can combine seamlessly (T3) Complex Simulations and Digital Twins focuses on the paradigm of building simulated environments, including healthcare settings or virtual patients, to make step-change advances in individual predictive models and to inform clinical and organisational decision-making. (T4) Trusted Next-Generation Clinical User Interfaces will place usability front and centre to ensure health data science applications are usable in clinical settings and are aligned with users' workflows (T5) Co-designing Impactful Healthcare Solutions, is a cross-cutting theme that ensures co-production and co-design in the context of health data science, engagement with stakeholders, evaluation techniques and achieving maximum impact. The theme training will be complemented with a cohort and programme-wide approach to personal, career, professional and leadership development. Students will be trained by an expert pool of 60+ supervisors from KCL and across partners, delivering outstanding supervision, student mentoring, opportunities, research quality and impact.

The bone marrow is a site of health and disease. In health, it produces all of the blood cells that we rely on to carry oxygen and protect us from infection. However, the stem cells that produce the blood and that reside in the marrow, the haematopoietic stem cells (HSCs), age and can tip over into disease states, such as developing leukaemia. Factors such as smoking and treatment of cancers elsewhere in the body (toxic effects of chemotherapy/radiotherapy) can accelerate ageing, and therefore, drive the transition to disease. Further, it forms a home to other cancer cells, that leave their original tumour and move, or metastasise, to the bone marrow. Once in the marrow, they can become dormant, hiding from chemotherapies and activating sometime later to form devastating bone cancers. The cues that wake cancer cells from dormancy are largely unknown. If models of the bone marrow that contain human cells and that can mimic key facets of the niche in the lab, such as blood regeneration, cancer evolution and dormancy, can be developed it would be a big help in the search for better cancer therapies. We are developing the materials and technologies required to meet this challenge. In this programme of research, we will tackle three biomedical challenges: 1) HSC regeneration. Bone marrow transplantation (more correctly HSC transplantation) is a one-donor, one-recipient therapy that can be curative for blood diseases such as leukaemia. It is limited as HSCs cannot be looked after well out of the body. Approaches to properly look after these precious cells in the lab could allow this key therapy to become a one-donor, multiple recipient treatment. Further, the ability to look after the cells in the lab would open up the potential for genetically modifying the cells to allow us to cure the cells and put them back into the patient, losing the need for patient immunosuppression. 2) Cancer evolution. As we get older, our cells collect mutations in their DNA and these mutations can be drivers of cancer. Lifestyle choices such as smoking, and side effects of treatments of other diseases can also add mutations to the cells. As blood cancers develop, the bone marrow changes its architecture to protect these diseased HSCs. Our 3D environments will allow us to better understand this marrow remodelling process and how drugs can target cancers in this more protective environment. The models will also allow us to study the potential toxicity of gene-edited HSCs to make sure they don't produce unwanted side effects or are not cancerous in themselves. 3) Dormancy. What triggers dormancy and activation from dormancy are poorly understood. By placing our 3D environments in a miniaturised format where we can connect other models that include infection and immune response, we can start to understand the factors involved in the activation of cancer cells from dormancy. Our vision is driven by materials and engineering, as the bone marrow niche is rich in structural and signalling biological materials (proteins). Therefore, we will establish three engineering challenges: (1) Cells can be controlled by the stiffness and viscous nature of materials (viscoelasticity). We will therefore develop synthetic-biological hybrid materials that can be manufactured to have reproducible physical properties and that have biological functionality. (2) We will develop these materials to interact with growth factors and bioactive metabolites, both of which are powerful controllers of cell behaviours. These materials will be used to assemble the HSC microenvironments in lab-on-chip (miniaturised) format to allow high-content drug and toxicity screening. (3) We will develop real-time systems to detect changes in cell behaviour, such as the transition from health to cancer using Raman and Brillouin microscopies. The use of animals in research provides poor predictivity. We will offer better than animal model alternatives.

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