Molecular sciences, such as chemistry, biophysics, molecular biology and protein science, are vital to innovations in medicine and the discovery of new medicines and diagnostics. As well as making a crucial contribution to health and society, industries in this field provide an essential component to the economy and contribute hugely to employment figures, currently generating nearly 500,000 jobs nationally. To enable and facilitate future economic growth in this area, the CDT will provide a cohort of researchers who have training in both aspects of this interface who will be equipped to become the future innovators and leaders in their field. All projects will be based in both molecular and medical sciences and will focus on unmet medical needs, such as understanding of disease biology, identification of new therapeutic targets, and new approaches to discovery and development of novel therapies. Specific problems will be identified by researchers within the CDT, industrial partners, stakeholders and the CDT students. The research will be structured around three theme areas: Biology of Disease, Molecule and Assay Design and Structural Biology and Computation. The CDT brings together leading researchers with a proven track record across these areas and who have pioneered recent advances in the field, such as multiple approved cancer treatments. Their combined expertise will provide supervision and mentorship to the student cohort who will work on projects that span these research themes and bring their contributions to bear on the medical problems in question. The student cohort approach will allow teams of researchers to work together on joint projects with common goals. Projects will be proposed between academics, industrial partners and students with priority given to those with industrial relevance. The programme of research and training across the disciplines will equip graduates of the CDT with an unprecedented background of knowledge and skills across the disciplines. The programme of research and training across the disciplines will be supplemented by training and hands-on experiences of entrepreneurship, responsible innovation and project management. Taken together this will make graduates of the CDT highly desirable to employers, equip them with the skills they need to envisage and implement future innovations in the area and allow them to become the leaders of tomorrow. A structured and highly experienced management group, consisting of a director, co-directors, theme leads and training coordinators will oversee the execution of the CDT with the full involvement of industry partners and students. This will ensure delivery of the cohort training programme and joint events as well as being accountable for the process of selection of projects and student recruitment. The management team has an established track record of delivery of research and training in the field across industry and academia as well as scientific leadership and network training coordination. The CDT will be delivered as a single, fully integrated programme between Newcastle and Durham Universities, bringing together highly complementary skills and backgrounds from the two institutions. The seamless delivery of the programme across the two institutions is enabled by their unique connectivity with efficient transport links and established regional networks. The concept and structure of the CDT has been developed in conjunction with the industrial partners across the pharmaceutical, biotech and contract research industries, who have given vital steer on the desirability and training need for a CDT in this area as well as to the nature of the theme areas and focus of research. EPSRC funding for the CDT will be supplemented by substantial contributions from both Universities with resources and studentship funding and from industry partners who will provide training, in kind contribution and placements as well as additional studentships.

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.