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Nobel Prize in Medicine 2019: How cells manage oxygen

This year’s Nobel Prize for Medicine/Physiology went jointly to Drs. Gregg Semenza, William G. Kaelin, and Sir Peter Ratcliffe.

Source: The Nobel Assembly at Karolinska Insitutet

They won this prestigious award for their pioneering research into the human bodies’ response to varying oxygen levels, particularly the lack of oxygen called Hypoxia.

The human body can quickly respond and adapt to changing oxygen levels. Oxygen-sensing molecular mechanisms within the cells help the body adapt to variations in oxygen in the air we breathe in. Lack of oxygen, Hypoxia, triggers signaling mechanisms in our body, enabling the increase of oxygen uptake and metabolic adaptation.

Let’s look at how the body senses the lack of oxygen and how it reacts to Hypoxia.

The human body needs a stable level of blood oxygen levels to keep functioning. Low blood oxygen levels caused by Hypoxia are called hypoxemia.

Some of the most common causes of hypoxemia are:

  • cardiovascular diseases,
  • asthma, lung disease such as chronic bronchitis, emphysema, smoking,
  • high altitudes,
  • sleep apnea.

Hypoxemia causes wheezing, headache, fast heartbeat, rapid and shallow breathing, and cognitive impacts such as confusion, disorientation, and loss of balance, to list a few.

Oxygen plays a very critical role in the metabolism of most animals and is required for the generation of ATP, the universal source of energy in humans, and the majority of animals. Therefore, organisms that depend on a steady level of oxygen, particularly the brain, are susceptible to changes in ambient oxygen levels called normoxia. Variations from normoxia, particularly chronic hypoxemia, offers a serious challenge to any oxygen-dependent life form and must be compensated.

How does the body sense change in ambient oxygen levels?

Hypoxemia is first sensed by the so-called chemoreceptors in our body. It is thought that the carotid body, a small sensor located in our carotid artery that supplies blood into our brain, is the primary sensor. The vertebrate skin is also discussed as another oxygen sensor that detects Hypoxia.

Upon detecting Hypoxemia, the body very quickly responds and activates mechanisms to compensate for the lack of oxygen.

The primary response to Hypoxemia in humans and most animals is the increased synthesis of erythropoietin (EPO), a factor that increases the red blood cell count in blood and increases the uptake of oxygen from the air into our bodies.

The therapeutic use of EPO is very efficient in increasing blood oxygenation. 

Therefore, increased numbers of red blood cells through elevated production of EPO is the immediate systemic answer of our body to hypoxia. However, in addition to this systemic response, individual cells developed their coping mechanisms with hypoxia.

How do cells sense hypoxemia?

Cells sense the lack of oxygen through two different mechanisms.

1.    Increased level of EPO:

Kidney and liver cells produce EPO and secrete it into the blood. EPO interacts with cells through its specific receptor, the EPO-Receptor (EPO-R), that is found on most cell membranes, including neurons, as I described in my earlier work.  

EPO binding to EPO-R induces cellular mechanisms in the cell to compensate for the lack of oxygen.

In bone marrow cells, this interaction stimulates the generation of new red blood cells, which increases the oxygen-carrying capacity of the blood and restores normal blood oxygen levels in hypoxia. 

Image by Cleveland Clinic Journal of Medicine. 2016 August;83(8):613-624

However, EPO has multiple effects that are not limited to the production of new red blood cells under hypoxic conditions.

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The Nobel Laureates, particularly Dr. Semenza, pioneered the research by investigating this cellular oxygen sensing mechanisms and its regulation.

Here is where that the Nobel Laureates discovered come into play.

2.    Cellular Hypoxemia sensors:

A critical factor in the cellular response to hypoxemia is the Hypoxia Inducible Factor 1 (or HIF1). In his publication from 2000, Dr. Semenza describes the role of HIF1 in hypoxia as an “essential mediator of O2 [oxygen] homeostasis [balance]”.

The two forms of HIF1, the HIF1 alpha and HIF1 beta, activate our genes and the production of proteins, such as EPO, in response to hypoxemia.

At normal ambient oxygen levels or Normoxia, a cellular factor called VHL quickly tags HIF1 alpha for removal and destruction through proteasome degradation (see figure below).

Image source: https://www.mdpi.com/1422-0067/15/6/10296/htm

However, in Hypoxia, HIF1 alpha is stabilized and not degraded. It partners up with its cousin HIF1 beta, and both travel into the nucleus, where the DNA for our genes is located. Here, both attach to an element called Hypoxia Responsible Element (HRE) and activate the genes to produce new proteins to counteract hypoxia (see figure above)

As mentioned above, EPO is one of the main targets for HIF1 response to hypoxia.

However, in recent years, scientists found many other activities of HIF1.

Increased EPO production by HIF1 not only normalizes the oxygen levels in the blood but prevents the degeneration and death of brain and cardiac cells suffering from hypoxia.

For a long time, EPO was thought to be only involved in hypoxia response and solely produced by the kidneys and the liver.

However, research done by me and others showed that HIF1 and EPO system is present in the brain and has functions other than hypoxia response. Among others, EPO plays a role in protecting specific brain cells, the neurons, from stroke-induced death. EPO and its synthetic variants are neuroprotectants against various insults to brain cells.

The HIF1-EPO system is beneficial in healthy cells and has enormous therapeutic benefits when used by licensed physicians for the proper indications.

Unfortunately, as potent cell protectors, this system also protects tumor cells from hypoxia. Most tumor cells live under hypoxic conditions due to a lack of blood flow and their sheer mass. Healthy cells would die under the hypoxia that tumor cells are exposed but not cancerous cells. 

As in healthy cells, hypoxia in tumors activates the HIF1-EPO system that prevents the death of tumor cells from lack of oxygen.

Abuse of EPO

In recent years, EPO was also used to artificially increase the red blood cell count in athletes, the so called blood doping, and illegally misused for doping purposes.

In addition, some “biohackers” promote or give guidelines to “self-hacking” using EPO.

EPO is a prescription medicine, and its use without prescription for doping and self-hacking purposes is illegal. In addition, unqualified use of EPO for self-hacking or doping, and most of the “biohackers” do not have medical licenses, is very dangerous and can result in death.

Uncontrolled and unqualified administration of EPO can increase the red blood cell count beyond tolerable and physiological levels and, through thickening it, turn your blood literally into jelly. The misuse of EPO can lead to heart diseases, stroke, cerebral and pulmonary embolism and to irreversible autoimmune diseases with serious lifelong consequences.  

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