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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

  • Angiogenesis

    Systems biology promises to impact virtually every scientific field. For example, “angiogenesis is a complex multistage process that involves many molecular players with numerous cross-talks and interactions. In a system like this, the use of systems biology is absolutely necessary to understand the process. It also is an effective tool to design novel therapeutics,” noted Aleksander Popel, Ph.D., professor of biomedical engineering and director of the systems biology laboratory at Johns Hopkins University.

    Angiogenesis is known to be involved in over 70 different diseases. Some, such as cancer and age-related macular degeneration, are characterized by excessive blood vessel sprouting while others (e.g., peripheral or coronary artery disease) are marked by insufficient angiogenesis.

    Computational modeling, bioinformatics, and in vitro and in vivo experimental methods are the major approaches that converge in Dr. Popel’s lab to provide a better understanding of the mechanisms of angiogenesis. They also show promise for designing novel therapeutic agents. By using these approaches, Dr. Popel’s lab characterized the involvement of several key vascular endothelial growth factor (VEGF) family members in angiogenesis, described a number of models for different applications, and validated model predictions against in vitro experiments and in vivo animal models for conditions such as cancer and ischemic disease.

    Investigators in the Popel lab are currently simulating administration of agents for pro- and anti-angiogenic VEGF therapies that can be used systemically or introduced by gene transfer to understand how they affect the balance of growth factors within the entire organism. The lab also has reconstructed the biochemical network that involves hypoxia-inducible factor 1α (HIF1α), a transcription factor acting upstream of VEGF and regulating over 200 genes involved in the hypoxic response. The group has developed a model to explain how in conditions such as ischemia and cancer, reactive oxygen species and antioxidants affect signaling through this pathway.

  • Understanding Cellular Networks

    The model organism S. cerevisiae fueled some of the most important advances in biology and helped scientists understand pivotal concepts in areas spanning signal transduction and DNA repair, cancer, neurodegenerative and cardiovascular pathology, and cholesterol metabolism.

    An effective way to gain insight into the regulation of biochemical processes is by exploring protein-protein interactions. Researchers estimate that the total number of interactions in S. cerevisiae ranges between 10,000 and 40,000. While many methods examine protein-protein interactions in vitro, the extent to which such interactions represent an accurate reflection of the in vivo cellular context emerges as an important question.

    Stephen Michnick, Ph.D., professor of biochemistry at the University of Montreal and the Canada Research Chair in Integrative Genomics, presented work at the Cold Spring Harbor venue that he performed together with several collaborators to characterize the S. cerevisiae protein interaction network in vivo. The team took advantage of a protein fragment complementation assay. Two proteins of interest, each fused to complementary fragments of a reporter protein, are brought together and reconstitute the reporter activity if an interaction is established between them.

    A genome-wide screen of protein-protein interactions identified 2,770 interactions among 1,124 endogenously expressed proteins and established a protein topology map at 8 nm resolution that promises to provide a valuable framework for future studies. A comparison with previous reports revealed that most interactions unveiled by this survey were previously unknown, pointing toward yet unexplored features of the yeast protein interactome.

    “The key is to utilize these facts because we now can study interactions in living cells, and we can manipulate live cells with drugs and changes in nutrients. We can ask how the network reorganizes itself and what these changes mean? We can do new things that we have not been able to do with other approaches and learn about the dynamics of the interactome,” said Dr. Michnick.

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