The 2019 Nobel prize for medicine was awarded for discovering how body's cell sense and react to the oxygen levels. This work has paved the way to fight against the disease like anemia, cancer, and other diseases.
This year’s winners: William G. Kaelin, Jr., MD, Gregg L. Semenza, MD, PhD, and Peter J. Ratcliffe, MD, FRS, FMedsci. Won for their work with mice.
Two of them are American and one is the British scientist.
Every year Nobel-winning animal research happens, 180 used animal models in their research. For instance, a German scientist won the first prize in 1901 for developing the diphtheria vaccine through research with the horse.
Afterward, ever year Nobel prizes were awarded for major discoveries most of the research involving animals.
The research
How cells sense and adapt to oxygen availability?
In almost all animal cells, the ability to rapidly respond and adapt to variations in oxygen availability is essential.
It is clear from studies of molecular taxonomy that during evolution, as animal cells began organizing themselves into multicellular three-dimensional structure, this response to oxygen flux became more than a cell-autonomous reaction allowing metabolic adaptions within individual cells.
It also allowed the development of complex physiological responses, cells need to adapt in many autonomous ways to variations in oxygen levels, in particular by adjusting their metabolic rates.
When they examine this response at the level of tissues and organs, it was found that multi-cellular organisms need to both remodel tissues to adapt to altered oxygen levels – (for example, by reconstructing vasculature following injury) and adapt the whole organism to compensate for changes in oxygenation (e.g., the increased ventilatory responses seen during exercise, or at exposure to high altitude.)
As an example: in humans at high altitudes, variations in oxygen levels in the blood are sensed by specialized cells in our kidneys that make and release the hormone erythropoietin (EPO). This hormone activates red blood cell synthesis (erythropoiesis) in the bone marrow.
One way of triggering this reaction is to be exposed to the low oxygen levels of high altitude: living at high altitudes boosts EPO production by the kidney, leading to increased concentration of erythrocytes on our blood, which in turn helps us adapt to lower oxygen partial pressures.
What about animal exposure to a low oxygen environment?
Animals can be exposed to oxygen environments, but importantly oxygen levels vary in tissues as well.
Tissue oxygen levels in animals vary both spatially and temporally; and this variation occurs during normal physiological events (drops in available oxygen in skeletal muscle during exertion for example) as well as in pathological processes such as cancer and infection.
It became clear from research in the 1970s and 1980’s that these local and transient variations in oxygen partial pressure regulate critical adaptive responses in both cells and tissues through changes in gene transcription.
These gene regulatory responses alter cellular metabolism and control fundamental development, regenerative and defense processes, including those as diverse as angiogenesis inflammation, and development.
This ability of animal cells to sense the different concentration of oxygen, and, as a result, re-wire their gene expression patterns, is essential for the survival of virtually all animals. The oxygen activated signaling pathways that are controlled by these pathways affect at least 300 genes belonging to a wide variety of regulatory networks.
These molecular pathways pervade numerous physiological processes, ranging from organ development and metabolic homeostasis to tissue regeneration and immunity, and play important roles in many diseases, including cancer.
Oxygen and erythropoietin response
Any signaling pathway of profound importance to animal life all almost certainly turn out to involve numerous layers of fine-tuning and points of intersection with other molecular pathways. The oxygen response pathway is no exception. As expected, therefore, the molecular details of oxygen response regulation did not stop unfolding once the discoveries now awarded with the 2019 Noble prize had been made.
On the contrary, these key discoveries opened the field and led to an explosion of work that has uncovered an immense molecular complexity to the response to oxygen flux.
Oxygen at Centerstage
Oxygen, with the formula O2, makes up about one-fifth of Earth’s atmosphere. Oxygen is essential for animal life: it is used by the mitochondria present in virtually all animal cells in order to convert food into useful energy. Otto Warburg, the recipient of the 1931 Noble Prize in Physiology or Medicine, revealed that this conversion is an enzymatic process.
Rapid adaption to low oxygen level (hypoxia)
In addition to the carotid body-controlled rapid adaption to low oxygen levels (hypoxia), there are other fundamental physiological adaptions. As a key physiological response to hypoxia is the rise in levels of the hormone erythropoietin (EPO), which leads to increased production of red blood cells (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 O2 remained a mystery.
Gregg Semenza studies the EPO gene and how it is regulated by varying oxygen levels. By using gene-modified mice, specific segments located next to the EPO gene were shown to mediate the response to hypoxia.
Sir peter Radcliffe also studies O2-dependent regulation of the EPO gene, and both research groups found the oxygen sensing mechanism was present in virtually all tissues, not only in the kidney cells where EPO is normally produced. These were important findings showing that the mechanism was general and functional in many different cell types.
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