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Oxygen is life's key ingredient

It is the third most abundant element in the universe, the most abundant in the Earth's crust and makes up 85.84 per cent of the oceans. It is oxygen. To say that oxygen is ubiquitous is a bit of an understatement. It makes up 20.
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It is the third most abundant element in the universe, the most abundant in the Earth's crust and makes up 85.84 per cent of the oceans. It is oxygen.

To say that oxygen is ubiquitous is a bit of an understatement. It makes up 20.9 per cent of the air we breathe and approximately 65 per cent of the human body. But molecular oxygen hasn't always been abundant.

Oxygen is in some ways toxic to life. High levels can overwhelm our defenses, leading to pulmonary and ocular toxicity, oxidative damage to cell membranes, and ultimately to diseases such as cancer. Of course, low levels are equally catastrophic. We can go weeks without food, days without water, but only minutes without oxygen. Any complex organism needs to regulate the amount of oxygen in its body. The importance of oxygen has been known since the late 1700s.

But while the requirement for oxygen was well understood, how cells adapt to changes in the levels of oxygen and how we manage the oxygen budget in our bodies at a cellular level long remained a mystery.

This year, William G. Kaelin Jr., Sir Peter J. Ratcliffe, and Gregg L. Semenza were awarded the Nobel Prize in Physiology and Medicine "for their discoveries of how cells sense and adapt to oxygen availability".

A key response to hypoxia (low oxygen levels) is a rise in the levels of the hormone erythropoietin (EPO) resulting in the production of more red blood cells. Semenza studied the EPO gene and using gene-modified mice was able to show DNA segments next to the EPO gene mediated the response to hypoxia.

At the same time, Radcliffe was also studying the oxygen-dependent regulation of the EPO gene. Both groups were able to show the mechanism for oxygen sensing was present in virtually all tissues and not just the kidneys where EPO is predominantly produced.

In 1995, Semenza published his result on a protein complex called the hypoxia-inducible factor (HIF) and its associated transcription factors, HIF-1a and ARNT. When oxygen levels are low, the amount of HIF-1a increases and regulates the EPO gene among others. At the same time, other researchers had shown a cellular machine called the proteasome degrades HIF-1a after it had been tagged with a molecule called ubiquitin.

How the whole system worked remained a question but the answer came from an unexpected direction. Kaelin was researching an inherited syndrome, von Hippel-Lindau's disease. The genes involved were somehow involved in controlling the cellular response to hypoxia. Ratcliffe was able to show the interaction with HIF-1a.

Many pieces of the puzzle had been worked out. It still needed a final synthesis of ideas and in 2001, Kaelin and Ratcliffe were both able to show that under normal oxygen levels, hydroxyl groups are added to two specific positions in HIF-1a. The gene activating function of HIF-1a is regulated by this oxygen-dependent hydroxylation. The Nobel Laureates had collectively elucidated the oxygen sensing mechanism and how it works.