07 October 2019

Nobel Prize in Physiology and Medicine – 2019

The Nobel Prize in Physiology and Medicine was given for the sense of oxygen

Kirill Stasevich, Science and Life (nkj.ru ), based on materials Nobel Committee


Nobel laureates, from left to right: William Kaelin Jr., Peter Ratcliffe, Gregg Semenza.

There is no need to say once again about the importance of oxygen: without it, almost all modern living organisms would simply cease to exist. But the level of oxygen can change, and our need for it can also change: for example, during rest we need it less than during hard physical work. And since oxygen is very, very important to us, we must have special mechanisms that help us to feel the changed oxygen conditions in time and adapt to them.

Everyone can observe one of these mechanisms directly by their own example: physical exercises make us breathe more often. Due to the load, cells spend a lot of nutrients that are oxidized with oxygen, extracting energy for life from them; the oxygen level in the blood drops, and this is felt by the so–called carotid corpuscles - special chemoreceptors in the carotid artery. They send a signal to the respiratory center of the brain, and as a result, the rhythm of breathing becomes faster. (This mechanism was awarded the Nobel Prize in Physiology or Medicine in 1938.) But there are other physiological and biochemical reactions involved in response to hypoxia. For example, the level of the hormone erythropoietin increases in the body, which stimulates the formation of red blood cells. As we well know, red blood cells contain hemoglobin, which binds oxygen, so the more red blood cells, the more oxygen from the lungs goes with the blood to the cells of the body.

But how does erythropoietin itself feel the oxygen level? If there is more of it, it means that its gene begins to work more actively – that is, molecular machines that read genetic information work more actively on the erythropoietin gene. One of the current laureates, Gregg Semenza, discovered that next to the erythropoietin gene there are sections of DNA that somehow feel a decrease in oxygen levels. Initially, these sections of DNA that "feel" oxygen were studied in kidney cells, but later Semenza and another current laureate, Peter Ratcliffe, found out that the same mechanism of "oxygen sense" works in a variety of cell types.

By 1995, Semenze and his colleagues managed to find and isolate a protein in its pure form, which was called HIF – hypoxia-inducible factor, or hypoxia-induced factor (in fact, HIF consists of two parts, which are called HIF-1α and ARNT).


The molecular mechanism of cellular oxygen sense: when there is a lack of oxygen, the HIF-1a protein activates in the nucleus.

If there is not enough oxygen for the cell, then the number of HIF molecules increases and they bind to certain regulatory DNA sites before the erythropoietin gene and before many more genes. HIF works as a transcription factor: by binding to regulatory regions of DNA, it activates genes that help the cell and the whole organism adapt to lack of oxygen. We emphasize that we are talking not only about erythropoietin – HIF activates a lot of genes, more than three hundred in number.

If there is enough oxygen for the cell, the HIF level drops: it is broken down by a special molecular machine called the proteasome, whose task is to rid the cell of unnecessary proteins. But how does the splitting machine understand that there is enough oxygen and it is necessary to reduce the amount of HIF? Here the answer was found by the third laureate William Kaelin, Jr., who studied Hippel-Lindau disease, a genetic disorder that ends in various malignant tumors. The gene, due to mutations in which Hippel-Lindau disease begins, is called VHL (from von Hippel-Lindau's disease). It turned out that if the VHL gene does not work, hypoxic genes begin to work too hard in cells – that is, those that are needed to adapt to hypoxia. It became obvious that VHL is connected with the "oxygen sense" system, and further experiments showed that the VHL protein in the composition of a large protein complex directly interacts with HIF and sends it to the proteasome, which HIF cleaves.

But where is the oxygen here? In 2001, Ratcliffe and Kaelin published an article each stating that with a sufficient amount of oxygen, chemical modifications appear on the HIF protein, and oxygen is directly involved in these modifications. And it is in this modified form that HIF "contacts" with the VHL complex. If oxygen is low, then there are no modifications to HIF, which means that it remains invisible to splitting enzymes and no one prevents it from activating hypoxic genes. The decoding of the mechanism of cellular oxygen sense has been completed.

Since, as already mentioned, this mechanism turned out to be universal, it is difficult to overestimate the significance of the discovery. The sense of oxygen works both in tense muscles, and in growing blood vessels, and in the immune system, and in the embryo growing in the womb. Accordingly, one can imagine that malfunctions in this system can lead to a variety of quite severe disorders. We have already said that one of the important proteins of the cellular oxygen sense system was found in the study of Hippel-Lindau disease, which usually leads to cancer.

Indeed, in tumors, the oxygen sense system works very actively, due to which, on the one hand, blood vessels feeding it appear in the tumor, and on the other hand, cancer cells rearrange their metabolism so that they continue to divide even with a lack of oxygen. Oxygen sense cannot be dispensed with if we want to overcome the consequences of a heart attack or stroke, and it also plays a big role in infections and healing processes – so a large field of activity opens up here for medical research and pharmaceutical companies.

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