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April 17, 2017

New Plant Gene Network Could Significantly Improve Drug Discovery

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    Vanderbilt geneticists have developed an effective method for identifying the plant genes that produce the chemical ammunition plants use to protect themselves from predation and is a natural source of many important drugs. [Jennifer Wisecaver/Rokas Lab, Vanderbilt University]

    The contribution that plants make to the drug discovery process is indispensable. Yet, identifying the networks of genes that plants use to make these biologically active compounds has vexed scientists for years, hindering efforts to tap this vast pharmacopeia to produce new and improved therapeutics. Now, a team of geneticists led by investigators at Vanderbilt University believes they may have developed an effective and powerful new way for identifying these elusive gene networks—potentially opening the door to creating new drug compounds.

    The findings from this study—published recently in The Plant Cell in an article entitled “A Global Co-expression Network Approach for Connecting Genes to Specialized Metabolic Pathways in Plants”—led to the identification of dozens, possibly even hundreds, of gene pathways that produce small metabolites, including several that previous experiments had identified.

    "Plants synthesize massive numbers of bioproducts that are of benefit to society. This team has revolutionized the potential to uncover these natural bioproducts and understand how they are synthesized," noted Anne Sylvester, Ph.D., program director in the National Science Foundation's Biological Sciences Directorate, which funded the research.

    The innovative approach is based on the well-established observation that plants produce these bioproducts in response to specific environmental conditions.

    "We hypothesized that the genes within a network that work together to make a specific compound would all respond similarly to the same environmental conditions," explained lead study investigator Jennifer Wisecaver, Ph.D., a postdoctoral scientist at Vanderbilt University.

    To test their hypothesis, the research team turned to Vanderbilt's in-house supercomputer at the Advanced Computing Center for Research & Education to crunch data from more than 22,000 gene expression studies performed on eight different model plant species.

    "These studies use advanced genomic technologies that can detect all the genes that plants turn on or off under specific conditions, such as high salinity, drought, or the presence of a specific predator or pathogen," remarked Dr. Wisecaver.

    However, identifying the networks of genes responsible for producing these small molecules from thousands of experiments and measuring the activity of thousands of genes is no trivial matter. Yet the researchers were undaunted—they devised a powerful algorithm capable of identifying the networks of genes that show the same behavior (for example, all turning on) across these expression studies.

    Collaborating with a number of other researchers across the globe, the Vanderbilt team was able to verify the predictions of the analysis in both corn and the model plant system Arabidopsis. Interestingly, the results of the analysis went against the prevailing theory that the genes that make up these pathways are clustered together in the plant genome.

    "This idea comes from the observation in fungi and bacteria that the genes that make up these specialized metabolite pathways are clustered together,” stated senior study investigator Antonis Rokas, Ph.D., professor, and chair of biological sciences at Vanderbilt University. "In plants, however, these genes appear to be mostly scattered across the genome. Consequently, the strategies for discovering plant gene pathways will need to be different from those developed in the other organisms."  

    Moreover, the authors noted that the results of their study show that their approach "is a novel, rich, and largely untapped means for high-throughput discovery of the genetic basis and architecture of natural plant products." If proven true, then it could help open the tap on new plant-based therapeutics for treating a broad range of conditions and diseases.

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