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May 1, 2009 (Vol. 29, No. 9)

Practical Applications of Systems Biology

Approach Provides New Perspectives for Biomedical Science Research Initiatives

  • Host-Pathogen Interaction

    RNAi screens have recently emerged as particularly powerful approaches to survey host-pathogen interactions. Nevertheless, as genetic tools that have a propensity to reveal indirect associations, they are not very informative on whether a specific interaction is direct or indirect.

    “We took an integrative approach,” noted Sumit Chanda, Ph.D., associate professor at the Burnham Institute for Medical Research. “We went in with the hypothesis that RNAi activity should not be the only criteria that one should chose when picking factors coming out from an RNAi screen.”

    At a recent Cold Spring Harbor Laboratory conference on “Systems Biology: Networks,” Dr. Chanda revealed how his group integrated RNAi data with protein network analysis to obtain a spatial representation of how the factors that are identified interact with each other and with HIV-encoded proteins. The team identified 295 genes involved in early infection.

    Around the same time, two other groups, led by Stephen J. Elledge from Harvard Medical School and Amy S. Espeseth from Merck & Co., used RNAi to identify host proteins involved in HIV infection. Interestingly, although each of the three screens identified approximately 300 genes, only 9 to 15 of the genes were shared between paired datasets.

    “Our hypothesis is that many of these factors are going to be indirect regulators of the same pathways or biological processes, and that is why there is such a low degree of overlap,” continued Dr. Chanda.

    “Most factors that are identified represent secondary or tertiary regulators of the process, such as a regulator of a regulator of a regulator. That is why this idea of integrating biochemical as well as genetic analysis, intersecting the two datasets, not only cleans up the data, but also provides a functional readout. It also offers a spatial and biochemical snapshot of how these host proteins mediate the phenotype through the interaction map.”

    Microbial pathogens represent a major cause of morbidity and mortality worldwide. Their ability to develop resistance to antibiotics is thought to forecast what some investigators have called “the postantibiotic era.” As past decades demonstrated, resistant bacteria invariably start emerging after specific antibiotics become commercially available, sometimes as soon as within a few months.

    “For some time we have been taking a systems biology approach to study how bacteria respond to antibiotics,” said James J. Collins, Ph.D., professor of biomedical engineering at Boston University and a Howard Hughes Medical Institute Investigator. At the Cold Spring Harbor meeting, Dr. Collins presented his group’s recent findings that all bactericidal antibiotics, regardless of their drug target, induce oxidative damage and cell death pathways that lead to the production of hydroxyl radicals and thus contribute to cell death.

    Targeting bacterial protective pathways that are induced to remediate reactive oxygen species damage, and in particular manipulating the DNA damage repair pathways, becomes, therefore, one potential approach to potentiate the effect of these antibiotics.

    “We believe that small molecules could be produced that would lead to the creation of super-Cipro, super-Gentamycin, or super-Ampicillin,” predicted Dr. Collins. Most recently, while examining the events following aminoglycoside interaction with ribosomes that lead to the formation of reactive oxygen species, Dr. Collins’ group revealed that these antibiotics lead to the mistranslation of membrane proteins and showed that the envelope stress response and two-component redox regulatory systems are involved in antibiotic-mediated oxidative stress and cell death. This provided additional insight into the common mechanism of killing induced by bactericidal antibiotics.

    “Systems biology approaches can help provide insight into bacterial cell death pathways and the protective mechanisms induced by antibiotics,” said Dr. Collins. “These network-based analyses will lead to the development of novel, more effective antibiotics, as well as ways to enhance existing antibacterial drugs. These efforts will be critical in our ongoing fight against antibiotic resistance.”

  • Protozoan Research

    In what represents the first effort of this kind involving a protozoan organism, Jason A. Papin, Ph.D., assistant professor of biomedical engineering at the University of Virginia, together with collaborators, reconstructed the first Leishmania major metabolic network that accounts for 560 genes, 1,112 reactions, 1,101 metabolites, and eight unique subcellular localizations.

    Moreover, in collaboration with Vitor Martins do Santos, Ph.D., from the Helmholtz Center for Infection Research in Germany, his group used available genetic, biochemical, and physiological data to perform a genome-scale reconstruction and constraint-based model of the Pseudomonas aeruginosa strain PAO1, mapping 1,056 genes whose products correspond to 833 reactions and connect 879 cellular metabolites. “It is such a great system,” emphasized Dr. Papin, “since it is relatively well characterized and it is a pathogen.”

    The model was validated with published genome-scale gene essentiality screens and with substrate-utilization assays that predict whether the organism can catabolize specific substrates.

    Although these comparisons provide important validation, they also have significant implications for understanding what makes certain genes essential, or why an organism is capable of utilizing one substrate but not another.

    “We think there is a real and unmet need. I think systems biology can have one of its earliest and largest successes in tackling infectious disease and in identifying and validating drug targets in these pathogens,” said Dr. Papin.

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