Like candles or furnaces, cells need oxygen to function correctly. If oxygen isn’t regulated properly, cells could die. Three physician-scientists learned today that they had won the 2019 Nobel Prize in physiology or medicine for their work on how cells sense and respond to this oxygen.
Gregg Semenza works at the Johns Hopkins University School of Medicine in Baltimore, Md. William Kaelin is a cancer biologist at the Dana-Farber Cancer Institute in Boston, Mass. Peter Ratcliffe works in England at the Francis Crick Institute in London. Each made pivotal discoveries relating to the HIF system. This system is made up of proteins that tell cells how much oxygen is around. It also helps keep cells from suffocating when there is too little oxygen. That HIF system plays a role in anemia, cancer, heart attack, stroke and other disorders.
The trio’s discoveries were made in the 1990s. But it often takes decades before the Nobel Assembly chooses whom to honor. It may wait for “the year when the full impact of the discovery has become evident,” according to the late Ralf Pettersson, who once chaired the Nobel selection committee. It’s part of the Karolinska Institute in Stockholm, Sweden.
Nobel committee member Randall Johnson took part in announcing who the Nobel Assembly chose to honor this year. He says the three researchers’ work has the potential to impact nearly every aspect of physiology (how the body works). It spans from metabolism and exercise, to immunity, the development of embryos and how the body deals with low oxygen concentrations at high altitudes.
“It’s very clear that we now understand this,” said Johnson. It works like a fundamental biological switch. And at last, he noted, “It seems like a complete and clear story.”
“Life as we know it wouldn’t exist without oxygen,” points out Dennis Brown. He’s a cell physiologist in Boston at Massachusetts General Hospital and Harvard Medical School. For many years, scientists understood that cells could adjust to differing levels of oxygen. However, Brown notes, no one knew how cells did it — until Semenza, Kaelin and Ratcliffe made their discoveries.
The three researchers will split the prize of 9 million Swedish kronor, or more than $900,000.
How their findings came together
Semenza and Ratcliffe each discovered that all cells can sense when oxygen levels drop. “Your body does all sorts of things to keep the level of oxygen appropriately high in your blood and in your tissues,” says Andrew Murray. He’s a cell biologist at Harvard University. At high altitudes, where the air is thinner, the body can’t get enough oxygen. Blood levels of this gas fall. This creates a condition known as hypoxia. And when this occurs, the kidneys respond by making a protein that works as a hormone. It's known as erythropoietin (Ee-REETH-roh-POY-eh-tin). Often called EPO, it signals the bone marrow to make red blood cells. These blood cells contain hemoglobin, which ferries oxygen throughout the body. So making more red blood cells boosts the amount of oxygen the body can deliver to cells and tissues.
Semenza went on to identify HIF — short for hypoxia-inducible factor. This is a group of proteins that function as a switch. It turns on the activity of the genes needed to make EPO and other proteins. And in doing that, HIF helps cells attempt to cope with low-oxygen conditions.
Ratcliffe is a kidney physiologist, an expert in the function of the kidneys. He discovered that cells constantly make HIF proteins. However, notes Murray, if there is enough oxygen, cells promptly chew up those proteins. HIF and other proteins slated for destruction get tagged with an “eat me” sign, he says. That sign consists of a small protein called ubiquitin (Yu-BIH-quih-tin).
At about the same time as Ratcliffe made his finding, Kaelin was studying an inherited cancer. People with this von Hippel-Lindau (VHL) disease often have tumors in their pancreas, kidneys and adrenal glands. They also can have tumors in the central nervous system (brain and other nerve tissues).
Nervous-system tumors may resemble tangles of blood vessels. Sometimes these tumors produce the same distress signals as cells that are low on oxygen. Kaelin discovered that proteins known as the VHL complex (because they go awry in these cancers), help hang that “eat me” tag on HIF. And that’s what triggers HIF’s destruction.
Kaelin probed how VHL knows when to tag HIF and when to leave it alone. When oxygen levels are normal, HIF sports hydroxyl groups (a hydroxyl group is a molecule, OH, made with an atom of oxygen and an atom of hydrogen). The hydroxyl groups are the signal for VHL to launch HIF’s breakup. When oxygen is low, hydroxyl groups don’t get added and VHL ignores it. This allows HIF to turn on creation of EPO and other proteins needed to survive low levels of oxygen.
Importance of these findings for medicine
Mutations are spontaneous changes to genes. Some mutations that inactivate VHL increase HIF levels. When this happens, cancer cells can boost their oxygen-scavenging activities. It helps tumors fuel the growth of new blood vessels. That process is known as angiogenesis (AN-gee-oh-JEN-eh-sis). It helps supply tumors with the energy they need to keep growing.
Indeed, the robust growth of cancer cells would quickly exhaust a tumor’s oxygen supply without these new blood vessels. Explains Murray, oxygen can diffuse only about half a millimeter away from a tiny blood vessels before the cells around it use up that oxygen. So to grow more than about 1 millimeter across, tumors must continue to make new blood vessels.
Some researchers are working on treatments to suffocate cancer cells by switching off their HIF system. Turning on low-oxygen responses also might help limit damage from heart attacks or kidney disease, Brown says.
A new drug known as roxadustat can control the HIF system. It has been approved in China to treat anemia in patients with chronic kidney disease. People with this condition get anemia when their kidneys fail and no longer make enough EPO. Roxadustat blocks the enzymes that normally break down HIF. That keeps this switch on to increase EPO levels and the production of red blood cells.
adrenal glands Hormone-producing glands that sit at the top of the kidneys.
anemia A disease caused by not having enough red blood cells. This reduces the body’s ability to carry oxygen efficiently to all tissues.
atom The basic unit of a chemical element. Atoms are made up of a dense nucleus that contains positively charged protons and uncharged neutrons. The nucleus is orbited by a cloud of negatively charged electrons.
biologist A scientist involved in the study of living things.
blood vessel A tubular structure that carries blood through the tissues and organs.
cancer Any of more than 100 different diseases, each characterized by the rapid, uncontrolled growth of abnormal cells. The development and growth of cancers, also known as malignancies, can lead to tumors, pain and death.
cell The smallest structural and functional unit of an organism. Typically too small to see with the unaided eye, it consists of a watery fluid surrounded by a membrane or wall. Depending on their size, animals are made of anywhere from thousands to trillions of cells. Most organisms, such as yeasts, molds, bacteria and some algae, are composed of only one cell.
chronic A condition, such as an illness (or its symptoms, including pain), that lasts for a long time.
concentration (in chemistry) A measurement of how much of one substance has been dissolved into another.
development (in biology) The growth of an organism from conception through adulthood, often undergoing changes in chemistry, size and sometimes even shape.
diffuse Spread out thinly over a great area; not concise or concentrated.
disorder (in medicine) A condition where the body does not work appropriately, leading to what might be viewed as an illness. This term can sometimes be used interchangeably with disease.
embryo The early stages of a developing organism, or animal with a backbone, consisting only one or a few cells. As an adjective, the term would be embryonic — and could be used to refer to the early stages or life of a system or technology.
enzymes Molecules made by living things to speed up chemical reactions.
erythropoietin (abbv. EPO) A hormone made in the kidneys that will stimulate the bone marrow to make red blood cells.
factor Something that plays a role in a particular condition or event; a contributor.
fundamental Something that is basic or serves as the foundation for another thing or idea.
gene (adj. genetic) A segment of DNA that codes, or holds instructions, for a cell’s production of a protein. Offspring inherit genes from their parents. Genes influence how an organism looks and behaves.
gland A cell, a group of cells or an organ that produces and discharges a substance (or “secretion”) for use elsewhere in the body.
heart attack Permanent damage to the heart muscle that occurs when one or more regions of it become starved of oxygen, usually due to a temporary blockage in blood flow.
hemoglobin A molecule that binds to oxygen in the blood, carrying it around to tissues.
hormone (in zoology and medicine) A chemical produced in a gland and then carried in the bloodstream to another part of the body. Hormones control many important body activities, such as growth. Hormones act by triggering or regulating chemical reactions in the body. (in botany) A chemical that serves as a signaling compound that tells cells of a plant when and how to develop, or when to grow old and die.
hydrogen The lightest element in the universe. As a gas, it is colorless, odorless and highly flammable. It’s an integral part of many fuels, fats and chemicals that make up living tissues. It’s made of a single proton (which serves as its nucleus) orbited by a single electron.
immunity The ability of an organism to resist a particular infection or poison by providing cells to remove, kill or disarm the dangerous substance or infectious germ. Or, when used colloquially, it means the ability to avoid some other type of adverse impact (such as firing from a job or being bullied).
kidney Each in a pair of organs in mammals that filters blood and produces urine.
marrow (in physiology and medicine) Spongy tissue that develops inside of bones. Most red blood cells, infection-fighting white blood cells and blood platelets form within the marrow.
metabolism (adj. metabolic) The set of life-sustaining chemical reactions that take place inside cells and bigger structures, such as organs. These reactions enable organisms to grow, reproduce, move and otherwise respond to their environments.
molecule An electrically neutral group of atoms that represents the smallest possible amount of a chemical compound. Molecules can be made of single types of atoms or of different types. For example, the oxygen in the air is made of two oxygen atoms (O2); water is made of two hydrogen atoms and one oxygen atom (H2O).
mutation (v. mutate) Some change that occurs to a gene in an organism’s DNA. Some mutations occur naturally. Others can be triggered by outside factors, such as pollution, radiation, medicines or something in the diet. A gene with this change is referred to as a mutant.
nerve A long, delicate fiber that transmits signals across the body of an animal. An animal’s backbone contains many nerves, some of which control the movement of its legs or fins, and some of which convey sensations such as hot, cold or pain.
nervous system The network of nerve cells and fibers that transmits signals between parts of the body.
Nobel prize A prestigious award named after Alfred Nobel. Best known as the inventor of dynamite, Nobel was a wealthy man when he died on December 10, 1896. In his will, Nobel left much of his fortune to create prizes to those who have done their best for humanity in the fields of physics, chemistry, physiology or medicine, literature and peace. Winners receive a medal and large cash award.
oxygen A gas that makes up about 21 percent of Earth's atmosphere. All animals and many microorganisms need oxygen to fuel their growth (and metabolism).
pancreas A gland found in animals with backbones that secretes the hormone insulin and enzymes that help break down foods in the gut.
physiologist A scientist who studies the branch of biology that deals with how the bodies of healthy organisms function under normal circumstances.
physiology The branch of biology that deals with the everyday functions of living organisms and how their parts function. Scientists who work in this field are known as physiologists.
protein A compound made from one or more long chains of amino acids. Proteins are an essential part of all living organisms. They form the basis of living cells, muscle and tissues; they also do the work inside of cells. Among the better-known, stand-alone proteins are the hemoglobin (in blood) and the antibodies (also in blood) that attempt to fight infections. Medicines frequently work by latching onto proteins.
red blood cell Colored red by hemoglobin, these cells move oxygen from the lungs to all tissues of the body. Red blood cells are too small to be seen by the unaided eye.
stroke (in biology and medicine) A condition where blood stops flowing to part of the brain or leaks in the brain.
suffocate To be unable to breathe, or to cause a person or other organism to be unable to breathe.
tag (in cell biology) A chemical change that allows the body to alter the activity of affected cells.
tissue Made of cells, it is any of the distinct types of materials that make up animals, plants or fungi. Cells within a tissue work as a unit to perform a particular function in living organisms. Different organs of the human body, for instance, often are made from many different types of tissues.
tumor A mass of cells characterized by atypical and often uncontrolled growth. Benign tumors will not spread; they just grow and cause problems if they press against or tighten around healthy tissue. Malignant tumors will ultimately shed cells that can seed the body with new tumors. Malignant tumors are also known as cancers.
tune (in engineering) Adjust to the right level.
Journal: N. Gupta and J. Wish. Hypoxia-inducible factor prolyl hydroxylase inhibitors: a potential new treatment for anemia in patients with CKD. American Journal of Kidney Diseases. Vol. 69, June 2017, p. 815. DOI: 10.1053/j.ajkd.2016.12.011.
Journal: N. Chen et al. Roxadustat treatment for anemia in patients with kidney disease not receiving dialysis. New England Journal of Medicine. Vol. 381, September 12, 2019, p. 1001. DOI: 10.1056/NEJMoa1813599.
Journal: N. Chen et al. Roxadustat treatment for anemia in patients undergoing long-term dialysis. New England Journal of Medicine. Vol. 381, September 12, 2019, p. 1011. DOI: 10.1056/NEJMoa1901713.