Nobel Prize winners of 2019: The Three Scienteers!

Oxygen is an essential component of life. Many discoveries have highlighted the necessity of oxygen for countless physiological processes – these include from constituting proteins to driving metabolic processes. Oxygen is the ‘fuel’ that operates the cells in our body. Muscle contraction, respiration, energy sourcing and reparation are all vital examples that prominence the fundamentality of oxygen.

Mice are widely used models in scientific research. The mouse has many similarities to humans in terms of anatomy, physiology and genomics. The genome is ~85% similar to humans, thus mice are useful for studying human diseases. Mice are cost effective, can reproduce quickly, are cheap and easy to look after and maintain.

Thus, it was therefore a momentous revelation when the mechanistic process of cellular adaptation to oxygen was uncovered. William Kaelin, Sir Peter Ratcliffe and Gregg Semenza have been awarded a Nobel Prize under Medicine and Physiology for their ground-breaking research on how cells detect and adapt to fluctuating oxygen availability.

Semenza using transgenic mice* has identified a hypoxia** detector component in the Erythropoietin (EPO) gene that detects inadequate levels of oxygen. The component was named the hypoxia-inducible factor (HIF) and binds to a sequence in the EPO gene named the hypoxia-inducible enhancer [1]. HIF levels increase in response to low levels of oxygen, leading to HIF binding to the EPO gene.

Despite the revelation of different components that are involved in oxygen detection, the mechanism behind maintenance of these components was still unanswered. Kaelin, a cancer scientist highlighted a gene that encodes a protein that prevents the onset of cancer that was later theorised to have a vital role in oxygen detection. Kaelin found that the Von Hippel-Lindau gene (VHL) if mutated leads to familial risk of cancer. This gene bridged the gap between what and how. Cancer cells that lacked the VHL gene led to high levels of hypoxia, but when the VHL gene was reinstated to the cancer cells, normal oxygen levels were re-established [2]. Using this basis, VHL was theorised to have an important role in controlling cell response to oxygen levels.

So, what does VHL gene do? VHL tags proteins with another smaller protein called ubiquitin. Ubiquitin is a way of marking unwanted or damaged cells for degradation and removal. Ratcliffe and Semenza established the crucial link between HIF and VHL. An oxygen sensing component in the HIF protein was found to be vital for the VHL-dependent degradation of hypoxic cells [3]. In a normal oxygen environment, HIF undergoes protein modification. This modification is prolyl hydroxylation, where hydroxyl groups are attached to HIF. In this case, hydroxyl added to HIF allows for VHL to recognise and undergo ubiquitin tagging. In a hypoxic environment, HIF is protected from degradation by a protein called ARNT***, this protein blocks hydroxyl group attachment permitting the coding of hypoxic-related genes.

The research undertaken by these three scientists has shed a light on the long-awaited answer of finding the mechanism of regulating oxygen in cells. This new discovery can help theorise treatments to diseases where oxygen levels are compromised. Diseases and syndromes such as anaemia, neonatal hypoxia, cancer and many more now have a promising scope in the future of developing therapeutics. The magnificent work of these Nobel Laurette’s will surely kick-start revolutionary medical research, for which their research will be the underpinning.

* A genetically modified mouse with altered genetic information

** Deficiency of oxygen in cells

*** Aryl Hydrocarbon Receptor Nuclear Translocator

For more information, visit the nobelprize.org website:

For an in-depth review of the research, see these published articles:

[1] Semenza, G.L, Nejfelt, M.K., Chi, S.M. & Antonarakis, S.E. (1991). Hypoxia-inducible nuclear factors bind to an enhancer element located 3’ to the human erythropoietin gene. Proc Natl Acad Sci USA, 88, 5680-5684.

[2] Maxwell, P.H., Wiesener, M.S., Chang, G.-W., Clifford, S.C., Vaux, E.C., Cockman, M.E., Wykoff, C.C., Pugh, C.W., Maher, E.R. & Ratcliffe, P.J. (1999). The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature, 399, 271-275

[3] Jaakkola, P., Mole, D.R., Tian, Y.-M., Wilson, M.I., Gielbert, J., Gaskell, S.J., von Kriegsheim, A., Heberstreit, H.F., Mukherji, M., Schofield, C.J., Maxwell, P.H., Pugh, C.W. & Ratcliffe, P.J. (2001). Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science, 292, 468-472

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