THOMAS BROENING FOR TIME

The Pioneers of Molecular Biology: Pat Brown
	His invention of the DNA microarray has helped geneticists start to ask the right questions about genes and disease
	By Alice Park

Posted Sunday, February 9, 2002; 10:31 a.m. EST
Each cell of the body is programmed to use a particular set of genes, depending what kind of cell it is and what it's supposed to be doing. But which genes? There is so much DNA and so many genes scattered within it that until quite recently, scientist had no practical way to compare one cell's genetic activity to another. It was like having clippings of random phrases from a Shakespearean drama and trying to read whole play. With only a few words here and there, how could the beauty of Romeo and Juliet emerge?

That's where Pat Brown comes in. He's the developer of one of modern genetics' most indispensible tools: the DNA microarray. The gene chip, as it's also known, is basically automated screening device that does for genes what a talented writer can do for words—take a jumble of fragments and organize them into a coherent whole.

"Every cell has an identical copy of the genome, yet there are tens of thousands of different cells in the body, and every cell has its own unique story," says Brown, now at Stanford University. "With the microarray, we can capture and look at that script, to see which genes are active, and how those genes are being used."

Schooled on James Watson's textbook The Molecular Biology of the Gene, which he read in college, Brown focused not on chromosomes, those tightly wound bundles of DNA, but on tiny fragments of DNA itself. Borrowing ideas from the computer chip industry and inspired by the mechanism of the humble quill pen, Brown and his team in 1992 arranged rows of tiny pen-like nibs in such a way that they could be dipped into different solutions of DNA. Moving swiftly over a glass plate, the tips were programmed to deposit, or spot, tiny drops of DNA in a series of neat rows, eventually laying out a grid of 40,000 gene snippets.

Using these grids, scientists can conduct experiments to answer a host of biological questions. To determine how a cancer cell's gene activity pattern differs from that of a normal cell, for example, researchers can mix samples of DNA from these two cell types with separate fluorescent dyes—red for cancer, green for the normal—and pour them over the plate. Because DNA fragments attract each other according to a fixed set of chemical rules, the grid acts like a genetic change sorter, bringing order to chaos. Genes from the two cell types quickly find their DNA "matches" from among the 40,000 snippets on the plate and attach themselves to their mates. A computer can then read the glowing patterns made by the fluroescent dye. If, for example, researchers were looking for drug treatments for this particular cancer, they would zero in on the products of the red-labelled genes and avoid the red-green ones that are churned out by both healthy and cancerous cells.

"What the microarray does is show us how the genome is controlled and orchestrated," says Brown. "That's the great exploration going on now, and that's a ton of fun."

Already, doctors using microarrays have learned that what they thought was one kind of leukemia is actually two different diseases, with different gene expression patterns, meaning doctors will need to follow different treatment strategies to help their patients. It's clear that the human genome has only just begun to tell its story. Thanks to Brown's microarry, however, it's starting to make sense.

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