The design of biological clocks

Department of Human Science, Faculty of Design
Education and Research Center for Mathematical and Data Science
Associate Professor Hiroshi Ito

   We go to bed and wake up according to a 24-hour cycle, which gives rise to a biological clock. While we do not notice it on a day-to-day basis, we are swiftly reminded of its existence[A1]  when we travel abroad and suffer the effects of jet lag.
   There is a long history of research on what exactly the biological clock is. It has been found that the biological clock in humans and other mammals is a network of several genes that activate and deactivate each other, and this result won the 2017 Nobel Prize in Physiology or Medicine [1].

   Though this discovery won a Nobel Prize, there are still many mysteries about the mammalian biological clock. However, there is one organism whose composition is better understood: a bacteria called cyanobacteria. Cyanobacteria are known to consist of just three kinds of proteins, which can be created in a test tube [2]. As there is no other such example where human hands have extracted the components of a biological clock and put them back together, cyanobacteria are ideal research material for thinking about the design of biological clocks.

Fig. 1 Biological clock rencostituted in a test tube. Mixing the three clock proteins, KaiA, KaiB and KaiC in a test tube lead to the oscillation of ratio. of KaiC phosphorylation.
Adopted from Ito et al.
Nature Struct Mol Biol 2008

   In our group, we have found that cyanobacteria’s biological clocks lose their function when chilled [3, 4], and that this loss is due to a mathematical structure called a Hopf bifurcation. In the Hopf bifurcation scenario, the clock’s amplitude shrinks and ultimately becomes zero, thereby losing its autonomic rhythm. After losing its rhythm, it changes into a damped oscillator, like a pendulum with some frictional force. We have thus found that biological clocks change into pendulums.

Fig. 2 Biological clock turns to a pendulum when chilled. There are two scnenarios for loss of rhythmicy. One is called Hopf bifurcation and the other is SNIC bifurcation. The difference between them is which of amplitude or period significantly changes. Hopf bifurcation occures when KaiC phosphoryolation rhythm is chilled around 20 ºC.
Adopted from Murayama et al. PNAS 2017.

   Pendulums vibrate with a large amplitude when an external force causes them to vibrate at just the right frequency, a phenomenon called resonance. The fact that biological clocks become pendulums at low temperatures suggests that a similar resonance effect may be at work here. When we tested this in our group, we discovered that causing a biological clock that stopped due to low temperature to vibrate increased its amplitude considerably.

   In Japan, which has four seasons, winter temperatures sometimes fall below freezing. Do organisms lose their biological clocks in winter? Perhaps they retain them through resonance. Starting from this hypothesis, we are in the process of advancing our research on the commonalities of wintertime biological clock design in general, beyond cyanobacteria.

Fig. 3 Resonance of biological clock. The temperature cycles with a specific period increases the amplitude of the chilled reconstituted clock.
Adopted from Murayama et al. PNAS 2017.

References

［1］Scientific Background Discoveries of Molecular Mechanisms Controlling the Circadian Rhythm
https://www.nobelprize.org/prizes/medicine/2017/advanced-information/
［2］Nakajima M, Imai K, Ito H, Nishiwaki T, Murayama Y, Iwasaki H, Oyama T, Kondo T.
Reconstitution of circadian oscillation of cyanobacterial KaiC phosphorylation in vitro
Science 308, 414-5 (2005)
［3］Murayama Y, Kori H, Oshima C, Kondo T, Iwasaki H, Ito H
Low temperature nullifies the circadian clock in cyanobacteria through Hopf bifurcation
Proceedings of National Academy of Sciences 114, 5641–5646 (2017)
［4］https://academist-cf.com/journal/?p=5375

Inquiries

Department of Human Science, Faculty of Design
Education and Research Center for Mathematical and Data Science
Associate Professor Hiroshi Ito