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VIEWPOINT
Meakins Christie Laboratories, McGill University Health Centre Research Institute, Montreal, Quebec, Canada
IN 1944 ERWIN SCHRODINGER, the Nobelist in physics, presented biology with an unprecedented challenge. In his monograph "What Is Life?" (18), he stated that life had two secrets: the passage of an encoded molecule from parents to offspring to explain heritable characteristics, and the spontaneous emergence of self-organized order. Biochemistry and biophysics responded to the first challenge with stunning success, resulting in today's revolution in genetics and molecular biology. The second is a challenge to physiology. It is physiology's job to provide a deep understanding of life, not merely a description. If we fail to do so, physiology will become a science secondary to biochemistry and biophysics.
Life's order is characterized by emergent phenomena. These I define as the spontaneous development of self-organized order among ensembles that can neither be predicted nor explained by examining component parts in isolation. Spontaneity and self-organization mean that no external agent is sculpting the organism: it sculpts itself. Ensembles mean that an emergent system is composed of many parts. And for the component parts to self-organize, they must intercommunicate, interact, and cooperate. Life provides many interconnections: hormones, nerves, gap junctions, cytokines, and so forth. Thus understanding emergence requires studying the behavior of integrated networks. Reductionism cannot solve the secrets of emergence.
Consciousness is the most striking (and difficult) example of an emergent phenomenon. But to understand emergence it is better to start with simpler examples and, once they are solved, to progress to more complex ones.
Understanding starts with the second law of thermodynamics because it is the only physical law dealing with order. It states that systems tend to evolve from improbable configurations to more probable ones. Order is improbable and disorder (called entropy) is more probable. A smoke ring illustrates this. When it emerges from a smoker's mouth it is in a highly ordered, improbable configuration. With time, the order disappears as the smoke particles diffuse and become randomly dispersed throughout the room. When dispersion is complete, entropy is maximal. This process is irreversible; left to itself, the improbable doughnut never spontaneously reforms.
It takes energy to create improbable configurations from disordered ones. Ilya Prigogine won the Nobel Prize for discovering that the importation and dissipation of energy into chemical systems could reverse the inexorable disintegration into disorder predicted by the second law (15). The second law only applies to closed thermodynamic systems with no exchange of energy or entropy with the environment, whereas life is an open thermodynamic system, in which energy is imported as food and oxygen and utilized in a process we call metabolism. Entropy in the form of waste products is exported. As entropy decreases, order must increase. Thus the imported energy is used to create the spontaneous development of self-organized, emergent phenomena. This is how eons of Darwinian evolution and much shorter gestational times for fetal development create the stunning order of life.
It is only when we die and stop importing energy that we obey the second law, with its inevitable decay into thermodynamic equilibrium when every chemical reaction goes equally in both directions, no thermal gradients exist, and all forces acting on us cancel so that movement is impossible. Life requires non-equilibrium thermodynamics.
In the spontaneous development of order, Prigogine and Stengers (15) emphasized the importance of non-linear feedforward loops by which a molecule catalyzed itself. Linear systems are highly predictable. Life is not. Nonlinearity allows systems to explore new domains and what develops can only be predicted as probabilities, not certainties. Subsequently, Kauffman (9, 10) showed that in an ensemble of peptides, as the number of different peptides increases, the probability of one catalyzing the reaction between others to synthesize a new peptide becomes a virtual certainty. With further diversity of different peptides, the ratio of reactions to molecules increases until suddenly "a giant catalyzed reaction web forms" in which the original peptide reproduces itself spontaneously. Such autocatalytic sets have now been created in the laboratory (7).
To further understand spontaneous self-organization it is instructive to examine a simple system, the formation of slime molds. The development of slime molds requires two emergent phenomena. The first is aggregation of previously independent amoebae into one large mass of densely packed cells. The second is the behavior of the aggregated mass as a single multi-celled organism. Here, I deal only with the first. Hopefully by understanding the simplest, we can describe features common to all emergent phenomena.
Aggregation starts when amoebae are starved. One of them, at random, sends out a chemotactic signal. Those that are close aggregate around this individual and are induced to send out their own chemotactic substance, initiating a feedforward loop by increasing the chemotactic concentration, which acts at progressively greater distances to attract more and more amoebae from farther and farther away (15) until one large mass of aggregated amoebae form. How does this chemotactic agent work?
Yanai et al. (23) measured intracellular pressure in starved amoebae, which are quasi-spherical, stable, and nonmotile. When food was put in the bath and a molecule came in contact with a hungry amoeba, the intracellular pressure abruptly rose without any change in the amoeba's shape. Then, over a small region of the cell membrane, a pseudopod extended and, as this occurred, the intracellular pressure fell.
They suggested that the contact of a food molecule initiated a generalized polymerization of submembranous actin, increasing the amoeba's wall tension, its internal pressure, and its potential energy. Then, with a suitable delay, at the point of original contact, there was local depolymerization of actin with conversion of potential to kinetic energy, resulting in the pseudopod. Statistically, the contact of the amoeba with food probably occurred on the high side of the concentration gradient, so the pseudopod would extend toward more food particles and the process would repeat itself. Chemokinesis would become chemotaxis and the amoeba, by statistical probability and a quasi-random walk, would be drawn inexorably to the point of highest concentration where it would stay.
A similar process presumably occurs with the aggregation of inflammatory cells in abscesses. Emergent phenomena not only characterize health but many diseases as well.
Aggregation allows us to list the minimum requirements for emergent biologic phenomena. They are 1) an open thermodynamic system of ensembles; 2) a positive feedback loop causing non-linear dynamic behavior; 3) interconnections between component parts. Like all of life, amoebae are open thermodynamic systems that import energy and export entropy and aggregation involves a large number of them. The chemotactic agent secreted by one amoeba initiates the feedforward loop, inducing other amoebae to secrete more chemotactic agent. Chemotaxis supplies the interconnections required for aggregation. Although positive feedback is essential, all such loops must be controlled somehow, or else the system could run away with itself. In the case of slime molds and abscesses, dense packing of cells provides the control: they can not get any closer together. However, in most emergent phenomena, order is preserved by negative feedback loops that prevent the feedforward loops from reverberating throughout the system and changing it completely (9, 10).
This brief sketch of the minimal requirements for emergence leads to a second important question. How much energy is needed to create order from disorder? There is a continuum of open thermodynamic systems from near-to-equilibrium to far-from-equilibrium systems. The former is characterized by crystals while the latter is characterized by weather. The amount of energy dissipated determines where a system is situated along the continuum. This is illustrated in the schematic shown in Fig. 1, which describes the continuum as a function of energy consumption. The ordinate describes another continuum from ordered through complex to chaotic systems. Crystals lie frozen and inadaptable deep within the ordered regimen. Deterministic chaos is found at the other extreme, characterized by weather-like instability and evanescence. Between crystals and weather a sudden phase transition occurs over a small range of energy consumption (5, 9, 10, 15). It is here that conditions necessary for life are found. We the living exist in a complex regimen in the phase transition between order and chaos. We are there because that is the only place we can be both ordered but adaptable, stable but able to evolve. Crystals are stable and ordered but cannot adapt or evolve. Weather evolves but is unstable and cannot survive. Darwinian selection allows both survival and evolution only in the phase transition. Survival requires adaptations, but it also requires that in adapting we must preserve our order by a mechanism we call homeostasis.
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The narrow range of energy consumption over which the phase transition occurs suggests that global and local changes in metabolic rate might have profound consequences in both health and disease. This has been shown for individual cells in which the rheological behavior is in the phase transition between solids and liquid (4, 20). Fluidization of cells occurs when they are activated and their "effective" temperature increases. This has important consequences for their behavior (4). However, the thermodynamic consequences of increased metabolic rate during exercise in whole organisms is largely unexplored. In disease states when local metabolic rate is decreased, as in myocardial ischemia, heart rate fluctuations decrease often with serious consequences (12, 13). Conversely, in asthma, an inflammatory disease of the airways, the local increase in metabolic rate is associated with increased variability of respiratory impedance to flow (16, 17). As Kauffman (10) says "we are poised on the edge of chaos," and disease states can take us into chaos or away from it depending on the energy dissipated. I believe we are on the threshold of a new theory of disease based on the consequences of living in a phase transition. Elements of such a theory have been published (1, 3, 6, 17, 20).
Life and emergence obey the laws of physics and chemistry. But life has a third secret not mentioned by Schrodinger. The design of living organisms is not determined by physico-chemical laws (11, 14). As Polanyi (14) says, in a painting the physical and chemical properties of the paint determine what remains on the canvas, but the meaning of the painting is determined by the artist. Who is our artist? We sculpt ourselves; but our survival depends on Darwinian selection. Appropriate designs survive, inappropriate ones become extinct. Life is more than the properties of our paint. Understanding life requires knowledge of how the design of living creatures and emergent phenomena, appearing spontaneously in self-ordered, reproducing, interacting, energy-consuming, non-linear, dynamic ensembles makes us what we are. I believe this will be the next biological revolution.
FOOTNOTES
Address for reprint requests and other correspondence: P. T. Macklem, PO Box 250, Lansdowne ON Canada K0E 1L0 (e-mail: peter.macklem{at}mcgill.ca)
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
REFERENCES
p.caimi/schrodinger.html.This article has been cited by other articles:
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