Time before time?

Pretty much anything that ever sees the sun goes through regular daily rhythms governed by the cycle of light and darkness. Humans tend to sleep at night and be more active during the day (students may not be quite human :-P). Many planktonic organisms feed near the ocean surface at night and migrate to greater depth to avoid predators during the day. External factors like light set the clock, but the cogwheels are the so-called clock genes. Clock genes such as Period and Bmal form an interacting network that results in each gene going through cycles of activity, which ultimately translates to the more obvious changes in physiology and behaviour that we see.

Or at least that’s the traditional wisdom. I came across this study today that challenges the role of clock genes, at least in the rather artificial environment of a stem cell culture. Paulose et al. (2012) used embryonic stem cells from mice to find out when the clock starts ticking. Their hypothesis, based on previous stem cell studies, was that it remains silent so long as the cells remain in a stem cell state. They expected daily rhythms to appear when the cells started differentiating.

Which is not quite what they found. The clock genes whose activity they measured did indeed begin cycling only when they let the cells differentiate. In undifferentiated stem cells, their expression was either absent or irregular. However, the stem cells’ metabolism went through cycles even when the scientists chemically prevented them from differentiating. They took up more glucose at certain times of the day than others, and they made more of a certain glucose-transporting protein at these times. The rhythm became like ten times stronger when the clock genes started working, but it was there even without them.

Now (disclaimer!), I didn’t read the study in detail, but on the face of it I find its results really interesting. It’s as if mammalian cells have several ways of keeping time. Why? Isn’t one enough? And how exactly do the stem cells achieve a rhythm if it’s not through the usual avenues? Are we going to discover another clock network? And, importantly, is this something that happens in real intact embryos, or only in stem cells living in a dish?



Paulose JK et al. (2012) Towards the beginning of time: circadian rhythms in metabolism precede rhythms in clock gene expression in mouse embryonic stem cells. PLoS ONE 7:e49555


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