Nobel Prize for Medicine to discover "how cells feel and adapt to available oxygen"

[Akrapovic]

The winners are the Americans William G. Kaelin Jr, Gregg L. Semenza and the English Sir Peter J. Ratcliffe. His work has paved the way for new and promising strategies against anemia, cancer and many other diseases.

How cells can adapt to changes in the oxygen reserve. That has been the key finding that has led William G. Kaelin Jr, Sir Peter J. Ratcliffe and Gregg L. Semenza to win this year the Nobel Prize in Physiology or Medicine. The three experts identified the molecular machinery that regulates the activity of genes in response to different oxygen levels. Its discovery reveals the mechanism of one of life's most essential adaptation processes. (Read: The researcher who unearthed the history of teachers in Colombia)

Thus, they established the basis for understanding how oxygen levels affect cell metabolism and physiological function. His work has also paved the way for new and promising strategies against anemia, cancer and many other diseases.

Oxygen (O2) constitutes approximately one fifth of the Earth's atmosphere. Essential for animal life, it is used by mitochondria present in virtually all animal cells to convert food into useful energy.

During evolution, mechanisms were developed to ensure a sufficient supply of oxygen to tissues and cells. The carotid body - adjacent to the large blood vessels on both sides of the neck - contains specialized cells that detect blood oxygen levels.

Corneille Heymans, Nobel Prize in Physiology or Medicine of 1938, described how the detection of oxygen in the blood through the carotid body controls our respiratory rate by communicating directly with the brain. In addition to the rapid adaptation controlled by the carotid body to low oxygen levels (hypoxia), there are other fundamental physiological adaptations. A key physiological response to hypoxia is the increase in the levels of the hormone erythropoietin (EPO), which leads to an increase in the production of red blood cells (erythropoietin).

The importance of hormonal control of erythropoiesis was already known in the early twentieth century, but the way in which this process was controlled by O2 remained a mystery.

 

The hypoxia machinery

There Gregg Semenza (New York, 1956) enters the scene, who studied the EPO gene and how it is regulated by varying levels of oxygen. Through the use of genetically modified mice, he demonstrated that specific segments of DNA located next to the EPO gene mediated the hypoxia response.

Using genetically modified mice, Gregg Semenza showed that segments of DNA located next to the EPO gene mediated the hypoxia response

On the other hand, Sir Peter Ratcliffe (Lancashire, United Kingdom, 1954) also analyzed the O2-dependent regulation of the EPO gene, and both groups found that the oxygen detection mechanism was present in virtually all tissues, not just cells kidney where the hormone is normally produced.

These findings showed that the mechanism was general and functional in many different cell types. Semenza, who wanted to identify the cellular components that mediated this response, discovered in cultured liver cells a protein complex that binds to the identified DNA segment in an O2-dependent manner.

He called this complex the hypoxia inducible factor (HIF), and thereafter they began to purify it. Thus, in 1995 Semenza published some of its key findings, including the identification of the genes encoding HIF.

It was found that HIF consists of two different DNA binding proteins, the so-called transcription factors: HIF-1α and tRNA. Then the researchers were able to begin solving the puzzle, allowing them to understand what additional components were involved and how the machinery works.
An unexpected partner

When oxygen levels are high, cells contain very little HIF-1α. However, when oxygen levels are low, the amount of HIF-1α increases so that the EPO gene can bind and regulate, as well as other genes with DNA segments that bind to HIF.

Several research groups demonstrated that HIF-1α, which normally degrades rapidly, is protected against degradation in hypoxia. At normal oxygen levels, a cellular machine called a proteasome - recognized by the 2004 Nobel Prize in Chemistry to Aaron Ciechanover, Avram Hershko and Irwin Rose - degrades HIF-1α.

Under such conditions, a small peptide (ubiquitin) is added to the HIF-1α protein. Ubiquitin functions as a label for proteins destined for degradation in the proteasome, but it was not known how it bound in an oxygen dependent manner.

The answer came from the hand of William G. Kaelin, Jr. (New York, 1957), a cancer expert. Almost at the same time that Semenza and Ratcliffe were studying the regulation of the EPO gene, Kaelin was investigating a hereditary syndrome, von Hippel-Lindau disease (VHL).

This genetic pathology carries an increased risk of certain cancers in families with inherited VHL mutations. In this way, Kaelin showed that the VHL gene encodes a protein that prevents the appearance of tumors.

The researcher also showed that cancer cells that lack a functional VHL gene express abnormally high levels of hypoxia-regulated genes; but that when the VHL gene was reintroduced into these cells, normal levels were restored.

This was an important indication that von Hippel-Lindau disease was somehow involved in the control of hypoxia responses. Finding that was confirmed by the Ratcliffe group, which conclusively linked VHL with HIF-1α.

Although experts had made great strides, there was still a lack of understanding how O2 levels regulate the interaction between VHL and HIF-1α. The search focused on a specific portion of the HIF-1α protein, and both Kaelin and Ratcliffe suspected that key to the detection of O2 resided somewhere in this protein complex.