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.

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

Over 3,500 dogs were used in UK laboratories in 2013 in the safety testing of new medicines, with many more used globally and use set to rise given changes in legislation on testing chemicals and safety assessment. Despite this, we do not have a sound evidence-base to determine the best practice for housing or scientific procedures in the dog. Our BBSRC Industrial CASE studentship project sought to identify the link between dog welfare and quality of data output, as well as developing Refinement strategies to improve and harmonise welfare and data quality. The results of the study showed an effect of welfare particularly on heart rate and blood pressure data, but also on behaviour, psychological state, and sensitivity to mechanical pressure. Our findings also showed significant benefits to welfare of implementing a short training protocol in the pre-study acclimatisation phase of a study where a compound was delivered directly to the dog's stomach through a tube (oral gavage). There are many more aspects of the laboratory dog's life cycle which remain to be Refined and data are still lacking on the best methods for doing so. We have hosted an Impact Workshop with our existing and other potential partners, as well as a member of the Home Office's Animals in Science Regulation Unit (ASRU), to identify procedures most suitable for Refinement and to develop practical strategies which can be integrated into existing protocols. We have three main objectives: (1) Despite new European legislation there is still a need to harmonise practices across multinational Industry to ensure that data are comparable. Our first objective is to for LH to acquire a broad understanding of the range of housing, husbandry, and procedure practice, together with the rationale for the existing practices, and provide a centralised resource, in the form of a website to share across all users. Much of this will be open access, providing details of welfare assessment in the dog. It will include photographs, videos and recent publications. A closed registration-only section will provide information on how to conduct procedures, such as oral gavage and inhalation, as humanely as possible. (2) Our Partners have highlighted four procedures, oral gavage, inhalation studies, jacketed telemetry and single housing, that could be modified to improve welfare. Data will be collected on the dogs' welfare and the quality of data output. We shall also collect data on the time investment as any changes must be feasible to implement. (3) Building up on the knowledge and experience gained from both the PhD and from the second objective, we shall deliver training and engagement activities that will be accredited by LASA for relevant staff to gain recognised qualifications. These will include training courses, talks and other activities, and will be delivered free of charge to all major companies using dogs in the UK (one Partner company will no longer be housing dogs, but is instrumental in the development of the engagement activities). Increasing understanding of welfare and learning theory would also allow responsible staff such as technicians and welfare officers to promote better welfare and understand the need for Refinement and its benefits to the quality of scientific data. The outcome of this project will be for LH to gain skills and experience, and to provide evidence-based recommendations to disseminated across a network of highly-experienced colleagues working with dogs to improve their welfare and scientific output, with the potential to reduce the number of dogs used in laboratory research and testing and impact on guidelines and policy.

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.