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