High‐order combination effects and biological robustness

Abstract

Biological systems are robust, in that they can maintain stable phenotypes under varying conditions or attacks. Biological systems are also complex, being organized into many functional modules that communicate through interlocking pathways and feedback mechanisms. In these systems, robustness and complexity are linked because both qualities arise from the same underlying mechanisms. When perturbed by multiple attacks, such complex systems become fragile in both theoretical and experimental studies, and this fragility depends on the number of agents applied. We explore how this relationship can be used to study the functional robustness of a biological system using systematic high-order combination experiments. This presents a promising approach toward many biomedical and bioengineering challenges. For example, high-order experiments could determine the point of fragility for pathogenic bacteria and might help identify optimal treatments against multi-drug resistance. Such studies would also reinforce the growing appreciation that biological systems are best manipulated not by targeting a single protein, but by modulating the set of many nodes that can selectively control a system's functional state. Subject Categories: genomic and computational biology; metabolic and regulatory networks

Adenosine A2A and Beta-2 Adrenergic Receptor Agonists: Novel Selective and Synergistic Multiple Myeloma Targets Discovered through Systematic Combination Screening

“…Gene set enrichment analysis (GSEA) using a 36-member gene set of IRF4 target genes ( Supplementary Fig. S10) 6), low-dose dexamethasone (25 nmol/L; lanes 7 and 8), high-dose dexamethasone (2 mmol/L; lanes 9 and 10), or combinations (CGS-21680 or salmeterol in combination with low-dose dexamethasone; lanes [11][12][13][14]. The data were normalized with Gene Pattern module ExpressionFileCreater using the GCRMA method.…”

“…A "dose matrix" was used to evaluate the combination effects between compounds, where all possible mixtures of serially diluted single agents at the indicated concentrations were evaluated including zero (12)(13)(14). Synergy was determined by the Loewe additivity model, a generally accepted reference for synergy (15)(16)(17).…”

Delineation of key regulatory elements identifies points of vulnerability in the mitogen-activated signaling network

“…In view of the pathway redundancies that are inherent to signaling networks, current emphasis is on approaches that involve a concerted pharmacological intervention at multiple key targets (Lehar et al 2008b). The challenge, however, is to identify the most appropriate combination of nodes to be targeted, and present approaches in this direction are limited by the vast space of high-order combinations that are theoretically possible (Lehar et al 2008a). Here, our present strategy of extracting vulnerable nodes from the core elements that process input signals in a context-specific manner alone serves to reduce the dimensions of combination space to be explored by several orders of magnitude.…”

An update on the strategies in multicomponent activity monitoring within the phytopharmaceutical field

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