“How Cells Sense and Adapt to Oxygen Availability”, 

DISCOVERY THAT GIVES THE 2019 NOBEL PRIZE IN                                             PHYSIOLOGY / MEDICINE

Dr Surjit Singh Bhatti, (Retd) Professor & Head, Physics, and Dean ( Sciences), Guru Nanak Dev University, Amritsar.

 Alfred Nobel developed deep interest in Physiology/Medical Science after he came in contact with a Swedish physiologist, Jons Johansson. Later, Jons worked in Nobel’s laboratory in France. The Nobel Prize in Physiology / Medicine is being awarded by the Nobel Assembly at the Karolinska Institute, Stockholm, Sweden, since 1901. This year the Nobel Prize in Physiology/Medicine has been awarded jointly to Dr William    G.Kaelin Jr,  Sir Peter J. Ratcliffe and Dr Gregg L. Semenza.

“for their discoveries of how cells sense and adapt to  oxygen availability.”

These three scientists have discovered how the essential adaptive processes work and explain how oxygen levels influence cell metabolism and regulate gene activity. These insights will help in treating diseases like cancer, anemia,   stroke and myocardial infarction.

Dr William G. Kaelin, Jr., born in 1957 in New York, earned M.D. from Duke University, with specialization in internal medicine and oncology. He became Professor at the Harvard Medical School in 2002. He is at the Howard Hughes Medical Institute since 1998.

Dr Sir Peter J. Ratcliffe, born in 1954 in UK, studied medicine at Cambridge University. He became Professor in 1996 at Oxford University. He is the Director of Francis Crick Institute, London and Member of the Ludwig Institute for Cancer Research.

Dr Gregg L. Semenza, born in 1956 in New York, received MD/ PhD from University of Pennsylvania in 1984. He is a specialist in pediatrics and had training at the Johns Hopkins University where he became Professor in 1999.  He is Director of Research at the Johns Hopkins  Institute for Cell Engineering since 2003.

Basics of the Role of Oxygen

Living cells undergo shifts in gene expression with changes in  oxygen levels around them. The changes alter cell metabolism, tissue remodeling and organism’s responses such as increases  in heart rate and ventilation. An important response to hypoxia (low levels of oxygen) is the rise in the level of the hormone, erythropoietin (EPO), which leads to increased Red Blood Cell (RBC) production (erythropoiesis). How this process is controlled, by oxygen availability, remained a mystery.

Hypoxia Inducible Factor

Gregg Semenza identified a factor which regulates the oxygen-dependent responses. He named it : Hypoxia Inducible Factor (HIF). It consists of an oxygen-sensitive part and a non-oxygen-regulated protein. William Kaelin, Jr., showed that it suppresses growth in mutant tumorigenic cells. Kaelin and Ratcliffe groups simultaneously confirmed that their regulation and the gene expression change with oxygen availability through HIF action.  

Adaptation due to Oxygen Sensing

Oxygen-sensing  leads to metabolic changes within individual cells. In tissues and organs, multi-cellular organisms remodel to adapt to altered oxygen levels and adapt the whole organism to compensate for changes in oxygen levels. For example, at high altitude, oxygen levels in the blood are sensed by some cells in kidneys that make and release the hormones that activate RBC synthesis in the bone marrow.  Variations in partial pressure of oxygen regulate critical adaptive responses in both cells and tissues through changes in genes. This alters regenerative and defense processes, including angiogenesis (formation of new blood vessels), inflammation and development.

Relation of Hypoxia with Genes

HIF underlines the ability of animal cells to sense different concentrations of oxygen and re-wire their gene expression patterns. It  is essential for the survival of  all animals.  The oxygen-activated signaling pathways affect at least 300 genes and the points of intersection with other molecular pathways, including oxygen response pathways. These discoveries revolve around the role of HIF and determination of the actual DNA sequence of the genes associated with the oxygen sensitivity.  Semenza studied the genes in transgenic mice, using different clones. He demonstrated changes in  RBC counts and, in addition, generation of new blood vessels. These are  essential during fetal development for controlling normal blood vessel formation and placenta development.

Results of Oxygen-sensing

 Oxygen-sensing allows  cells to adapt their metabolism to low oxygen levels; as in our muscles during exercise. Patients with chronic renal failure often suffer from severe anemia due to decreased EPO expression. The hormone EPO is produced by cells in the kidney and is essential for controlling the formation of RBC. In tumors, the oxygen-regulation is utilized to  stimulate blood vessel formation and reshape metabolism for effective control of cancer cells. Efforts are now being made to develop drugs that can interact with different disease states by either activating or blockage of oxygen-sensing. This is important in our metabolism, immune response and ability to adapt to exercise. The pathological processes are also affected. These include infections and wound healing in addition to some chronic diseases.