Academic journal article Genetics

Salad Days in the Rhythms Trade

Academic journal article Genetics

Salad Days in the Rhythms Trade

Article excerpt

ONE of the nicest things anyone ever said about our workwas ina(necessarily) anonymous grant review fromthe early 1990s inwhich the author commented that our lab had contributed greatly to moving the study of circadian rhythms "out of the era of spoon-bending." Some years later Bob Metzenberg, who always cherished a well-turned phrase, fessed up to having written this,and it is easy to see his quick wit and word play. I mention it here because it nicely encapsulates the 25 years that I want to cover, a period that extends from the era when belief in intracellular circadian rhythms stretched the credibility of all but devotees to the years when the problem was cracked and rhythms truly entered mainstream science (SCIENCE NEWS and EDITORIAL STAFFS 1997, 1998). During this time, analysis of rhythms moved from the use of genetics-which opened up the black box and exposed the feedback loops-to molecular biology, where the field is now. Although it is tempting to write about all the vistas that opened up during this time based on work in Neurospora, from clock mechanism to clock output, I have restricted this Perspectives to studies on the circadian mechanism and will leave output to other, highly capable hands (LOROS 2008). It is an account of what drew me to rhythms work and to the Neurospora circadian system and of what led our lab to identify the factors and interactions that contributed to the denouement of the question of the molecular bases of circadian rhythms: the assembly, a little over a decade ago, of a complete interconnected regulatory cycle.

EARLY DAYS: THE LURE OF IGNORANCE

I never intended to study rhythms or work on Neu-rospora. My undergraduate degrees in oceanography and chemistry were aimed at a career in oceanography, but on a whim I also applied to graduate school in biology at Harvard where I ended up. Interactions with J.W. ("Woody") Hastings led me to bioluminescence in marine organisms, and it was a short step from there to circadian regulation of bioluminescence and to circadian biology. (Why bother to make light during the daytime?) Rhythms struckmeas a field in which few were even pursuing the right questions and where an ultimate molecular resolution was nowhere even remotely in sight. This impression was confirmed during a 10-week summer course on rhythms run by Colin Pittendrigh at the Hopkins Marine (dubbed Murine Station, since Pitt then worked on mice) in Pacific Grove, California, in 1977, where nearly an entire generation of rhythms biologists from the United States first met each other. The truly vast biology of the field-from microbial rhythms in bioluminescence to photoperiodism in plants, to activity rhythms in mice, to psychiatric illness in people-was unified by the characteristics of the underlying clock to the extent that one dared to hope that a single mechanism might underlie all of it. Those unifying characteristics, needed to accommodate and explain all this biology, were sufficiently distinct to delineate a field: a circadian rhythm, as the name suggests, has a period of about a day (absent any environmental cues) but can be entrained by environmental cycles to exactly match their periods. Moreover, the period length is close to the same when measured under different ambient temperatures ornutritional conditions (SWEENEY 1976). Other biological rhythms-those with extra long or really short period lengths, those whose period changed markedly with temperature, and those measured only under light-dark cycles-were not (and are not) counted as circadian rhythms; this distinction kept research focused on a single mechanism and this focus was crucial to solving the problem.

CIRCADIAN BIOLOGY IN THE PREMOLECULAR ERA

By the late 1970s, genetic approaches to the pursuit of rhythms had virtually ground to a halt, given the near impossibility of pursuing genetic leads at the molecular and biochemical level. An additional and influential factor was the open disbelief in the validity of this approach expressed by leaders in the field of rhythms, whose backgrounds were chiefly in physiology and anatomy. …

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