On October 7, 2019, three scientists- William G. Kaelin, Gregg L. Semenza, and Peter J. Ratcliffe- won the 2019 Nobel Peace Prize in Physiology or Medicine for their groundbreaking discovery in the 1990’s of how cells detect and respond to the presence of oxygen. That may not seem very significant-even Ratcliffe’s colleague’s dimissed his facination with how organs respond to oxygen availability-but the applications are profound. In fact, the Nobel prize was not awarded until recently for this very reason: to evaluate the “when the full impact of the discovery has become evident” (Ralf Pettersson, a former Nobel Selection comittee chairman). Well, their research has provided an possible explaination for the rapid metastasis for which cancer cells are notorious.
According to Ratcliffe’s research, cells produce a complex of proteins called the hypoxia-inducible factor, HIF, that help increase the level of oxygen when cells are oxygen deficient. The HIF turns on genes necessary for the production of the hormone erythropoietin, EPO. In turn, the EPO protein hormone signals for red blood cells to be produced in the bone marrow. Through oxygen-carrying hemoglobin, the red blood cells carry more oxygen to tissues and cells. For example, when the body undergoes hypoxia in response to lack of oxygen, like when people occupy high altitudes, HIF turns on production of EPO.
However, when the oxygen levels are sufficient in the cell, proteins called ubiquitin will bind to the HIF and induce it’s destruction. In this way, cells sense when oxygen levels are low or high and can respond accordingly by regulating the presence of HIF.
That’s pretty cool right? It gets better.
Through the individual work of Semenza and Kaelin, cancer cells were discovered to sense oxygen levels by manipulating VHL. While conducting their separate research, both Semenza and Kaelin hypothesized that cancer cells were searching for oxygen when they spread. Kaelin, as a cancer biologist, took specific interest in von Hippel-Lindau disease, a rare hereditary disease in which either malign or benign tumors form in mostly in the nervous system, pancreas, adrenal glands, and kidneys. The VHL protein, which the VHL gene codes for, in humans helps prevents tumor formation by recognition of the indicator hydroxyl groups placed on HIF by enzymes when the oxygen level are normal. In this case, VHL knows to destroy HIF. On the other hand, if the oxygen levels are low, the HIF lack the hydroxyl groups and are ignored by VHL. During research, he discovered that in these type of cancers, the VHL genes are mutated so that VHL becomes inactive. As a result, it can no longer regulate the quantity of HIF proteins thus, the HIF level increases. Increased HIF levels mean more oxygen for cancer cell, which multiply rapidly because of their now readily available supply of oxygen. This knowledge is vital since Harvard cell biologist Andrew Murray say that “tumors can grow to only about 1 millimeter across without making new blood vessels, because oxygen can diffuse only about half a millimeter away from a capillary before cells consume it”.
The trio’s research is fascinating to me, because this knowledge could be revolutionary in preventing the development and spread of cancer cells. What other biological issue do you think that the discovery of oxygen sensing could solve?