J Appl Physiol 104: 1848-1850, 2008;
doi:10.1152/japplphysiol.zdg-7945-vpcomm.2008
8750-7587/08 $8.00
LETTER TO THE EDITOR
Commentaries on Viewpoint: Emergent phenomena and the secrets of life
EMERGENT PHENOMENA—A MISSING PHYSICAL PRINCIPLE
TO THE EDITOR: Peter Macklem (1) makes important points relating to life most cogently. What we observe on the surface of the earth is most decidedly not what we might immediately predict from the Second Law of Thermodynamics, and this arises only through the constant supply of energy. In a sense, however, this is a permissive explanation—it says that we may observe ordered systems, but not necessarily that we should. Why should we observe ordered systems? At the heart of this lies an asymmetry. On the one hand, disordered configurations are much more likely than ordered configurations, but because of their very nature (disordered) they cannot replicate. On the other hand, rare ordered configurations have the potential through their very nature (ordered) to self-replicate. It is this asymmetry that allows imposition of order onto disorder and that generates the phenomena that we observe on earth. Within his article, Peter Macklem (1) describes autocatalytic sets in peptide chemistry as examples of such systems that have been generated in the laboratory. We lack, however, a more abstract understanding of the process. Questions include what sorts of objects and interactions have to be present for self-replicating systems to develop; how big do such sets have to be; how long do interactions have to run; and, so important to life, how do hierarchical layers of self-replicating systems develop? In this sense, life should be seen as the remarkable result of some physical law concerning a fundamental asymmetry between order and disorder.
REFERENCE
- Macklem PT. Viewpoint: Emergent phenomena and the secrets of life. J Appl Physiol; doi: 10.1152/japplphysiol.00942.2007.[Free Full Text]
Peter A. Robbins
Academic
Department of Physiology, Anatomy and Genetics
University of Oxford
EMERGENT THOUGHTS ON THE SECRETS OF LIFE
TO THE EDITOR: Man has always speculated on the secrets of life. For millennia, explanations invariably touched on the supernatural. But in 1944, Nobel Prize-winning physicist Erwin Schrödinger (3) attempted an answer based on chemistry and physics. He proposed two essential ingredients: order from order and order from disorder. The first influenced the discovery of DNA and the subsequent revolution in biology. The second has been taken up only recently. Schrödinger asked: how can living matter withstand the pressures of the second law of thermodynamics, namely, the tendency to decay into molecular chaos and death. In his essay, Dr. Macklem (1) uses concepts from non-equilibrium thermodynamics and the sciences of complexity to demystify the self-organizing aspects of life and disease. He asks "How much energy is needed to create order from disorder?" Another way of putting it is to say that complex systems organize themselves to best absorb non-equilibrium energy gradients to which they are exposed (2). If this is right, then perhaps the only essential difference between inanimate and living complex systems is that the latter is able to incorporate the long memory of Darwinian selection through genetic inheritance. In this picture, disease would emerge when a deficiency appears either in the system's ability to inherit the memory accumulated by previous generations or in its self-organizing capacity to dissipate the flow of energy that maintains life. Whether these thoughts are meaningful, they constitute emergent phenomena in the author's brain arising in response to the non-equilibrium constraints Dr. Macklem's provoking essay has generated.
REFERENCES
- Macklem PT. Viewpoint: Emergent phenomena and the secrets of life. J Appl Physiol; doi: 10.1152/japplphysiol.00942.2007.[Free Full Text]
- Schneider ED, Kay JJ. Order from disorder: the thermodynamics of complexity in biology. In: What is Life? The Next Fifty Years: Speculations on the Future of Biology, edited by Murphy MP and O'Neill LAJ. Cambridge, UK: Cambridge University, 1995, p. 161–174.
- Schrödinger E. What is life? Cambridge, UK: Cambridge University Press, 1992.
Béla Suki
Professor
Department of Biomedical Engineering
Boston University
BEING UNCOMFORTABLE
TO THE EDITOR: Colleague A tells you that he has discovered a novel gene that codes for a previously unidentified protein that plays a key role in an unanticipated signaling pathway. This discovery may be altogether novel and extremely important, but fits nonetheless within a framework that we have seen many times before and that we know how to think about. The next day, Colleague B tells you that she has discovered a system-wide pattern of gene expression with perturbations that propagate over wide ranges of time and space, and in doing so defines a transition between disorganized versus organized phases. This discovery, too, is altogether novel and extremely important. But would we know how to think about it? This latter discovery is real (5), not hypothetical, and serves thereby to illustrate Macklem's (4) main point. Indeed, to celebrate the special 125th anniversary edition of Science magazine, the editors highlighted the 125 greatest unsolved problems in all of science (3), among which were: 1) open systems that sustain fluxes of energy and are thus displaced far from thermodynamic equilibrium; 2) systems that become trapped in the glassy state of matter (2, 6); and 3) the nature of protein interactions. (1) In biological systems, these great unsolved problems come together and seem to be universal, but neither biologists nor physicists have yet figured out how to think about them in any systematic way. That this makes us uncomfortable is precisely the point, and defines the grand challenge that Macklem (4) brings to our attention.
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- Macklem P. Viewpoint: Emergent phenomena and the secrets of life. J Appl Physiol; doi: 10.1152/japplphysiol.00942.2007.[Free Full Text]
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Jeffrey J. Fredberg
Professor
Harvard School of Public Health
RESPONSE TO MACKLEM'S VIEWPOINT "EMERGENT PHENOMENA"
TO THE EDITOR: Macklem's definition of "emergent phenomena" lists features we biologists intuit, but it is not a settled issue in physics where many come close to denying the importance of emergence because everything ultimately rests on quantum field theory. Philip Anderson and Steven Weinberg, both Nobelists in physics, have taken strongly contrasting positions on reductionism and emergence. I think discussion of the issue should begin with them.
Macklem invokes some almost ritual citations to make his points, viz., to Schrödinger, Prigogine, Kauffman, slime molds, and the Second Law. Like emergence, the Second Law is not warmly welcomed by physicists; many regard it as merely a statistical feature of non-equilibrium macroscopic fields not evident microscopically. (The great theories of physics deal mainly with conservative fields where the Second Law plays little or no role.)
In biology, time has a direction from past to present to future. In powerful physical theories, time is isotropic, reversible in the laws.
These three disjunctions between biology and physics may seem to justify the phrase "secret of life" in Macklem's title, but there are many versions of the "secret," from autopoiesis to Boolean networks on the edge of chaos. They address varying aspects of the mystery of life, but not the core. Meanwhile, "The Secret sits in the middle and knows" (Robert Frost).
The best part of the article is the figure. However, I would position LIFE closer to equilibrium. Biological processes mostly run smoothly with low duty cycles—they don't "knock."
REFERENCE
- Macklem PT. Viewpoint: Emergent phenomena and the secrets of life. J Appl Physiol; doi: 10.1152/japplphysiol.00942.2007.[Free Full Text]
F. Eugene Yates
Department of Medicine
University of California, Los Angeles
EMERGENCY MEDICINE
TO THE EDITOR: Macklem (1) hits the nail on the head when he identifies emergence as the key mechanism underlying life and disease. Indeed, emergent phenomena are manifest at every level of scale in both space and time (2), which is what gives richness to our existence. Without complex, nonlinear and dynamic interactions between multiple entities, the universe would be a pretty boring place, and we would be too boring to notice. Fortunately, nature has seen to it that complex emergent phenomena abound, ensuring that we shall be trying to understand them for a very long time. In fact, the challenge of understanding the grand emergent phenomena of life is so daunting that it takes considerable moral fortitude to even look it in the eye; it is much safer to focus on circumscribed issues amenable to conventional investigative techniques. Nevertheless, at the end of the day, we still want to know how the body works, and how to fix it when it goes wrong. This is why Macklem's essay is so important; medical science needs a broader perspective on disease than the conventional viewpoint that things ought to be fixable if we can just find the right magic bullet. In fact, an understanding of emergence may eventually teach us that some diseases are not fixable at all once they are underway. This would then fuel the growing trend toward preventative medicine, which is effectively the manipulation of biological emergence. In fact, this is really what we should be calling "emergency" medicine.
REFERENCES
- Macklem PT. Viewpoint: Emergent phenomena and the secrets of life. J Appl Physiol; doi: 10.1152/japplphysiol.00942.2007.[Free Full Text]
- Morowitz HJ. The Emergence of Everything. How the World Became Complex. Oxford: Oxford University Press, 2002.
Jason H. T. Bates
Professor of Medicine
University of Vermont
LIFE IS CHAOS... FORTUNATELY
TO THE EDITOR: Peter Macklem sketches, with characteristic detachment and vision, how applying the concept of emergent phenomena to physiology and medicine could revolutionize our understanding of life in health and disease (3). Given that living organisms are "self-ordered, energy-consuming, nonlinear dynamic ensembles," pragmatic, but important, questions arise for physiologists and physicians, like "how to characterize the behavior of such systems and use resulting information?" Logically by measuring fluctuations in a biological variable over time. Mathematics and physics offer many methods, simple—coefficient of variation, describing "variability"—or sophisticated, nonlinear analysis. Not all provide equivalent information. Optimizing the knowledge transfer advocated by Peter therefore requires attention to semantics. "Chaos" has a vernacular, pejoratively connoted sense—Kauffman's (3) "we are poised on the edge of chaos." Yet systems with "several interconnected ensembles and governed by nonlinear positive feedforward loops themselves regulated by negative feedback loops"—e.g., the breathing control system—are propitious to chaos, but in the mathematical acceptation. Mathematical chaos, one of the forms of complexity, can denote health; less chaos, as a reduced variability, can foretell threats (2). Interestingly, chaos and variability can respond differently to perturbations: in normal humans reacting to CO2, ventilatory chaos increases while ventilatory variability decreases (1). This emphasizes the importance of context (adaptive vs. maladaptive—as Peter indicates, exercise response might be the revealer) and also the variable (phase space trajectory of flow might relate to intimate central pattern generator function; breath-to-breath variability of discrete indexes like tidal volume might be less specific). When the revolution announced by Peter comes and we begin to think in terms of complexity, we shall have to master vocabulary (4), tools and concepts, under penalty of generating confusion.
REFERENCES
- Fiamma MN, Straus C, Thibault S, Wysocki M, Baconnier P, Similowski T. Effects of hypercapnia and hypocapnia on ventilatory variability and the chaotic dynamics of ventilatory flow in humans. Am J Physiol Regul Integr Comp Physiol 292: R1985–R1993, 2007.[Abstract/Free Full Text]
- Goldberger AL, Amaral LA, Hausdorff JM, Ivanov P, Peng CK, Stanley HE. Fractal dynamics in physiology: alterations with disease and aging. Proc Natl Acad Sci USA 99: 2466–2472, 2002.[Abstract/Free Full Text]
- Macklem PT. Viewpoint: Emergent phenomena and the secrets of life. J Appl Physiol; doi: 10.1152/japplphysiol.00942.2007.[Free Full Text]
- Rickles D, Hawe P, Shiell A. A simple guide to chaos and complexity. J Epidemiol Comm Health 61: 933–937, 2007.[Abstract/Free Full Text]
Thomas Similowski
Head of Respiratory Medicine and Intensive Care
Christian Straus
Marie-Noelle Fiamma
Université Paris 6, EA2397, Paris, France
RESPONSE TO MACKLEM'S VIEWPOINT "EMERGENT PHENOMENA"
TO THE EDITOR: Peter Macklem's essay (3) raises questions related to the analysis of nonliving and living systems. Classic methods of statistical mechanics compute phase transitions in closed physical systems based on the minimization of free energy. Although Prigogine (4) extended these concepts to nonequilibrium systems "near equilibrium," it has not been easy to predict organization in dynamic systems based on Prigogine's principle of minimum entropy production.
Rather, changes of stability and dynamics in complex systems are analyzed using nonlinear dynamics. As parameters in nonlinear equations change, there may be a qualitative change of dynamics—a bifurcation (1).
Michael Mackey and I (2) used the term "dynamical disease" to capture the concept that qualitative changes in dynamics as a consequence of changes in the structure or parameters of physiological systems can lead to abnormal dynamics associated with disease. This approach continues to find rich applications: for example, it forms a foundation for theoretical and experimental studies of mechanisms of cardiac arrhythmias and sudden cardiac death (6).
Nonlinear dynamic concepts lend a definiteness to discussion of dynamic phenomena in living systems. To me the phrases "edge of chaos" and "living in a phase transition" are vague. A program for studying cellular and physiological dynamics is to formulate equations based on chemical kinetics and nonlinear control and to analyze the bifurcations in the dynamics using nonlinear dynamics. Of course, the multiple time and space scales combined with inevitable stochastic effects due to small numbers make this a challenge (5).
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- Macklem PT. Viewpoint: Emergent phenomena and the secrets of life. J Appl Physiol; doi: 10.1152/japplphysiol.00942.2007.[Free Full Text]
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Leon Glass
Isadore Rosenfeld Chair in Cardiology and Professor of Physiology
Department of Physiology
McGill University
LIFE, EMERGENCE AND ENTROPY PRODUCTION
TO THE EDITOR: Peter Macklem (2) challenges physiologists to grapple with "a deep understanding of life, not merely a description," and invokes non-equilibrium thermodynamics as fundamental to this understanding. While the second law of thermodynamics explains why there is degradation of quality of energy available to do work, why nature seeks to break down gradients and why order tends to disorder, it also informs us that the process of emergence of internal order (negative entropy) within complex systems must be accompanied by export of even greater quantities of entropy to the environment, as net change in entropy must be greater than zero. Understanding life as entropy producing systems, we return to Peter Macklem's provocative figure and the contention that "we the living exist in the phase-transition between order and chaos," that is between near- and far-from equilibrium open-thermodynamic systems. While "phase transition" requires further clarification in this context, Macklem's distinction between near and far-from equilibrium systems is further supported with evidence regarding entropy production (3, 4). For systems near equilibrium with fixed boundary conditions, steady states are characterized by minimal entropy production (3), whereas non-linear systems far-from equilibrium with no fixed boundary conditions select steady states characterized by maximal entropy production (1). Although not yet well characterized, living organisms appear to display optimal entropy production, tuned to changing environmental conditions, and variable metabolic needs for growth, reproduction, and repair. Understanding how and why entropy production is optimized, and indeed how it is altered by illness, represent critical components to addressing Peter Macklem's insightful challenge.
REFERENCES
- Kleidon A, Lorenz RD (editors). Non-Equilibrium Thermodynamics, and the Production of Entropy: Life, Earth and Beyond. New York: Springer, 2005.
- Macklem PT. Viewpoint: Emergent phenomena and the secrets of life. J Appl Physiol; doi: 10.1152/japplphysiol.00942.2007.[Free Full Text]
- Prigogine I. Introduction to Non-Equilibrium Thermodynamics. New York: Wiley International, 1962.
- Schneider ED, Sagan D. Into the Cool: Energy Flow, Thermodynamics and Life. Chicago: University of Chicago Press, 2005.
Andrew J. E. Seely
Clinician Scientist
Ottawa Health Research Institute
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P. T. Macklem
Last Word on Viewpoint: Emergent phenomena and the secrets of life
J Appl Physiol,
June 1, 2008;
104(6):
1851 - 1851.
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