The 2019 Noble prize in Physiology or Medicine was awarded to Sir Peter Ratcliffe, alongside William Kaelin and Gregg Semenza, for his contribution to discovering how cells sense and adapt to oxygen availability. The critical importance of oxygen has long been understood, but exactly how cells can interpret oxygen supply and in turn adapt cellular mechanisms and metabolism has only been unearthed in recent years, largely due to Ratcliffe’s and the other laureates pioneering research.
Understanding the molecular machinery which regulates a wide range of genes in varying oxygen concentrations, particularly in response to hypoxia, has impacted numerous fields of predominantly disease focused research. This understanding is helping to develop drugs that interfere with the oxygen sensing machinery. One such field is the study of anaemia, where the developing understanding of the regulation of erythropoietin led to new approaches for the stimulation of red blood cell production. Perhaps the most critical outcomes are the ensuing developments in cancer research, in particular regarding angiogenesis and the development of angiogenic inhibitors like bevacizumab and sunitinib. These inhibitors prevent the vascularisation of tumours, thereby limiting their ability to grow past a certain size, due to lack of oxygen supply, and reducing the metastatic potential of a tumour. A variety of cancers are treated with angiogenesis blockers, typically in combination with other anti-cancer therapeutics such as chemotherapy.
Sir Peter Ratcliffe founded a laboratory at Oxford University to explore the intricacies of cellular oxygen sensing pathways, including the control of the hormone erythropoietin (EPO) which promotes red blood cell formation from the bone marrow. Ratcliffe studied the regulation of the erythropoietin gene, as did Semenza, discovering specific DNA sequences next to the EPO gene were responsible for mounting a response to hypoxia
Hypoxia inducible factor (HIF) is a heterodimeric DNA binding complex, which binds to and activates the hypoxia response element upstream of the EPO gene under hypoxic conditions, generating a rapid accumulation of Epo protein. HIF is comprised of the alpha subunit HIF-1α, containing a basic helix-loop-helix PAS domain (bHLH-PAS) and ARNT (aryl hydrocarbon receptor nuclear translocator). HIF activation is now known to stimulate the transcription of multiple genes, including VEGF and erythropoietin, which increase the number of red blood cells and initiate angiogenesis.
Ratcliffe and his lab helped to uncover cellular signalling by prolyl and asparaginyl hydroxylase enzymes (FIH and PHD1, 2 and 3) which post-translationally hydroxylate specific residues within HIF. This generates a binding side for the VHL tumour suppressor protein, leading to proteasomal degradation of HIF. This entire process is completely dependent upon oxygen, with the PHD proteins belonging to the oxygenase superfamily. Under hypoxic conditions, the PHD and FIH proteins cannot catalyse these hydroxylation modifications, allowing HIF to induce the transcription of its target genes. This means cells can appropriately adapt metabolism and processes to the declining oxygen availability.