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Large-Scale Screens to Study Diabetes

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  • Title: Group Leader in Pancreatic Cell Biology and Metabolic Disease, Broad Institute of Harvard & MIT
  • Education: PhD, Harvard University, 2003
  • Recommended By: Stuart Schreiber

Running large-scale chemical screens isn't easy, even if you're at a world-class facility like the Broad Institute. As a research fellow at the Broad's chemical biology program for four years and now the group leader for pancreatic cell biology and metabolic disease, Bridget Wagner spends most of her days optimizing the basics of her small molecule screens, with an eye on drug targets for type 1 diabetes.

Her research focuses on finding ways to stop or slow down the destruction of pancreatic beta cells, which, in diabetes, cease producing insulin and die off. Wagner's approach takes advantage of large-scale biology tools and the Broad's extensive screening facility. "What we're trying to do is see if we can identify compounds that can be used to promote beta cell growth and health in the case of type 1 diabetes," she says.

Her approach to stimulate the body to regenerate beta cells is three-pronged. The first tack is to "stimulate the beta cell itself to divide," she says, which would restore insulin production. The second is to try to prevent cell death in the first place by identifying "compounds that could overcome the autoimmune-based attacks on beta cells," she says. The third method is through "trans-differentiation of other cell types in the pancreas." To this end, her lab develops cell-based assays to observe different aspects of beta cell function and health, and then performs screens with small organic synthetic compounds. "All three of these approaches use high-throughput screening as one of their main technological foci," she notes.

Wagner says she's lucky to have the Broad's resources, which include an enviable screening facility. "There's a very large push towards synthesizing libraries of compounds here that are all slightly structurally related to each other, and that gets us a little bit closer to understanding why some of the chemistry is having an impact in the cells."

One of the toughest challenges is identifying a positive assay readout to serve as a control. "It's often useful if you already have a compound that does what you want or a particular cell culture condition that mimics the state that you want to have," she says. Another hurdle is finding a good model for the beta cell. "There are a number of mouse cell lines, called insulinoma cell lines," she says, "[and] they produce insulin, they act like a beta cell, but they're a poor substitute for an actual beta cell."

Wagner says that while current screening technology works well, her work would be greatly accelerated with improved culturing techniques for pancreatic islet cells to bring that process into the high-throughput realm. The ideal scenario, she says, would involve being able to specify cell identity on command. "The same way that genetically it's now possible to turn a human skin cell into an iPS cell, we'd love to have small molecules [where we] can say, 'All right, you're starting out to be a pancreatic exocrine cell, but now you'll be a beta cell,' or vice versa," she says.

Publications of note

Her work promises much clinical application. In a collaboration with  fellow Broad member Vamsi Mootha this year that was published in Nature Biotechnology, Wagner used cell-based assays to screen almost 2,500 small molecules to probe mitochondrial gene expression patterns. What she found was, among other things, cholesterol-lowering statins resulted in mitochondrial toxicity. "It's important because statins cause a kind of rare but very serious muscle myopathy as a side effect," she says.

And the Nobel goes to …

As for the Nobel, Wagner would like to take her current research focus all the way. "I would think for curing diabetes, but that's fairly ambitious," she says.

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