Chronobiology Researchers Say Their Field's Time Has Come

Sidebars: Chronobiology Resources A Survey of Clock Genes Like many life sciences, chronobiology is a field that has transitioned from the organismal level, to anatomical dissection, to molecular analysis. The emerging biochemical view of circadian and other biological rhythms is revealing how organisms assess and respond to oscillating (back and forth) environmental cues that result from the Earth's movements. "All such biological clocks are adaptations to life on a rotating world," says William Schwartz, a professor of neurology at the University of Massachusetts Medical School in Worcester. Early work in the field focused on documenting the existence of biological rhythms, and then on identifying parts of the nervous system that could be, or house, a clock mechanism. Today, researchers are pinpointing genes whose protein products constitute the workings of biological clocks. EVOLUTIONARY CLUE: Michael Young says biological clock mechanisms may help to determine species origin. Researchers have long suspected that biological clocks are both ancient and essential, simply because all organisms seem to have some variation on the clock theme, from bacteria to complex plants, fungi, and animals. "The players [species] today may look different, but in the long run, I'd bet this kind of strategy -- a biological clock -- is widespread in evolution," says Michael Young, Howard Hughes Medical Institute investigator and director of the Center for Biological Timing at Rockefeller University. Different species that have clock molecules in common suggest descent from a common ancestor, Young notes. With this diversity of organisms to choose from to study internal clocks, professional gatherings of chronobiologists are an interesting mix, according to researchers in the field. The Society for Research on Biological Rhythms, based at Northwestern University, meets every other year, alternating with Gordon Conferences on chronobiology. Most chronobiologists also belong to the Society for Neuroscience -- because biological clocks are rooted in the brain and often involve behavior -- as well as to other organizations specific to their model organisms. "Meetings are wonderful. People from all kinds of fields are thrown together," comments Schwartz. "I'm a clinical neurologist, yet one of my friends from the society works with fruit flies, another with Neurospora. I don't know any other neurologist who keeps that kind of crowd!" His own work illustrates that diversity -- Schwartz helped to identify the anatomical seat of the biological timeclock in rats in the 1970s, yet recently published a short report in Nature evaluating the effect of jet lag on performance of professional baseball players (L.D. Recht, R.A. Lew, W.J. Schwartz, Nature, 377:583, 1995). Biological clocks provide two functions, according to Schwartz -- they permit awareness of local change, like a sundial, and also measure the passage of time, like an hourglass. "This allows the organism to maintain an internal temporal order, and to anticipate change. If you are a mouse, it is useful to be able to anticipate when an eagle will fly and already be in your burrow, rather than be caught scurrying into it," he adds. At the molecular level, a biological clock is a system of oscillating levels of proteins, controlled by transcription factors, which are proteins that turn particular genes on or off. In a suite of three papers,Young's group reports in the November 3 issue of Science on the molecular workings of a major clock in Drosophila, consisting of two proteins that control and carry out oscillation (M.P. Myers et al., 270:805- 8, 1995; A. Sehgal et al., 270:808-10, 1995; N. Gekakis et al., 270:811-5, 1995). GOING BACK AND FORTH: Jay Dunlap says "everyone is working on" questions regarding oscillation. Oscillation lies at the heart of chronobiology. "The three questions everybody is working on are: How does the oscillator work?; How is it synchronized with external cues?; and How is time information given by the oscillator transduced to the rest of the cell?" observes Jay Dunlap, a professor of biochemistry at Dartmouth Medical School. Work on different organisms is illuminating different portions of the circadian biological clock -- environmental input, the oscillating mechanism, and the organism's response. Dunlap relates that work on plants focuses on the output; research on Drosophila concentrates on the oscillator mechanism; and studies of the bread mold Neurospora crassa target the oscillator and output genes (see accompanying story). Chronobiologists identify a few key people and events as pivotal to their field. Dunlap calls Colin Pittendrigh, a professor, emeritus, of biology at the University of Montana in Bozeman, the "dean of rhythms." Dunlap explains: "Almost everyone working on clocks traces their lineage to him. He studied Drosophila, but phenomenologically, focused on circadian rhythms, not genetics [C.S. Pittendrigh, Proceedings of the National Academy of Sciences, 40:1018-22,1954]." In 1972, two key papers drove the field a giant step forward. Robert Moore, director of the University of Pittsburgh's Center for Neuroscience, and Irving Zucker, a professor of psychology and integrative biology at the University of California, Berkeley, identified the brain's seat of circadian cycling in rats -- the suprachiasmatic nuclei (SCN) -- in a pair of articles (R. Moore, V.P. Eichler, Brain Research, 42:201-6, 1972; I. Zucker, F.K. Stephan, PNAS, 69:1583-6, 1972). "These two papers were critical because neuroscientists all of a sudden had locations in the brain to study," says Fred Turek, director of the Center for Circadian Biology and Medicine at Northwestern University. At about the same time, the first piece to the genetic puzzle underlying biological clocks was uncovered by Ron Konopka, a grad student in the California Institute of Technology laboratory of biology professor Seymour Benzer. They discovered the gene period (per). Mutations in this gene alter or abolish the daily cycle of locomotor activities and eclosion (emerging from pupae) in Drosophila melanogaster. "The genetic approach to chronobiology really began in 1971, with the isolation of the per mutation in Drosophila. Still, everyone thought they [Konopka and Benzer] were crazy, because behavior was too complicated to analyze," recalls Joseph Takahashi, a professor of neurobiology at Northwestern University, who works on a gene called clock in mice. In 1984, senior investigator Michael Young at Rockefeller University and professors of biology Michael Rosbash and Jeffrey Hall at Brandeis University cloned and characterized the per gene. SETTING THE CLOCK: Joseph Takashashi's mice with mutant clock genes are on different schedules. "Identification of the SCN and per kept the field chugging along from 1972 to 1985. By then, the field's diversity was becoming unmanageable," says Turek. The time was right for a journal and organization to unite the field. The Journal of Biological Rhythms debuted in 1985, and the Society for Research on Biological Rhythms was formed in 1987, with Turek its first president. As chronobiology gained acceptance in the life science community, funding grew. Turek and Takahashi at Northwestern, Michael Young at Rockefeller, and Gene Block, director of the Center for Biological Timing at the University of Virginia, applied as a consortium to the National Science Foundation's science and technology center program, which, according to Turek, "funds everything from cement science to superconductors, but not much in biology." However, the group won an 11-year, $1 million-a-year grant in 1989. Recently the consortium added Rosbash and Hall's groups at Brandeis. NSF support of chronobiology is very visible, says Turek, because of the consortium-center setup. But other agencies contribute. "Who's funding the other 400 researchers? Ninety percent of it comes from [the National Institutes of Health], particularly the National Institute on Aging, the National Institute of Neurological Diseases and Stroke, the National Institute for Child Health and Human Development, and the National Institute of Mental Health," says Turek. The Howard Hughes Medical Institute partially supports Young's laboratory. Potential practical applications have fueled funding, says Turek. "As the field evolved scientifically, at the same time, human applications were becoming more apparent -- such as jet lag, shift-worker problems, and sleeping disorders," he explains. "If we understand the biologic basis of circadian rhythms, we can get a handle on the etiology of these other disorders," he adds. Ricki Lewis, a writer based in Scotia, N.Y., is the author of several biology textbooks. She is online at 76715.3517@compuserve.com

Chronobiology Researchers Say Their Field's Time Has Come

Like many life sciences, chronobiology is a field that has transitioned from the organismal level, to anatomical dissection, to molecular analysis.

Interested in reading more?

Become a Member of