“Lack of knowledge is the true bottleneck to clinical translation. We need to stop telling basic scientists, especially trainees, that their work’s value lies in its translatability.”
That is the unexpected advice of none other than William Kaelin Jr., whose scientific discoveries have proved to be both top-rate science and very translatable indeed. His work, for which Kaelin has won the 2019 Nobel Prize in Physiology or Medicine and a host of other awards, has enabled the development of multiple therapies targeting anemia and cancer, including vadadustat.
Vadadustat and other drugs in its class work by inhibiting prolyl hydroxylase-hypoxia induced factor 1 (PH-HIF1). And their discovery was driven by scientific curiosity about how cells sense and cope with changing oxygen levels.
Cells are both highly dependent on oxygen, and have no way of making it on their own. As a result, they have evolved mechanisms to sense oxygen levels and to deal with a dip in those levels by changing their gene expression programs.
Peter Ratcliffe and Gregg Semenza, who shared the 2019 Nobel Prize with Kaelin, and their laboratories first showed that HIF1 was the transcription factor responsible for the production of erythropoietin (EPO), which stimulates the production of oxygen-transporting red blood cells. They also showed that when oxygen levels are normal, HIF1 is constantly produced, but it does not accumulate because it is degraded as quickly as it is made.
Kaelin and his colleagues demonstrated that HIF1 is tagged for destruction in a two-step process that involves PH and the tumor suppressor von Hippel-Lindau (VHL) protein. When oxygen levels are low, that process cannot proceed, leading to the accumulation of HIF1 and the induction of genes, including EPO. Vadadustat and its peers inhibit the hydroxylation of HIF-1, allowing those same gene expression programs to proceed.
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