Comparative Biochemistry and Physiology Part A 120 (1998) 3 9

Review

The thermodynamics and evolution of complexity in biological systems

Olivier Toussaint a,*, Eric D. Schneider b
a

Laboratory of Cellular Biochemistry and Biology, The Uni6ersity of Namur, Rue de Bruxelles 61, B-5000 Namur, Belgium b Hawkwood Institute, P.O. Box 1017, Li6ingston MT 59047, USA Received 15 September 1996; received in revised form 20 August 1997; accepted 20 January 1998

Abstract Recent advances in nonequilibrium thermodynamics leads to the conclusion that similar processes, constrained by the second law of thermodynamics, give rise to the emergence of structure and process in a broad class of dissipative systems. The second law suggests that, in systems moved away from equilibrium, processes can emerge so that the system organizes in a way that reduces the effect of the applied gradient. If dynamic and or kinetic conditions permit, self organization processes can be expected. As biosystems grow and develop, they should increase their total dissipation, and develop more complex structures with more energy ow, increase their cycling activity, develop greater diversity and generate more hierarchical levels. As a corollary to this general statement, biosystems which do not increase their total dissipation, are organisms dedicated to death, like observed during the aging of any biosystem. Species which survive in ecosystems are those that funnel energy into their own production and reproduction and contribute to autocatalytic processes which increase the total dissipation of the ecosystem while at same time surviving within the constraints of their changing environment. In a broad class of biosystems, stress and aging have similar thermodynamic properties and suggests common underlying principles. 1998 Elsevier Science Inc. All rights reserved. Keywords: Nonequilibrium thermodynamics; Gradient dissipation; Stress; Aging; Ecosystem stability

1. Introduction Schrodinger [24], trying to reconcile biology with chemistry and physics, suggested that scientists pursue two research programs, order from order and order from disorder. The order from order research program was launched by Watson and Crick and is now part of the central dogma of biology. The order form disorder research program has lay dormant and only now are we opening the curtain to this exciting area of research. Schrodinger wondered how life could appear from disorder in thermodynamical terms. He noted that at rst glance, living systems seem to defy the second law of thermodynamics as it insists that, within closed
* Corresponding author. oltou@biocell.fundp.ac.be Fax: + 32 81 724135; e-mail:

systems, entropy should be maximized and disorder should reign. To solve this dilemma, Schrodinger turned to thermodynamics of nonequilibrium systems, that is, he recognized that living systems exist in a world of energy and material uxes. An organism stays alive in its highly organized state by taking energy from outside itself to build and maintain their structures and functions. Schrodinger proposed that life is a far-from equilibrium process which maintains its local level of organization at the expense of the larger global entropy budget. He also proposed that to study living systems from a nonequilibrium perspective would reconcile biological self-organization and thermodynamics [24]. In this paper, we shall take the principles of far-from-equilibrium thermodynamics as a basis to describe the apparition, maintenance of life, and the ontogenic and phylogenic evolution of living processes, from the cell to the ecosystems.

1095-6433/98/$19.00 1998 Elsevier Science Inc. All rights reserved. PII S1095-6433(98)10002-8

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2. Thermodynamic preliminaries Thermodynamics has been shown to apply to all work and energy systems including the classic temperature volumepressure systems, chemical kinetic systems, electromagnetic and quantum systems. Thermodynamics can be viewed as addressing the behavior of systems in three different situations: (1) systems at or near thermodynamic equilibrium, (classical thermodynamics), i.e. the actions of large numbers of molecules in a closed ask; (2) systems that are some distance from equilibrium, and will return to equilibrium, i.e. molecules in two asks connected with a closed stopcock; one ask holds more molecules than the other and upon opening the stopcock the system will come to its equilibrium state with an equal number of molecules in each ask; and (3) systems that have been moved away from equilibrium and are constrained by gradients to be at some distance from the equilibrium state, i.e. two connected asks with a pressure gradient holding more molecules in one ask than the other. The rst law of thermodynamics arose from efforts to understand the relation between heat and work. The rst law says that energy cannot be created or destroyed and that the total energy within a closed system remains unchanged. However, the quality of the energy in the system may change, i.e. the exergy content. The second law of thermodynamics requires that if there are any processes underway in the system, the quality of the energy in that system will degrade. The second law can also be stated in terms of the quantitative measure of irreversibility, entropy, which for any process is greater than zero or that any real process can only proceed in a direction which results in an entropy increase. We will focus our attention toward the above mentioned third class of thermodynamic phenomena belonging to systems that are open to energy and or material ows and reside at quasi stable states some distance from equilibrium. These systems are open and are moved away from equilibrium by the uxes of material and energy across their boundary and maintain their form or structure by continuous matter and energy exchanges. This is done at the cost of increasing the entropy of the larger global system in which the dissipative structure is imbedded; thus following the second law, that overall entropy in the global sense must increase. Non living organized systems (like convection cells, tornadoes and lasers) and living systems (from cells to ecosystems) are dependent on outside energy uxes to maintain their organization in a locally reduced entropy state. The entropy relationships in dissipative systems was put forward by Denbeigh [5] and Prigogine [16] in the following thermodynamic relationship: dS= dSi +dSe, where dS is the total en-

tropy change in a system, dSi is the internal production of entropy in the system. According to the second law of thermodynamics, dSi is always greater than or equal to zero and dSe is the entropy exchange with the environment, which may be positive, negative or zero. For the system to maintain itself in a nonequilibrium steady state, dSe must be negative, and larger than the entropy produced by internal processes, dSi, i.e. metabolism. To deal with this class of thermodynamics of nonequilibrium systems that are moved away from equilibrium and held at some distance from that equilibrium state, we propose the following corollary that follows from the proof by Kestin of the Unied Principle of Thermodynamics, that a system will tend toward its unique equilibrium state [16]. Implicit in this observation is that a system will resist being removed from the equilibrium state. The degree to which a system has been moved from equilibrium can be measured by the gradients imposed on the system. As systems are moved away from equilibrium, they will utilize all avenues available to counter the applied gradients. Attractors can emerge so that the system organizes in a way that reduces or degrades the gradient. As the applied gradients increase, so does the systems ability to oppose further movement from equilibrium. If dynamic and or kinetic conditions permit, self organization processes are to be expected. The building of organizational structure and associated processes degrades the imposed gradient more effectively than if the dynamic and kinetic pathways for those structures were not available [21]. This corollary of the second law of thermodynamics holds for a very important class of systems (Benard cell, Krebs cycle, life, ecosystems) and describes their expected behavior in nonequilibrium conditions. Thermodynamic systems exhibiting temperature, pressure, and chemical equilibrium resist movement away from these equilibrium states. When moved away from their local equilibrium state they shift their state in a way which opposes the applied gradients and moves the system back towards its local equilibrium attractor. Prigogine and others have shown that dissipative structures self-organize through uctuations and instabilities which lead to irreversible bifurcations and new stable system states. Dissipative structures are stable over a nite range of conditions and are sensitive to uxes and ows from outside the system. Glansdorff and Prigogine have shown that these thermodynamic relationships can be represented by coupled nonlinear relationship, i.e. autocatalytic positive feedback cycles, many of which lead to stable macroscopic structures which exist away from the equilibrium state [6]. Convection cells, hurricanes, autocatalytic chemical reactions and living systems are all examples of nonequilibrium dissipative structures which exhibit coherent behaviour.

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When highly ordered complex systems emerge, they develop and grow at the expense of increasing the entropy at higher levels in the systems hierarchy. This behavior appears universally in physical and chemical systems. Life is viewed as a system that exhibits structures and processes of informed, self-replicating, dissipative autocatalytic cycles. This paradigm provides for a thermodynamically consistent explanation of why there is life, including the origin of life, biological growth, the development of ecosystems, and patterns of biological evolution observed in the fossil record. We illustrate the use of these concepts through a discussion of two separate biological processes.

appearance of more and more complex multi-cellular organisms where more and more complex metabolic pathways use and degrade the exergy present in their environment, thus optimizing the free energy production and use in function of the available substrate.

3. Weakening, aging and death of the living organism At the present stage of evolution, mechanisms exists which lead to the decrease in the number of individuals of a species, like predation, parasitism or infectious diseases. With aging the risks increase for weakening, getting sick, being caught by a predator, or starving. Death will be caused by aging itself only if the individual dies at the end of a long process of physiological deterioration which origin is intrinsic to its cells. We have seen above that a possible criterion of growth, differentiation, development and evolution, is the capacity of the cells and organisms to degrade energy gradients from the environment. A logical corollary is that this capacity must decrease with aging, explaining that the old individual must die because its capacity to degrade energy is too low. Bortz wrote that when aging is viewed as a thermophysical event, it is implicit that its origin is intrinsic to the organism. It is the result of molecular decay inherent to the nite rate of entropy production in metabolizing systems. In such a conception, death becomes a moment of disruption of ordering capacities, hence a rush towards equilibrium [3]. If we remember that entropy production inside an open system, like a cell which is in a stationary state, represents the differences between the entropy of the molecules and uxes leaving and entering the system, the entropy production is linked to the total free energy converted inside the cells since all this free energy will nally be converted into entropy. This means that the capacity of the cell to transform energy into work is decreasing with time, which is experimentally observed in numbers of biological systems. Mainly two factors can be responsible for this decrease: the effect of stochastic stresses and the role of the genome. To consider the effects of stochastic stresses, we classied them in three different groups depending on their intensity. First, the small normal stresses which are ubiquitous such as small uctuations in pH, temperature, or ionic composition, such as oxygen-derived free radicals existing at low amounts, or chemical variations in the source of nutrients, reversible damages in DNA, etc. Thermodynamically such little stresses would correspond to a weak variation in one or several forces, leading to a weak increase in internal disorder directly corrected by the cell using its defense system corresponding to that stress. It is a uctuation that produces some exportable internal entropy so this uctuation leads to a positive excess of entropy production, that

2.1. Cell stress and aging

Thermodynamics of far from equilibrium open systems have been used as a theoretical framework to understand how stresses considered as uctuations of the inner or external cellular environment can alter any highly organized biological system. The nature of stresses and of their mechanisms of action may change, but the fate of the biological system may be the same, i.e. acceleration of aging or cell death.

2.2. Ecosystem de6elopment

As ecosystems grow and develop, they should increase their total dissipation, develop more complex structures with more energy ow, increase their cycling activity, develop greater diversity and generate more hierarchical levels, all to abet energy degradation. Species which survive in ecosystems are those that funnel energy into their own production and reproduction and contribute to autocatalytic processes which increase the total dissipation of the ecosystem. Our thesis is that growth, development, and evolution are the response to the thermodynamic imperative of dissipating gradients. The above principle provides a criterion for evaluating growth, development, and aging in living systems. Biological growth occurs when the system adds more of the same types of pathways for degrading imposed gradients. Biological development occurs when new types of pathways for degrading imposed gradients emerge in the system. The larger the system, i.e. the larger the system ow activity, the more reactions and pathways are available for gradient destruction. In biological terms, growth means an increase in the amount of substrates entering pre-existing metabolic pathways, whereas a new step of development means the appearance of supplementary pathways. However, a limitation in the growth and development, therefore in the size and/or number of living organisms, can be imposed by the limited intensity of the energy gradients, thus by the total substrate disposability [21]. This can explain for instance the

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does not alter the stability of the system. Indeed to protect itself against that kind of stress, the cell has two solutions. First the defense system will react and eliminate the increase in internal entropy, by exporting heat and the products of the reactions out of the cellular system. Second, despite a low amount of irreversible errors possibly caused by the stress, the cellular system can behave in such a manner that other cellular functions will act in order to counteract those irreversible errors. However, even when the system comes back to its previous steady state, some forces can be lowered and some increased, this giving the possibility of internal modications (for instance genome modications) in normal conditions where the cell stays at its steady state of entropy production. This second solution is interesting because it can explain how cells will shift to a new steady state when the level of these modications has reached a critical threshold [29]. The second group of stresses are repeated stresses occurring in a short period of time or stresses of great intensity resulting from abnormal situations for the cells. Biological examples could be inammation in a tissue, anoxiareoxygenation phenomena, exposure to radioactivity, UV irradiation, toxic chemicals, etc. In those cases, there will not only be a small increase in the internal entropy production but the specic defense system corresponding to the specic stress will be overwhelmed or even altered. As a consequence the risk of error accumulation in the cell greatly increases. In the case of an important or of repeated stresses, errors will be large enough so that the specic defense system corresponding to the stress will not be sufcient and other defense systems are required. If these systems are able to correct all the errors, then the cell remains stable with a positive excess of entropy production. But if they can not correct quickly all the errors, numerous cellular constituents will be altered. It could lead to a transient increase in the level of intracellular errors, and thus of the non-exportable entropy; leading to a decrease in the internal entropy production. That decrease corresponds in fact to a negative excess of entropy production. Negative excess of entropy production can destabilize the steady state of far from equilibrium systems; as a consequence strong stresses will bring a destabilization of the cellular steady state and the cell has to search for a new steady state. If the cell nds a new steady state, there will be two major irreversible differences between this new steady state and the previous one, i.e. a higher level of internal errors and a lower internal entropy production [29]. In the third type of stress, the injury is so important that the cell can not nd a new steady state: the level of intracellular errors becomes so high and the production of entropy so small that it is impossible for the cell to achieve its basic pathways and to stay alive [29].

During the early development of biological systems, no difference in the resistance to stresses will be seen between systems with small intracellular errors. With aging, it will be possible to observe that cells are less able to resist a stress they would have been able to cope with when they were younger [29]. As Bortz wrote: homeostasis is reciprocal to aging as energy production retards entropy [3].

4. Experimental testing of the theory Human embryonic lung broblasts and adult skin broblasts were used as in vitro aging models to test the effects of stresses on cellular aging. These broblasts have a nite life-span of about 50 population doublings [9]. More recently, in vitro broblast aging has been proposed to result from an irreversible shift through seven morphotypes, the four latest being post-mitotic cells [2]. These morphotypes have been biochemically and morphologically discriminated by their specic polypeptide patterns observed in two-dimensional electrophoresis and their characteristic morphological appearance [2,8,18,25,26,28]. Since the passage through the seven morphotypes is a natural and progressive process occuring along with the subcultures, they could be considered as stable steady states and experiments were devised in order to test if stresses would speed up this passage. The proportions of the various morphotypes were recorded after a single or successive stresses performed either under ethanol or in the presence of a molecule generating oxygen-derived free radicals: tertbutylhydroperoxide (TBHP). Morphotypes I evolved into II and later III, which became much more abundant. Morphotypes IV also increased, with morphotypes V and VI completely disappearing, being shifted into degenerative VII morphotypes. The percentages of morphotypes III and IV obtained after these successive stresses were dependent on the stress intensity [25,26,28]. Similar results were obtained after successive stresses of other kinds: under UV light, mitomycin C, strong electromagnetic elds [1719]. Honda and Matsuo performed successive oxidative stresses on cultivated broblasts and found a decrease in the maximum population doublings [10]. If the shift from one morphotype to the other, and nally cell death, after a stress are the result of a destabilization process which is energy dependent, it is theoretically possible to modulate the shift from one morphotype to the other or cell death by acting on the cell energetic level. This prediction was tested by stressing cells in conditions of partial mitochondria uncoupling, thus lowering the ATP turn-over compared to the numbers of electron given by NADH and FADH2. In these conditions, stresses with TBHP or with ethanol gave a synergistic effect of cellular mortality with the

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mitochondria uncoupling. Since TBHP and ethanol act on different molecular targets, these results suggest that this synergism between stress and energy depletion could be a general phenomenon. On the other hand, energetic substrates like glucose, pyruvate, glutamate, malate were found protective for cell survival in these conditions as well as two pharmacological stimulators of the energetic metabolism: naftidrofuryl oxalate and bilobalide. These energetic substrates and molecules effectively protected cell survival by increasing the energetic potential of the cell as they kept the intracellular amount of ATP at a high level during the stresses [27]. The presence of these protective molecules also protected cells against the shift of young morphotypes towards late morphotypes observed after non lethal stresses [28]. Thermodynamics can help to integrate these experimental results in a more general picture since the passage from one steady state to the other can be inversely related to the level of free energy production and utilization [29]. Under stress, an additional energy utilization is required for the defense systems, for the induction of the synthesis of new molecules like all the stress protein families, for the replacement of damaged cell components, or for the repair of cellular components like DNA, membranes, etc. For instance, in response to DNA strand breaks induced by H2O2, poly-(ADP-ribose) polymerase is activated, leading to depletion of cellular NADH and ATP, and loss in cell viability [12]. The needs for free energy availability under stress can be fullled for example by upregulating the glucose uptake [15]. It was also shown that the ubiquitous glucose transporters GLUT-1 belongs to the glucose-regulated protein family of stress-inducible protein [31]. Glucose has also been found to protect normal thymocytes against TBHP stresses by preventing ATP depletion which is followed by intracytoplasmic Ca + + elevation [1,4]. In conclusion, different steps can be proposed for the accelerated aging or death of cells in stressful conditions. The rst step is the cell damages generated by the stress, then increases in energy utilization and repair functions take place. A lack of energy may then occur, which can be reinforced by alterations of the energyproducing systems, in turn leading to a decrease in the efciency of defence, repair and regulation systems, and then accelerated cell aging or cell death.

5. The thermodynamics of ecosystem development Ecology is the science of the interactions of living organisms with their enveloping environment. Ecosystems are as much process, as entities and are part of a nested hierarchies of scale seen in biology [7]. Ecosystems can exist in the dirt under your ngernail, they

exist in the rumen of a cow, and exist on the regional, continental and global scale [13]. We view ecosystems as the biotic, physical, and chemical components of nature acting together as non-equilibrium dissipative processes. We suggest that as ecosystems develop or mature they should develop more complex structures and processes with greater diversity, more cycling and more hierarchical levels all to abet energy degradation. Species which survive in ecosystems are those that funnel energy into their own production and reproduction and contribute to autocatalytic processes which increase the total dissipation of the ecosystem. In short, during succession ecosystems develop in a way which systematically increases their ability to degrade the incoming solar energy. Keeping in mind that the more processes or reactions of material and energy within a system, i.e. metabolism, cycling, building higher trophic levels, the more entropy production or degradation is possible. It is a complimentary process, on one hand, building more and more complex, organized, low entropy structures, while on the other hand, the larger global entropy budget must increase. In 1969 Eugene Odum [14] synthesized the common characteristics of ecosystem development. He showed that different ecosystems follow similar patterns of process through their developmental pathway. During ecological succession, ecosystems increase their energy throughput, build trophic structure, increase retention of nutrients and include more of their energy ow in cycles. Schneider [20] and Kay and Schneider [11] showed that these ecological attributes can be explained by ecosystems behaving in such a manner as to degrade as much of the incoming energy as possible and provides causality for most, if not all, of Odums phenomenological attributes of maturing ecosystems. If ecosystems develop into dynamic quasi-stable states, one would expect them to respond to changes in boundary conditions that perturb these states by retreating to congurations with lower energy degradation potential. Stressed ecosystems will retreat down their thermodynamic branch into more primitive systems and often appear similar to earlier successional stage ecosystems and will reside at some distance closer to thermodynamic equilibrium [20]. Previous studies have presented a classic data set for carbon-energy ows in two aquatic tidal marsh ecosystems adjacent to a large power generating facility on the Crystal River in Florida [20,30,23]. The ecosystems in question were a stressed and a control marsh. The stressed ecosystem was exposed to hot water efuent from the nuclear power station. The stress in this study was an approximately 6C water temperature increase compared with the control marsh. The control ecosystem was not exposed to the efuent but was otherwise exposed to the same environmental conditions. We determined the effect of the change in envi-

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ronmental conditions on the structure and processes of the stressed ecosystem. In absolute terms all the material ows dropped in the stressed ecosystem. Overall the drop in ows was about 20%, in particular the imported ows, that is the resources available for consumption, dropped by 18%. The total system throughput, the total ow activity in the system dropped by 21%. The biomass dropped by about 35%. The implication of these numbers is that the stress has resulted in the ecosystem shrinking in size, in terms of biomass, its consumption of resources, and its ability to degrade and dissipate incoming energy. The stressed ecosystem exported material more quickly than the control ecosystem. The detrital component of the stressed ecosystem exported 30% more material than its unstressed counterpart. It was a leaky ecosystem. The number of cycles in the stressed ecosystem was 51% of the number in the control. and the overall length of these cycles were shorter. The effective grazing chain was shortened, however the number of trophic levels was not changed. Trophic efciencies were reduced, as was the ow of material to the top trophic levels. These are all indicators of a stressed ecosystem [11,22]. Overall the impact of the efuent from the power station heating water has been to decrease the size of the stressed ecosystem and its consumption of resources while impacting its ability to retain the resources it has captured. In short the impacted ecosystem was smaller, had lower trophic levels, recycled less material, and leaked nutrients and energy. All of these are signs of disorganization and a step backward in development. This analysis suggests that the function and structure of developing ecosystems follow the path predicted by the behavior of nonequilibrium systems.

changes in the environment on the stability of ecological as well as cellular systems in processes where the availability of usable free energy and the resistance to stresses are key parameters responsible for the stability of those systems.

Acknowledgements O. Toussaint is a scientic collaborator of the Belgian FNRS. O. Toussaint is also grateful to the European Union Biomed and Health Research Programme, Concentrated Action Programme on Molecular Gerontology, BMH1 CT 941710 and to the Hawkwood Institute.

References
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6. Conclusions We have examined the energetics of two greatly different biological systems. We have seen that with an updated version of the second law of thermodynamics, that both cell and ecosystems have common energetic traits. In both systems stress and/or aging will result in lower energy ow and lower specic entropy production (weight normalized entropy). The main features of such approach is that cells optimize their free energy production and utilization by lowering their entropy production which is kept to a minimum. Instabilities can however occur which can lead the cell from one steady state to another. The process will continue and the cell will go from one state to another until a critical level is reached where the cell can no longer cope and keep its organization and dies. The view of thermodynamic to ecology provides a theoretical framework for understanding the effects of

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