Journal of Theoretical Biology 252 (2008) 411–418 Self-organization at the origin of life $ Athel Cornish-Bowden à , Marı´a Luz Ca´rdenas Unite´de Bioe´nerge´tique et Inge´nierie des Prote´ines, Centre National de la Recherche Scientifique, 31 chemin Joseph-Aiguier, B.P. 71, 13402 Marseille Cedex 20, France Received 15 May 2007; received in revised form 20 July 2007; accepted 20 July 2007 Available online 14 August 2007 Abstract The concept of an ðM; RÞ system with organizational invariance allows one to understand how a system may be able to maintain itself indefinitely if it is coupled to an external source of energy and materials. However, although this constitutes an important step towards understanding the difference between a living and a non-living system, it is not clear that an ðM; RÞ system with organizational invariance is sufficient to define a living system. To take a further step towards defining what it means to be alive it is necessary to add to a simple ðM; RÞ system some property that represents its identity, and which can be maintained and modified in subsequent generations. r 2007 Elsevier Ltd. All rights reserved. Keywords: (M, R) systems; Metabolism-repair systems; Robert Rosen; Metabolic closure 1. Introduction Reinhart Heinrich was one of the great biologists of recent years, and one of the founders of what is now called systems biology. His major contributions to our under- standing of biological systems have yet to attain the full recognition that they deserve, but this will come: eventually it will be realized that the reductionist approach that has dominated biochemistry for a century is coming to the end of what it can achieve, even though it has been responsible for the tremendous advances in knowledge and under- standing in biochemistry that have occurred since Buchner (1897, 1997) found that alcoholic fermentation could occur in cell-free extracts of yeast. In showing that at least some of the properties of living organisms could be explained in terms of their components Buchner made a major step away from the mystical idea of vitalism that had preceded him, but to go from this to the idea that all of the properties of organisms are just the sum of the properties of the components is to go too far. Heinrich’s earliest papers (Heinrich and Rapoport, 1973, 1974a, b) were revolutionary, as he was one of the first to break away from the traditional way of thinking of metabolism as just a collection of reactions catalysed by a collection of more or less independent components. His ideas, together with those of Kacser and Burns (1973), forced biochemists to start looking at systems as integrated wholes. Metabolic control analysis, which grew out of these landmark papers, is sometimes seen, for example by Atkinson (1990), as antithetical to the classical view of metabolic regulation in terms of cooperativity, allosteric interactions and feedback inhibition, and even some authors in metabolic control analysis write as if they regard the classical approach as irrelevant. In fact, however, although the classical approach puts the empha- sis on individual enzymes, whereas metabolic control analysis puts it on systems of enzymes, they are both necessary for a full understanding of metabolic regulation (Hofmeyr and Cornish-Bowden, 1991, 2000; Letelier et al., 2005). Understanding metabolic regulation is itself only a step towards understanding the logic of a living organism, which involves much more than that. A vital point that is usually entirely absent from discussions of life is that nearly all of the catalysts used by organisms are themselves products of the organism. This not only makes the usual ARTICLE IN PRESS www.elsevier.com/locate/yjtbi 0022-5193/$ - see front matter r 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.jtbi.2007.07.035 $ This paper is dedicated to the memory of Reinhart Heinrich (1946–2006), who did much to foster the idea that living systems cannot be understood just as collections of components, because they need to be studied as complete systems, with properties that make sense only in terms of the complete systems. à Corresponding author. Tel.: +33 491 164138; fax: +33 491 164661. E-mail address: acornish@ibsm.cnrs-mrs.fr (A. Cornish-Bowden).