Bow ties, metabolism and disease

Csete, Marie; Doyle, John C.

doi:10.1016/j.tibtech.2004.07.007

Cited by 423 publications

(405 citation statements)

References 13 publications

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“…Here we explore both important 'design' (with no implication of a 'designer') features of metabolism and the sense in which stoichiometry itself has highly organised and optimised tolerances and tradeoffs (HOT) [3] for functional requirements such as flexibility, efficiency, robustness and evolvability, constrained by conservation of energy, redox and small moieties. This paper illustrates these features using the wellunderstood stoichiometry of metabolic networks in bacteria and reviews, compares and extends the results in [4,5]. We then propose a simple HOT model of an abstract metabolism to clarify the essential elements of its architecture.…”

Section: Introductionmentioning

confidence: 80%

“…It facilitates both great robustness and efficiency but is also a source of fragility [4]. A side-effect of this architecture is high variability in total metabolite node degree despite low variability in all metabolite and reaction modules.…”

Section: Discussionmentioning

confidence: 99%

“…Combination of Figs. 1 and 2 is a good illustration of the 'bowtie' structure of metabolism [4], where a large 'fan-in' of nutrient inputs is catabolised to produce a small handful of activated carriers and precursor metabolites, which then 'fan-out' to the biosynthesis of a large number of primary building blocks (Fig. 3) through long chains of reactions.…”

Section: Basic Features Of Metabolic Networkmentioning

confidence: 99%

“…Of particular importance is the adaptability that is facilitated through tolerance of various perturbations, and flexibility and evolvability on longer time scales. This all occurs in the face of a large number of domain-specific constraints on conserved quantities [4]. In contrast, if every nutrient -product combination had independent pathways without shared precursors and carriers, the total genome would be vastly larger and/or enzymes would be vastly more complex.…”

Section: Basic Features Of Metabolic Networkmentioning

confidence: 99%

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Highly optimised global organisation of metabolic networks

Tanaka¹,

Csete

Doyle

2005

IEE Proc. Syst. Biol.

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High-level, mathematically precise descriptions of the global organisation of complex metabolic networks are necessary for understanding the global structure of metabolic networks, the interpretation and integration of large amounts of biologic data (sequences, various -omics) and ultimately for rational design of therapies for disease processes. Metabolic networks are highly organised to execute their function efficiently while tolerating wide variation in their environment. These networks are constrained by physical requirements (e.g. conservation of energy, redox and small moieties) but are also remarkably robust and evolvable. The authors use well-known features of the stoichiometry of bacterial metabolic networks to demonstrate how network architecture facilitates such capabilities, and to develop a minimal abstract metabolism which incorporates the known features of the stoichiometry and respects the constraints on enzymes and reactions. This model shows that the essential functionality and constraints drive the tradeoffs between robustness and fragility, as well as the large-scale structure and organisation of the whole network, particularly high variability. The authors emphasise how domainspecific constraints and tradeoffs imposed by the environment are important factors in shaping stoichiometry. Importantly, the consequence of these highly organised tradeoffs and tolerances is an architecture that has a highly structured modularity that is self-dissimilar and scale-rich. IntroductionMetabolic networks, which have been extensively studied for decades, are emblematic of how evolution has sculpted biologic systems for optimal function. In addition to unambiguous functional descriptions of core metabolism, this conserved network has been recently described in detail in terms of its stoichiometry (mass and energy balance). A higher level, mathematically defined description of the global organisation of complex metabolic networks is critical for a deep understanding of metabolism, from the interpretation of huge amounts of biologic data (sequences, various -omics) to design of therapies for disease processes. The stakes are high for obtaining the big picture right: biologic data plugged into a distorted model or interpreted in the context of a flawed universal law propagates misinterpretations. In flux analyses [1], stoichiometry is considered as a constraint, and fluxes are optimised to satisfy a global objective, typically growth. Previous studies, however, have not directly addressed whether the stoichiometry itself is highly optimal or organised in any sense and contributes to the origins and purpose of complexity in biological networks. Yet biochemistry textbooks describe metabolism as having evolved to be 'highly integrated' with the appearance of a 'coherent design' [2]. Here we explore both important 'design' (with no implication of a 'designer') features of metabolism and the sense in which stoichiometry itself has highly organised and optimised tolerances and tradeoffs (HOT) [3] for fun...

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Section: Introductionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Basic Features Of Metabolic Networkmentioning

confidence: 99%

Section: Basic Features Of Metabolic Networkmentioning

confidence: 99%

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Highly optimised global organisation of metabolic networks

Tanaka¹,

Csete

Doyle

2005

IEE Proc. Syst. Biol.

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“…These few common currencies are then used to build the large number of complex macromolecules required to power the cell. Tilting the hourglass metaphor on its side, Csete and Doyle noted that this ''bow tie" structure is a nearly universal feature of complex systems [16].…”

Section: Parallel Structuresmentioning

confidence: 99%

A taxonomy of biologically inspired research in computer networking

2010

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a b s t r a c tThe natural world is enormous, dynamic, incredibly diverse, and highly complex. Despite the inherent challenges of surviving in such a world, biological organisms evolve, self-organize, self-repair, navigate, and flourish. Generally, they do so with only local knowledge and without any centralized control. Our computer networks are increasingly facing similar challenges as they grow larger in size, but are yet to be able to achieve the same level of robustness and adaptability. Many research efforts have recognized these parallels, and wondered if there are some lessons to be learned from biological systems. As a result, biologically inspired research in computer networking is a quickly growing field. This article begins by exploring why biology and computer network research are such a natural match. We then present a broad overview of biologically inspired research, grouped by topic, and classified in two ways: by the biological field that inspired each topic, and by the area of networking in which the topic lies. In each case, we elucidate how biological concepts have been most successfully applied. In aggregate, we conclude that research efforts are most successful when they separate biological design from biological implementation -that is to say, when they extract the pertinent principles from the former without imposing the limitations of the latter.

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The Theory of Biological Robustness and its Implication to Cancer

Kitano

2009

Systems Biology and Synthetic Biology

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Bow ties, metabolism and disease

Cited by 423 publications

References 13 publications

Highly optimised global organisation of metabolic networks

Highly optimised global organisation of metabolic networks

A taxonomy of biologically inspired research in computer networking

The Theory of Biological Robustness and its Implication to Cancer

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