Three researchers bagged the Nobel Prize in Medicine 2019 for their study on how the body senses and copes with varying oxygen levels.
In this article:
- The Winners
- What Are the Studies About?
- The Hypoxia-Inducible Factor (HIF)
- Enter the VHL Gene
- What Does It Mean for Health?
- Nobel Prize for Medicine 2019 Is a Big Step
Nobel Prize in Medicine 2019 Goes to Three Scientists and Oxygen
The lives of three scientists changed forever after they won the Nobel Prize in Medicine 2019:
- Sir Peter J. Ratcliffe from the Francis Crick Institute and the University of Oxford
- William G. Kaelin Jr. from Johns Hopkins University and Dana-Farber Cancer Institute
- Gregg L. Semenza, Ph.D., from Johns Hopkins Institute for Cell Engineering
All of them are independent researchers whose works are now helping other scientists understand the oxygen-sensing mechanisms of the body.
What Are the Studies About?
You can get a better idea of their discoveries in this Nobel Prize press release. The content, however, is technical.
Here are the critical points:
- The essence of oxygen and definition of hypoxia
- Changes in the body during hypoxia
- Hypoxia-inducible factor (HIF)
- VHL gene
- Hydroxyl groups
Why is oxygen so vital? Oxygen comprises a significant percentage of the world’s atmosphere for a good reason: virtually all living things need it.
Every cell in the body needs oxygen to create fuel or energy in the mitochondrion. Your brain requires it to work as an efficient command center.
The oxygen levels in the body, though, fluctuate. For example, when you are at high altitudes, oxygen is scarce.
It may also drop on wound-healing sites, and your brain may not receive it when you suffer from a stroke.
Fortunately, the body possesses oxygen-sensing mechanisms. In other words, it tries to cope or adapt to the changing levels.
One of the well-known systems is the carotid artery. When the blood that travels through the brain contains lower levels of oxygen, the body sends a signal, increasing your metabolic rate.
Other research also found that hypoxia correlates to increased production of a hormone known as erythropoietin (EPO).
Produced by the kidneys, this stimulates the creation of red blood cells. These are the ones that deliver oxygen to various tissues.
What the scientists didn’t know is how oxygen regulates EPO. Both Semenza and Ratcliffe found the answer.
The Hypoxia-Inducible Factor (HIF)
Both of the researchers studied the EPO gene and oxygen regulation. Semenza mainly worked with mice, where he discovered that DNA segments close to the EPO gene are sensitive or responsive to oxygen.
They also learned that while the kidneys produce EPO, they’re not the only organ that has sensing abilities. Most of the tissues of the body have one.
It was the discovery of hypoxia-inducible factor (HIF); however, that served as a turning point.
HIF is a transcription factor, which binds itself to the DNA segments that then regulate the EPO gene expression. This factor has two proteins: HIF-1α and ARNT.
Of the two, HIF-1α is more reactive to oxygen. It degrades because of the proteasome, which functions like an incinerator.
However, when oxygen is low, the protein level is high. It eventually associates with ARNT. Together, they bind to the DNA sequence of genes that regulate hypoxia.
The body also uses a peptide called ubiquitin, which serves as a tag for HIF-1α protein. It determines which should degrade.
The scientists didn’t understand how it happens and the role oxygen played in it.
Enter the VHL Gene
In another lab, cancer researcher Kaelin was busy learning about a genetic condition called von Hippel Lindau syndrome or VHL disease. Those who carry the gene mutation are at a higher risk for certain cancers.
He and his team learned that, under normal conditions, the VHL gene could prevent cancer by encoding a particular protein. The aha moment came when they discovered that the same protein connects ubiquitin to HIF.
That’s not all. In a process called prolyl hydroxylation, oxygen adds hydroxyl groups to hypoxia-inducible factor. They guide the VHL protein when tagging HIF for degradation.
In summary, it goes like this:
- Oxygen levels drop, and to compensate the kidneys produce EPO.
- The HIF regulates the EPO gene that expresses the hormone.
- One of the HIF proteins, HIF-1α, increases or decreases depending on the oxygen levels. If the levels are normal, then it degrades rapidly.
- Proteasome leads to the degradation of HIF-1α. To do that, it needs ubiquitin, a peptide, to determine which protein it should destroy.
- The VHL gene attaches ubiquitin to HIF, while the hydroxyl groups that oxygen introduce guides the VHL gene when tagging HIF proteins to degrade.
What Does It Mean for Health?
One of the primary reasons why they deserve the Nobel Prize in Medicine 2019 is the impact their work has on healthcare, particularly therapies.
Their studies can be the foundations for the creation of drugs and treatments on the following diseases:
- Heart disease
- Kidney disease or renal failure
What is anemia? It is a condition wherein the body produces fewer red blood cells to deliver oxygen.
Take, for example, cancer. Tumor or cancer cells also need nutrients and oxygen to generate; even hijack the same sensing system to build new blood vessels.
But since they multiply rapidly, even the blood vessels they create won’t be enough to sustain them. They can then learn to thrive in low-oxygen environments.
Tumors that grow in these environments tend to be more resistant to chemotherapy, leading to a poorer prognosis.
Companies and research labs can now develop therapies, particularly medications, that will help regulate these oxygen-sensing mechanisms.
One of these drugs is Roxadustat from China. It is an oral inhibitor for prolyl hydroxylase.
The manufacturers intend to give this to patients with chronic kidney disease and anemia. These diseases often go together due to the organ’s failure to produce erythropoietin.
The phase 3 trial results had been positive.
The medication increased the levels of EPO within or close to the normal range. Levels of hemoglobin, a protein molecule that carries oxygen, also went up.
Nobel Prize for Medicine 2019 Is a Big Step
These three scientists worked for more than 15 years before they received the much-coveted award. These were fruitful decades, however.
The medications and therapies that could end dreaded diseases from anemia to cancer may still be years into the future. What these researchers did was shorten the gap and personalize treatment plans.
Most of all, they now serve as inspiration for others toiling tirelessly in labs and hospitals, hoping to experience their eureka moment.
“I’d like to point out our story is one of trying to generate knowledge and to understand how things work, and if you go deep enough and you understand things well enough occasionally the opportunities for translation will arise,” Kaelin said on CNN.
What do you think about the Nobel Prize for Medicine in 2019? Share your thoughts in the comments section below.