Understanding the parts in terms of the whole

Abstract

Metabolism is usually treated as a set of chemical reactions catalysed by separate enzymes. However, various complications, such as transport of molecules across membranes, physical association of different enzymes, giving the possibility of metabolite channelling, need to be taken into account. More generally, a proper understanding of the nature of life will require metabolism to be treated as a complete system, and not just as a collection of components. Certain properties of metabolic systems, such as feedback inhibition of the first committed step of a pathway, make sense only if one takes a broader view of a pathway than is usual in textbooks, so that one can appreciate ideas such as regulation of biosynthesis according to demand. More generally still, consideration of metabolism as a whole puts the emphasis on certain systemic aspects that are crucial but which can pass unnoticed if attention is always focussed on details. For example, a living organism, unlike any machine known or conceivable at present, makes and maintains itself and all of its components. Any serious investigation of how this can be possible implies an infinite regress in which each set of enzymes needed for the metabolic activity of the organism implies the existence of another set of enzymes to maintain them, which, in turn, implies another set, and so on indefinitely. Avoiding this implication of infinite regress represents a major challenge for future investigation.

Fundamental issues in systems biology

“…It is crucial, they argue, 'to analyse systems as systems, and not as mere collections of parts' in order to understand the emergent properties of component interactions. (43,27,34) Systems are taken to constitute a fundamental ontological category, and differences between biological and 10 human-made (engineered) systems are considered less important than their similarities. (44,34) Although this form of systems biology developed in response to the genomics 'revolution', it draws on much earlier systems theorists such as cyberneticists Norbert Wiener (45) and W. Ross Ashby (46) , general and organismal system theorist Ludwig von Bertalanffy, (47,48) mathematical biophysicists Nicolas Rashevsky (49) and Robert Rosen, (50) …”

Putting the Systems Back into Systems Biology

“…If we regard it as unsatisfactory or just wrong, we need to propose an alternative; we cannot pretend that there is no question to be answered. In summary, the classical reductionist approach to science can be understood as a way of understanding the functioning of a whole system in terms of the properties of its parts, but now we must learn to understand the parts in terms of the whole (Cornish-Bowden et al 2004).To make Rosen's ideas more easily intelligible to biologists, they will need to be put in the context of current knowledge of biology, and the limits within which his interpretation of the circular organization of living organisms can apply need to be specified (Letelier et al 2006). I have concentrated here on Robert Rosen's ideas, because of all the current approaches to our understanding of the nature of life they appear to me to be the most promising.…”

Strengths and Weaknesses of Selected Modeling Methods Used in Systems Biology

“…Such changes of concentration are expressed as a function of rates of reaction and appropriate stoichiometric coefficients. Reaction rates, in turn, can be of several types, such as the mass action law (Guldberg and Waage 1879), the Michaelis-Menten rate law (Briggs and Haldane 1925;Michaelis and Menten 1913), or more complicated forms to attain some specific kinetics (Cornish-Bowden et al 2004;Klipp et al 2005;Koshland, Nemethy, and Filmer 1966;Liebermeister and Klipp 2006;Monod, Wyman, and Changeux 1965). The use of kinetic ODE modeling using rate laws has been the cornerstone of our traditional biochemical terminology and thinking.…”