been PERFRQT, reflecting the Drosophila period gene Dartmouth Medical School and the Neurospora frequency gene (the fruits of the Hanover, New Hampshire 03755 first decades of genetic and molecular genetic analysis of clocks) and the fact that the Drosophila timeless gene, tim, was still in the process of arriving. This era was Life is a cyclical chemical process that is regulated in spent convincing ourselves that such genes really were four dimensions. We distinguish parts of the cycle: dethe key to understanding how clocks work. Flies and velopment describes the changes from single cell to fungi were PERFRQT systems for working out basic adult, and aging the changes from adult to death. Birth tools, paradigms, and approaches-gene products whose to death, a cycle, and there are cycles within cyclesexpression levels themselves oscillate, the importance circannual rhythms, menstrual cycles, semilunar cycles, of negative feedback, criteria to begin to distinguish and daily 24 hr or circadian cycles. which oscillatory gene products might contribute to the Twice a year we get a reminder of the importance of action of an internal timer as distinct from being output our internal circadian biological clocks. Daylight sav-(reviewed in Dunlap, 1996), and a universal appreciation ings: in October we fall back just an hour, and yet we of the importance of genetics. If overall this left us with wake up an hour early on Monday anyway and think a less than PERFRQT understanding of timing in genmeals are late-but only for a day, until our clocks are eral, at least many found optimism in the sense that we reset. The reminder is about the way we process enviwere, finally, asking the right questions. This naturally ronmental information and time, namely that we use segued into an interlude where light resetting was exexternal time cues (light and temperature changes that plained by two different mechanisms, through transcriptrack the day without) to set an internal clock that guides tional induction of oscillator components in Neurospora the day within. This internal clock is the lens through (Crosthwaite et al., 1995) or protein turnover in Drosophwhich we survey acute external factors; it takes the lead ila (reviewed in Young, 1998). But by mid 1997 the word in determining what we perceive as time. was PASWCCLK (the first clock components with known It used to be that research in chronobiology moved biochemical functions [transcriptional activators], the along at a gentlemanly pace. It was a field in that it first mammalian clock gene, and the first protein domain shared a common set of problems, a common vocabu-[PAS] conserved among clock molecules from different lary, and a series of common assumptions: only eukaryphyla) and then MPERMPER (mammalian orthologs and otes had real clocks and they probably evolved just paralogs of model system clock genes), and then in mid once, since the basic properties of the rhythms were 1998 the already ungainly CYCBMALJRKDBT (and a generally the same. Any cell in fungi, plants, or protists grand unifying theory for clocks within the animal/fungal could be a clock cell, but only neurons kept time in clade of the crown eukaryotes; e.g., Dunlap, 1998b), and organisms that had them. Input to the clock was readily for the close of 1998 [WHAT WORD?]. So if you can be separable from how the clock itself worked. But within satisfied by intoning the four words in a dimly lit room, the past few years progress in understanding how then enjoy your evening; and if not, read on to find out clocks work in this assemblage of organisms has been who's who in the phylogeny of timers. increasing exponentially, coming to a crescendo during the final half of 1998 in an eruption of data that has Clocks in Cells largely disproven the assumptions and permanently It is now common to begin from a general assertion that, changed the face of the field. The dust is still settling, at the most basic level, circadian oscillators (but not but what we now see, albeit in broad outline, is probably systems) will be describable as a circular list of causes the outline of how a large part of biological timing works and effects that closes within the bounds of a single at the molecular level. It's been quite a ride. cell, even in the most complicated systems like the ver-How'd we get this far? One ought naturally to be able tebrate suprachiasmatic nucleus (SCN) (reviewed in to consult reviews, but there have been so many con-Block et al., 1995; Welsh et al., 1995; Herzog et al., 1998). cerning the molecular analysis of rhythms that clearly Events that happen outside the cell, or interactions of what is needed here is a review of the survey of the the cell with surrounding cells (e.g., Liu et al., 1997a) or reviews. This brings to mind a short story by H. L.
the environment will influence the behavior of the clock-Mencken in which peace of mind was brought to the in-cell, but they are not necessary to describe its progliterary populace in the early 1900s only through the ress. However, events outside clock cells will affect the synthesis and condensation of all of the pertinent literary clock's progress, thus giving rise to the distinction becritiques each week into reviews of reviews and ultitween the circadian oscillator and the circadian system. mately into a grand review word (the first week being Here, the oscillator is taken to mean the minimal set something like MIFLHMP) that readers could read, be of molecular causes and effects sufficient to describe satisfied that they were up to date, and enjoy their evecircadian cycles as they might operate (i.e., what you'd nings being at home, content (Mencken, 1919). For such want to add in a reconstruction experiment to make it a telegraphically quick review of the molecular basis of go). There are three general questions which, if anthe currently understood transcription/translation feedback loop (we'll get to this) circadian oscillators, the swered in terms of genetics and biochemistry, would