Sensors permeate our society, measurement underpins quantitative action and standardized accurate measurements are a foundation of all commerce. The ability to measure parameters and sense phenomena with increasing precision has always led to dramatic advances in science and in technology - for example X-ray imaging, magnetic resonance imaging (MRI), interferometry and the scanning-tunneling microscope. Our rapidly growing understanding of how to engineer and control quantum systems vastly expands the limits of measurement and of sensing, opening up opportunities in radically alternative methods to the current state of the art in sensing. Through the developments proposed in this Fellowship, I aim to deliver sensors enhanced by the harnessing of unique quantum mechanical phenomena and principles inspired by insights into quantum physics to develop a series of prototypes with end-users. I plan to provide alternative approaches to the state of the art, to potentially reduce overall cost and dramatically increase capability, to reach new limits of precision measurement and to develop this technology for commercialization. Light is an excellent probe for sensing and measurement. Unique wavelength dependent absorption, and reemission of photons by atoms enable the properties of matter to be measured and the identification of constituent components. Interferometers provide ultra-sensitive measurement of optical path length changes on the nanometer-scale, translating to physical changes in distance, material expansion or sample density for example. However, for any canonical optical sensor, quantum mechanics predicts a fundamental limit of how much noise in such experiment can be suppressed - this is the so-called shot noise and is routinely observed as a noise floor when using a laser, the canonical "clean" source of radiation. By harnessing the quantum properties of light, it is possible reach precision beyond shot noise, enabling a new paradigm of precision sensors to be realized. Such quantum-enhanced sensors can use less light in the optical probe to gain the same level of precision in a conventional optical sensor. This enables, for example: the reduction of detrimental absorption in biological samples that can alter sample properties or damage it; the resolution of weak signals in trace gas detection; reduction of photon pressure in interferometry that can alter the measurement outcome; increase in precision when a limit of optical laser input is reached. Quantum-enhanced techniques are being used by the Laser Interferometer Gravitational Wave Observatory (LIGO) scientific collaboration to reach sub-shot noise precision interferometry of gravitational wave detection in kilometer-scale Michelson interferometers (GEO600). However, there is otherwise a distinct lack of practical devices that prove the potential of quantum-enhanced sensing as a disruptive technology for healthcare, precision manufacture, national security and commerce. For quantum-enhanced sensors to become small-scale, portable and therefore practical for an increased range of applications outside of the specialized quantum optics laboratory, it is clear that there is an urgent need to engineer an integrated optics platform, tailored to the needs of quantum-enhanced sensing. Requirements include robustness, miniaturization inherent phase stability and greater efficiency. Lithographic fabrication of much of the platform offers repeatable and affordable manufacture. My Fellowship proposal aims to bring together revolutionary quantum-enhanced sensing capabilities and photonic chip scale architectures. This will enable capabilities beyond the limits of classical physics for: absorbance spectroscopy, lab-on-chip interferometry and process tomography (revealing an unknown quantum process with fewer measurements and fewer probe photons).

It is estimated by Cancer Research UK that there are 17 million people developing cancer worldwide each year - which sadly causes 9.6 million death annually, making cancer one of the deadliest diseases of our time. Cancer remains a very challenging disease to cure despite the significant research effort that has been made through several decades. This is because cancer is a complex disease that is caused by multiple genetic mutations that occur in important cellular proteins - named oncogenic proteins. Oncogenic proteins are proteins that once mutated become hyperactive and causes several types of cancer. They contribute in the signaling and activation of several cellular pathways that are involved in cellular growth and proliferation. One of the major oncogenic protein families that causes almost 20% of human cancer is the RAS family of proteins. RAS proteins oscillate between two states, ON and OFF. The ON state of RAS interacts with several downstream enzymes to control cellular growth and proliferation. Oncogenic mutations in RAS lock it into the ON state, which causes constant and uncontrolled cellular growth and several types of cancers. Since the discovery of RAS protein in the 1980s, many efforts have been made to find inhibitors against oncogenic RAS. However, RAS proteins are challenging drug targets, despite the development of inhibitors that target one specific RAS mutation, G12C, which only represents 14% of total RAS oncogenic mutations. Therefore, applying new strategies that targets oncogenic-RAS mutants is an urgent requirement. Previous work in the Downward laboratory at the Francis Crick Institute (Crick) has established that blocking the interaction of RAS proteins with a particular downstream target enzyme named p110a inhibits tumour growth driven by RAS oncogenes in mice. Importantly blocking the KRAS/p110a interaction had no toxic effects in normal adult mice. These studies strongly support the idea that the complex of RAS with p110a protein may be an important drug target for future cancer therapies. Although these results are very encouraging, the nature of the weak RAS/p110a interaction makes it difficult to use available screening assays to discovery novel inhibitory chemicals which might be developed into drugs for treating cancers. We therefore initiated a collaboration with the pharmaceutical company AstraZeneca to develop a suitable screening assay for the RAS/p110a interaction. This was successfully achieved, resulting in a joint publication between the Crick and AstraZeneca in 2020. This secondment will strengthen our already successful collaboration with AstraZeneca and enable us to take the project to the next stage. I will apply the newly developed assay system to carry out high throughput screening of libraries of millions of chemical compounds to identify inhibitors that blocks RAS/p110a interaction. By combining expertise from two world class organisations - from academia, the Crick and from the pharmaceutical industry, AstraZeneca - we will maximise the chances of success for the project. Finding inhibitors that blocks the RAS/p110a interaction could lead the way to developing future treatments for all cancers driven by oncogenic RAS mutations, or around 20% of all human cancers.

Fibrosis of the lung is the gradual replacement of alveolar of air sacs with scar tissue that prevents the organ from carrying out efficient gas exchange and currently has no cure. Lung fibrosis can occur as a result of chronic disease such as idiopathic pulmonary fibrosis (IPF) or severe epithelial injury during respiratory infection. There are 6000 new cases of IPF each year in the UK, it is increasing in incidence and survival is only 3-5 years after diagnosis. Fibrosis remains one of the largest threats to health after recovery from COVID-19 and influenza. There is an urgent and unmet need to develop new therapies that can alter the progression of fibrosis. Repeated lung injury and an inability to repair properly play a central role in lung fibrosis, suggesting that repair processes could be important targets for therapy. Epithelial basal cells (BCs) are adult stem cells of the lung that can self-renew or differentiate to all types of lung epithelium after injury. They normally function to repair lungs efficiently, however recent studies suggest that basal cell function might be impaired in fibrosis. Further investigation is required to understand whether these cells can be manipulated to control how they function. Growth factors play an essential role in coordinating growth and regeneration of lung tissue. Fibroblast growth factor 7 (FGF7) binds specifically to FGF receptor 2-IIIb (FGFR2b) expressed only on epithelial cells including BCs to promote growth and differentiation. FGF7 has been shown to be dysregulated in lung fibrosis, as a result there is interest in supplementing FGF7 to promote repair and reduce fibrosis in the lung for disease modifying therapy. Delivery of FGF7 protein after lung injury in human and animal models has demonstrated its powerful influence on lung repair but it's use has been hindered because it must be delivered by intravenous injection which results in rapid elimination from the body, poor distribution to the lung and high toxicity. Synthetic messenger RNA (mRNA) is an emerging technology that instructs the body's own cells to produce a specific protein with transformative potential for how growth factors are applied clinically. Growth factors encoded by mRNA are being tested for heart and skin repair in humans but has never been attempted for the lung, partly due to challenges in delivery. We have previously developed materials to protect synthetic mRNA and facilitate its delivery into lung cells following nebulised delivery. This proposal will bring together our experience in mRNA delivery, with expertise in lung repair and fibrosis to investigate mRNA encoded growth factors as a novel strategy to guide lung repair after injury. In order to achieve our goal, we aim to address three key questions: 1. What is the influence of FGF7 mRNA on survival, proliferation and migration of human basal cells from normal and IPF lungs? 2. Can FGF7 mRNA promote differentiation of basal epithelial cells in human lung organoids? 3. Does local delivery of FGF7 mRNA reduce fibrosis and improve lung function following injury in a murine model? The outcomes of our research will be instrumental for the application of synthetic mRNA as a platform for protein production in the lung that could be broadly applied to different protein targets and will bring this pioneering technology closer to improving human health.

Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at https://www.ukri.org/apply-for-funding/how-we-fund-studentships/. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.

Chemistry is a dynamic subject that is at the centre of many different scientific advances. Organic chemistry is concerned with the reactivity of carbon in all its different forms and can be viewed as the chemistry taking place within living things. Chemists are constantly looking for new ways of designing and building molecules (synthetic chemistry is molecular architecture) and this proposal describes a short and powerful new way of making valuable molecules using a new type of catalyst. The molecules at the heart of the proposal are compounds containing a carbon-oxygen double bond (a carbonyl group) which have special properties and are the building blocks of many known pharmaceutical agents. The novel chemistry proposed here will provide a new, efficient and powerful way of making carbonyl compounds using catalysis to control all aspects of the structures of the products formed: this will be of great benefit to both academia and industry who will be able to make interesting molecules (some that were otherwise inaccessible) in new ways. Plans have also been made to screen the compounds that we make for a wide range of biological activity. Given all of the above, it is imperative that we have novel, efficient and powerful methods for making new carbonyl containing compounds so that we can study and use them. In addition, the development and application of new catalysts and catalytic systems is also important because catalysis makes chemical reactions run faster, and become cleaner with less waste: this is clearly a good thing for industry and also for the environment. The Fellowship aspect of this proposal is designed to allow the principal investigator the time to study and develop a new research direction. Plans have been made to interact and collaborate with other academics who can provide specialist knowlege and also with two project partners (one a multi-national pharmaceutical company and the other a leading academic in the United States of America) so that industrial problems and mechanistic details can be identified and addressed at all stages of the project. Three post-doctoral assistants will be employed to carry out the exprimental work, and the project will provide a thorough and comprehensive training in science and the attendant areas of communication/ presentation and creativity. This will equip them very well for the job market afterwards.