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Dec 1, 2011 (Vol. 31, No. 21)

Systems Biology Delivers Higher Level Analysis

Combination of Experimental and Computational Views Brings Tremendous Power

  • Yeast Screens

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    Researchers at UC San Diego conducted an extensive screen of the yeast GFP strain collection. The screen revealed six novel distinct filaments in the budding yeast.

    Jim E. Wilhelm, Ph.D., assistant professor in cell and developmental biology at the University of California, San Diego, and colleagues recently conducted an extensive screen of the yeast GFP strain collection to identify proteins that assemble into intracellular structures that were not captured in previous screens.

    “We knew that there are things that the original screens missed,” said Dr. Wilhelm. This more extensive screen unveiled six novel distinct filaments in the budding yeast. “We were particularly excited to find cytidine triphosphate synthase assemble into filament systems.”

    Investigators in Dr. Wilhelm’s lab found that an inhibited form of CTP synthase is necessary for assembly into filaments, indicating that enzymatic regulatory activity is linked to incorporation into supramolecular complexes, establishing a link between enzymatic regulation and structural organization of cytoskeletal filaments. Dr. Wilhelm and colleagues subsequently revealed that CTP synthase filaments also exist in the fruit fly, but only in certain tissues, pointing toward the existence of tissue-specific regulation.

    “We think that what is going on is very analogous to the principles behind tubulin organization,” Dr. Wilhelm added. Many studies revealed that soluble tubulin subunits do not hydrolyze GTP unless they become incorporated into filamentous structures, in which the plus end of the filament acts as a GTPase activating protein that regulates the enzymatic activity.

    Investigators from Dr. Wilhelm’s lab are applying the same principles to study entire metabolic pathways. “This type of regulation is not a random feature but, instead, it seems to be coordinated, and there is a systems biology principle at work,” explained Dr. Wilhelm.

  • Pathogens

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    Metabolic network model with nodes accounting for genes, metabolites, and reactions for which the model has a mathematical representation.[University of Virginia School of Medicine]

    At the meeting, Jason A. Papin, Ph.D., assistant professor of biomedical engineering at the University of Virginia School of Medicine, talked about systems biology approaches that his lab uses.

    Another pathogen that Dr. Papin and colleagues focus on is Clostridium difficile. “Particularly in our work on Clostridium difficile, we very much focused on the host side of this interaction, to understand how the intestinal epithelium responds to toxins made by the pathogen,” revealed Dr. Papin.

    While many pathogens were characterized at the molecular level, and host factors involved in the interaction with pathogens have also started to be unveiled, albeit at a somewhat slower pace, systems biology now enables investigators to integrate all the information into computational predictive models.

    “Characterizing the dynamics of the host-pathogen relationship is an exciting field, and represents one of the opportunities in which systems biology can have one of its first major impacts,” said Dr. Papin.

    Systems biology can be used to understand how pathogens behave in a variety of environments or in different mutational backgrounds, or to predict therapeutic targets.

    “Within infectious diseases, there are many clinically relevant aspects, such as the challenges that surround emerging pathogens and antibiotic resistance, for which systems biology approaches are becoming increasingly important,” Dr. Papin emphasized.

    “The field is moving past metabolism, into the bottom-up network reconstruction of protein synthesis pathways, regulons, and stimulons, and these are important because antibiotic targets and virulence factors can be found in these processes,” said Bernhard Ø. Palsson, Ph.D., professor of bioengineering and adjunct professor of medicine at the University of California, San Diego.

    Dr. Palsson and colleagues illustrated the strengths of this approach with the reconstruction of the leucine-responsive E. coli regulon involved in regulating nitrogen metabolism. The analysis revealed multiple distinct regulatory modes for open reading frames and different types of regulatory network motifs, illustrating an approach that can be applied to other organisms to allow the reconstruction of transcriptional regulatory networks.

    An important advance in Dr. Palsson’s lab is the recent characterization of the genome-scale metabolic network in several bacteria of biomedical and industrial importance, including Yersinia pestis, Salmonella, and Klebsiella pneumoniae, and the publication of an updated version of a previously released E. coli metabolic network that includes many newly characterized genes and biological reactions and emerges as the most comprehensive metabolic reconstruction of a microorganism to date.

    “Looking at transcriptional regulatory networks at the genome scale will become particularly important for infectious diseases because pathogens are constantly sensing the microenvironment, as they decide how to interact with a host,” said Dr. Palsson.

    A rapidly expanding field that thrives on a combined experimental and computational perspective, systems biology explores biological processes at levels that were previously impossible to capture. This vibrant discipline marks a paradigm shift from the reductionist approach, which focuses on individual cellular components, to an integrated approach that aims to capture the complex networks established by the interacting components. One of the most relevant portrayals of the transition that systems biology catalyzes, conveying its most important characteristic, is offered by Denis Noble, in his book “The Music of Life”: “[i]t is about putting together rather than taking apart”.

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