The new era: the Tivoli of life

Hans V. Westerhoff1, Karin A. Reijenga1, Jacky L. Snoep1,2, Jasper A. Diderich1, Henk W. van Verseveld1, Martin Bier3, Boris N. Kholodenko4, Barbara M.Bakker1 and Bas Teusink5

 

1BioCentrum Amsterdam, EU, 2University of Stellenbosch, RSA, 3Thomas Jefferson University, Philadelphia, PA, USA, 4East Carolina University Department of Physics, Greenville, USA, and 5TNO-Leiden, EU

 

 

The completion of the inventory of a number of living organisms that took place at the end of the previous millenium, has invalidated the excuse that biology cannot be exact because it is necessarily incomplete. Indeed, the concentrations of the transcripts of all the genes of the Baker's yeast S. cerevisiae can now be measured. The results have surprised some observers: a functional change appears not to be accompanied by the altered expression of a single, 'key' gene, but rather by a multitude of genes. Others recognized that all but the simplest living organisms are much more complex that simple.

The concept that important cellular processes at steady state need not be determined by a single molecular process was made scientific for metabolic fluxes by Metabolic Control Analysis, and for gene expression and signal transduction by Hierarchical Control Analysis. However, life is not always steady and we have sought to extend the quantitative analysis of subtle control to dynamic and talkative cells. Here we shall discuss the quantitative experimental and theoretical analysis of a steady dynamic system, i.e. that of communicating yeast cells engaging in sustained glycolytic oscillations.

We shall review a few of the experimental requirements for the observation of sustained glycolytic oscillations and demonstrate that the oscillations are (almost) implied by yeast biochemistry, as evident from computational biochemistry. We shall also develop some of the control theory for autonomous and forced oscillations. This then leads us back to the bench to demonstrate that the frequency of the oscillations is not only controlled by phosphofructokinase, bringing home the message that also cell dynamics is controlled in a distributed fashion. Perhaps the most important message is that we need no longer be limited to the study of dead or dull cells. It is time for Tivoli: the science of cell dynamics is there to stay, as a science with precise experimentation and precise theory on an exciting and most important topic.