Thinking Dynamically About Biological Mechanisms: Networks of Coupled Oscillators

Explaining the complex dynamics exhibited in many biological mechanisms requires extending the recent philosophical treatment of mechanisms that emphasizes sequences of operations. To understand how nonsequentially organized mechanisms will behave, scientists often advance what we call dynamic mechanistic explanations. These begin with a decomposition of the mechanism into component parts and operations, using a variety of laboratory-based strategies. Crucially, the mechanism is then recomposed by means of computational models in which variables or terms in differential equations correspond to properties of its parts and operations. We provide two illustrations drawn from research on circadian rhythms. Once biologists identified some of the components of the molecular mechanism thought to be responsible for circadian rhythms, computational models were used to determine whether the proposed mechanisms could generate sustained oscillations. Modeling has become even more important as researchers have recognized that the oscillations generated in individual neurons are synchronized within networks; we describe models being employed to assess how different possible network architectures could produce the observed synchronized activity.

[1]  S. Burger An Introduction to the Study of Experimental Medicine , 1950, The Pharos of Alpha Omega Alpha-Honor Medical Society. Alpha Omega Alpha.

[2]  W. Wimsatt,et al.  Consciousness and the Brain: A Scientific and Philosophical Inquiry , 1979 .

[3]  Jeffrey C. Hall,et al.  Feedback of the Drosophila period gene product on circadian cycling of its messenger RNA levels , 1990, Nature.

[4]  M. Vansteensel,et al.  Seasonal Encoding by the Circadian Pacemaker of the SCN , 2007, Current Biology.

[5]  William J Schwartz,et al.  Forced Desynchronization of Dual Circadian Oscillators within the Rat Suprachiasmatic Nucleus , 2004, Current Biology.

[6]  K. Ruiz-Mirazo,et al.  A Universal Definition of Life: Autonomy and Open-Ended Evolution , 2004, Origins of life and evolution of the biosphere.

[7]  G. Ermentrout,et al.  Symmetry and phaselocking in chains of weakly coupled oscillators , 1986 .

[8]  P. Erdos,et al.  On the evolution of random graphs , 1984 .

[9]  D. Pidhayny,et al.  The origins of feedback control , 1972 .

[10]  A. Winfree Biological rhythms and the behavior of populations of coupled oscillators. , 1967, Journal of theoretical biology.

[11]  W. O. Friesen,et al.  Dissociation of circadian and light inhibition of melatonin release through forced desynchronization in the rat , 2009, Proceedings of the National Academy of Sciences.

[12]  B. Bollobás The evolution of random graphs , 1984 .

[13]  D. J. Felleman,et al.  Distributed hierarchical processing in the primate cerebral cortex. , 1991, Cerebral cortex.

[14]  R J Konopka,et al.  Clock mutants of Drosophila melanogaster. , 1971, Proceedings of the National Academy of Sciences of the United States of America.

[15]  William Bechtel,et al.  Generalization and Discovery by Assuming Conserved Mechanisms: Cross‐Species Research on Circadian Oscillators , 2009, Philosophy of Science.

[16]  Shin Yamazaki,et al.  Constant light desynchronizes mammalian clock neurons , 2005, Nature Neuroscience.

[17]  A. Goldbeter,et al.  Modeling the mammalian circadian clock: sensitivity analysis and multiplicity of oscillatory mechanisms. , 2004, Journal of Theoretical Biology.

[18]  W. Wimsatt Reductionism, Levels of Organization, and the Mind-Body Problem , 1976 .

[19]  J. Griffith Mathematics of cellular control processes. II. Positive feedback to one gene. , 1968, Journal of theoretical biology.

[20]  Achim Kramer,et al.  Synchronization-Induced Rhythmicity of Circadian Oscillators in the Suprachiasmatic Nucleus , 2007, PLoS Comput. Biol..

[21]  Erik D Herzog,et al.  Small-World Network Models of Intercellular Coupling Predict Enhanced Synchronization in the Suprachiasmatic Nucleus , 2009, Journal of biological rhythms.

[22]  J. Griffith,et al.  Mathematics of cellular control processes. I. Negative feedback to one gene. , 1968, Journal of theoretical biology.

[23]  G. Ermentrout,et al.  Frequency Plateaus in a Chain of Weakly Coupled Oscillators, I. , 1984 .

[24]  W. Bechtel,et al.  Explanation: a mechanist alternative. , 2005, Studies in history and philosophy of biological and biomedical sciences.

[25]  A. Goldbeter,et al.  A Model for Circadian Rhythms in Drosophila Incorporating the Formation of a Complex between the PER and TIM Proteins , 1998, Journal of biological rhythms.

[26]  William Bechtel,et al.  DECOMPOSING, RECOMPOSING, AND SITUATING CIRCADIAN MECHANISMS: THREE TASKS IN DEVELOPING MECHANISTIC EXPLANATIONS , 2013 .

[27]  Helen E. Longino,et al.  Discovering Complexity: Decomposition and Localization as Strategies in Scientific Research , 1995 .

[28]  S. Bernard,et al.  Spontaneous synchronization of coupled circadian oscillators. , 2005, Biophysical journal.

[29]  Duncan J. Watts,et al.  Collective dynamics of ‘small-world’ networks , 1998, Nature.

[30]  E. Wilson Consilience: The Unity of Knowledge , 1998 .

[31]  A. Goldbeter A model for circadian oscillations in the Drosophila period protein (PER) , 1995, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[32]  George E. P. Box,et al.  The Royal Society of London , 2013 .

[33]  Cliff Hooker Philosophy of complex systems , 2011 .

[34]  Paul Thagard,et al.  Pathways to Biomedical Discovery , 2003, Philosophy of Science.

[35]  R. Moore,et al.  Loss of a circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat. , 1972, Brain research.

[36]  Olaf Sporns,et al.  The small world of the cerebral cortex , 2007, Neuroinformatics.

[37]  Markus Meister,et al.  Individual neurons dissociated from rat suprachiasmatic nucleus express independently phased circadian firing rhythms , 1995, Neuron.

[38]  W. Cannon ORGANIZATION FOR PHYSIOLOGICAL HOMEOSTASIS , 1929 .

[39]  William Bechtel,et al.  Complex Biological Mechanisms : Cyclic , Oscillatory , and Autonomous , 2008 .

[40]  M. A. Henson,et al.  A molecular model for intercellular synchronization in the mammalian circadian clock. , 2007, Biophysical journal.

[41]  B. Goodwin Oscillatory behavior in enzymatic control processes. , 1965, Advances in enzyme regulation.

[42]  T. Prescott,et al.  The brainstem reticular formation is a small-world, not scale-free, network , 2006, Proceedings of the Royal Society B: Biological Sciences.

[43]  Erik D Herzog,et al.  Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons , 2005, Nature Neuroscience.

[44]  Yoshiyuki Sakaki,et al.  Temporal Precision in the Mammalian Circadian System: A Reliable Clock from Less Reliable Neurons , 2004, Journal of biological rhythms.

[45]  A. Ghosh,et al.  DAMPED SINUSOIDAL OSCILLATIONS OF CYTOPLASMIC REDUCED PYRIDINE NUCLEOTIDE IN YEAST CELLS. , 1964, Proceedings of the National Academy of Sciences of the United States of America.

[46]  P. Machamer,et al.  Thinking about Mechanisms , 2000, Philosophy of Science.

[47]  William Bechtel,et al.  Dynamic mechanistic explanation: computational modeling of circadian rhythms as an exemplar for cognitive science. , 2010, Studies in history and philosophy of science.

[48]  S. Strogatz Exploring complex networks , 2001, Nature.

[49]  A. Goldbeter,et al.  Toward a detailed computational model for the mammalian circadian clock , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[50]  Sen Song,et al.  Highly Nonrandom Features of Synaptic Connectivity in Local Cortical Circuits , 2005, PLoS biology.