We all need oxygen to live. More specifically, the trillions of cells which make up our body need oxygen to keep us alive. But oxygen isn’t always plentiful. Mountain climbers need to be aware of the dangers of the effects of high altitude, and even a morning run starves our muscles of oxygen. Of course, experience tells us that we can adapt to these conditions, but how do our cells ‘know’ whether our oxygen levels are normal or not?
This is the question which has been answered by the winners of the 2019 Nobel Prize for Medicine or Physiology, William Kaelin, Peter Ratcliffe and Gregg Semenza. The prize has been split equally between the three scientists for their contributions to our understanding of how cells sense and respond to oxygen. It was described by a Nobel Prize committee member as a 'textbook discovery,' which will become universal knowledge amongst biology students in the years to come.
To set the scene, Semenza and Ratcliffe focused on a hormone produced by the kidney. The hormone was called EPO (erythropoietin), which is produced by the kidneys when oxygen is scarce (a state known as hypoxia). EPO then stimulates the bone marrow to produce red blood cells, which carry oxygen around the body to the tissues which need it. But how do kidney cells sense hypoxia, and how do they know when to trigger this process?
A key puzzle piece came in the form of a protein called HIF (hypoxia-inducible factor). Semenza looked at the gene which codes for EPO. Next to it, he discovered sections of DNA which were switched on in hypoxic conditions. What is the missing link between hypoxia and the activation of these sections of DNA? Anything which binds to this DNA could provide the answer. As Semenza continued his research, he uncovered a crucial protein – HIF. HIF binds to the DNA when the oxygen is scarce. What’s more, it could be found not just in the kidney, but in cells throughout the body. This was a major breakthrough for Semenza and Ratcliffe.
Kaelin was on a very different path. He was interested in a genetic disorder called von Hippel-Lindau syndrome, a condition where tumours can develop in many different organs in the body. A gene called VHL usually helps stop tumours from developing, but people with von Hippel-Lindau syndrome have a mutated form of this gene which is unable to do this. Kaelin studied the mutated VHL gene and it is here that the two paths start to merge. Kaelin found that in cells where the VHL gene is mutated, many genes affected by hypoxia are active. Perhaps the VHL gene and HIF are connected?
Sure enough, Ratcliffe found the link. When oxygen levels are normal, the VHL protein (coded for by the VHL gene) binds to HIF, causing it to be broken down. This means that there is no HIF to activate the DNA sequences linked to hypoxia. Still, the question of the exact role of oxygen remained. Ratcliffe and Semenza simultaneously put the final piece into place. When oxygen is present, it ‘tags’ HIF. This ‘tag’ means that VHL can bind to HIF. Without oxygen, HIF remains free to bind and activate DNA in the nucleus. This triggers an array of adaptive measures to return our oxygen levels to normal.
This is not just a fascinating insight into how we stay alive. It has exciting potential to treat numerous diseases. Cancers have long been associated with hypoxia. They can hijack the oxygen-sensing system to grow new blood vessels which will sustain the tumour, allowing it to grow and spread. Armed with knowledge about how the intricate molecular system works, researchers can precisely target the pathway to develop new treatments.
This discovery has not only been linked to multiple different cancers, but also to diseases of the circulatory system (which pumps blood and oxygen around the body) and anaemia caused by kidney failure. Kaelin, Ratcliffe and Semenza’s discovery reaches far beyond DNA and proteins. For many, this could be life-changing.
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