Inside the body of animals are chemicals that work together like the gears of a timekeeping device. Scientists refer to the actions of this system as the body’s “clock.” For helping discover how this clock works on the molecular level, three Americans have just won the Nobel Prize in physiology or medicine.
All three worked with fruit flies. Their findings, however, appear to relate well to many other animals, including humans. Indeed, “an awful lot of what was subsequently found out in the fruit flies turns out also to be true and of huge relevance to humans,” says John O’Neill. He’s a cell biologist in England. There, he too has been probing the body’s clock in studies at the MRC Laboratory of Molecular Biology in Cambridge.
Two of the three new Nobel Prize winners performed their groundbreaking work at Brandeis University in Waltham, Mass. Jeffrey C. Hall is a geneticist. Michael Rosbash is a molecular biologist. In 1984, the pair identified a gene called period. At the same time, Michael W. Young also found the period gene. He’s a geneticist at Rockefeller University in New York City.
Genes are like blueprints. Proteins are the chemicals that those blueprints make to do the work of a gene. It wasn’t clear, right away, how period controlled the activity of flies. The gene made a protein called PER. It turned out that PER’s role was to turn off its own production. That means it works like a feedback system. But it wasn’t clear how this clock could work with only one hand. And there were other mysteries.
For instance, the protein PER is made in a cell’s cytoplasm (SY-toh-PLAZ-um). That’s a cell’s jelly-like guts. But the period gene is located with the rest of a cell’s DNA in a compartment called the nucleus. No one knew how the protein got into the nucleus to stop its own production.
In 1994, Young discovered a second clock gene. He called this one timeless. Like period, it is found in virtually every cell of the body. And the protein that this gene produces (TIM) teams up with PER. Together the two proteins slip into the nucleus and shut off their own genes.
Those are just two important inner gears of the clock. Those gears not only make the clock go around but also make sure other body activities follow a schedule. Young also discovered a third clock gene, known as doubletime, and its protein DBT. This last protein helps set the clock’s pacing.
But this internal clock is even more complex. Hall and Rosbash have found additional clock gears in their research.
National Science Foundation Director France Córdova notes that all three of this year’s winners have benefitted from her agency’s funding. Their findings, she says, “have significant implications for health and wellness, and connect with our daily lives every time we go to sleep or wake up.” These discoveries also show yet again that putting public funds to work probing biology across of a wide variety of organisms and scientific disciplines “yields results that benefit society.”
All three of this year’s winners will pick up their prizes at a December ceremony in Stockholm, Sweden. At the event, they will each receive a medal and a Nobel Diploma from King Carl XVI Gustaf of Sweden. They also will also share a monetary award now valued at slightly more than $1 million.
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What is a body clock?
The body’s clock is known as a circadian (Ser-KAY-dee-un) system. That term means “almost a day.” So the body’s clock runs on a schedule that is nearly — but not precisely — 24 hours long.
Circadian clocks consist of networks of genes and the proteins that carry out their functions. Together, these pairings control the body’s daily rhythms and cycles. These clocks control everything from when we sleep and when the body releases hormones, to the daily change in body temperature, blood pressure and other phenomena. Circadian rhythms also help organisms, from plants to people, anticipate and adapt to daily cycles of light and darkness and to temperature changes caused by the Earth’s rotation.
When circadian rhythms are thrown out of whack, people feel uncomfortable with what commonly is known as jet lag (even if you never set foot on a plane). Shift workers and people who regularly get too little sleep may experience long-term jet lag. This has been linked to serious health problems. Among diseases linked to such a chronic lack of enough sleep: cancer, diabetes, heart disease, obesity and depression.
Hall, Rosbash and Young are hardly the first scientists to work on the body’s clock. Other scientists had already established that plants and animals show circadian rhythms. In 1971, for instance, Seymour Benzer and Ronald Konopka found that mutations in single fruit-fly gene disrupted the insects’ circadian rhythms. These flies were active at different times of day than normal. The affected gene? It was none other than period.
“But then people got stuck,” says Erik Herzog. He’s a chronobiologist (KRO-no-by-OL-oh-gizt) at Washington University in St. Louis. “We couldn’t figure out what that gene was or how that gene worked.” It took more than 20 years before Hall, Rosbash and Young figured out how the gene fits into the body clock.
“Time is indeed engraved in those molecular mechanisms,” says Derk-Jan Dijk. He’s a sleep and body-clock researcher in England at the University of Surrey in Guildford. Learning how the clock works, or doesn’t, he says, “adds a new dimension” to understanding why the body does what it does, when it does it.
The body has at least one master “clock” in the brain. But since the early discoveries by Hall, Rosbash and Young, other scientists have shown that nearly every cell in the body contains its own circadian clock. What’s more, almost every gene follows circadian rhythms in at least one type of cell. (For instance, some genes have rhythm in the liver but not in skin cells.) Explains Herzog, it’s normal to change over the course of a day.
Trouble develops when the body’s clocks get out of sync with each other, says Joseph Takahashi. He’s a neuroscientist at the University of Texas Southwestern Medical Center in Dallas. Genes such as cMyc and p53 help control cell growth and division, for instance. Scientists now know they are governed, in part, by the body’s circadian clock. Altering the clock’s smooth running could lead to cancer-promoting mistakes.
But while bad timing might lead to disease, scientists also have realized that giving drugs at the right time of day could make them more effective, notes Herzog. Such things show that in the body, as is so much else, timing is everything.
Rosbash joked during a news conference that the Nobel committee’s early morning phone call today disrupted his own circadian rhythms. When he heard that he’d won, “I was shocked, breathless really. Literally," he told an interviewer from the Nobel committee, "My wife said, ‘Start breathing!’"
Young’s sleep was untroubled. His home phone is in the kitchen, so he didn’t hear it ring. The Nobel committee had to make its announcement without him. “The rest of the world knew, but I didn’t,” he recalls. He finally learned about it when Rockefeller University president Richard Lifton called Young on his cell phone. “This really did take me surprise,” Young said later at a news conference. “I had trouble even putting my shoes on this morning. I’d go pick up the shoes and realize I needed the socks. And then ‘I should put my pants on first.’”
biology The study of living things. The scientists who study them are known as biologists.
blood pressure The force exerted against vessel walls by blood moving through the body. Usually this pressure refers to blood moving specifically through the body’s arteries. That pressure allows blood to circulate to our heads and keeps the fluid moving so that it can deliver oxygen to all tissues. Blood pressure can vary based on physical activity and the body’s position. High blood pressure can put someone at risk for heart attacks or stroke. Low blood pressure may leave people dizzy, or faint, as the pressure becomes too low to supply enough blood to the brain.
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.
chemical A substance formed from two or more atoms that unite (bond) in a fixed proportion and structure. For example, water is a chemical made when two hydrogen atoms bond to one oxygen atom. Its chemical formula is H2O. Chemical also can be an adjective to describe properties of materials that are the result of various reactions between different compounds.
chronic A condition, such as an illness (or its symptoms, including pain), that lasts for a long time.
chronobiologist A scientist who studies circadian rhythms.
circadian rhythms Biological functions, such as cycles of body temperature and sleeping or wakefulness, that occur on a roughly 24-hour schedule.
cytoplasm The liquid or jellylike material that makes up most of a cell and exists outside of its nucleus. Some important functional components of a cell exist in this cytoplasm, such as mitochondria, which break down nutrients and convert them into a form of useful energy.
depression A low spot, such as in a field or the surface of a rock. (in medicine) A mental illness characterized by persistent sadness and apathy. Although these feelings can be triggered by events, such as the death of a loved one or the move to a new city, that isn’t typically considered an “illness” — unless the symptoms are prolonged and harm an individual’s ability to perform normal daily tasks (such as working, sleeping or interacting with others).
diabetes A disease where the body either makes too little of the hormone insulin (known as type 1 disease) or ignores the presence of too much insulin when it is present (known as type 2 diabetes).
feedback A process or combination of processes that propel or exaggerate a change in some direction. For instance, as the cover of Arctic ice disappears with global warming, less of the sun’s warming energy will be reflected back into space. This will serve to increase the rate of Earth’s warming. That warming might trigger some feedback (like sea-ice melting) that fosters additional warming.
fruit flies Tiny flies belonging to the species Drosophila melanogaster. Scientists often use these short-lived animals as a “guinea pig” for lab studies because they are easy to grow, can mature into adults in a short time and their bodies share many of the same traits and responses as more complex animals — including mammals.
function A relationship between two or more variables in which one variable (the dependent one) is exactly determined by the value of the other variables.
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.
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.
jet lag A temporary disruption of bodily rhythms caused when someone travels across several time zones in a matter of hours.
mechanism The steps or process by which something happens or “works.” It may be the spring that pops something from one hole into another. It could be the squeezing of the heart muscle that pumps blood throughout the body. It could be the friction (with the road and air) that slows down the speed of a coasting car. Researchers often look for the mechanism behind actions and reactions to understand how something functions.
molecular biology The branch of biology that deals with the structure and function of molecules essential to life. Scientists who work in this field are called molecular biologists.
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.
network A group of interconnected people or things. (v.) The act of connecting with other people who work in a given area or do similar thing (such as artists, business leaders or medical-support groups), often by going to gatherings where such people would be expected, and then chatting them up. (n. networking)
neuroscientist Someone who studies the structure or function of the brain and other parts of the nervous system.
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.
nucleus Plural is nuclei. (in biology) A dense structure present in many cells. Typically a single rounded structure encased within a membrane, the nucleus contains the genetic information.
obesity (adj. obese) Extreme overweight. Obesity is associated with a wide range of health problems, including type 2 diabetes and high blood pressure.
organism Any living thing, from elephants and plants to bacteria and other types of single-celled life.
phenomena Events or developments that are surprising or unusual.
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.
Journal: J. L. Price et al. double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation. Cell. Vol. 94, July 10, 1998, p. 83. doi:10.1016/S0092-8674(00)81224-6.
Journal: L. B. Vosshall et al. Block in nuclear localization of period protein by a second clock mutation, timeless. Science. Vol. 263, March 18, 1994, p. 1606. doi: 10.1126/science.8128247.
Journal: P. E. Hardin, J. C. Hall and M. Rosbash. Feedback of the Drosophila period gene product on circadian cycling of its messenger RNA levels. Nature. Vol. 343, February 8, 1990, p. 536.
Journal: P. Reddy et al. Molecular analysis of the period locus in Drosophila melanogaster and identification of a transcript involved in biological rhythms. Cell. Vol. 38, October 1984, p. 701.