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Jin Zhang of Pharmacology and Molecular Sciences examines the current and future rewards of intimately observing the cell's signaling molecules:
You’ve explained how looking at kinase activity up close will help reveal how malfunctions in such systems can contribute to disease. Could you elaborate on what you’ve found so far?
ZHANG: We are beginning to appreciate more and more the importance of precise spatiotemporal regulation in signaling—that is, how cells control precisely where and when signaling occurs. Changes in such spatiotemporal regulation are enough to trigger a disease event. A mutation in the AKT gene, for example, alters the subcellular location of this kinase, and that apparently is enough to lead to transformation of cells and leukemia in mice. So we’d like to understand such regulation.
How might this observation be put to practical medical use?
ZHANG: One idea is to use these biosensors to look at drug candidates that have shown promise in in vitro assays and see whether the drugs behave as predicted in living cells. We have also engineered biosensors and used them in a high-throughput screening system to look for novel hits that perturb the spatiotemporal regulation of signaling.
We might also use biosensors for detection and activity profiling of underlying disease; that is, to detect when activity levels or spatiotemporal patterns of a signaling molecule are abnormal. These tools would pick up such changes and help guide the appropriate treatment—a step toward personalized medicine. The National Cancer Institute is funding us to test this idea.
Your next project, for which you’ve received the Pioneer Award, will involve applying a technique in a way no one has. Do you worry that it might not work?
ZHANG: It is risky. That’s what the Pioneer Award program is for—high-risk, high-impact research. So it is possible we won’t get it to work. For potentially high-impact research, you need to take risks, and the potential reward is high.
Again, the exact approach that we originally had in mind may not work. But I’m confident in our vision—that we will generate novel molecular tools to study the native behaviors and properties of molecules in cells. The resources and flexibility provided by the Pioneer Award will allow us to explore untested research territory and make new discoveries.
What sort of obstacles do you anticipate in your research?
ZHANG: The cell system is very, very complex. Regulatory networks are multilayered. There’s a cascade of signaling events and, more importantly, many parallel cascades and crosstalk between the different parallel systems.
So we’re in the process of combining our current methods for visualizing intracellular signaling with mathematical modeling to get a more quantitative understanding of cell signaling.