Gene Detective

By Dan Cray

As difficult as it was to sequence the 3.1 billion chemical "letters" that make up human DNA, the harder task may be to figure out what they mean. Trying to determine what's going on in a particular cell--which contains the entire complement of 30,000 or so genes but uses only a small fraction of them--is like watching a full-length movie a few pixels at a time.

That approach didn't make sense to Stanford biochemist Patrick Brown. Convinced that tissues and cells could be studied as collective systems rather than as individual components, he devised a method to mechanically print more than 20,000 gene molecules onto 45,000 tiny spots on a conventional microscope slide.

The result--the DNA microarray--is one of the most powerful tools in modern biology. Genetic material from the cell being studied is poured over the microarray and incubated in a solution containing fluorescent snippets of the same genes. If a gene is active, a corresponding gene on the microarray glows under UV light--a visual snapshot of the cell's genetic script. "Microarrays," says Brown, "offer an easy way to see the language the genome uses to send instructions that define every cell in your body."

Brown's technique proved so effective that it has been adopted by geneticists and drug designers around the world. Brown uses microarrays to compare the genetic script in healthy cells with the script in diseased cells, and he recently discovered that several malignancies assumed to be the result of a specific cancer were actually two or more distinct cancers when viewed on a molecular level. "It was like thinking a stomachache has only one cause," Brown says. "Recognizing the distinctions makes it possible for us to do a better job of treating these cancers."

The DNA microarray is the latest in a long line of scientific coups for Brown, who was among the first to learn how the AIDS virus replicates within healthy cells. "I'm just a scientist who's always daydreaming," he says, "and any time I think I have an interesting idea, I pursue it."

As a graduate student at the University of Chicago in the late 1970s, he baffled peers by enthusiastically throwing himself into the study of topoisomerases--the enzymes whose job it is to twist circular DNA molecules into tight coils. No one knew how the twisting occurred until Brown, playing with a rubber band, realized that by creating a break in the band, curling the opened band into a figure eight, then resealing the loose ends, he could introduce two twists into the rubber band for every split. "Everybody laughed and thought I was crazy," Brown recalls. But as it turned out, that is exactly how the enzymes operate. The discovery put Brown on the scientific map.

Today the only maps he's interested in are the ones that can guide him through the byways of human DNA. "It's like exploring unknown territory," he says. "We're toddlers just now starting to discover our world."