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ControlLing Cell Signaling Tissue Engineering:
Preorganization allows signalinduced changes to occur faster
A Proc. Natl. Acad. Sci. USA
signaling molecule will readily send its message when it encounters a preorganized array of receptors on a cell’s surface, a new study shows (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/ pnas.1101454108). The work is the first time preorganized surfaces have been used to spatially control cell signaling, according Cell interior TGF-𝝱 receptors TGF-𝝱
Peptide ligand
Greet And Meet Binding to surface-immobilized peptide ligands causes T𝝱RI (green) and T𝝱RII (purple) cell-surface receptors to preorganize in just the right way (left) for TGF-𝝱 binding (right), thereby facilitating cell signaling. to the researchers—grad student Lingyin Li, chemistry and biochemistry professor Laura L. Kiessling, and coworkers at the University of Wisconsin, Madison. Potential applications include creating biological tissues with patterned functionality by causing cells to differentiate into other cell types in specific locations. Kiessling and coworkers were inspired by the late chemist Donald J. Cram’s concept of “preorganiza-
tion,” the idea that host-guest interactions are most favorable when host and guest have complementary shapes. They set out to apply the concept to TGF-β, a signaling molecule that plays key roles in development, wound healing, cell differentiation, cancer, inflammation, and other biological processes. For signaling to occur, TGF-β must land on a cell surface and gather together and bind TβRI and TβRII, receptor dimers required for its activation. Kiessling and coworkers speculated that using peptide ligands to preorganize both receptor dimers in the correct pattern on cell surfaces would facilitate TGF-β-induced signaling. The strategy worked. When they coat the peptide ligands on slides, epithelial cells bind to the slides, and the ligands preorganize cell-surface TβRI and TβRII. When they then add TGF-β, it binds the receptors, generating signals that cause nearly all the epithelial cells to differentiate to mesenchymal cells within 48 hours. In contrast, far less differentiation occurs on nonpreorganized cell surfaces. Preorganization-induced signaling causes the same changes in gene expression as those caused by unaided signaling. The peptide ligands do not compete with TGF-β for binding sites on the receptor dimers; they simply arrange the receptor dimers to be ready for TGF-β, as a chef might collect all the ingredients for a recipe in advance. The researchers believe the preorganization approach will also prove applicable to rapidly activating other types of cell-signaling molecules. “Kiessling and coworkers have achieved a synthetic tour de force here,” comments biophysicist Dennis E. Discher of the University of Pennsylvania, whose areas of specialization include cell adhesion and differentiation. “They have made novel peptides that are intelligently immobilized in clusters to activate a major growth-factor pathway. In showing that thousands of genes are activated by their peptide-coated surfaces in a manner similar to the naturally soluble TGF-β, one can imagine all sorts of new applications such as smart bandages that help close wounds.”—Stu Borman
Biotechnology Bayer agrees to pay $750 million to U.S. rice farmers Bayer CropScience will pay up to $750 million to U.S. rice farmers to resolve claims that the company’s experimental LibertyLink rice contaminated crops, making them unfit for export. The agreement ends several lawsuits representing more than 11,000 long-grain-rice farmers in Arkansas, Louisiana, Mississippi, Missouri, and Texas. The LibertyLink rice traits were originally developed by AgrEvo, which was bought by Aventis CropScience. Bayer acquired Aventis CropScience in 2001. The rice was genetically modified to be toler-
ant to glufosinate, the active ingredient in Liberty herbicide. Tests of the rice were conducted at Louisiana State University. In 2006, Bayer CropScience alerted USDA that LibertyLink rice had contaminated the U.S. rice supply. At the time, no genetically modified rice varieties were being grown commercially in the U.S. In response to the contamination, Japan and Russia banned imports of long-grain rice from the U.S., while Mexico and the European Union required that U.S.-grown rice be tested and proven free of genetically modified traits.
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Bayer agreed to the settlement after losing several other court cases brought by rice farmers. In a statement, the company said it “acted responsibly in the handling of its biotech rice,” but opted to resolve the suits to focus on new products for farmers. Philipp Mimkes of the German group Coalition against Bayer Dangers cautioned the EU against approving LibertyLink imports. “The incident in the U.S. shows that risks linked with genetically modified crops cannot be controlled in the long term,” he said.—Melody Bomgardner
