The recipients of this year’s Nobel Prize in Physiology or Medicine are William G. Kaelin of Harvard Medical School, Sir Peter J. Ratcliffe of Oxford University and Gregg L. Semenza of Johns Hopkins University. They won for their pioneering research into how the cells sense and adapt to low oxygen conditions.
Understanding how cells talk to each other in a low oxygen environment – like a tumor – is critical for learning how cancers grow and progress. The pioneering work from these three eminent scientists laid the foundation for my research and that of many others studying disease.
Oxygen flux within the cells
Adapting to varying oxygen levels is one of the key evolutionary adaptations for most life forms on Earth. Every cell in the human body requires oxygen for its normal function.
Both the environment and the physiological status of the body determines how much oxygen is available to cells. For example, in higher altitudes, oxygen availability decreases. This is especially important for mountain climbers, who must adapt to altitude in order to help their body increase the oxygen carrying capacity in the blood. This is essential to avoid mountain sickness and other altitude-associated health issues such as pulmonary and cerebral diseases.
Oxygen levels in the human body are constantly fluctuating, depending on whether the individual is eating or fasting, exercising or resting and even whether they are stressed or calm. For example, during exercise, the oxygen supply to the muscles is increased to supply energy. This leaves less oxygen for other organs such as the liver.
In many diseases, damage to the blood vessels can drop blood supply, and thus oxygen supply, to the affected organ, which may make the patient even sicker. Thus, the oxygen levels within the cell are important to both healthy and sick people.
Nobel Prize: Sensing oxygen is vital in health and disease
In the early 1990s, Semenza and Ratcliffe independently discovered that cells adapt to changes in oxygen levels by making more of a protein called hypoxia-inducible factor-1 or HIF-1. When oxygen levels decrease, the HIF protein inhibits oxygen-consuming processes of the cells by altering the activity of numerous genes, thereby enabling the cells to adapt quickly and survive the low oxygen environment.
In the last decade, these Nobel Prize researchers have shown that HIFs have a pivotal role in promoting the growth of tumors. Cancer cells divide and grow rapidly and have a larger appetite for both nutrients and oxygen. But the blood vessels feeding the tumor cannot keep up with the cancer growth.
The clever cancer cells survive by producing higher quantities of HIF protein. The HIF proteins trigger changes in cancer cell metabolism, and switch them to a low oxygen and low energy mode. This helps the cancer cells to survive in oxygen- and nutrient-poor conditions, and keep growing and spreading.
As oxygen is involved in all cellular processes, the discovery of the mechanisms by which cells are able to detect and rapidly respond to changes in oxygen levels has revolutionized biomedical research and helped to identify novel targets for various diseases treatments.