Once, in early December 1999, George was driving to see LaDonna at the hospital in Olympia and stopped at a Safeway to buy a newspaper. Mr. No Serious is an avid reader, had even briefly run a bookstore with LaDonna, and he devoured the paper in her hospital room. As it happened, an experimental leukemia treatment was then making headlines. “Leukemia Pill Holds Promise,” the Associated Press reported, saying CML patients “had normal blood counts within a month of beginning treatment.” The study was then underway at the Oregon Health & Science University (OHSU) in Portland.
George hurried out of the hospital room to find LaDonna’s oncologist.
Target for Intervention
A steep, winding, tree-lined road leads to the main campus, which is perched near the summit of 574-foot-high Marquam Hill and on foggy days appears to float above the city like a castle in a fairy tale. Another route up to OHSU is the Portland aerial tram: two Swiss-made gondola cars of gleaming steel soar on cables high over Interstate 5, whizzing people back and forth between the west bank of the Willamette River and a hospital platform perched closer to the edge of a cliff than disembarking heart patients might wish it to be.
Brian Druker arrived at OHSU in 1993, years before the tram would be built and the hall-of-fame mural in the adjacent passageway would include a picture of him. Tall, as lanky and lightfooted as a greyhound, soft-spoken, Druker was 38 and had just spent nine years at the Dana-Farber Cancer Institute, part of Harvard Medical School, in Boston. “I saw cancer as being a tractable problem,” he recalled of the research path he chose after finishing medical school at the University of California, San Diego. “People were beginning to get some hints and some clues and it just seemed to me that in my lifetime it was likely to yield to science and discovery.”
At Dana-Farber, Druker landed in a laboratory studying how a normal human cell gives rise to runaway growth—malignancy. Among other things, the lab focused on enzymes, proteins that change other molecules by breaking them down (gut enzymes, for example, help digest food) or linking them up (hair follicle enzymes construct silky keratin fibers). Enzymes also figure in chain reactions, with one enzyme activating another and so on, until some complex cellular feat is accomplished; thus a cell can control a process such as growth or division by initiating a single reaction, like tipping the first domino. Under the lab’s chief, Thomas Roberts, Druker mastered numerous techniques for tracking and measuring enzymes in tissue samples, eventually turning to one implicated in CML.
Working out the details of why this particular enzyme is the key to CML had involved hundreds of scientists around the world—research that would lead to several Nobel Prizes—but here’s basically where Druker started:
First, all CML patients have the renegade enzyme in their white blood cells.
Second, the enzyme itself is the product of a freakish gene, called BCR-ABL, formed during a single myeloid stem cell’s division and thereafter transmitted to billions of descendants: the tips of two chromosomes, those spindly structures that store DNA, actually swap places, causing separated genes called BCR and ABL to fuse (see illustration). The new mutant BCR-ABL gene sits on a peculiar chromosome discovered in 1960 by scientists at the University of Pennsylvania. This “Philadelphia chromosome,” visible through a microscope, is CML’s hallmark.
Third, the BCR-ABL enzyme is the evil twin of a normal enzyme that helps control the production of white blood cells. But like a switch stuck in the “on” position, the mutant spurs the wild proliferation that is leukemia.