The 2019 Nobel Prize in Physiology or Medicine has been awarded jointly to William Kaelin of the Dana-Farber Cancer Institute and Harvard Medical School, Peter Ratcliffe of the University of Oxford and the Francis Crick Institute, and Gregg Semenza of the Johns Hopkins University School of Medicine “for their discoveries of how cells sense and adapt to oxygen availability.” Unsurprisingly, all three of them won the 2016 Lasker award for their fundamental medical research — the American equivalent of the Nobel Prize.
These discoveries resulted from long lines of research that included studies depending on whole animals and cells from many species of animals — monkey, pig, Chinese hamster, rat, mouse, rabbits, frogs, and roundworm.
Oxygen is crucial for survival, but at the same time, too much can be toxic for cells and damage DNA and proteins. Thus, it is crucial for cells to be able to sense and respond to the concentration of oxygen in their environment. Semenza and Ratcliffe discovered that under low-oxygen conditions the protein hypoxia-inducible factor-1a (HIF-1α) turns on many genes. Subsequently Kaelin and Ratcliffe discovered that under high-oxygen conditions, an enzyme called prolyl hydroxylase caused HIF-1a to be destroyed by the protein von Hippel-Lindau (VHL). VHL is mutated in von Hippel-Lindau disease, which is characterized by large tumors made of blood vessels. In the disease, HIF-1α levels are artificially high due to a defective VHL protein, thus tricking the body into thinking it needs more oxygen, and mistakenly growing unneeded blood vessels to carry oxygen to seemingly low-oxygen tissues.
The discovery of the full pathway for how cells respond to differing levels of oxygen has fueled new research. Stopping the destruction of HIF-1α can help with anemia, a condition where low iron makes red blood cells less effective at carrying oxygen, by increasing the production of red blood cells. Cancer treatment applications can also now be envisioned: some tumors’ survival depends on HIF-1α to spur the development of new blood vessels.
Like so many of the previous Nobel Prizes in Physiology and Medicine, this year’s award owes much to animal research. The first study by Ratcliffe that indicated a wide-spread response to low oxygen used multiple cell culture systems from monkey, pig, Chinese hamster, rat, and mouse cells. In later studies by Kaelin, Ratcliffe, and Semenza, reticulocytes—precursors to red blood cells—from rabbits were used to generate HIF-1α protein to study in vitro. Xenopus laevis (frog) cells were used to study how prolyl hydroxylase was involved in the destruction of HIF-1α. C. elegans (roundworm) were used to investigate how mutations in VHL affected a whole organism’s ability to respond to low oxygen levels. Mice were used to study how HIF-1a might be involved in anemia.
This year’s Nobel Prizes also reflect the value of publicly-funded basic research. The new awards add to the long list of science supported by the U.S. National Institutes of Health (NIH). The NIH’s Nobel Laureate webpage provides a list and detail about past awardees and notes that:
“Dozens of NIH-supported scientists from around the world have received Nobel Prizes for their groundbreaking achievements in Physiology or Medicine; Chemistry; Physics; and Economic Sciences. To date, 160 NIH supported researchers have been sole or shared recipients of 94 Nobel Prizes.” (emphasis added)
In a time when some anti-animal research campaigns question whether NIH’s animal research leads to discoveries, we hope that NIH, the research community, media, and policymakers make the connection between the Nobel Prizes, the animal studies, and how the discoveries came to be. Toward that end, we’d encourage NIH to add a column to their table and a few words to their press releases:
“This science depended on nonhuman animal studies.”
~Speaking of Research