The findings of Kelling, Ratcliffe, and Semenza not only shed light on the fundamental life science problems of how animal cells perceive and adapt to changes in oxygen, but also provide new ideas for the treatment of diseases such as anemia and cancer.
On October 7, 2019, Beijing time, the Swedish Nobel Prize Committee announced in Stockholm that William Kaelin of Harvard Medical School in the United States, Peter Ratcliffe of Oxford University in the United Kingdom, gregg Semenza of Johns Hopkins University in the United States and Gregg Semenza of Johns Hopkins University jointly won the 2019 Nobel Prize in Physiology or Medicine, and the reasons for the award of the three were " Discover how cells perceive and adapt to an ever-changing supply of oxygen."
William Kaelin, Peter Ratcliffe and Gregg Semenza, winners of the 2019 Nobel Prize in Physiology or Medicine, were awarded the Lasker Prize in Medicine in 2016. (Infographic/Figure)
<h3>Make a fuss about "oxygen"</h3>
As we all know, oxygen is essential for animals and humans to maintain life, and how oxygen participates in life activities, and how animal and human cells perceive and adapt to changes in oxygen, is the research direction that scientists are obsessed with.
German physiologist Otto Warburg discovered the properties and modes of action of respiratory enzymes and won the 1931 Nobel Prize in Physiology or Medicine. Belgian scientist Corneille Heymans won the 1938 Nobel Prize in Physiology or Medicine for discovering how carotid arteries perceive blood pressure and blood oxygen levels and transmitting this information to the brain to control respiratory rate. In 1962, Max Perutz and John Kendrew of the University of Cambridge in the United Kingdom shared that year's Nobel Prize in Chemistry for cracking the myoglobin and hemoglobin structures that transport oxygen.
In the early 20th century, scientists had observed that mammalian bodies could sense hypoxia and alleviate oxygen deficiency in the body by secreting more erythropoietin (EPO) to produce more red blood cells, but little was known about the role of oxygen in it.
In the early 1990s, Semenza and colleagues, who were working on postdoctoral research at the Johns Hopkins University School of Medicine, studied the expression of the EPO gene in liver and kidney cells in anemic mice, and found that a small piece of DNA located near the EPO gene was a key factor in mediating the adaptive response of the EPO gene to oxygen concentration. Shortly thereafter, Dr. Ratcliffe's team also confirmed that this oxygen-sensing mechanism is present in almost all cells in mammals.
The two teams further found that this DNA fragment can bind to some transcription factors, which they call hypoxia-inducible factor (HIF), and purify two transcription factors that can bind to each other, HIF-1α and ARNT. They then found that in the case of adequate oxygen, the content of HIF-1α in the cells was very low, indicating that its degradation rate was accelerated. When oxygen is insufficient, the HIF-1α content will rise significantly, which will stimulate the increase in EPO secretion, and when this DNA fragment is inserted near other genes, the stimulation of low oxygen can also increase the expression level of these genes.
Next, scientists ask new questions: What is driving the degradation of HIF-1α? At this time, William Kellin of Harvard Medical School was studying a familial hereditary syndrome, vonHippel-Lindau disease (VHL disease), which led to a significant increase in the incidence of some cancers, but accidentally discovered the mystery of HIF-1α degradation. Originally, the VHL gene just encodes a protein that inhibits tumorigenesis, once the VHL gene is mutated, the VHL oncogen function is lost, which is easy to stimulate the cancer of the cell, and the gene that is susceptible to hypoxia regulation such as EPO is abnormally highly expressed, if the normal VHL gene is transferred to the tumor cell, the expression level of the hypoxia regulatory gene will return to normal.
Seeing the results of The Kellyn's team, Ratcliffe and colleagues followed up and confirmed that normal VHL proteins are essential for the degradation of HIF-1α. In 2001, Kelling's team and Ratcliffe's team published two papers back-to-back in the journal Science, revealing that when the oxygen content was normal, the two proline sites of the HIF-1α protein, with the assistance of oxygen molecules, were catalyzed by proline hydroxylase to undergo hydroxylation modifications, and the normal VHL was followed by the hydroxylated HIF-1α protein, which accelerated the degradation of the latter.
Oxygen is essential for animals and humans to sustain life. (Infographic/Figure)
<h3>The Lasker Prize has once again become a "Nobel Prize weather vane"</h3>
The discoveries of William Kailin, Peter Ratcliffe and Greg Semenza not only revealed the basic life science problems of how animal cells perceive and adapt to changes in oxygen, but also provided new ideas for the treatment of diseases such as anemia and cancer, and the Nobel Prize in Physiology or Medicine was well deserved. This is also the 110th Nobel Prize in Physiology or Medicine, which has been awarded since 1901 and is currently awarded in SEK 9 million (about 6.467 million yuan), which is divided equally between the three of them.
Back in 2016, William Kelling, Peter Ratcliffe and Greg Semenza were awarded the Albert Lasker Prize in Medicine. Funded by American businessman Albert Lasker and his wife, the Lasker Foundation under his wife Mary Lasker, the prize has been held annually since 1945 to honor major breakthroughs in the field of basic or clinical medicine. According to science magazine statistics, nearly 90% of Lasker Prize winners eventually won the Nobel Prize, the Lasker Prize in medicine is also known as the Nobel Prize "weather vane", such as the 2015 Nobel Prize in Physiology or Medicine winner, Chinese scientist Tu Youyou, 2018 Nobel Prize in Physiology or Medicine winners James Allison and Ben Shuyou have both won the Lasker Prize in Medicine.
<h3>Bringing new hope to the treatment of diseases</h3>
Led by William Kailin, Peter Ratcliffe, and Greg Semenza, more and more scientists are turning to the study of oxygen perception mechanisms, leading to a clearer understanding of how mammalian cells adapt to different oxygen levels. For example, how humans and some animals adapt to high altitude, how to fine-tune the immune system and other physiological activities according to the oxygen perception mechanism, how to control normal blood vessel formation and placental development through the oxygen perception mechanism during fetal development, and so on.
What is more exciting is that the research on oxygen perception mechanism has been extended to the study of disease mechanism and treatment. For example, scientists have found that excessive expression of HIF in tumor cells can not only stimulate the production of EPO that promotes the synthesis of red blood cells, but also produce glucose transporters that promote cell ingestion of glucose and vascular endothelial growth factors that promote blood vessel growth, in order to alleviate the problems of hypoxia and lack of energy caused by overgrowth of tumor cells.
In 2004, the anti-cancer drug Avastin developed by Genentech Corporation that targets tumor vascular endothelial growth factor was approved for marketing, and its main function is to inhibit the growth of blood vessels in the tumor, to "starve" and "choke" tumors, mainly for the treatment of rectal colon cancer, non-small cell lung cancer, kidney cell carcinoma and ovarian cancer and other cancers, the global market sales have reached 7 billion US dollars.
However, scientists are currently developing small molecule inhibitors against the overexpression of HIF-1α, including inhibiting the production of mRNA of HIF-1α, inhibiting the translation of HIF-1α protein, promoting HIF-1α degradation, inhibiting the formation of HIF-1α and ART dimers, and preventing HIF-1α from binding DNA. Enzon Pharmaceuticals has developed an antisense nucleotide drug EZN-2698 that inhibits the production of HIF-1α gene mRNA, and preclinical trials and phase I trials have shown that the drug can be used as a potential drug in adult patients with refractory advanced solid tumors. Some small molecule drugs that inhibit the translation of the HIF-1 alpha protein have successfully passed Phase III clinical trials and received FDA marketing approval for the treatment of metastatic renal cell carcinoma.
Southern Weekend Contributing Writer Tombo