The 2019 Nobel Prize in Medicine or Physiology has been jointly awarded to three scientists: William G. Kaelin Jr., professor of medicine at Dana-Farber Cancer Institute and Brigham & Women’s Hospital Harvard Medical School; Sir Peter J. Ratcliffe, director of clinical research at the Francis Crick Institute in London and director of the Target Discovery Institute at Oxford; and Gregg L. Semenza, professor of genetic medicine at Johns Hopkins – for their work on how cells sense and adapt to oxygen availability.
All three scientists contributed majorly to our current understanding of how animal cells adapt to the changes in oxygen levels. Their seminal discoveries led to the identification of molecular machineries that function to regulate the activity of genes following changes in the levels of oxygen.
So why is this year’s prize important?
Oxygen as we all know is required for cellular metabolism by the cells’ mitochondria, which are generally regarded as the powerhouses of our cells. As we exercise, fly on the plane, go hiking, climb mountains to high altitude, the levels of oxygen in the body changes accordingly. But how cells sense and adapt to these changing levels of oxygen has remained elusive for years. Hence, the discoveries by these scientists provided more insights into the molecular and genetic aspects of this puzzle.
According to the Royal Swedish Academy of Sciences, ‘’ The seminal discoveries by this year’s Nobel Laureates revealed the mechanism for one of life’s most essential adaptive processes. They established the basis for our understanding of how oxygen levels affect cellular metabolism and physiological function. Their discoveries have also paved the way for promising new strategies to fight anemia, cancer and many other diseases’’
As highlighted by the Nobel Assembly above, the discoveries by this year’s Nobel laureates have key implications for diseases such as cancer, where rapidly growing cancer cells are normally deprived of oxygen – a medical condition termed hypoxia.
What did the researchers discover about how cells sense and adapt to changing oxygen levels?
In response to low oxygen levels (hypoxia), cells upregulate the physiological levels of the hormone erythropoietin (EPO), which consequently leads to increased production of red blood cells. While the relationship between hypoxia and increased production of red blood cells has been known since the beginning of the 20th century, the role of oxygen in controlling this process had remained elusive. The work of both Dr Gregg Semensa and Sir Peter Ratcliffe provided answers to this puzzle. Their work unravelled the fact that cells respond to hypoxia by regulating specific DNA segments near the EPO gene. Dr Semensa went further to discover the hypoxia-inducible factor, a combo of two transcription factors called HIF-1α and ARNT that bind to the DNA sequence of EPO genes of cells in hypoxic state.
And so what? The binding of HIF complex to the DNA sequence of EPO mediates the response to hypoxia by upregulating the expression and circulation of the EPO hormone, which consequently increased the production of red blood cells. This ultimately delivers oxygen to cells that would normally be deprived of oxygen due to hypoxia as exemplified in cancer cells.
But how’s hypoxia-inducible factor regulated in normoxic cells?
Normoxic cells are cells with normal and adequate supply of oxygen. Knowledge from research shows that normoxic cells have very reduced levels of HIF-1α compared to hypoxic cells, which are characterised by an increase in the levels of HIF-1α. So what is responsible for the reduced level of HIF-1α in normoxic cells? Research from other research groups identified the proteasome to be responsible for the rapid degradation (by addition of ubiquitin) of the HIF-1α in normoxic cells; thus, reducing its cellular levels and consequently, reduced EPO levels.
But how does ubiquitin recognise and bind to HIF-1α for degradation by the proteasome?
The answer to this question was unravelled by Dr William Kaelin who was, at about the same time as the other two researchers, studying an inherited syndrome called von Hippel-Lindau’s disease (VHL disease). This condition is known to increase the risk of developing cancer in families that have inherited mutations in the VHL genes. Dr Kaelin showed that cells that eventually progress to develop cancer lack an important protein encoded by the VHL gene. In addition, research from Kaelin also revealed that cancer cells lacking a functional VHL gene have high levels of hypoxia-regulated genes. As well as revealing its link to the onset of cancer, Dr Kaelin provided the initial clue that the VHL gene might be controlling responses to hypoxia. Other research groups provided substantive evidence that show that VHL is part of a complex that tags proteins with ubiquitin for subsequent degradation. This was an important milestone that led Dr Ratcliffe and his research group to the discovery that the VHL protein can interact with HIF-1α and was required for its degradation at normal oxygen levels.
It now appears that the puzzle has been solved! But there is gap that is yet to be filled. What’s that?
How does a change in oxygen levels regulate the interaction between a protein that makes cells prone to develop cancer when it loses its normal cellular function and a transcription factor that is involved in increasing red blood cell formation in hypoxic cells?
Gene activating function of HIF-1α is regulated by oxygen-dependent hydroxylation:
Both Kaelin and Ratcliffe thought that the answer to this final puzzle could lie within the specific domain of the HIF-1α protein. In two independent but simultaneous publications in 2001, both researchers show that under normoxic condition, hydroxyl groups are added at two specific positions in HIF-1α, a protein modification called prolyl hydroxylation. This modification ushered in two things: recognition and binding of the VHL protein to HIF-1α as well as its (HIF-1α) degradation. Speaking from a Biochemistry (enzymology) point of view, a third protein must have come into the scene. And guess that that protein is? It’s prolyl hydroxylase, an oxygen-sensitive enzyme that adds the hydroxyl group onto the two positions on HIF-1α. Uhm! the enzymatic chemical equation is balanced, right? Almost, I would say. Ratcliffe and others went on to identify the specific prolyl hydroxylase. A disturbing puzzle has now been finally resolved. Hence, the 2019 Nobel Prize in Medicine or Physiology has been jointly awarded to these scientists for their seminal discoveries.
Please note that most of the information in this article has been modified from the press article on the Nobel Assembly’s website. Interested readers are encouraged to read the full story on the NobelPrize website