Nobel Prize in Biomedical 2019 for studying cell response when oxygen changes

The Nobel Committee on October 7 announced that the 2019 Biomedical Prize belonged to a group of three authors: William G. Kaelin Jr, Sir Peter J. Ratcliffe and Gregg L. Semenza.

The Nobel Prize for Medicine in 2019 was awarded to scientists William G. Kaelin, Peter Ratcliffe and Greff Semenza for "the findings on how cells sense and adapt to the presence of oxygen".

The Nobel Committee says that while it has long been known that oxygen is essential for life, the molecular mechanism behind the way cells respond when oxygen supply decreases or increases is still a mystery. And the scientists who won this year's prize are the ones who can explain that mechanism.

"These foundational findings help us broaden our understanding of how our bodies adapt to change. The applications of these findings have begun to change the way we treat medical treatments," says Randall. Johnson, a member of the Nobel Committee, commented on the merits of the scientists at the press conference on October 7.

According to the Nobel Committee, the mechanism for adapting to changing oxygen is one of the reasons animals can adapt to many living conditions.

Three scientists were awarded the Nobel Prize in Biomedical 2019. (Image: Nobel Prize Twitter).

William G. Kaelin is a professor of medicine at Harvard University in the United States. According to the Guardian, the Nobel Committee didn't have Kaelin's phone number, so they had to wake up his sister to give him the phone.

Peter Ratcliffe is an English physician specializing in cell and molecular biology, known for his work on cell responses to hypoxia.

Gregg L. Semenza is a professor of pediatrics, oncology, biomedical chemistry, medicine and oncology at Johns Hopkins Medical University. He is the director of the vascular program at the Cell Engineering Institute. He was the recipient of the 2016 Lasker Award for basic medical research.

Scientists will divide 3 amounts of Swedish 9 million kronor (over 908,300 USD).

Paving the way for new therapies for cancer treatment

Three scientists Kaelin, Ratcliffe and Semenza have discovered a cellular mechanism that regulates the activity of genes that respond to different levels of oxygen. These studies explain how different oxygen levels affect cell metabolism and physiological function.

The findings of the three scientists also help pave the way for new therapies to treat cancer, anemia and many other diseases.

The carotid artery wall, located next to the largest blood vessels on the sides of the neck in the human body, has evolved into specialized cells that sense the level of oxygen in the blood thanks to evolution. The relationship between this sensory system and the respiratory activity, the carotid artery and the brain, brought the 1938 Nobel Prize in Medicine to the scientist Cornelle Heymans.

Three scientists Kaelin, Ratcliffe and Semenza have discovered a cellular mechanism that regulates the activity of genes that respond to different levels of oxygen.(Photo: New York Times).

The findings of Kaelin, Ratcliffe and Semenza go deeper into the body cell level, other fundamental physiological adaptations. The key reaction to low oxygen levels in the blood (hypoxia) is an increase in the erythropoietin hormone (EPO), leading to increased red blood cells. The body's hormonal control mechanism was discovered in the early 20th century, but the way this process adjusts to oxygen levels remains a mystery.

Semenza studied the EPO gene and how it is regulated by different oxygen levels. Using transgenic mice, he discovered a piece of DNA next to the EPO gene that regulates the response to hypoxia. Ratcliffe also has similar research. Both groups found that oxygen receptors occur in nearly every cell, not just the kidney cells where EPO is produced.

Semenza also found in liver cells a protein complex attached to the DNA fragment he found involved in the reaction to hypoxia. He calls this protein the hyoxia sensing agent (HIF). In 1995, Semenza began to publish many of his key findings, including identifying the genes that make HIF. The protein complex was discovered to consist of two separate DNA-binding proteins, called decoding agents, including HIF-1α and ARNT.

Breakthrough discovery

The findings of the Nobel committee's findings on sensing and adjusting oxygen levels were summarized at the announcement of the Medical Prize. Studies show that when oxygen levels are high, cells contain very little HIF-1α. But when the oxygen level is low, the amount of HIF-1α increases to attach to DNA that can connect and regulate the EPO gene as well as other genes that have DNA attached to HIF.

Many studies show that HIF-1α usually disappears very quickly but is protected in anoxic environment. When oxygen levels are normal, a cellular mechanism called proteasome recognizes and decays HIF-1α. The mechanism of proteasome identification of HIF-1α was unexpectedly explained by another Kaelin study of Von Hippel-Lindau genetic disease (VHL). This syndrome increases the risk of certain types of cancers of the family that inherit the VHL gene.

Kaelin's research showed that the VHL gene creates a protein that prevents the formation of cancer early. He also found that cancer cells lacking normal VHL genes had abnormally high levels of hypoxia regulation; but when the VHL gene was introduced back into the cancer cell, the gene level that regulates hypoxia returned to normal. This is an important clue that the VHL gene is involved in the mechanism to respond to hypoxia.

Many other studies combine that VHL is part of the physiological mechanism of marking proteins in the body with a small protein called ubiquitin, which helps the proteasome mechanism to identify and degrade proteins that cells do not need. From here, Ratcliffe and colleagues discovered that VHL can react with HIF-1α and require that the proteasome mechanism degrade this protein when oxygen levels are normal.

The sketch shows that (1) HIF-1α is undifferentiated, binding to the ARNT protein attached to the DNA fragment in the gene that responds to low oxygen status.(2) At normal oxygen level, HIF-1α rapidly dissociates (3) The presence of oxygen in cells regulates the process of denaturation by hydroxide group on HIF-1α.(4) VHL found that the OH group binds and marks a proteasome mechanism.

In two research papers published at the same time in 2001, Kaelin and Ratcliffe found that in normal oxygen environment, two special positions on HIF-1α protein appeared hydroxide group (-OH, hydroxyl). This protein regulation is called prolyl hydroxylation, allowing VHL to detect and attach to HIF-1α to differentiate the protein. Without enough oxygen, HIF-1α attaches to the DNA of the gene that responds to hypoxia.

Since the award was established by Alfred Nobel, 109 Biomedical Nobel Prizes have been awarded to 216 scientists in the field of Medicine or Biology, including 12 women. The prize was awarded by the Nobel Committee of the Karolinska Institute, located in Stockholm, Sweden.

The 2018 Biomedicine Award goes to two scientists James P. Allison (USA) and Tasuku Honjo (Japan) for "detecting cancer therapy with a negative immunosuppressive mechanism".

Nobel Committee Secretary Thomas Perlmann phoned to congratulate the winner of the 2019 Nobel Prize in Biomedical Sciences (Image: NobelPrize.org).

In his last will, the scientist Alfred Nobel claimed to leave 94% of his fortune in honor of those who have made 'the greatest contribution to humanity' in the fields of Physics, Chemistry, Biomedical, Literature and Peace. The person entrusted by the Nobel to perform the will is two young engineers, Ragnar Sohlman and Rudolf Lilljequist.

They set up the Nobel Foundation to manage the wealth left by the inventor of the dynamite. There were the first 5 Nobel prizes awarded in 1901.

In 1969, the Bank of Sweden Prize for Nobel Memorial Economics (commonly known as the "Nobel Prize in Economics") was born and was awarded in honor of Alfred Nobel.