The Nobel Prize in Physiology or Medicine 2019 was awarded jointly to William G. Kaelin Jr, Sir Peter J. Ratcliffe, and Gregg L. Semenza for identifying the molecular switch that regulates how our cells adapt when oxygen levels drop.
Jeff Knight, PhD, associate professor in chemistry at CU Denver, will lead a discussion about the discoveries that led to the groundbreaking, physiological discovery for the November 14th Nobel at Noon Series.
The Nobel at Noon Series spotlights each Nobel Prize with an informal presentation and discussion. CU Denver faculty experts discuss the meaning and importance of the Nobel Prize while drawing the audience into a discussion about why this award matters to society as a whole.
- When: Thursday, Nov. 14, 12:30 p.m.
- Where: CU Building, room 2005
- Light refreshments will be provided. Feel free to bring your lunch.
Cell behavior amidst a lack of oxygen
Oxygen is essential for life and almost all animal cells rely on it to convert food into energy. During the Nobel Prize announcement, Randall Johnson, member of the Nobel Assembly, described it as similar to the way available oxygen levels can affect the way a candle burns.
“Cells need to adjust metabolic rates based on how much oxygen is available to them,” said Johnson. “This allows each cell and our bodies to efficiently and safely burn fuel to create heat, do work, and build new tissues.”
Cells and tissue constantly experience change, and need a way to adjust to oxygen levels while doing their jobs. Coloradans know fluctuating oxygen levels well: our bodies experience a lack of oxygen—or hypoxia—while climbing fourteeners or backcountry skiing at high elevation. But even small wounds can change oxygen levels by interrupting local blood supply. As a result, new blood vessels or red blood cells may form, and cells may go through glycolysis, which converts glucose into energy for tissue. This hypoxia is an expression of the kidney hormone EPO.
Identifying the “molecular switch”
Gregg L. Semenza, PhD, director of the Vascular Program at the Institute for Cell Engineering and professor of Genetic Medicine at Johns Hopkins University, found the increase in EPO stemmed from a specific region of the EPO gene, recognizing it as a hypoxia response element (HRE). It turns out that the protein complex called HIF within the EPO region is oxygen sensitive: present when oxygen levels plummet and destroyed when levels rise.
In 1995, William G. Kaelin, Jr., MD, professor of medicine at the Dana Farber Cancer Institute at Harvard University, studied VHL, a tumor suppressor gene mutated in a cancer syndrome called von Hippel Lindau disease. He found that cells lacking VHL increase expression of hypoxia-inducible genes.
At the same time, Sir Peter Ratcliffe, PhD, director for the Target Discovery Institute at Oxford University and director of clinical research at Francis Crick Institute, London, found the presence of VHL leads to HIF destruction.
Together, the trio’s work found the switch: high levels of oxygen create HIF, and when VHL recognizes it, it orders the HIF destroyed.
The effects of HIF range across every aspect of physiology, affecting metabolism, exercise, embryonic development, immunity, and changes wrought by altitude. Diseases with a HIF response include anemia, cancers, strokes, infections, and heart attacks. Since the Nobel laureates’ discoveries, doctors are now able to increase HIF to help anemia and suppress it to treat some forms of cancer, upending the way medicine is practiced.