Oxygen Sensing Cell Mechanism wins the 2019 Nobel Prize in Physiology or Medicine.

Oxygen Sensing Cell Mechanism wins the 2019 Nobel Prize in Physiology or Medicine.

Couple of years ago the whole of India witnessed what was called as the ‘Siachen Miracle'. Lance Naik Hanumanthappa Koppad, aged 32, an Indian brave heart Soldier,(one of those 9 Indian soldiers on duty in the treacherous Siachen Glaciers who were struck by a sudden snow avalanche) had defied certain death and survived for all of six days, buried under snow, until succumbing later to multi organ failure, pneumonia and blood clotting at the Army Hospital in Delhi, where he was airlifted from Siachen. It is generally believed by experts that nearly 90% of completely buried avalanche victims can be revived if and only if they are recovered within 15 minutes. The chances of survival beyond a day are almost non existent. But then was it a miracle that Hanumanthappa could survive for six days under the wall of snow? Perhaps not. The science underpinning the so called miracle of Hanumanthappa’s survival, can now be explained in the works of this year’s Noble laureates in Physiology or Medicine, who have been awarded this year’s Nobel prize for their work on 'how cells adapt to oxygen availability’. The significance of their work can best be seen in the statement of Venki Ramakrishnan, President of Britain’s Royal Society, who said ‘Oxygen is the vital ingredient for the survival of every cell in our bodies. Too little – or too much – can spell disaster. Understanding how evolution has equipped cells to detect and respond to fluctuating oxygen levels helps answer fundamental questions,”. He added, “This work.. also gives insights into the way these processes continue to shape our health and wellbeing.”

The three physician researchers; William G Kaelin, Sir Peter Ratcliffe and Gregg L Semenza have been jointly awarded this year’s Noble prize in Physiology or Medicine for their research on Hypoxia. The three of them - physicians as well as scientists - share an astounding prize money of 9 Million Swedish Krone (7.41 Crore ₹). One third of the prize money goes to William Kaelin, a Howard Hughes investigator at the Dana-Farber Cancer Institute at Harvard. One third to Gregg Semenza, who is at the Johns Hopkins University. And the third part of the prize money goes to Sir Peter Ratcliffe, who is with the Oxford University. Their combined research work has established the basis for understanding of how oxygen levels are sensed by cells, a discovery that is being explored by medical researchers seeking to develop treatments for various diseases that work by either activating or blocking the body's oxygen-sensing machinery. Their work centres on the hypoxic response - the way the body reacts to oxygen flux - and reveals the elegant mechanisms by which our cells sense oxygen levels and respond. The statement of the Nobel prize announcing committee says “The seminal discoveries by this year’s Nobel Laureates revealed the mechanism for one of life’s most essential adaptive processes. They established the basis for our understanding of how oxygen levels affect cellular metabolism and physiological function. Their discoveries have also paved the way for promising new strategies to fight anaemia, cancer and many other diseases.”

Oxygen is inextricably linked to life on planet Earth and it is used by the mitochondria, present virtually in all animal cells, to convert food into useful energy. The Oxygen we inhale, through our lungs, crosses over into tiny blood vessels, where it piggybacks on the hemoglobin protein - that are present in red blood cells- to serve as the life delivering services in human system. The Red blood cells (RBC) transport oxygen to each tissue where the cells let in just enough oxygen to carry out a precise amount of work. However the body has to adjust its requirements of oxygen to different atmospheric conditions of the planet and in different situations. How and what cell mechanism is used to sense the precise requirements of oxygen in different conditions had remained a mystery until the works of this year’s Nobel laureates made head way in unravelling it. Moreover there aren’t consistent levels of oxygen available everywhere on this planet. For example the higher the altitude we travel (Siachen or the Himalayas), the thinner the air, and less the presence of oxygen and this condition is called hypoxia. Our cells need to make more or less energy depending on the place where we are or whether we are active or sedentary and accordingly we need more or less oxygen. This year’s Nobel laureates have conducted years of research that helps explain how cells sense oxygen levels, and how they adapt to higher or lower amounts of the molecules in the atmosphere. When the body detects that less oxygen is present, the kidneys release a hormone called erythropoietin, or EPO, which tells the body to make more red blood cells to carry more oxygen around (erythropoiesis).The importance of hormonal control of erythropoiesis was already known at the beginning of the 20th century, but how this process was itself controlled by Oxygen had remained a elusive.

Decades of work from Semenza and Ratcliffe identified how this system works in more detail. They found that a protein called hypoxia-inducible factor, or HIF, rises when there is less oxygen around. HIF then bonds to sections of DNA near the gene that produces EPO. Extra HIF protein around the EPO gene acts like a turbo charge for the hormone’s production, which is how the body knows to make more RBC. When there’s sufficient oxygen available, HIF levels drop, as do RBC counts. These were important findings that showed the mechanism was general and functional in many different cell types.

It was around this time that William Kaelin, Jr. a cancer physician was researching on an inherited syndrome, von Hippel-Lindau's disease (VHL disease). This genetic disease leads to dramatically increased risk of certain cancers in families with inherited VHL mutations. Kaelin showed that the VHL gene encodes a protein that prevents the onset of cancer. Kaelin also showed that cancer cells lacking a functional VHL gene express abnormally high levels of hypoxia-regulated genes; but that when the VHL gene was reintroduced into cancer cells, normal levels were restored. This was an important clue showing that VHL was somehow involved in controlling responses to hypoxia. Additional clues came from several research groups showing that VHL is part of a complex that labels proteins with ubiquitin, marking them for degradation in the proteasome. Ratcliffe and his research group then made a key discovery: demonstrating that VHL can physically interact with HIF-1alpha and is required for its degradation at normal oxygen levels. This conclusively linked VHL to HIF-1alpha.

The discovery of a molecular switch that regulates how cells adapt to fluctuating oxygen levels have opened up new approaches to treating heart failure, anaemia and cancer. Now that the scientists know and have understood how the body regulates oxygen uptake, they can now develop new therapies for individuals for whom that process has gone wrong and help in saving millions of lives.

Long live oxygen the life sustainer on Earth.