The Control Analysis of Signal Transduction - Systems Biology of Metabolic and Signaling Networks - page 36

3.1 From Physics to Life Through Systems Biology
For many years, in what has been referred to as the reductionist approach, it was
believed that once all the parts of a living organism would have been characterised,
the whole organism or any subsystem thereof would be understood without further
ado. Obtaining the complete genome sequence of the human was partly driven by
this motivation: knowing all the genes would imply understanding of the
corresponding living system. For cell biology, the system could correspond to the
functioning of a particular cell, the components being all the pathways, genome-
wide, inclusive of signal transduction, gene expression, and metabolism. For
biochemistry, a subsystem might be a particular metabolic pathway, and the
components would be all enzymes and metabolites in that pathway. Such pathways
can now be found as elementary modes or extreme pathways in the consensus
metabolic map of the human (Thiele et al. 2013 ).
Is the concept that the whole is the sum of the parts always true, always false, or
does it depend on the property one takes into consideration and the type of system at
hand? Well, there are cases where the concept does apply: If the focus of interest
were the mass of an organism, or the number of grams of carbon flowing out of a
system, then the reductionist approach would be perfectly alright; the whole mass is
the sum of the masses of the components and the carbon influx is the simple sum of
the number of grams of carbon flowing through all fluxes into the system. Also, the
sum of all the fluxes that consume leucine or virtually any other metabolite in any
living organism must equal the sum of all the fluxes that produce it, at steady state, a
property defining much of flux and flux balance analysis, which thereby is a
powerful linear methodology leading to analytical solutions (Westerhoff and
Palsson 2004 ).
In many such cases where the whole equals the sum of the parts, biology has in
common with physics. Biology is also different from physics however: biology
relates to function (Boogerd et al. 2005 ; Westerhoff et al. 2009b ; Kolodkin
et al. 2012 ), where function is defined by what promotes maintenance and amplifi-
cation in a dynamic environment. This functional aspect requires improving on
physics in terms of accelerating processes that also happen in physics, such as the
breakdown of glucose to lactic acid. It also requires carrying out processes that are
impossible in physics alone. It requires robustness of these processes vis- ` -vis
intrinsic noise as well as perturbations or extrinsic noise. And it requires proper
adjustment of processes when conditions change.
The acceleration has been achieved by the evolution of protein-based catalysts,
the concentration of which a living organism can increase by increasing gene
expression. The “impossible processes” have become possible by enzymes and
networks that couple “endergonic” processes, which are uphill in terms of Gibbs
free energy, to other processes that are downhill (Caplan and Essig 1969 ;
Westerhoff and Van Dam 1987 ). The synthesis of ATP from ADP and inorganic
phosphate, for instance, is thermodynamically impossible at the intracellular
concentrations of the reactants, yet proceeds because it is coupled to the oxidation