Radiotherapy treats cancer through the precise delivery of high doses of radiation to tumours, killing cancerous cells by damaging their DNA. Radiotherapy is highly effective because radiation can be accurately targeted to tumours and avoid normal tissue, preventing the unwanted side effects which would result from killing healthy cells. The introduction of new advanced treatment techniques and better imaging to improve tumour targeting has significantly improved patient outcomes following radiotherapy in recent years. However, while radiotherapy benefits from a high degree of physical personalisation, more can be done to improve treatment outcomes. Cancer is a highly complex disease, and is associated with a large number of different types of mutation. These mutations can significantly affect the radiation sensitivity of a given patient's cancer. Despite this, all patients with cancer in a particular organ are typically treated with the same dose and treatment schedule. While these doses have been tailored to cancer at a population level, this almost certainly under- and over-treats some patients. If individual radiosensitivity can be precisely defined before treatment, significant improvements in outcome could be achieved, in terms of improved tumour control or reduced side effects, depending on the patient's particular genetics. This project seeks to address this challenge by developing models of how cells respond to radiation, which can accurately predict the sensitivity of an individual's disease based on the mutations present in their particular cancer. This work seeks to answer a number of questions, including: 1. How the initial radiation interacts with the cell to cause DNA damage. This will use mathematical modelling techniques from the physical sciences to calculate how energy is deposited in individual cells, and how this causes damage to individual DNA strands. 2. How cells respond to this initial damage. Here, we will model how cells respond to different distributions of DNA damage, including how likely they are to repair this damage, and how likely the cell is to survive following a given radiation exposure. 3. How patient genetics impacts on these responses. While we know the processes which determine how sensitive a cell is to radiation (for example, its ability to repair DNA damage), it is difficult to measure these for each patient. Instead, we will develop methods to predict how effective these processes are based on the genetics of the individual's disease, which can be directly measured before treatment. 4. How clinical treatments can be optimised to incorporate this knowledge. Based on these models, we will then develop a tool which will allow for the best radiotherapy treatment to be designed taking into account both physical and biological personalisation, to maximize the chance that each patient's disease will be successfully treated with minimal side-effects. If successful, this research programme will deliver a unique tool to enable the targeting of radiotherapy using both physical and biological factors, offering more personalised therapy and better treatment outcomes for patients suffering from cancer in the future.

Abnormal electrical conduction through the heart is associated with dangerous heart rhythms that can cause sudden death. At present, the exact causes of these abnormal heart rhythms are unknown, however research has shown that genetics plays a significant role in an individual's risk profile. Genes are made of DNA, and they provide instructions to make proteins which influence growth and development of all cells in the body. Small changes in the make up of a gene can alter its function or change the way it provides information to the body. It is becoming increasingly understood that a person's risk of sudden death is due to many small variations in genes combined rather than one single change. Electrocardiograms (ECGs) are a non-invasive method of recording electrical activity within the heart. Different time points on the ECG refer to when the bottom chambers of the heart (ventricles) contract to pump blood around the body, or relax to their resting state. The QRS interval on an ECG is related to ventricle contraction, while the JT interval is specific for when the ventricles return to their resting state. The QT interval refers to the period from the beginning of the QRS interval to the end of the JT interval. Another important marker which is calculated from many leads on an ECG is spatial QRS-T angle. This represents electrical conduction in the heart in a three dimensional manner during ventricle contraction and relaxation and could represent different biological processes compared with other ECG parameters. Changes in the duration of these ECG parameters are associated with the development of abnormal heart rhythms and sudden cardiac death. Previous smaller studies have identified genetic changes (variants) influencing the duration of QT, JT and QRS intervals however a large proportion of the genetic contribution to these ECG markers remains unexplained. This is likely due to the size of previous studies and lack of power to detect rare variants. We will conduct the largest study to date, for QT, JT and QRS intervals which will have greater power to detect variants that are as yet unidentified including less common or rare variants which may have a greater effect on the duration of these ECG traits. We will also perform a study to determine the genetic contribution to spatial QRST angle, which has never been studied before. As it offers a global assessment of cardiac ventricular conduction compared with other ECG traits, we anticipate we will identify new pathways and biological mechanisms for the generation of abnormal heart rhythms. Significant genetic variants identified from these studies will be extensively investigated using publically available datasets to map variants to pathways in cardiac function and arrhythmia generation. These analyses will help to improve our understanding of the role of these genetic variants in causing abnormal heart rhythms and could give insights into how to prevent or treat them in the future. We will also test for association between genetic variants and clinical outcomes including hospital admissions for abnormal heart rhythms, changes in heart chamber dimensions on scans and the risk of heart attacks or death. At present, current markers for predicting abnormal heart rhythms and sudden death are not specific or sensitive enough to be used to test the general population. This research is designed to identify new genetic contributions to abnormal heart rhythms in order to improve risk prediction for sudden cardiac death and other adverse cardiac events. It will help identify people in the general population who would benefit from early treatment or monitoring to prevent disease. The results will aid physician decision making and help us understand what influences the health of the general population and their risk of significant cardiac disease.

Currently, radiotherapy patients are treated lying on their backs. Complex machinery weighing at least six tonnes is rotated around them. As it rotates, this machinery delivers radiation beams from different angles. Leo Cancer Care are a small British company who adopted a "design thinking" approach to re-imagine and simplify radiotherapy. Together with ergonomics experts, they developed a flexible and comfortable robotic positioning system that rotates an upright patient. The radiotherapy beam remains fixed. This project draws upon the fellow's international clinical experience and strong scientific track-record to optimise Leo Cancer Care's simplified radiotherapy solution for clinical use. This will enable the fellow and Leo Cancer Care to deliver cancer treatments that are better, cheaper, more efficient and more accessible. Better treatments: radiotherapy side-effects can be devastating. For certain types of cancer, treating patients upright will enable us to better target radiotherapy treatment beams, reducing normal-tissue damage. For breast cancer, sitting upright with a forward tilt moves the breast away from the heart and lungs, improving beam access. For prostate cancer, day-to-day variations in bladder filling and rectal gas will have less impact for upright patients. For lung cancer, lung volumes are greater and lung motion is reduced when patients are upright, enabling better sparing of the heart. Additionally, upright positioning will make many patients feel physically more comfortable (e.g. by enabling patients with lung cancer to breathe more easily) helping them to tolerate their treatment. Cheaper treatments: the cost of a LCC upright X-ray treatment room is half that of a conventional, supine treatment: £2m compared to £4m. More efficient treatments: LCC's simpler technology will lead to (1) reduced equipment maintenance costs (2) easier upgrades of beam delivery technology (3) simpler machine QA & therefore lower expertise barriers (4) substantial reductions in shielded treatment room volume (5) improved patient throughput due to upright positioning. More accessible treatments: worldwide access to radiotherapy is unacceptably low. There is potential to save one million lives per year by 2035 through optimal access to radiotherapy. 80% of cancer patients live in low- and middle-income countries which host only around 5% of the world's RT resources. By halving the cost of an X-ray treatment room and also delivering more efficient RT, LCC solutions stand to make RT more affordable and accessible, improving cancer survival worldwide. To conduct this research the fellow will build new partnerships between Leo Cancer Care, the NHS and universities/hospitals worldwide. Partners include: University College London NHS Foundation Trust, Clatterbridge Cancer Centre, the Royal Surrey NHS Foundation Trust, Massachusetts General Hospital, Centre Léon-Bérard, University College London, the University of Surrey, Sheffield Hallam University, Loughborough University and the University of Sydney. The shared goal is to rapidly deliver the benefits of upright radiotherapy to patients. To do this, a number of key scientific challenges will be addressed: Challenge 1: patient immobilisation systems must be developed. These must enable the patient to sit/stand comfortably for ~20 mins for each radiotherapy treatment. Radiotherapy is delivered daily, in up to 30 treatment 'fractions', each lasting ~20 mins. Challenge 2: upright radiotherapy workflows (for patient treatments and machine testing) must be streamlined. Streamlined workflows will reduce the expertise barrier associated with treatments, improving access. Challenge 3: algorithms must be developed to transfer biological data from MRI/PET to upright radiotherapy. Challenge 4: to incorporate tomorrow's imaging technologies into upright RT, bringing live MRI-guidance to our treatment rooms. This will further improve tumour targeting.

Oxygen plays an important role in life on earth. The air that we breathe provides cells with the oxygen required for energy production. This need for oxygen increases for cells that rapidly multiply such as those associated with cancer; however, the supply is limited. As a tumour increases in size not all parts will be located near to vessels carrying oxygen rich blood. This results in a reduction in the oxygen levels in cells located furthest away from the blood vessel. It has been shown that these cells with low levels of oxygen (termed hypoxic) are more resistant to damage from radiation than those that are well oxygenated. This is also known to be the case for irradiation with protons. In proton therapy, a beam of protons is fired at the tumour in order to destroy the DNA in the cancerous cells, thus killing the tumour. The amount of energy and number of protons required to achieve this is determined by the tumour volume. Currently in proton therapy the tumour is irradiated such that the whole tumour volume receives the same dose (energy deposited per unit mass). If, however, parts of the irradiated tumour are more resistant to the radiation than others this technique of delivering a uniform dose across the tumour volume is not optimal. The research planned in this project aims to address this through the use of computer modelling and imaging to produce a method of increasing the dose to those low-oxygen radiation-resistant parts of the tumour whilst delivering an appropriately lower dose to the well oxygenated regions. This advancement will improve proton beam therapy and benefit any patient undergoing this form of cancer treatment. The benefits will include increased chance of survival and fewer side effects associated with the treatment

Light has been used for centuries to image the world around us, and continues to provide profound insights across physics, chemistry, biology, materials science and medicine. However, what are the limits of light as a measurement tool? For example, we can use light to image single bacteria, but can we also use light to trap a single bacterium, identify the bacterial strain and assess its susceptibility to antibiotics? How can we image over multiple length scales, from single cells to multiple cellular tissue, in order to comprehensively map all the neuronal connections in the brain? Can we use a combination of resonance with the wave nature and momentum of light to measure the forces associated with the natural and stimulated motion of a single neuronal cell, or even the extremely small forces associated with phenomena at the classical-quantum interface? This proposal aims to answer these questions by exploring new and innovative ways in which we can use light to measure the natural world. This research builds on our recent advances in photonics - the science of generating, controlling and detecting light - and in particular will exploit resonant structures and shaped light. These provide us with tools for controlling the interaction of light and matter with exquisite sensitivity and accuracy. We will run three research strands in parallel and by combining their outputs, we aim to address major Global Challenges in antimicrobial resistance, neurodegenerative disease, multimodal functional imaging and next generation force, torque and microrheology. Our work is supported by a suite of UK and International project partners (both academic and industry) who are enthused to work with us and have committed over £0.5M in kind to the programme.