Liver cancer in the paediatric population is rare with an incidence approximately 1-1.5 per million population. The commonest tumour seen in the childhood population is hepatoblastoma (HB), usually seen in young children and infants. Much rarer (about 10% of paediatric liver cancers) is hepatocellular carcinoma (HCC), usually seen in the teenage population and sometimes associated with underlying cirrhotic liver diseases. The ChiLTERN project relates to topic PHC 18 ‘establishing effectiveness of health care interventions in the paediatric population’. The ChiLTERN project builds on a unique opportunity to undertake a comprehensive research programme linked to an ambitious global partnership which will see the single largest clinical trial (the Paediatric Hepatic International Tumour Trial - PHITT) ever undertaken in this population of patients, with several randomised questions in six subgroups of patients. ChiLTERN will allow us to move towards an era of personalised therapy in which each patient will receive the correct amount of chemotherapy and will undergo has the best surgical operation (surgical resection or liver transplant). By using both clinical and biological information, we can assign patients more accurately to risk groups based on their survival. Using genetic tests and biomarkers, we will determine those children who may be at risk of developing long term side effects (deafness, heart failure, kidney damage). In addition, biomarkers will allow us to monitor during therapy and detect toxicities early before serious damage is done so that we can adapt treatment and prevent these problems. Finally, we will be using imaging technology tools which will help our surgeons plan liver operations more safely and effectively. Ultimately ChiLTERN will allow us to cure more children with liver cancer, expose fewer children to toxic chemotherapy and ensure their surgery is both effective and safe.

The bottom-up construction of synthetic cells or protocells from inanimate molecules and materials is one of the grand challenges of our time. While research thus far has been focused on increasing the biochemical complexity individual protocells, this research proposal intends to pioneer the first scientific advancements towards the controlled assembly of protocell building blocks into forms of adaptive and self-regulating protocellular materials (PCMs) that can integrate with living cells and target their mechanochemical sensory pathways. To achieve this, I am proposing to work at the interface of synthetic chemistry, materials science, microfluidics, and tissue engineering to address the following unprecedented aspects of PCM design and synthetic construction: (1) the engineering of PCMs with mechanical properties that mimic those of soft living tissues; (2) the engineering of PCMs with rudimentary adaptive and self-regulating higher-order behaviours; and (3) the development PCMs capable of interacting and integrating with living cells. I will start by developing the first experimental methodologies to assemble PCMs with a range of elastic moduli that mimic those of soft living tissues from protocells endowed with synthetic polymeric cytoskeletons of different composition. I will then engineer the first adaptive PCMs capable of autonomously converting environmental luminous stimuli into mechanical motions and reconfigurations that will self-regulate their endogenous enzymatic reactivity. Finally, I will develop the first forms of PCMs capable of delivering both mechanical and biochemical cues for living cell spreading, proliferation and differentiation in vitro. Overall, the proposed work will pioneer new internationally leading science at the life/non-life interface that will generate transformative ideas in the field of bottom-up synthetic biology with profound fundamental and applied consequences, especially in tissue engineering and regenerative medicine.