“Designing proteins is not the hard part anymore,” he says. “What’s harder and more interesting is determining which proteins to work on, what they do, and how.”
Simply improving one of a protein’s important properties is often not enough to improve its performance as a drug. “Most people are pretty naïve about what’s necessary to make a drug potent,” says Wittrup. The naïve approach, of which he says he has been guilty, is to test therapeutic proteins only for how tightly they bind to their cancer target; but such tests, he says, presuppose that “affinity equals potency.” They are conducted completely out of context, in a drop of cell culture solution in a plastic plate–outside the body, outside the tumors the cells came from.
Wittrup learned his lesson the hard way. He used directed evolution in an effort to improve the performance of an antibody against carcinoembryonic antigen (CEA), a protein that is overabundant on the surfaces of some tumors. The CEA-binding antibody he started out with falls off the cell and is filtered out of the blood before it can prompt a strong immune response. So he developed a version that bound much more strongly to proteins on the surfaces of cancer cells. The binding strength of his engineered antibody was two orders of magnitude greater than that of any other antibody known at the time; by all accounts, it appeared to be a great success. But when he tested it in living mice carrying human colon cancer, it didn’t work any better than the original. How could this be?
Turning back to the tools of engineering, Wittrup and his grad students adapted mathematical models normally used for studying industrial catalysts in order to examine the kinetics of his CEA-binding protein in tumors. In living mice, the engineered antibody was still being disposed of too fast–in this case because it got recycled before it had time to reach the center of a tumor. Proteins cycle rather quickly through all cells, normal and cancerous, generally staying intact only for minutes or hours. They get chopped up into smaller pieces so that they can be reused in new proteins. It’s part of normal cell maintenance; just as your home would be a dump if you never took out the trash, cells would be overwhelmed if they held onto every molecule they ever made or took in.
“Even if the bond lasts a week, it doesn’t matter,” Wittrup says. “It all goes down the garbage disposal.”
Using his models and working with imaging specialists to watch the progress of his protein through live mice, Wittrup is now attempting to modify the protein so that it will diffuse through the tumor too quickly for tumor cells to dispose of it in time. But the CEA-targeted antibody is just one of many therapies he’s developing. Another is a safer version of a toxic drug for kidney cancer and melanoma, which he’s working on with a fellow Koch Institute professor, immunologist Jianzhu Chen.
“We don’t know everything about cancer,” says Wittrup. But he adds that we “know enough to do more” to develop new therapies. Spoken like an engineer.
Cells as Systems
“People say cancer arises from some kind of disregulation of cell function,” says Douglas Lauffenburger, director of MIT’s Biological Engineering Division and an affiliated Koch Institute faculty member. So he’s taking an engineering approach to the question of how cell functions are regulated. His answers could help researchers predict whether a given drug will work.
The Human Genome Project has led biologists to the unfortunate conclusion that there is no simple explanation for how genes interact and how these interactions cause cells to move, grow, and die. Instead, Lauffenburger says, it “alerted everybody to how complex this was going to be.” Researchers had hoped to tackle diseases, including cancer, by tracing them to individual proteins or genes that they could fix with a “magic bullet.” But genome analysis suggests that cell functions are regulated by “lots of genes, lots of proteins interacting.”