On 7 October 2019, Prof. Thomas Perlmann, Secretary of the Nobel Committee for Physiology or Medicine announced that the Nobel Assembly at the Karolinska Institutet has decided to award the Nobel Prize in Physiology or Medicine 2019 jointly to William G. Kaelin Jr, Sir Peter J. Ratcliffe and Gregg L. Semenza "for their discoveries of how cells sense and adapt to oxygen availability." The need for oxygen to sustain life has been understood since the onset of modern biology; but the molecular mechanisms underlying how cells adapt to variations in oxygen supply were unknown until the prize-winning work.
Animal cells undergo fundamental shifts in gene expression when there are changes in the oxygen levels around them. These changes in gene expression alter cell metabolism, tissue re-modelling, and even organismal responses such as increases in heart rate and ventilation. In studies during the early 1990’s, Gregg Semenza identified, and then in 1995 purified and cloned, a transcription factor that regulates these oxygen-dependent responses. He named this factor HIF, for Hypoxia Inducible Factor, and showed that it consists of two components: one a novel and oxygen-sensitive moiety, HIF-1α, and a second, previously identified and constitutively expressed and non-oxygen-regulated protein known as ARNT.
William Kaelin, Jr. was in 1995 engaged in the study of the von Hippel-Lindau tumour suppressor gene, and after isolation of the first full-length clone of the gene showed that it could suppress tumour growth in VHL mutant tumourigenic cell lines. Von Hippel-Lindau’s disease is a genetic disease that leads to increased risk of certain cancers in families with inherited VHL mutations. Kaelin showed that the VHL gene encodes a protein that prevents the onset of cancer. Kaelin also showed that cancer cells lacking a functional VHL gene express abnormally high levels of hypoxia-regulated genes; but that when the VHL gene was reintroduced into cancer cells, normal levels were restored. This was an important clue showing that VHL was somehow involved in controlling responses to hypoxia. Additional clues came from several research groups showing that VHL is part of a complex that labels proteins with ubiquitin, marking them for degradation in the proteasome.
Ratcliffe then demonstrated in 1999 that there was an association between VHL and HIF-1α, and that VHL regulated HIF-1α post-translational and oxygen-sensitive degradation. Finally, the Kaelin and Ratcliffe groups simultaneously showed that this regulation of HIF-1α by VHL depends on hydroxylation of HIF-1α, a covalent modification that is itself dependent on oxygen.
Through the combined work of these three laureates it was thus demonstrated that the response by gene expression to changes in oxygen is directly coupled to oxygen levels in the animal cell, allowing immediate cellular responses to occur to oxygenation through the action of the HIF transcription factor.
The discovery of the proline hydroxylases that regulate HIF-1α stability enabled a search for hydroxylase inhibitors to increase HIF levels; and this has now opened up new pathways for pharmacologic discovery. In fact, a number of potential drugs that increase HIF function by inhibiting the PHD enzymes are already far along in clinical trials, with a recent series of publications demonstrating their clinical efficacy in treatment of anaemia.
Future applications to inhibit the HIF pathway are also on the horizon; these are envisioned as a mean to slow the progression of some cancers that are induced by VHL mutations. One of these is a specific blocker of EPAS1 function that was recently described by Kaelin and colleagues as capable of slowing tumour growth of VHL mutant cells in animal models.
Pharmacologically increased HIF function may aid in the treatment of a wide range of diseases, as HIF has been shown to be essential for phenomena as diverse as immune function, cartilage formation, and wound healing. Conversely, inhibition of HIF function could also have many applications: increased levels of HIF are seen in many cancers as well as in some cardiovascular diseases, including stroke, heart attack, and pulmonary hypertension. It is thus likely that we are only at the beginning of applications of these Nobel Prize-winning discoveries, since it is clear that the response to oxygen in cells, tissues and organisms is one of the most central and important physiological adaptations that animals have.
The Nobel Prize in Physiology or Medicine 2019. NobelPrize.org. Nobel Media AB 2019. Wed. 9 Oct 2019.