VHL – BioQuakes

On October 7th, it was announced that the Nobel Prize in Medicine would be awarded jointly to scientists William G. Kaelin Jr., Sir Peter J. Ratcliffe and Gregg L. Semenza for their contributions in the discovery of how cells detect and react to the levels of oxygen in their environments. Each contributor will be receiving 1/3 of the prize share for their work in this topic.

The “Textbook Discovery”

Before we are able to understand the gravity of the discovery being awarded one of the world’s most prestigious scientific prizes, let’s set up some essential vocabulary we will need to break this concept down. Firstly, HIF-1α is the main protein that has been found to be essential to the identification of Oxygen. We have known that there exists an EPO gene which encodes for a steroid known to increase levels of Oxygen but the discovery of the HIF-1α protein is what is so astounding. What this protein does is regulate the activity of the EPO gene. Another factor which plays a large role in this discovery is the VHL gene, a gene known to be responsible for preventing occurrences of cancer. It was discovered that VHL had a link to the regulation of oxygen when low levels of the gene were linked to low level of oxygen (hypoxia). However, as more VHL was reintroduced, oxygen

Visual depiction of how HIF-1α works

levels were restored to normal.

How do HIF-1α proteins, VHL genes and EPO genes come together to create an understanding for how cells react to oxygen variation? Well, for HIF-1α to degrade, a peptide known as ubiquitin must link onto the HIF-1α and begin proteasomal degradation. It just so happens to be that VHL codes for a complex which tags proteins with ubiquitin allowing them to degrade. Finally, it was discovered that Oxygen was what binded theses two together, moving ubiquitin from the VHL over to the HIF-1α protein, thus degrading it. In other words, the more oxygen there is present, the more HIF-1α which gets degraded. Finally, the mechanism by which oxygen levels are controlled has been uncovered.

The Men Behind The Discovery

Over the span of 2 decades of research, three scientists were able to form an understanding on how our bodies respond to one of the most essential molecules in biology.

William G. Kaelin Jr. is a professor of medicine at at Dana-Farber Cancer Institute and Brigham & Women’s Hospital Harvard Medical School. As a cancer researcher, Kaelin’s main contribution was in the creation of a full understanding of the VHL disease which allowed for the link between VHL and HIF-1α to be formed.

Sir Peter J. Ratcliffe is the director of clinical research at the Francis Crick Institute in London. Ratcliffe and his team’s main contribution was establishing the connection between VHL and HIF-1α.

Gregg L. Semenza is a professor in genetic medicine at John Hopkins. His work focused on the EPO gene and how it controlled oxygen levels. He found out how oxygen is regulated, leaving only the cause a mystery.

For even more information on the scientists responsible, look into this New York Times article about them.

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.

An image released by the National Cancer Institute, part of the National Institute of Health, that depicts malignant breast cancer cells (brown stained) metastasizing within the liver.

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?

BioQuakes

AP Biology class blog for discussing current research in Biology

Tag: VHL

And The Nobel Prize in Medicine Goes To…

The “Textbook Discovery”

The Men Behind The Discovery

The Oxygen Sensing Discovery: A Huge Impact on Cancer Research

Archives