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WIREs Syst Biol Med
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The reverse control of irreversible biological processes

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Most biological processes have been considered to be irreversible for a long time, but some recent studies have shown the possibility of their reversion at a cellular level. How can we then understand the reversion of such biological processes? We introduce a unified conceptual framework based on the attractor landscape, a molecular phase portrait describing the dynamics of a molecular regulatory network, and the phenotype landscape, a map of phenotypes determined by the steady states of particular output molecules in the attractor landscape. In this framework, irreversible processes involve reshaping of the phenotype landscape, and the landscape reshaping causes the irreversibility of processes. We suggest reverse control by network rewiring which changes network dynamics with constant perturbation, resulting in the restoration of the original phenotype landscape. The proposed framework provides a conceptual basis for the reverse control of irreversible biological processes through network rewiring. WIREs Syst Biol Med 2016, 8:366–377. doi: 10.1002/wsbm.1346 This article is categorized under: Biological Mechanisms > Regulatory Biology
A unified conceptual framework. (a) The cell has a signaling network and a gene regulatory network. Each protein and corresponding node of the network share the same alphabetic notation. (b) The cellular networks can be represented as nodes (circles) and links (arrows). Sharp and blunted arrows indicate ‘activation’ and ‘repression’, respectively. Input nodes receive an external stimulus and output nodes determine the phenotypic response of the cell. (c) The dynamics of the network evolves by interaction among nodes over time. Red circles represent active nodes and white circles inactive nodes. We can define a network state from the activities of nodes. The network states at time L and L + 1 are the same; such a network state that is not changed over time is called an attractor. (d) From all possible network states, we can obtain the attractor landscape. Output nodes of the attractor state determine the phenotype (color) of a basin. (e) The phenotype landscape is obtained from the attractor landscape. Note that the relative dominance of green phenotype is represented as a green area and basins of two green attractors are projected onto the green area.
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The relationship among networks, attractor landscape, and phenotype landscape. Networks and attractor landscapes show a one‐to‐one relationship. However, more than one attractor landscape can be projected to one phenotype landscape. Therefore, although two network topologies are different, they can be functionally equivalent in terms of the phenotype landscape.
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Three strategies for the reverse control of an irreversible biological process. The original phenotype landscape is lost by network rewiring during the irreversible process. To recover the original phenotype, we can consider three strategies: recovering the original attractor landscape, the original phenotype landscape, or a landscape having the same dominant phenotype. Red X marks represent deletion of links during the irreversible process, whereas red arrows indicate the recovered links as possible means for the reverse control. Note that the strategy of recovering the original phenotype landscape is highlighted with a red background.
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