Nobel Assembly member, Randall Johnson (R), speaks to announce the winners of the 2019 Nobel Prize in Physiology or Medicine (L-R) Gregg Semenza of the US, Peter Ratcliffe of Britain and William Kaelin of the US, seen on a screen during a press
Dr. William G. Kaelin, Jr., Sir Peter J. Ratcliffe, and Dr. Gregg L. Semenza now have an extra line to add to their resumes or LinkedIn profiles. The Nobel Assembly announced on Monday that these three physician-scientists have been awarded the 2019 Nobel Prize in Physiology or Medicine for helping find ways that your body can sense and adapt to different levels of oxygen:
Winning this Prize will bring each of them a third of a 9 million Swedish kronor or $907,000 cash prize and an amazing retort to anyone else who may brag too much at a cocktail party. Of course, the Nobel Prize isnt their first accomplishment but instead serves as a tribute to three careers that have brought discoveries that may lead to new treatments for anemia and cancer.
Kaelin is currently a Professor at Harvard Medical School and the Dana-Farber Cancer Institute. Born in 1957, he eventually got his M.D. from Duke University, Durham, and trained in internal medicine and oncology at Johns Hopkins University and the Dana-Farber Cancer Institute.
Ratcliffe wasnt a Sir yet when he was born in 1954. After studying medicine at Cambridge University and completing nephrology training at Oxford, he subsequently became the Nuffield Professor of Clinical Medicine at Oxford and the Director of Clinical Research at the Francis Crick Institute in London, Director for Target Discovery Institute at Oxford, a Member of the Ludwig Institute for Cancer Research, and knighted.
Semenza is a Professor of Medicine at Johns Hopkins University and Director of the Vascular Research Program at the Johns Hopkins Institute for Cell Engineering. He was born in 1956, obtained both an MD and a PhD from the University of Pennsylvania and completed residency training in pediatrics at Duke University and a post-doc at Johns Hopkins University.
To understand the importance of their discoveries, its important to understand the how your body needs complex ways to regulate oxygen levels. As you first learn when you try to put a sock over your head (dont try this, by the way), oxygen is pretty fundamental to everything that you do. Without it, the trillions and trillions of cells in your body couldnt survive and function. Each cell uses oxygen to help break down nutrients into energy. Thus, no oxygen, no energy. No energy, no cells, and no you. And no Instagramming and texting.
The trouble is oxygen, like macaroni and cheese and anything else good in life, isnt always present at the levels that you and all your cells would like. Oxygen levels can fluctuate in the air that you breathe and in different parts of your body. The ability of each of your cells to get oxygen can depend heavily on location, location, location, as the old real estate saying goes.
Think of your body as a large and complex metropolitan area with many different neighborhoods. Red blood cells are like little Ubers picking up oxygen at your lungs and then carrying the molecules of oxygen along your blood vessels, which serve as roads to different parts of your body. Just as the roads are different in different parts of the Boston area, the density and networks of blood vessels vary throughout your body. Thus, not every part of your body will always get the same amount of blood and oxygen. These differences can be exacerbated when your blood circulation in general decreases, such as when you are lying on the coach after eating way too much macaroni and cheese, or blood flow in a particular part of your body gets interrupted, such as when you are bleeding or have a blood clot.
Therefore, like a well-run city, your body needs ways of sensing whats going on in each of the neighborhoods and adjusting oxygen levels accordingly. One way of adjusting your bodys oxygen supply in general is by changing your breathing rate. The carotid arteries are the major blood vessels in your neck and the ones that often spurt blood in slasher horror movies. These arteries include structures called carotid bodies that can check the oxygen levels in the passing blood. If oxygen levels are too low, the carotid bodies sends signals through nerves to increase your breathing rate. If the oxygen levels are too high, the carotid bodies will signal to slow your breathing. While this may help the overall amount of oxygen getting into your lungs and blood circulation, it alone cant monitor and adjust the oxygen thats getting to more local levels throughout your body.
Another thing that regulates oxygen levels is EPO, which is pronounced like Emo but with a p instead of an m. EPO is short for erythropoietin, a hormone that can stimulate your body to produce more red blood cells and thus have more Ubers to deliver oxygen. When EPO levels rise, erythropoiesis, a fancy name for red blood cell production, increases. However, before the work of Semenza, Ratcliffe, and Kaelin and their respective teams, it wasnt clear exactly how oxygen levels were able to affect EPO levels.
Here is Dr. Gregg L. Semenza M.D., Ph.D at a press conference at Johns Hopkins Hospital after learning that he had won the Nobel Prize for Medicine. (Photo by John Strohsacker/Getty Images)
In the 1990s, both Semenzas and Ratcliffes teams found that all types of body tissues have the ability to sense oxygen levels, not just the kidney cells that produce EPO. Semenzas team found DNA sequences near the genes that code for EPO and continued to search for ways that the EPO gene is regulated. A HIF, HIF hooray moment came when they found a protein complex, which they named HIF for hypoxia-inducible factor. Hypoxia is a medical term for low oxygen. Thus, when George Costanza said on an episode of Seinfeld, oxygen, I need oxygen, he could have said, I have hypoxia, instead. Thus, hypoxia-induced means something that will be stimulated by low oxygen levels. The team eventually realized that this protein complex actually consists of two different proteins that can bind DNA, which they named HIF-1 and ARNT.
Experiments showed that when oxygen levels are high, cells have very low levels of HIF-1 because the HIF-1 thats produced gets rapidly degraded. However, when oxygen levels dip low, HIF-1, in the words of the Supremes, keeps on hanging on and doesnt degrade as quickly. Therefore, there is more HIF-1 around to stimulate the EPO genes to produce more EPO.
The difference seemed to be ubiquitin. Ubiqutin can bind to HIF-1 and mark it to go bye bye, which is what host of the game show The Weakest Link says to contestants before they must exit. In this way, ubiquitin serves as a label to say, please get rid of this.
But it still wasnt yet clear how lower oxygen levels could keep ubiquitin from binding to HIF-1. This is when Kaelins team entered the mix. They had been studying something seemingly unrelated, von Hippel-Lindaus disease, which is often abbreviated VHL disease. This is a condition that is inherited and includes mutations in the VHL gene. They observed that normally the VHL gene codes for proteins that seem to prevent certain cancers from developing. In VHL disease, mutations prevent this gene from working properly, allowing a number of different cancers to emerge.
William G Kaelin Jr., MD, speaks at the Dana Farber Cancer Institute on October 7, 2019 in Boston, Massachusetts. (Photo by Scott Eisen/Getty Images)
Here is an example of how starting on one path doesnt necessarily lead you to where you thought you would go and how the most interesting things in life can be unexpected. Kaelins team eventually realized that such cells with mutations in the VHL gene also expressed abnormally high levels of hypoxia-regulated genes, which made them wonder whether VHL played a role in regulating the response to low oxygen levels. This wasnt totally surprising since cancer cells also need oxygen to survive, and such cells cant always get the same access to blood and oxygen when they sit deep in the middle of tumors.
Indeed, additional work showed that the VHL genes produce proteins that then help connect ubiquitin to HIF-1 and thus label HIF-1 for destruction. In essence, VHL is like a warehouse inventory manager using ubiquitin as a label for get rid of this. But the scientists were still left with the question, how do oxygen levels influence whether VHL labels HIF-1 with ubiquitin?
The mystery step turned out to be prolyl hydroxylation. What-yl what-xylation? This is a process by which enzymes (calledprolyl hydroxylases) add hydroxyl groups to two parts of the HIF-1 protein. A hydroxyl group is a combination of an oxygen atom (designated by O) and hydrogen atom (designated by H) and symbolized by -OH. This process is necessary for the HIF-1 protein to be labeled and destroyed. Think of it as OH, lets get rid of this. When oxygen levels are lower, many HIF-1 proteins may not get this OH thus preventing the VHL-ubiquitin labeling process from occurring. The work of Kaelin, Semenz, and their teams thus found the final piece of the puzzle and said OH, thats how it works.
You can see how prolyl hydroxylases could play major roles in the treatment of anemia (which occurs when your red blood cell counts are low) and various cancers with their ability to ultimately regulate red blood cell production and oxygen delivery. Again, cancer cells need oxygen to survive. Starve them of oxygen and you may have a way of killing them.
It didnt seem like this trio of investigators started their independent scientific careers with the intent of all of this happening. While science needs some direction, you cant just go into a lab and start mixing things together, the best science often emerges from exploration and being curious and open to different possibilities. Semenza, Ratcliffe, and Kaelin clearly had the minds and abilities to do such science but they also had the time and resources to do so. Like body tissues do for varying oxygen levels, science and scientists need to have the ability and opportunity to adapt to what they may find. This may not occur as often these days when research funding is more limited and people and institutions are pushing for immediate returns on work. For the eventual benefit of humankind, scientists need to be able to say, OH, lets try this, and then find OH, what do we have here?
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