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April 11, 2017

CRISPR Awakens Sleeping Genes, Brings Drug Candidates to Light

  • CRISPR is most celebrated as a biomedical technology, a way to explore the cell’s secrets and potentially resolve genetic disorders. But CRISPR also deserves recognition for another sort of application, one that has a lower profile but is also, in its quiet way, necessary and important. CRISPR is not just a high-flying star of biology research, it is also deep in the trenches of drug discovery.

    Energetic digging sounds can be heard from the direction of the University of Illinois at Urbana-Champaign, where a research team led by chemical and biomolecular engineering professor Huimin Zhao, Ph.D., has been using a CRISPR/Cas9 gene-editing technology to look for new drug candidates. Specifically, Dr. Zhao and colleagues, including colleagues from Singapore’s Agency for Science, Technology, and Research, have been using a CRISPR/Cas9 knock-in strategy to activate silent biosynthetic gene clusters (BCGs) in bacteria.

    In the fight against disease, many weapons in the medicinal arsenal have already been plundered from bacteria. But Dr. Zhao’s team reports that they have now uncovered even more potential treasure formerly hidden in silent genes. Details of this work appeared April 10 in the journal Nature Chemical Biology, in an article entitled, “CRISPR–Cas9 Strategy for Activation of Silent Streptomyces Biosynthetic Gene Clusters.”

    “We applied this one-step strategy to activate multiple BGCs of different classes in five Streptomyces species and triggered the production of unique metabolites, including a novel pentangular type II polyketide in Streptomyces viridochromogenes,” wrote the article’s authors. “This potentially scalable strategy complements existing activation approaches and facilitates discovery efforts to uncover new compounds with interesting bioactivities."

    Essentially, the scientists turned on unexpressed, or "silent," gene clusters in a common class of bacteria that naturally produce many compounds already used as antibiotics, anticancer agents, and other drugs. "In the past, researchers just screened the natural products that bacteria made in the lab to search for new drugs," Dr. Zhao explained. "But once whole bacterial genomes were sequenced, we realized that we have only discovered a small fraction of the natural products coded in the genome."

    "The vast majority of biosynthetic gene clusters are not expressed under laboratory conditions, or are expressed at very low levels. That's why we call them silent. There are a lot of new drugs and new knowledge waiting to be discovered from these silent gene clusters. They are truly hidden treasures."

    To mine for undiscovered genomic treasure, the researchers first used computational tools to identify silent biosynthetic gene clusters—small groups of genes involved in making chemical products. Then they used CRISPR technology to insert a strong promoter sequence before each gene that they wanted to activate, prompting the cell to make the natural products that the genes clusters coded for.

    "This is a less-explored direction with the CRISPR technology,” Dr. Zhao emphasized. “Most CRISPR-related research focuses on biomedical applications, like treating genetic diseases, but we are using it for drug discovery."

    His lab was the first to adapt the CRISPR system for Streptomyces. "In the past, it was very difficult to turn on or off a specific gene in Streptomyces species. With CRISPR, now we can target almost any gene with high efficiency."

    The team succeeded in activating a number of silent biosynthetic gene clusters. To look for drug candidates, each product needs to be isolated and studied to determine what it does. As a demonstration, the researchers isolated and determined the structure of one of the novel compounds produced from a silent biosynthetic gene cluster and found that it has a fundamentally different structure from other Streptomyces-derived drugs—a potential diamond in the rough.

    Dr. Zhao asserted that such new compounds could lead to new classes of drugs that elude antibiotic resistance or fight cancer from a different angle.

    "Antimicrobial resistance is a global challenge,” he continued. “We want to find new modes of action, new properties, so we can uncover new ways to attack cancer or pathogens. We want to identify new chemical scaffolds leading to new drugs, rather than modifying existing types of drugs."

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