Courtesy- Image by Florian Pircher from Pixabay 

Written By  – Jatin Kumar (Biotech Communicator)

Oxygen is essential for the majority of living organisms on earth, for the conversion of food into useful energy. But have you ever thought how cells adapt to changes in oxygen levels? It has long be unknown until William G. Kaelin Jr., Sir Peter J. Ratcliffe and Gregg L. Semenza independently identified the molecular machinery that regulates the activity of genes in response to variation in oxygen  levels. Oxygen in atmosphere is utilized by the mitochondria of majority of the animal cells in order to convert food into useful energy i.e. ATP by the oxidation reaction.

In case of humans, it has been seen that as one goes at the high altitudes the oxygen levels in the blood decreases, this is because at the high altitudes the air becomes thin and the oxygen in the air also decreases. Now when the oxygen level in the blood decreases, this decrease in oxygen is sensed by the specialized cells in the kidneys that makes erythropoietin. This in turn increases the synthesis of RBCs in the bone marrow. The increase in the number of RBCs helps to cope up with the decrease level of oxygen in the atmosphere. Now here comes a very important question, how does the cell know that the levels of oxygen have increased or decreased? To answer this question, the researchers exposed animal cells through various levels of oxygen concentration and they found the expression of many genes changes when the oxygen level changes.

Highlights: 

  • William “Bill” G. Kaelin Jr. -A professor of medicine(Harvard University & Dana–Farber Cancer Institute).

  • Sir Peter John Ratcliffe, FRS, FMedSci (British physician-scientist).

  • Gregg Leonard Semenza, MD, PhD is a professor of pediatrics, radiation oncology, biological chemistry, medicine, and oncology(Johns Hopkins University School of Medicine).

Genes on the DNA has all the information about which proteins are to be made by the cells, transcription is a process in which the information in the DNA is passed to RNA which is further used to make proteins and the transcription of genes in eukaryotes is controlled by the proteins known as the transcription factor and the cells can have many such transcription factors to control the expression of genes. Transcription factors switch on or switch off the genes when required. In short, they make sure that the genes are expressed at the right time, in right cell and in the required amount. 

Now to solve the mystery, how cells know the levels of oxygen have increased or decreased, the Nobel laureates started searching the transcription factor that regulates the expression of erythropoietin at low levels of oxygen, and discovered a transcription factor called HIF (Hypoxia inducible factor). This transcription factor has a role in increasing the expression of EPO gene which makes erythropoietin. Further experiment suggested that when oxygen levels are high, the alpha subunit of HIF gets hydroxylated. This hydroxylation occurs on the proline residues in the alpha subunit. The alpha hydroxylated subunit is recognised by the protein VHL(von Hippel-Lindau) , which finally causes proteasomal degradation. This research is a major breakthrough for the treatment of diseases like cancer, because the Oxygen-regulated machinery stimulates the blood vessel formation and alters the metabolism for effective proliferation of cancer cells. Further research is required to develop new drugs that can inhibit or activate such oxygen-regulated machinery to treat the anaemia, cancer and other diseases.

 References:

The Nobel Prize in Physiology or Medicine 2019

https://www.nobelprize.org/prizes/medicine/2019/press-release/