For his landmark, Nobel Prize-winning contributions to the understanding of the molecular responses to oxygen depletion, specifically the identification of oxygen sensing and signaling pathways that link hypoxia-inducible factor 1 to the availability of oxygen, which has proven to be critically important to the understanding of tumor initiation and progression.
Globally celebrated, Dr. Ratcliffe has made landmark contributions to our understanding of molecular responses to oxygen depletion. He is credited for the identification of the oxygen sensing and signaling pathways that link the hypoxia inducible factor to the availability of oxygen. On his path to understanding how erythropoietin (EPO), which was known to be released by the kidneys, could regulate red blood cell production, he demonstrated that Epo mRNA levels responded to changing oxygen levels in isolated rat kidneys, demonstrating that the tissue had all the required elements for Epo expression. Dr. Ratcliffe’s research also demonstrated for the first time that Epo mRNA is present in tissues outside of the kidney, also under hypoxic conditions. Using the mouse Epo gene, he uncovered a non-coding regulatory element downstream of the gene that was responsive to fluctuations in oxygen levels in multiple cell lines, including those not expressing EPO. Ultimately, it was demonstrated that this regulatory element is bound by the HIF-1 heterodimer composed of HIF-1α and HIF-1β sub-units.
In a subsequent series of elegant experiments, Dr. Ratcliffe and his research group uncovered the mechanism behind oxygen sensing, specifically shedding light on the binding of the von Hippel-Lindau (VHL) protein to HIF-1α sub-units. Cells exhibit sustained HIF-1α protein levels in the absence of the ubiquitin ligase VHL. Dr. Ratcliffe determined that proper binding would only occur if two specific proline residues in HIF-1α were hydroxylated, ultimately targeting the protein for degradation. In addition, his laboratory identified prolyl hydroxylase enzymes (PHDs) which require molecular oxygen as the hydroxylating agents. Together, these results showcased the cellular response to decreasing oxygen levels, which leads to a decrease in HIF-1α hydroxylation and binding by VHL, and ultimate HIF-1α accumulation. These pathways have since proved critically important to tumor development and progression. In recognition of this seminal work, he was awarded the Nobel Prize in Physiology or Medicine in 2019, together with colleagues from the Dana-Farber Cancer Institute and Johns Hopkins University.
Selected Awards and Honors
2019 ~ Nobel Prize in Physiology or Medicine
2018 ~ Massry Prize, The Meira and Shaul G. Massry Foundation, Beverly Hills, California
2017 ~ Buchanan Medal, The Royal Society, London, United Kingdom
2016 ~ Albert Lasker Basic Medical Research Award, Albert and Mary Lasker Foundation, New York, NY
2014 ~ Knight Bachelor of the British Empire, New Year’s Honours List, London, United Kingdom
2010 ~ Canada Gairdner International Award, Gairdner Foundation, Toronto, Ontario, Canada
2009 ~ Louis-Jeantet Prize for Medicine, Geneva, Switzerland
2002 ~ Elected Fellow, The Royal Society, London, United Kingdom
2002 ~ Buchanan Medal, The Royal Society, London, United Kingdom