Nordic Life Science 1
he question was now how oxygen levels regulated t
he interaction between VHL and HIF-1α? Kaelin and Ratcliffe suspected that the key to oxygen-sensing resided somewhere in a specific protein domain of HIF-1α. In 2001 they both published results that showed that under normal oxygen levels hydroxyl groups are added at two specific positions in HIF-1α. This modification, called prolyl hydroxylation, allows VHL to recognize and bind to HIF-1α and they had now explained how normal oxygen levels control rapid HIF-1α degradation with the help of oxygen-sensitive enzymes, prolyl hydroxylases. It was also shown that the gene activating function of HIF-1α was regulated by oxygen-dependent hydroxylation. “Piece by piece of the puzzle, the Laureates explained a sensitive machinery that compensates when the vital oxygen is not available in exactly the right amount. Their groundbreaking discoveries have shed light on a beautiful mechanism explaining our ability to sense and react to fluctuating oxygen levels,” says Professor Anna Wedell, Member of the Nobel Assembly at Karolinska Institutet, Adjunct member of the Nobel Committee for Physiology or Medicine, at the Nobel Prize Award Ceremony, December 10th 2019. The Laureates’ findings have given us a better understanding of how different oxygen levels regulate fundamental physiological processes. Oxygen sensing allows cells to adapt their metabolism to low oxygen levels, for example in our muscles during intense exercise. Other examples of adaptive processes controlled by oxygen sensing are the generation of new blood vessels and the production of red blood cells. Our immune system is also fine-tuned by the oxygen-sensing machinery. It has also been shown to be very important during fetal development for controlling normal blood vessel formation and placenta development. Oxygen sensing is also central in several diseases and the Laureates’ discoveries have paved the way for promising new strategies to fight anemia, cancer, infection and wound healing, as well as many other diseases. Researchers at both universities and in the pharmaceutical industry are now focusing on developing drugs that can interfere with different disease states, either by activating or blocking the oxygen-sensing machinery. Professor Randall Johnson’s group at Karolinska Institutet uses genetic models to study the effects of hypoxia in physiological and pathological contexts and they are especially dissecting the roles of different isoforms of HIF as regulators of the hypoxia response in different cell types. “My research is about how immune cells adapt themselves to different amounts of oxygen. The immune defense is something that often occurs in damaged tissues, where lack of oxygen is a great challenge. To understand how immune cells adapt themselves through transcription made us understand which genes are the most important when immune cell activation and hypoxia occurs,” describes Johnson. He believes science has come the furthest when it comes to the treatment of anemia and it is probably in this field where we will have the first breakthrough as an effect of the Nobel discoveries. A medicine that treats anemia by increasing the quantity of HIF has been approved in China and more are being developed. “After that I think we will see a breakthrough application within cancer treatment and I believe that maybe we will look at immunotherapy in a new way – through the manipulation of T cells’ oxygen adaptation,” he says. Clinical trials are taking place involving substances that inhibit HIF in order to reduce tumor growth in certain forms of cancer. ia Phillipson’s research at the University of Uppsala is in part also connected to the Nobel Prize in Physiology or Medicine. She is for example investigating how the cells of the immune system contribute to the repair of damaged tissue. At the sites of different types of damage the blood flow is impaired and anemia occurs. In order for the damage to be repaired new blood vessels must be formed and Phillipson and her colleagues are trying to understand how different immune cells are contributing to this. ”If we understand what the immune cells are doing to recover the blood flow we can also develop pharmaceuticals that improve the possibilities for the immune cells to do their job and hence improve the healing and repair process,” she says. NLS Randall Johnson, Professor, Karolinska Institutet PHOTO STEFAN ZIMMERMAN