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The combination of high-throughput methods of molecular biology with advanced mathematical and …

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- The intricate side of systems biology

The intricate side of systems biology

Eberhard Voit, Ana Rute Neves , and Helena Santos

The Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology and Emory University, 313 Ferst Drive, Suite 4103, Atlanta, GA 30332-0535; and Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Rua da Quinta Grande 6, Apartado 127, 2780-156 Oeiras, Portugal.


The combination of high-throughput methods of molecular biology with advanced mathematical and computational techniques has propelled the emergent field of systems biology into a position of prominence. Unthinkable a decade ago, it has become possible to screen and analyze the expression of entire genomes, simultaneously assess large numbers of proteins and their prevalence, and characterize in detail the metabolic state of a cell population. Although very important, the focus on comprehensive networks of biological components is only one side of systems biology. Complementing large-scale assessments, and sometimes at the risk of being forgotten, are more subtle analyses that rationalize the design and functioning of biological modules in exquisite detail. This intricate side of systems biology aims at identifying the specific roles of processes and signals in smaller, fully regulated systems by computing what would happen if these signals were lacking or organized in a different fashion. We exemplify this type of approach with a detailed analysis of the regulation of glucose utilization in Lactococcus lactis. This organism is exposed to alternating periods of glucose availability and starvation. During starvation, it accumulates an intermediate of glycolysis, which allows it to take up glucose immediately upon availability. This notable accumulation poses a nontrivial control task that is solved with an unusual, yet ingeniously designed and timed feedforward activation system. The elucidation of this control system required high-precision, dynamic in vivo metabolite data, combined with methods of nonlinear systems analysis, and may serve as a paradigm for multidisciplinary approaches to fine-scaled systems biology.

biochemical systems theory | control system | feedforward activation | lactococcus lactis | metabolic pathway

PNAS, June 20, 2006, vol. 103, no. 25, 9452-9457.


As is typical with any new focus in science, the community has not yet agreed on a generally accepted definition of systems biology. Nonetheless, despite its young age, a perception is crystallizing that systems biology might be synonymous with the analysis of large networks that describe entire genomes, the totality of protein–protein interactions, the comprehensive mapping of metabolic pathway systems, or the combination of these systems at different levels of biological organization. Only a decade ago, such assemblies were unattainable both experimentally and analytically, but with modern high-throughput data acquisition techniques and ever-increasing computational power, they have come within reach. Their sheer size and high connectivity, presented with modern means of visualization, are indeed awe inspiring and have led to insights unimaginable only a few years back.

The focus on comprehensiveness is appealing, yet it would be shortsighted to make it exclusive. Biological systems are not just large, but they are organizationally complex, which, in addition to their often large numbers of components and processes, is manifest in properties like dynamics, regulation, and adaptation. These more subtle features tend to be ignored in large-scale analyses, because they create mathematical complications that presently cannot be captured or analyzed at the level of all-encompassing systems. Nevertheless, these features govern the life and responsiveness of cells and organisms in a very significant fashion, and it therefore is necessary to investigate their specific roles and functions. Because of the intrinsic complexity associated with the nonlinear dynamics or regulatory systems, it seems prudent at this point to pursue rigorous and detailed analyses of representative "sandbox examples" that help us discover successful patterns of design and operation. It is widely expected that much of biological organization is hierarchical and modular, and, if this supposition is true, insight into a variety of smaller systems will create a foundation on which to approach a deeper understanding of the functionality of large-scale integrated systems.

As an example for the intricate nature of the regulatory aspects of systems biology, we present here a model analysis of a mechanism that allows the bacterium Lactococcus lactis to respond very effectively to changes in glucose availability. The functionality of this regulatory mechanism is not detectable with the typical approaches of linear large-scale analysis. Instead, we demonstrate how explanations of the rationale and functioning of this controller become possible through a combination of relatively low-throughput, yet very precise, data on the dynamics of metabolic pools that were obtained through in vivo measurements (1), kinetic analysis by using cell extracts (2), and techniques of nonlinear systems modeling (3).

Lactococcus lactis is a member of the lactic acid bacteria widely used in the industrial manufacture of milk-fermented products. This homofermentative microorganism converts glucose (or lactose) to lactic acid, via the Embden–Meyerhof glycolytic pathway (Fig. 1), with >95% yield. The notable production of lactic acid is responsible for the protection of dairy products against spoilage by other microorganisms. In comparison with the canonical model bacteria E. coli and B. subtilis, L. lactis is a simpler system and, therefore, is well suited for integrative study.

NMR spectroscopy is a noninvasive technique that allows unique measurements of the kinetics of intracellular pools of metabolites directly in living cells (4). We monitored the pools of labeled intermediates and end products, with a time resolution of 30 s, in nongrowing L. lactis cell suspensions after a pulse of [6-13C]-labeled glucose (5). In addition to lactate and glucose, the levels of fructose 1,6-bisphosphate (FBP), glucose 6-phosphate (G6P), 3-phosphoglycerate (3-PGA) and phosphoenolpyruvate (PEP) were measured online (Fig. 2).

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