Philosophical basis and some historical aspects of systems biology: from hegel to noble - applications for bioenergetic research. Valdur A. Saks, Claire Monge, Rita Guzun To cite this version: Valdur A. Saks, Claire Monge, Rita Guzun. Philosophical basis and some historical aspects of sys- tems biology: from hegel to noble - applications for bioenergetic research.. International Journal of Molecular Sciences, 2009, 10 (3), pp.1161-92. ￿10.3390/ijms10031161￿. ￿inserm-00391381￿ HAL Id: inserm-00391381 https://www.hal.inserm.fr/inserm-00391381 Submitted on 8 Jan 2013 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Int. J. Mol. Sci. 2009, 10, 1161-1192; doi:10.3390/ijms10031161 OPEN ACCESS International Journal of Molecular Sciences ISSN 1422-0067 www.mdpi.com/journal/ijms Review Philosophical Basis and Some Historical Aspects of Systems Biology: From Hegel to Noble - Applications for Bioenergetic Research Valdur Saks 1,2,*, Claire Monge 1 and Rita Guzun 1 1 INSERM U884, Laboratoire de Bioénergétique Fondamentale et Appliquée, Université Joseph Fourier 2280 Rue de la Piscine, BP 53, Grenoble Cedex 9, France; E-Mails: [email protected] (C.M.); [email protected] (R.G.) 2 Laboratory of Bioenergetics, National Institute of Chemical Physics and Biophysics, Akadeemia tee 23,12618 Tallinn, Estonia * Author to whom correspondence should be addressed; E-Mail: [email protected] (V.S.); Tel. +33-476635627; Fax: +33-476514218 Received: 3 February 2009; in revised form: 7 March 2009 / Accepted: 12 March 2009 / Published: 13 March 2009 Abstract: We live in times of paradigmatic changes for the biological sciences. Reductionism, that for the last six decades has been the philosophical basis of biochemistry and molecular biology, is being displaced by Systems Biology, which favors the study of integrated systems. Historically, Systems Biology - defined as the higher level analysis of complex biological systems - was pioneered by Claude Bernard in physiology, Norbert Wiener with the development of cybernetics, and Erwin Schrödinger in his thermodynamic approach to the living. Systems Biology applies methods inspired by cybernetics, network analysis, and non-equilibrium dynamics of open systems. These developments follow very precisely the dialectical principles of development from thesis to antithesis to synthesis discovered by Hegel. Systems Biology opens new perspectives for studies of the integrated processes of energy metabolism in different cells. These integrated systems acquire new, system-level properties due to interaction of cellular components, such as metabolic compartmentation, channeling and functional coupling mechanisms, which are central for regulation of the energy fluxes. State of the art of these studies in the new area of Molecular System Bioenergetics is analyzed. Int. J. Mol. Sci. 2009, 10 1162 Keywords: Systems Biology; Molecular Systems Bioenergetics; cellular energy metabolism; regulation; compartmentation; energy transfer systems. Contents 1. Systems Biology – new paradigm and new perspectives of biological research. 2. Systems Biology and Hegel’s dialectic, some important steps in history. 3. Application of the Systems Biology approach to metabolic studies. Metabolic compartmentation as system level property. 4. Molecular System Bioenergetics: structural and dynamic organization of cellular energy metabolism: mitochondrial-cytoskeletal interactions, mitochondrial dynamics, energetic modules and regulation mechanisms. 5. Mathematical models of energy metabolism, useful and not very useful. Wherever there is movement, wherever there is life, Wherever anything is carried into effect in the actual word, there Dialectic is at work. It is also the soul of all knowledge which is truly scientific. Hegel’s Logic Translated by William Wallace Oxford University Press, Oxford UK, 2005, p. 116 1. Systems Biology – New Paradigm and New Perspectives of Biological Research Within last decade, biological sciences have witnessed a radical change of paradigms [1-19]. Reductionism, which used to be a philosophical basis of biochemistry and molecular biology when everything – from genes to proteins and organelles – were studied in their isolated state is leaving its place to Systems Biology, which favours the study of integrated systems at all levels: molecular, cellular, organ, organism, and population [1-19]. The importance and rapid expansion of Systems Biology become clear when one opens PubMed with this keyword – tens of thousands of entries from different fields of the biological sciences appear. Hundreds, if not thousands of books have been published in recent years on this topic; references [1- 9] are just very few examples of them, mostly related to the topics of this article. Indeed, suddenly Systems Biology is everywhere. Given the very rapidly increasing number of publications, it may even be that the term Systems Biology is not always understood in the same way, but nevertheless, there are general and rather precise commonly accepted definitions of this scientific direction. In 2005 Alberghina and Westerhoff edited a whole book analyzing the definitions and perspectives of Systems Biology [4]. The shortest and most clear definition of Systems Biology is given by Westerhoff’s group: “Systems Biology is the science that Int. J. Mol. Sci. 2009, 10 1163 aims to understand how biological function absent from macromolecules in isolation, arises when they are components of their systems” [15]. Very similar definitions have been given by many other authors [1-19]. These very intensive developments make it interesting and necessary to discuss its origins – the philosophical basis and historical aspects of System Biology. This is especially interesting for scientists who have spent almost all of their time and efforts in studies of mechanisms of integrated cellular metabolism (not even knowing before that what they study is Systems Biology). For many of them the topics are very familiar, but what is most helpful for them is the development of new concepts within Systems Biology that help to make general conclusions and give new tools for further research. One of these areas of research concerns the study of integrated energy metabolism in cells which we call now Molecular System Bioenergetics, as one can see from the titles of this Special Issue and a recent volume published by Wiley VCH [7]. Metabolic studies are not new, for example studies of cardiac metabolism started more than 50 years ago, after pioneering works by Richard Bing [20]. The great value of Systems Biology for metabolic research is mostly conceptual because of the clear definition of system-level properties [1-10,15]. System-level properties are the results of interactions between components of the system [1,2,4,7,10-15]. Systems Biology gives also the tools for these studies, most important among them are the quantitative methods of modeling and network analysis [4-6,8-19] . Already several books and articles have been written on the philosophy and origin of the systemic approach in biology [1-4,13,21,22]. Among them are recent publications by Noble [2,13,14], who has traced Systems Biology back to the works by Claude Bernard [23], concluding that Systems Biology is in fact physiology at new higher level [2,13,14] and that a genuine, quantitative theory of biology is to be developed in future research [14]. This is a very optimistic conclusion for new generation of scientists - they still have immense task ahead to work on, and this task attracts both attention and funding. Landmark precedents of Systems Biology are the work of N. Wiener associated with the development of cybernetics, along with the impact of E. Schrödinger’s contributions [24,25]. Another aim of this review is to show that the philosophical foundations of Systems Biology may be found in Hegel's dialectical philosophy, as applied to biology [26-30]. Finally, a critical analysis of the current state of the art in Molecular System Bioenergetics will be given, in addition to those discussed in our recent book [7]. We have found this general presentation of Systems Biology and Molecular System Bioenergetics very useful for explaining and teaching these new disciplines to doctoral students at Grenoble University. 2. Hegel’s Dialectic and Systems Biology. Some Important Steps in History According to Thomas Kuhn’s definition, a paradigm represents a specific, widely accepted way of viewing reality in science [26]. In this sense, Systems Biology is a new paradigm of biological sciences; it has been became widely popular within the last 10 - 15 years [1-19]. However, its history can be traced back into the two last centuries of biological and medical research, starting with Claude Bernard’s theory of permanence of the internal milieu of organisms, later called homeostasis [13,23]. From that time and up to the modern times of Systems Biology, life sciences appear to perfectly fit and strictly follow the dialectic principles of general historical developments discovered by Hegel [27-30]. Int. J. Mol. Sci. 2009, 10 1164 2.1. Hegel’s dialectic laws Georg Wilhelm Friedrich Hegel (1770 – 1831), one of most famous German philosophers, gave in his philosophy the most profound description of the logic and rules of historical developments [27-30]. An excellent description of this rather complicated philosophy is given by Bertrand Russell in his famous book “History of Western Philosophy” [30], explaining in easily way the dialectic laws. Hegel, as a most serious philosopher, was thinking about the relations of our thinking and the real world. For him, the real knowledge was to understand not only parts but the Whole, the Absolute Idea [27-30]. From our practical point of view (not to be involved in deep discussions between materialism and idealism in philosophy), Absolute Idea may be taken to represent the perfect, detailed knowledge of the integrated, whole systems. That in fact is what Systems Biology wants to find out, to know all about the life in its complexity, to comprehend the Whole, an Absolute Idea of the living systems. The process of development, the way to achieve this, the logic of finding out the Absolute Idea, according to Hegel, is the triadic movement called dialectic [30]. Dialectic consists of thesis, antithesis and synthesis [30]. Thus, knowledge as a whole has its triadic movement, and the process is essential to understand the results. To move from one stage to another, thinking as a dialectic process must “fall into the negative of itself” ([27], p. 35). Each later stage contains all the early stages, and all stages are given their proper place as a movement [30]. Thus, a thesis is first giving rise to its reaction, an antithesis which contradicts or negates the thesis, and the tension between the two being resolved by means of a synthesis [30]. Figure 1. Hegelian dialectic of historical movement from thesis to antithesis to synthesis. These dialectic movements were explained by Hegel and his followers by three basic concepts: 1) everything is made out of opposing forces/opposing sides (contradictions); 2) gradual changes lead to turning points, where one force overcomes the other (quantitative change leads to qualitative change); 3) change moves in spirals not circles (sometimes referred to as "negation of the negation") [30]. These Hegelian dialectic rules are illustrated by the Scheme in Figure 1. Thomas Kuhn’s description of the structure of scientific revolutions [26] gives an excellent illustration of the second basic concept of Hegelian dialectic when applied to science. When we look into the history of Systems Biology, we find an excellent illustration of the validity of these dialectic laws. If Hegel had been a biologist, he could have predicted the appearance of Systems Biology as a necessary and inevitable step in our way to find out the final truth, the Absolute Idea of the life. What we know now is only the beginning of this long way. Int. J. Mol. Sci. 2009, 10 1165 2.2. Claude Bernard and the theory of permanence of internal milieu – homeostasis Claude Bernard (1813-1878), a famous French physiologist, was a founder of experimental medicine, and according to Denis Noble [13] the first system biologist, one of the first instigators of Systems Biology (or integrative biology). The scope of his works was very wide: discovery of the pancreas function, discovery of the gluconeogenesis in liver, neurophysiology, toxicology, anesthesia and asphyxia. One of the main theories developed by Claude Bernard is the theory of the permanence of the milieu intérieur (later called homeostasis) due to integrated regulatory mechanisms. Analysis of the milieu intérieur is the study of the physiological mechanisms with which the organism can adapt itself to the milieu extérieur and maintain its functional balance in spite of the external constraints [23]. According to Claude Bernard “the fixity of the interior medium is the condition of a free and independent life” [23]. At his time, he had to separate himself and fight against popular theory of vitalism [21,22]. This theory postulated, in some way analogously with Systems Biology, that the whole living cell or organism is more than simple sum of its parts, but explained life by action of a vital force which neutralizes the “negative effects of physico-chemical forces” in living organism [21,22]. Bernard had to fight against this mystification of life [23]. He emphasized that an organism is able to adjust itself to external physical and chemical variations by maintaining permanence of its milieu intérieur and this adaptation is possible because the cells, the organs or the organisms are integrative systems. He was always attentive not to explain all his observations only by anatomy, claiming that anatomy has to serve physiology because of its complexity. He indicated that the function of an organ is not a strict one and that a function can be due to the interactions of two or several organs (for example the digestion process). According to him, physiologists must start from studies of physiological phenomena to explain them in the whole organism and not try to explain a function from an organ [23]. The strength of Claude Bernard’s theories comes also from his ability to extrapolate his works to chemistry, physics and mathematics. He understood the importance of the mathematical modeling to understand the natural phenomena because “Cette application des mathématiques aux phénomènes naturels est le but de toute science, parce que l’expression de la loi des phénomènes doit toujours être mathématique” - “This mathematical application at natural phenomena is the aim of all sciences, because the expression of the laws of phenomena should always be mathematical” [23]. And time proved that he was right. Applied mathematics, cybernetics and computer sciences are now very powerful tools in biological research. But Bernard understood also that the application of mathematical modelling should be based on very firm experimental data, which were not available at his time: « C’est par elle seule [l’application mathématique] que, dans la suite, la science se constituera; seulement j’ai la conviction que l’équation générale est impossible pour le moment, l’étude qualitative des phénomènes devant nécessairement précéder leur étude quantitative. » « It is by it alone [the mathematical application] that, in the continuation, science will be created but I have the conviction that the general equation is impossible at the moment, the qualitative study of phenomena must necessary precede their quantitative study” [23]. Thus, he understood the possible danger of misuse of the powerful method of mathematical modelling in biology: construction of mathematical models of a metabolic pathway or network can indeed lead to an erroneous model if the amount of physiological data is not sufficient. The richness of Int. J. Mol. Sci. 2009, 10 1166 experimental data ensures the fidelity of the model. And we always have to keep in mind that a model is only a reflection of a complex system, a model will never be a system but only a representation of a system or a part of a system. The computer sciences are a very useful tool in Systems Biology but this tool must be used with caution inseparably from collection of experimental data, to avoid creating a virtual world far from reality. This very clever advice of Claude Bernard is still often forgotten or simply ignored in our times by a new generation of applied mathematicians coming into biological research with easy access to computing technologies but with rather weak knowledge of experimental data (see below). What we need to do first is to collect the maximally possible amount of experimental data describing the system level properties, with the aim to finally reach the “general equation” evoked by Claude Bernard. What did lack in Claude Bernard’s time was a sufficient amount of quantitative experimental data. Systems Biology is now in much more favourable position and following the advices given by Claude Bernard, we can go ahead taking up the challenge of finding the general equation of life, its Absolute Idea. 2.3. Cybernetics of Norbert Wiener and Systems Biology Norbert Wiener (1894 – 1964) was an American mathematician who studied the communication and control processes both in technical electronic systems and in biology, notably in physiology, by analysis of information transmission and treatment processes [24]. He was a founder of cybernetics, a science of control and governing, which studies the structure and function of regulatory systems [24] and has very wide application in computer sciences, engineering, logic modeling as in electronic and information network (including Internet) theories, in physiology, evolutionary biology, neuroscience, anthropology, psychology, sociology. Application of cybernetics in biology is now known in general as biocybernetics, which is a part of theoretical biology, and plays a major role in systems biology, seeking to integrate different levels of information to understand how biological systems function. One of the most important achievements of cybernetics developed by Wiener was the theory of feedback regulation and its application for explanation of the mechanisms of homeostasis [24] discovered by Claude Bernard and described above. Discovery of the feedback mechanisms by Wiener is still probably the most important contribution of cybernetics into Systems Biology. Another direct application of biocybernetics is network biology [18,19]. As it was emphasized by Barabasi in his reviews on network biology, “quantifiable tools of network theory offer unforeseen possibilities to understand the cell’s internal organization and evolution, fundamentally altering our view of cell biology. The emerging results are forcing the realization that, notwithstanding the importance of individual molecules, cellular function is a contextual attribute of strict and quantifiable patterns of interactions between the myriad of cellular constituents” [19]. That tells us that understanding cell biology means understanding of system level properties. 2.4. Systems Biology: from Hegel to Noble Systems Biology uses the methods of both experimental studies and computing, focusing on the studies of interactions within the system with the aim of understanding the biological function. In this vast area, there are many new particular directions of research, such as the Physiome Project [17]. And Int. J. Mol. Sci. 2009, 10 1167 there are very numerous scientists and groups who have made significant contributions into this area [1-19]. The philosophy, general principles of these important studies on cellular and organ level have been analyzed and described by Denis Noble, who has summarized them in 10 basic principles, “10 commandments” [14]. Figure 2. Presentation of development of biological sciences as Hegelian dialectic movement. In times of Claude Bernard, the problems of experimental physiology and medicine were formulated from the point of view of the theory of homeostasis at the organ level. To solve these problems, the components of the cell (proteins, genes, mitochondria etc.) were studied in the isolated state. In Systems Biology, these components are again studied in their interaction within the intact systems of interest. Among these principles, transmission of information by feedback mechanisms is most important, but these mechanisms are to be discovered yet [2,14]. Thus, the whole process of development of biological sciences during last 150 years, from the times of Claude Bernard (experimental physiology, medicine) to that of molecular and structural biology, enzymology, membrane bioenergetics and then to Systems Biology perfectly follows the Hegelian dialectic principles, with triadic movement from thesis (formulation of problems of experimental biology and medicine) to antithesis (the systems are divided into components which are studied separately) to synthesis (coming back at new level to studies of biological function of whole system), as it is shown in Figure 2. Int. J. Mol. Sci. 2009, 10 1168 2.5. Erwin Schrödinger: negentropy production as a basis of metabolism, central role of bioenergetics In the history of biological sciences, one of the most influential events has been publication of Erwin Schrödinger’s book “What is life?” in 1944 [25]. And it is still one of the most influential books in biology. Probably, it is not too much to say that scientists working in biology have successfully accomplished, with brilliant results, realizing the ideas described in the first chapters of this book related to foundation of molecular genetics, and are now busy in collectively reading the chapter 6 in this short book, related to the principles of organization of cellular metabolic processes, and all that together is now called Systems Biology. Figure 3. General scheme of cellular metabolism. A cell is a thermodynamically open system, in accordance with the Schrödinger’s principle of negentropy extraction. Increasing the entropy in extracellular medium, and decreasing it in the cell via metabolism is necessary for maintenance of the structural organization of both biopolymers as proteins, DNA and RNA, and also maintenance of the fine structural organization of the cell for effectively running compartmentalised metabolic processes. In this way, the cell can live in agreement with the thermodynamic laws (see the text). The Scheme shows the central role of bioenergetic processes in the cellular life by coupling catabolism with anabolism. Adapted from ref. [7]. ∆S > 0 ex CO Fatty acids   2     CATABOLISM H O 2 Carbohydrates    O   2   ADP ATP Wc +Pi   ANABOLISM ∆S < 0 in The main conclusion made by Schrödinger was that the living cells need to be open systems with energy and mass exchange with surrounding medium, with the aim of maintaining their high structural and functional organization and thus internal entropy low, achieving this by means of increasing the entropy of the medium by catabolic reactions. Thus, Schrödinger wrote: “ The essential thing in Int. J. Mol. Sci. 2009, 10 1169 metabolism is that the organism succeeds in freeing itself from all entropy it cannot help producing while alive” [25]. In cellular metabolic systems, catabolic reactions which increase entropy in surrounding medium are coupled to anabolic reactions (biosynthesis) which maintain cell structure and organization with necessary decrease in entropy. Catabolic reactions are mostly oxidative degradation of fatty acids and carbohydrates such as glucose. They are also the source of metabolic energy for the performance of any kind of cellular work. This is shown by the general scheme in Figure 3 describing the integrated metabolism of the cell as an open system exchanging both energy and masses with surrounding medium. This Scheme shows that the processes of free energy conversion are central for coupling catabolism to anabolism, emphasizing the central role of bioenergetics in studies of integrated metabolism of the cells. To live, the metabolic systems need to be in the steady state far from equilibrium, and how they maintain intracellular organization and low entropy state is explained by non-equilibrium thermodynamics: the organized states are maintained by energy and matter dissipation, therefore they are also known as dissipative structures [31-34]. 3. Application of the Systems Biology Approach to Metabolic Studies. Metabolic Compartmentation as System Level Property In studies of integrated metabolic processes, one of the most important problems is that of diffusion in the organized intracellular medium. In fact, all mathematical models of metabolism, and practical values of these models depend upon the authors’ views on cell structure and diffusion of metabolites, and still popular oversimplified theories of cell interior as a homogenous diluted solution of metabolites are sources of grave errors and may lead to meaningless models (see below). In our recent article in International Journal of Molecular Sciences we have analyzed in details the problems of diffusion of metabolites in organized intracellular medium [35]. Here, we emphasize some of the important conclusions made. The problem starts with the intracellular mobility of water, which is significantly reduced, leading to partitioning of metabolites between different water phases and to changes in binding constants [36-38]; then there is low-affinity adsorbtion of metabolites, especially if charged as ATP, to intracellular surfaces increasing the viscosity, and due to this the diffusion coefficient of metabolites is decreased by a factor of (1+C/K )-1 where C is concentration of binding d sites and Kd is dissociation constant of solute from these complexes [36]; macromolecular crowding and cytoskeletal structures create the barriers which increase the effective path-length of diffusion, and again diffusion coefficient is decreased by λ-2 where λ is relative increase in path attributable to the barriers [36-38]; finally, the movements of individual molecules become co-ordinated and vectorially directed due to organization of enzymes into the complexes, and the randomness of molecular events may be lost [36]. The results of these local diffusion restrictions are microcompartmentation of metabolites and their channeling within organized multienzyme complexes which need to be accounted for to explain biological phenomena [39,35]. Compartmentation and microcompartmentation of metabolites are system-level properties resulting from interactions between cellular components. Indeed, none of important observations in cellular bioenergetics could be explained by a paradigm describing a viable cell as a “mixed bag of enzymes” with homogenous metabolite distribution still sometimes in use: this simplistic theory excludes any possibility of metabolic regulation of cellular functions [35]. Due to macromolecular crowding and hindered