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Dawn to Dusk

How small can a biological clock get?

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Whether we are early birds or night owls, our routine relies on internal mechanisms called circadian clocks that orchestrate 24-hour cycles of activity. Dr. Gad Asher of the Biomolecular Sciences Department of the Weizmann Institute of Science and his team are studying the mechanisms that make these clocks tick. Circadian clocks are found in every organism that can sense light, including humans. Until several years ago it was believed that a master clock in the brain dictates the timing for all the different organs in the body. Nowadays, we know that every one of our bodies’ cells contains a circadian clock, and these keep time independently – even if the cell is removed from the body and grown in a lab dish.

Research student Rona Aviram in Asher’s lab has been exploring the question of whether circadian clocks exist in even smaller units – the subcellular organelles. The answer to this question may shed light on the evolution of circadian clocks, particularly the development of the molecular, cellular and organ-wide systems in mammals.   

(l-r) Dr. Marina Golik, Meytar Zabar, Dr. Benjamin Ladeuix, Rona Aviram, Dr. Gad Asher, Dr. Yaarit Adamovich and Gal Manella

How does one measure internal time? The botanist Carl Linnaeus created his Horologium florae, or “flower clock,” based on the fact that different flowers open their petals at different hours of the day, each according to its circadian clock. In researching cells, says Aviram, scientists often use changes in gene expression as a proxy for the clocks: The expression of many genes peaks just once a day, some early in the morning others late at night. “We needed an equivalent measure for clocks in organelles, and we chose to observe lipid levels – fatty molecules that have many metabolic functions in the cell. Lipids are found in the nucleus as well as in the organelles known as the mitochondria, and they often play a role in the interactions each organelle has with its surroundings, participating in a large number of cellular processes over the course of the day,” she says.

The scientists thus performed detailed measurements of various lipids, around the clock, in cell nuclei and mitochondria that had been isolated from the livers of mice. Indeed, an unexpected 30% of the lipids the group measured in both organelles showed circadian rhythms, peaking once a day. More surprising was their finding that the circadian peaks differed from organelle to organelle. In the cell nucleus, the lipid build-up occurred at the beginning of the daylight hours, while in the mitochondria, the opposite took place, the lipids accreting there as night fell. It seemed as if each organelle was in a different “time zone.”

Circadian clocks may serve to coordinate the daily rhythms among the different organelles

Are such lipid peaks also linked to mealtimes? In the original trial, the mice had unlimited access to food; since they are naturally nocturnal, they ate around 70% of their food at night. The scientists then restricted their mealtimes to night, alone. This time, the lipid profile was overturned, the nuclear lipid levels now peaking at dusk, while those of the mitochondria, which had formerly peaked at dusk, now did so at dawn. This suggests that these two rhythms are not completely independent – some mechanism may synchronize them so that the peak of one always coincides with the low point of the other.

The scientists think that circadian clocks may serve to coordinate the daily rhythms among the different organelles. Do the cycles the research group observed reflect the individual clocks in the organelles? Does the ticking of our biological clocks start from the bottom up, or are the peaks and lows of the organelle activities controlled at a higher level? The scientists hope that future research will answer these questions. 

Dr. Gad Asher's research is supported by the Yeda-Sela Center for Basic Research; the Adelis Foundation; and the Crown Endowment Fund for Immunology Research. Dr. Asher is the incumbent of the Pauline Recanati Career Development Chair. 


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