Biochemical networks are the central processing units of life. They can perform a variety of computational tasks analogous to electronic circuits. Their design principles, however, are markedly different: in a biochemical network,computations are performed by molecules that chemically and physically interact with each other. The aim of the Biochemical Networks group and group leader Pieter Rein ten Wolde is to unravel their design principles using a combination of database analyses, theory and computer simulation.
The biological clock in dividing cells: a robust design
Researchers from FOM institute AMOLF and the University of Michigan have discovered how the biological clock of an organism remains stable, even when the cells of that organism grow and divide. On March 28, 2016, in the Proceedings of the National Academy of Sciences (PNAS) USA, they provide a mathematical model that explains the robust functioning of the biological clock.
Nearly all organisms have a day-night rhythm as a result of which certain activities, such as eating and sleeping, take place at fixed moments of the day. This rhythm is dictated by biochemical oscillators in the cells of the organism with a period of 24 hours: the circadian clock (from the Latin words circa -about – and diem – day). Up until now it was not clear how that clock is able to continue to tick with a stable rhythm in growing and dividing cells, which also duplicate the components of the clock.
Growing and dividing cells go through a cell cycle in which all the components of the cell are copied, including the DNA and the genes it contains. This results in a periodic doubling of the production rate of the proteins that form the biological clock. In existing theories of how clocks work, this doubling of the production rate dramatically perturbs the 24-hour rhythm of the clock. This periodic perturbation can lock the circadian clock to the cell cycle, meaning that the clock no longer ticks with its own rhythm, but with that of the cell cycle. “The clock and the cell cycle tick in synchrony, just as the physicists Huygens showed back in the 17th century for two connected pendulums,” says Joris Paijmans, PhD researcher in the Biochemical Networks group of AMOLF. “Depending on the growth conditions, the cell cycle has a duration of several hours to several days. Therefore it would be impossible for a biological clock coupled to the cell cycle to maintain a fixed period of 24 hours.”
Figure 1. Artist’s impression of the cycle of the circadian clock.
The figure shows clocks that are broken down over time but are replaced every 24 hours. Researchers from FOM institute AMOLF have revealed how these clocks can nevertheless continue to tick stably.
For one of the best characterized clocks in biology, that of a cyanobacterium, Paijmans and his colleagues identified two mechanisms that might protect the biological clock from the disruption caused by cell division. On the one hand the most important clock proteins were found to undergo various chemical changes in the 24-hour cycle. This modification cycle makes the clock less sensitive to changes in the production rate of the clock proteins. In addition, the cell contains several chromosomes that do not divide simultaneously, as a result of which the production rate of the clock proteins proceeds more evenly. Paijmans: “Mathematical modeling revealed that a biological clock with these two ingredients is stable and ticks with a period of 24 hours, irrespective of the growth rate of the cell.”
Radio interview Joris Paijmans
Biologische klokken lopen verrassend goed
Figure (left). Snapshot of a simulation of a signal transduction pathway (MAPK)
The Biochemical Network group develops and applies new numerical techniques that make it possible to simulate biochemical networks at the particle level in time and space