EGFR: A Molecular Lab Rat Let Loose In Systems Biology

EGFR is the veritable lab rat of molecular systems. Going on five decades now, biologists in labs around the world, not unlike motorheads under the hood with carburetors and plugs, have plucked out and examined every conceivable component of the EGFR network.

Along comes systems biology, shiny-new and bursting with promise, outfitted with high-powered computing and modeling capabilities that are being brought to bear on the fundamental problems of human physiology and disease pathology. And what undiscovered country does H. Steven Wiley and his colleagues at the Pacific Northwest National Laboratory choose to flood with the piercing light of this new science?

Why, naturally, this same receptor network.

"A lot of people ask, 'Why this system? It's the prototypical receptor system. We know everything about it. We know all the parts,' " says Wiley, chief scientist and director of the Biomolecular Systems Initiative at the Department of Energy lab in Richland, Wash.

Wiley's reply: The whole is much more than the sum of its parts - receptors, ligands, enzymes, substrates - and a great starting point if you know what each of those parts is.

"We're looking at the whole family of parts that govern cell behavior," Wiley says. "We need to know how they react with each other and other parts of the system."

Wiley likens the known world of the EGFR to a big-city phone book. It's all there, in black and white and yellow, and it tells you next to nothing about the city or how its inhabitants interact.

"The systems approach," Wiley says, "enables us 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."

Knowing how and what information is being passed inside a cell is the key in "network biology," Wiley says. "To kill a cancer, you have to attack a network. The cancer is set up to survive. A part of a normal cell might ask, 'am I in the right place, at the right time?' If the answer is no, the cell commits suicide."

Cancer cells are adept at either shutting out the signal or convincing themselves they are in the right place. "How do we hammer the proper signal through to a cancer cell? What parts of the network say 'live,' and what parts say 'die.' We have to find a way to make that decision process come out the way we want it to go. We have to talk to the cancer, persuade it to die. Then the patient can live."