William G. Kaelin

The von Hippel-Lindau hereditary cancer syndrome led Kaelin to speculate that the VHL gene is critical for oxygen sensing and the finding that the VHL protein (pVHL) forms an ubiquitin ligase-like complex that suppresses hypoxia-inducible mRNAs. Kaelin and Peter Ratcliffe showed that pVHL is the HIFα ubiquitin ligase and that an oxygen-sensitive modification on HIFα, prolyl hydroxylation, promotes pVHL-association. They and Steven McKnight identified the oxygen-sensing prolyl hydroxylases, which Kaelin showed could be inhibited with drug-like molecules in animals. Kaelin also showed that HIF2α drives pVHL-defective kidney cancers. First-generation HIF2α inhibitors appear promising in the treatment of kidney cancer. Honored with the 2019 Nobel Prize in Physiology or Medicine.