to make counterintuitive predictions, and then test them." Systems biologists must check their assumptions at the lab door. It was once dogma in drug development, for example, that the molecules of choice were those with high binding affinity to their receptors, the proverbial locksets on the cell membranes. Clicking the deadbolt either blocks or unlocks the desired reaction in the cell. It turns out that a strong and decisive snap of the bolts -- the high-affinity binding -- works for a while, but keeping the arrangement in place can drain the system.

"In one case, we were able to predict that a growth factor with a lower affinity will bind longer" -- not unlike a long-distance runner pacing for a marathon as opposed to, say, the 60-meter-dash of the high-affinity molecule.

The systems approach, he says, also forces "us to be better molecular biologists." In order to test a model that calls for a mathematically precise solution, Wiley and his colleagues have to cajole molecules into performing unnatural acts. In one experiment, to test their assumptions about what EGFR molecules called ligands actually do, they had to re-engineer a cell, move the ligands in time and space, "swap out ligand parts."

"There are five ligands for the EGF receptor," Wiley says. "We wondered why five? Few people cared about the number of ligands. They figured domain 1 in the first ligand does the same thing in the second ligand, so what's the difference?"

Big, it turns out. If you swap domains, you alter the rates of secretions on the surface of the cell, and the cells can't organize into tissues. "We can make cells come together and come apart by swapping domains."

By defining the functional domains, Wiley listened in on a previously unheard conversation inside the cell. And he didn't care so much about why they were talking as what they were saying. "We just wanted to know what information that functional domain has on it."

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Contact: Bill Cannon
cannon@pnl.gov
509-531-7345
DOE/Pacific Northwest National Laboratory
17-Dec-2003

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