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What led you to develop the protein chip?
ZHU: I was at Yale in 1999, studying enzyme-substrate specificity using yeast enzymes—protein kinases—as a model system. The problem was that proteins, unlike DNA, are very unstable. So we needed to create a high-throughput system that would allow us to purify them quickly. We came up with a chip technology that let us study 112 kinases, each in its tiny indentation in a silicone sheet. It took a year, but, in the end, we had developed a 96-well format. Later we decided to map the entire yeast proteome of 6,000 proteins.
What's the chip's main advantage?
ZHU: Its speed is very high—we can purify 11,002 proteins in a day. We also invented a protocol for imprinting the chip proteins on a surface. But, we faced one more challenge: Imprinting takes a long time and only tiny volumes of proteins go into the wells, so you worry about the proteins drying out. When we added glycerol, it worked beautifully.
What can chips let you do?
ZHU: We use them to track the chemical cascade that follows downstream from a particular enzyme's activity. Using traditional genetic or cell biology approaches, that's hard to do. But protein chips make it straightforward, because you can set up little in-vitro assays simultaneously on the chip's surface and in one experiment look for all the enzyme's potential targets.
Are there pressures from making a significant discovery so early in your career?
Yes, absolutely. Developing a technology gives you an advantage, career-wise, but only for a year or two. We're always trying to develop something new.