The importance of the lymphatic circulation to human biology and health is hugely underestimated. A major reason for this is an absence of ways to investigate the lymphatics in humans. Veins on the back of the hand are easily seen, but the lymph vessels are invisible. Standard methods of analysing them such as x-ray, ultrasound, CT and MRI cannot easily detect the lymphatic vessels. Consequently, the lymphatic system has been largely underrated and its role in disease not widely appreciated. Through cellular and animal research we now know that the lymphatics play an important part in heart disease, cancer, infection, and fat metabolism; the four main challenges in healthcare today. Knowledge of how lymphatics do and do not work in humans has not kept pace, largely because of difficulties with investigation. While circulating blood is the main supply system for the body (providing water, nutrients, and oxygen to all cells), lymphatics are the returning, recycling and cleansing system. Lymphatic vessels are like veins but instead carry lymph fluid from tissues to lymph glands. The lymphatic system houses most of our immune cells such as lymphocytes. Infections, including Covid, must enter the lymph vessels and reach the lymph glands to activate lymphocytes. This develops effective immunity against that infection. The main consequence of a failure of lymphatic function is a condition called lymphoedema - where swelling occurs due to fluid accumulation, often in a limb and more commonly the legs. People with the condition also have reduced circulation of immune cells, which leads to an increased risk of infection that can be recurrent and life threatening. Lymphoedema is common (with 400,000 people in the UK, and 250 million people affected worldwide) but is not often diagnosed due to lack of awareness amongst clinicians. There are two different types - secondary lymphoedema (a result of damage to a previously healthy lymphatic system), and the much rarer primary lymphoedema (due to a genetic fault). Unlike cardiovascular disease and cancer, not one drug is licensed to treat lymphoedema and no universally successful surgical treatment exists. Thus, currently, lymphoedema cannot be cured and is managed through a range of physical therapies such as massage and compression to improve swelling. At St George's Hospital we operate a primary and paediatric lymphoedema clinic to which patients are referred from across the UK. More than 20 years of seeing patients with primary lymphoedema and lymphatic malformations, collectively known as primary lymphatic anomaly (PLA), has resulted in the discovery of several causal genes. Consequently, the St George's Hospital lymphoedema clinic is internationally renowned and has been appointed a Centre of Excellence, and has the largest collection of patients with lymphoedema anywhere in the world. The research proposed here is designed to improve our understanding of the mechanisms that lead to lymphoedema in humans through use of newly developed and more powerful investigatory methods. Patients with PLA - because of an inborn fault in lymphatic function caused by a gene mutation - will be studied so we can piece together how these faults are a driver of lymphoedema. This process has already begun in one type of PLA where the gene (PIK3CA) fault is not inherited but develops only in some cells and tissues of the body, a so-called somatic mosaic disorder. A drug now exists to block the effects of the faulty gene causing this lymphatic problem. Trials using this drug are now underway with St George's as one of a few centres for recruitment. Knowledge of other causal genes and the mechanisms producing the lymphoedema as planned in this research project, will create opportunities for new treatments. We believe the results of our work can be extended to other types of lymphoedema, such as those secondary to for example breast cancer treatment.