Long before Sir Peter Ratcliffe was in line for a Nobel prize, Ximbio was working with the technology transfer office at University of Oxford, to make reagents generated in his laboratory available to researchers around the world. We are delighted the 2019 Nobel 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.