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As Time Glows By: Circadian Rhythms in Cyanobacteria from Molecules to Populations

Van Leeuwenhoek Lecture on BioScience.

Carl Johnson is Stevenson Professor of Biological Sciences and Professor of Molecular Physiology and Biophysics at Vanderbilt University, Nashville. His specialization is Cellular, Molecular and Evolutionary Analyses of Biological Clocks.

Organisms and even single cells have endogenous biological “clocks” that allow them to tell the time of day. Research in his laboratory is directed towards understanding the cellular and molecular basis of these timing mechanisms in a variety of organisms: cyanobacteria, plants and animals.

To analyze the molecular nature of the clock in the prokaryotic cyanobacteria, his group has developed a bioluminescent reporter strain that expresses a daily rhythm of light emission. Using this bioluminescence rhythm as a marker, clock mutants have been identified.

In cooperation with others, his group is applying biophysical methods to explain how bacterial clock proteins oscillate in vitro.

His group also studies the neuroscience of the circadian rhythm in mammals (brain slices in vitro). As a model a fibroblast cell line is used, which is stably transfected with a luciferase reporter and which glows rhythmically.

Recently the studies are extended to the genetics of the human biological clock.

His group developed BRET (Bioluminescence Resonance Energy Transfer). This technique has allowed them to develop new reporters for intracellular calcium and hydrogen ions.

“Chronobiologists” study biological oscillators, the most prominent being circadian rhythms that are circa-24h “clocks” that act as biological timekeepers to help organisms adapt optimally to the daily light/dark (and temperature) cycles that result from the earth’s rotation. Twenty-five years ago, chronobiologists did not believe that prokaryotic organisms (aka bacteria) had circadian oscillators. This idee fixe was overturned by discoveries from our laboratory and others that demonstrated a bona fide circadian clock system in prokaryotic cyanobacteria (aka blue-green algae). Since that time, tremendous strides have been accomplished in our understanding of this bacterial clock system, which has remained at the forefront of circadian rhythm research. For example, the cyanobacterial system provided the first rigorous tests of the adaptive significance of circadian clocks. Moreover, the cyanobacterial clock proteins KaiA, KaiB, and KaiC were the first to have their crystal structures solved. Most remarkable was the first demonstration of a biochemical oscillator reconstituted from purified KaiA, KaiB, and KaiC proteins in vitro. In a fundamental sense eukaryotic clock systems may be organized very similarly to the cyanobacterial system, including multiple oscillators that are coupled to promote resilience. Moreover the cyanobacterial circadian program regulates gene activity and metabolic pathways, and it can be manipulated to improve the expression of practically useful bioproducts (e.g. , biofuels, biopharmaceuticals) using cyanobacteria as bioreactors. Finally, we are extending our studies on the adaptive value of circadian rhythms in cyanobacteria to other bacteria that have KaiB and KaiC genes to illuminate the steps by which biological clocks may have evolved.