by Francesco Suman
Correct oxygenation essential for the immune system.
It is the first of the Nobel prizes awarded in 2019 and the announcement arrived on time at 11.30 am. William G. Kaelin Jr, Sir Peter J. Ratcliffe and Gregg L. Semenza were awarded the prize for medicine or physiology for having identified a fundamental mechanism underlying the functioning of all animal cells: the regulation of gene expression at the vary in oxygen levels.
It is a physiological mechanism that has allowed us to colonize the Earth at different altitudes, which allows us to recover from the fatigue of physical exercise and which allows our body to regenerate itself from a wound. The genes discovered by researchers are widespread throughout the animal kingdom and represent one of the most important adaptive responses of life on Earth.
Like a candle’s fire needs it to burn, our cells need oxygen to convert nutrients into energy. The regulation of oxygen is very important for the formation of new blood vessels (angiogenesis), in the development of the placenta, in the metabolic activity of the cell (regulated by the mitochondria) and for many other physiological functions of our immune system.
An incorrect regulation of oxygen in the cells is found in many pathological conditions: patients with kidney failure have anemia problems (ie they have few red blood cells that carry oxygen); tumors grow by using the oxygen they find in the cellular environment; in regenerative processes the cells release factors that allow to draw more oxygen; and again in heart attack and infections.
Kaelin, Ratcliffe and Semenza have identified the molecular mechanism that regulates the response of cells to varying oxygen availability. Their discovery has opened the way to new strategies for the treatment of many diseases and is destined to end up in all the medical textbooks that will be studied by future generations.
Gregg Semenza, a 1956 New Yorker, a professor at Johns Hopkins University in Baltimore, discovered Hre (Hypoxia-response elements), those genes responsible for restoring normal oxygen levels in response to hypoxia (too low oxygen levels).A crucial physiological response to hypoxia is the increase in the concentration of a hormone, erythropoietin (Epo), produced in the kidneys, which stimulates greater production of red blood cells. The Epo level goes up when the oxygen level goes down. The importance of the role of hormones in this process (erythropoiesis) was known since the beginning of the twentieth century, but how oxygen was included was not yet understood.
Parallel to Semenza, Sir Peter Ratcliffe, born in 1954 in Lancashire, UK, professor at the University of Oxford and director of clinical research at the Francis Crick Institute in London, was studying how the expression of erythropoietin genes was regulated by the vary in oxygen. The two groups discovered that some gene sequences located next to the Epo genes were responsible for the response to hypoxia: it was the HRE that promoted the production of Epo when the availability of oxygen decreased. Today we know that there are about 300 of these Hre genes in the human genome and that they are expressed in many tissues.
Semenza also identified Hif (hypoxia-inducible factor), the protein complexes that bind to Hre thanks to the mediation of oxygen. He identified the genes responsible for it and discovered that they were composed of two proteins: Hif-1α and Arnt. Under hypoxic conditions Hif-1α accumulated in the cellular environment, while in the presence of oxygen it was degratated by the proteasomes. Having found the main protagonists, subsequent studies managed to understand how they interact with each other and how the molecular machinery complex is able to regulate the concentration of oxygen in the cell.
William Kaelin, also a New Yorker from 1957, a professor at Harvard Medical School and a researcher in the laboratories of the Dana – Farber Cancer Institute in Boston, was studying von Hippel-Lindau’s genetic syndrome, whose hereditary mutations lead to the development of certain types of cancer . Kaelin discovered that a gene involved in the syndrome (Vhl gene) was responsible for controlling the cellular response to hypoxia. Ratcliffe confirmed that Vhl interacted with Hif-1α and was necessary for proteasominal degradation for the restoration of normal oxygen levels.
Further confirmations of these studies, which began in the early 1990s, came in the 2000s, outlining the complete mechanism that regulates oxygen levels in the cell. Ratcliffe and Kaelin put the last piece when they discovered that a high concentration of oxygen triggered a chemical reaction (the hydroxylation of Hif-1α), necessary for the action of Vhl and subsequent degradation.
The resultant mechanism is an elegant control system: Hif accumulates at low oxygen concentrations and activates a series of genes (Hre) responsible for the response to hypoxia; as the oxygen level increases, Hif is hydroxylated, recognized by Vhl and degraded by proteasomes.
“At Global Health we provide an extensive range of Oxygen Therapy and Ozone to help optimise your wellbeing. Our work is based on this research and the work of other credible scientists, especially medical research by Dr Otto Warburg, a double Nobel Laureate who was nominated 47 times for the Nobel prize“.
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