Piecing Together the Puzzle
Cancer research might seem an unlikely place for James Heath to have ended up. As a graduate student at Rice University in Houston during the early 1980s, he began studying the properties of tiny chunks of materials. He was part of the team that, in 1985, discovered the soccer ball–shaped carbon molecule C60; the discovery won Heath’s professor, Richard Smalley, a Nobel Prize 11 years later and helped launch today’s interest in nanotech. But Heath later shifted his focus to semiconductors, such as silicon, used by the microelectronics industry, looking for ways to fashion them into ever smaller devices. Recently, he and collaborators at the University of California, Santa Barbara, devised a method for making silicon wires just a few nanometers wide, about ten times smaller than the smallest features in today’s integrated circuits.
The advance was a milestone in the continued miniaturization of electronics. And, says Heath, “We hoped that by solving such a difficult problem, other opportunities would present themselves.” They did: Heath realized these nanowires could also serve as ultrasensitive biosensors.
He also realized, however, that incorporating nanowires into an effective diagnostic tool would not be easy. Changes in a person’s state of health are reflected in wild swings in concentrations of biomolecules as different genes switch on and off. But over the past several years, geneticists and molecular biologists have come to realize that genes don’t generally act independently. They tend to operate in groups and networks, and they can regulate each other’s expression. So making sense of the molecular “fingerprints” of disease requires a systems-level understanding of how genes and proteins work together.
That’s where Heath’s collaborator, Leroy Hood, founder of the Institute for Systems Biology in Seattle, comes in. Systems biologists look at the cell much as an electrical engineer looks at a complex circuit: as a highly interconnected system of components that switch each other on and off and relay signals. Heath’s sensors might provide thousands of clues to a person’s state of health, but Hood’s systems-biology approach is needed to piece all those bits of information together into a coherent picture.
Hood and his team have, for example, looked at how genes are expressed to produce proteins in cells and tissues affected by prostate cancer. “Our idea,” says Hood, “is that the difference between normal and diseased cells is that the protein and gene regulatory networks in diseased cells have been perturbed, and these disease perturbations are reflected in altered patterns of protein expression controlled by the networks. A fraction of these perturbed proteins will find their way into the blood and constitute molecular fingerprints that are diagnostic not only of health and disease but of what disease and what type of a particular disease.” (There are at least three different types of prostate cancer, for example.)
“We have identified 300 [cancer marker] genes that are uniquely expressed in the prostate,” says Hood, “and we predict that about 62 of these may be secreted into the blood. We tested one of these by making antibodies against it and demonstrated that it was only present in the blood of patients with prostate cancer.” Hood’s team is now testing five more prostate cancer–secreted proteins. It has also found a similar array of genes that should be diagnostic for ovarian cancer.