The Nobel Prize in Physiology or Medicine in 2019 was awarded to three physician scientists, William G. Kaelin Jr, Sir Peter J. Ratcliffe and Gregg L. Semenza “for their discoveries of how cells sense and adapt to oxygen availability.” Kaelin and Semenza attended this year’s 70th Lindau Nobel Laureate Meeting and presented the stories behind their discoveries, as well as new findings.
Oxygen – Friend and Foe
“Oxygen is both providing us with energy for the enjoyment of life but at the same time is decreasing the length of time that we will be around for such enjoyment.” This quote from Nobel Laureate Paul Boyer’s lecture at Lindau in 2002 encapsulates the balancing act of oxygen in our bodies, known as oxygen homeostasis. Gregg L. Semenza began his lecture by describing the levels of oxygen in the Earth’s atmosphere at different stages of its history. 250 million years ago the atmosphere consisted of 35 percent oxygen, which resulted in insects with a huge body mass. Currently, oxygen has to be delivered to each one of our 50 trillion cells, which explains the complex circulatory and respiratory systems of humans and animals.
Hypoxia – inducible factor-1
As a post-doc, Semenza began studying the gene of the hormone erythropoietin (EPO). EPO levels rise when not enough oxygen reaches tissues, a condition known as hypoxia. During hypoxia more red blood cells are produced. Semenza identified the protein complex that regulates the cell’s response to hypoxia, and named it hypoxia-inducible factor – 1 (HIF-1). During the lecture, Semenza explained the critical role HIFs play in such processes as iron uptake, the development of the circulatory system in embryos and protection against cardiovascular disease. However, the role of HIFs may also be pathogenic; HIF-1 increases in various types of cancer.
Von Hippel-Lindau’s Disease
In the late 1980s, William G. Kaelin Jr started to work on the Von-Hippel-Lindau syndrome (VHL), a genetic illness that often leads to several types of cancer (the name of the disease is not derived from the town of Lindau but from the names of the scientists who first described the disease, Eugen von Hippel and Arvid Lindau). Under normal oxygen levels, HIF-1α, a DNA-binding protein which is part of the HIF-1 complex, binds to the VHL protein. This leads to the rapid degradation of HIF-1α. At low oxygen levels (hypoxia), HIF-1α levels are maintained. HIF activates the genes for vascular endothelial growth factor (VEGF), a key regulator of blood vessel formation, and EPO, which promotes red blood cell production. These processes drive tumor growth and the spread of cancer. “VHL loss (the inactivation of the VHL tumor suppressor gene) is the initiating event in most sporadic clear cell renal cell carcinoma,” said Kaelin, noting that VEGF inhibitors have been approved as treatment for this type of kidney cancer. A HIF-2α inhibitor, which treats anemia resulting from chronic kidney disease, is currently in a phase III study. Kaelin concluded his lecture by showing social media messages from patients whose health has improved after this treatment, including a video from one patient, who felt well enough to travel.
A Half Century of Research
Harvey J. Alter, Michael Houghton and Charles M. Rice were awarded the Nobel Prize in Physiology or Medicine in 2020 “for the discovery of Hepatitis C virus.”
At this year’s Lindau Nobel Laureate Meeting, Harvey J. Alter told the captivating story of the search for the causative agent of hepatitis C, a blood-borne disease, which may lead to liver cancer and causes 400 thousand deaths each year. In the late 1960s, Alter began to study transfusion-associated hepatitis at the National Institutes of Health. In those days, 30 percent of patients who had had blood transfusions became ill with hepatitis. There was no way to screen blood for hepatitis from donors.
By 1975, both the hepatitis B and A viruses had been discovered, but there appeared to be another agent that caused hepatitis, which was called “non-A, non-B.” Alter described how the infected blood of one particular patient, Mr. H, was used in many experiments, which provided valuable information on the type of virus and also on disease progression (Mr. H died 32 years later, but not of liver failure). However, due to the limited technologies of the time, Alter was not able to isolate the virus’s DNA. The clone was found by Michael Houghton and his colleagues in the late 1980s: “They looked at six million clones over a period of six years,” remarked Alter. The virus was officially named hepatitis C in 1990 and with the availability of an assay, post-transfusion hepatitis rates dropped to 4.1 percent in 1990 and zero by 1997. Milestones in therapy have also been reached, with drugs able to cure 95-98 percent of cases in 8-12 weeks. However, there is still no vaccine for hepatitis C.
Alter commented on his long research career by showing a slide of a card he had received after winning the Nobel Prize: “There is no elevator to success, you have to take the stairs.”