Abstract

The maintenance of oxygen homeostasis is a fundamental physiological challenge, inadequate oxygen (hypoxia) being a major component of most human diseases. The lecture will trace insights into human oxygen homeostasis from the founding work of William Harvey on the circulation of the blood to the molecular elucidation of a system of oxygen sensing that functions to measure oxygen levels in cells and control adaptive cellular and systemic responses to hypoxia. It will describe how work that commenced with studies of the regulation of the erythropoietin (EPO) gene by blood oxygen availability led to the unexpected discovery that the underlying oxygen sensitive process is present in all animal cells. The lecture will outline how the actual oxygen sensitive signal is generated by a set of ‘oxygen splitting’ enzymes that modify the key transcription factor (HIF) to signal its degradation (and hence inactivation) in the presence of oxygen. It will attempt to illustrate and rationalise the unexpected in biological discovery and discuss the interface of discovery science with the development of medical therapeutics.