Looking Deep, Deep Into Your Genes

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The process works this way: Every cell in your body contains the same DNA, but DNA activity -- or expression -- is different in a liver cell, say, than it is in a lung, brain, or immune cell. Suppose a scientist wishes to analyze the effect of a particular pesticide on gene activity in liver cells. (This makes sense, since it is the liver that processes and purges many toxins from the body.) A researcher would first expose a liver cell culture in a test tube to a precise dose of the chemical. A gene's activity is observed through the action of its RNA, molecules that convey the chemical messages issued by DNA. RNA is extracted from the test tube, suspended in a solution, then poured over the gene chip. Any given RNA molecule will latch on only to the specific gene that generated it. The genes on the chip with the most RNA stuck to them are the ones that were most active in the liver cells, or most "highly expressed." The genes that don't have any RNA stuck to them are said to be "turned off" in those cells. Scientists use the microarray to compare the exposed cells to non-exposed, control cells (see sidebar). Those genes that show activity in the exposed cells but not in the control cells, or vice versa, are the ones that may have been most affected by the pesticide exposure.

DNA microarrays open the door to an entirely new way of safety-testing synthetic chemicals: Each chemical alters the pattern of gene activity in specific ways, and thus possesses a unique genetic fingerprint. If a chemical's genetic fingerprint closely matches that of another substance already known to be toxic, there is good reason to suspect that that chemical can also do us harm. Ultimately, government agencies charged with regulating chemicals and protecting our health could use this method, one aspect of a field called toxicogenomics, to wade through the thousands of untested or inadequately studied chemicals that circulate in our environment. In other words, these agencies could make our world safer by identifying -- and, one hopes, banning -- hazardous substances.

For such a young field, toxicogenomics has already begun to challenge some fundamental assumptions about the origins of disease and the mechanisms through which chemicals and various environmental exposures affect our bodies. Consider the case of mercury, which was identified as poisonous many centuries ago. Its potential to wreak havoc on the human nervous system was most tragically demonstrated in the mass poisoning of the Japanese fishing village of Minamata in the 1950s. More recently, scientists have begun to amass evidence suggesting that mercury also harms the immune system. In 2001, Jennifer Sass, a neurotoxicologist and senior scientist at the Natural Resources Defense Council (NRDC), who was then a postdoctoral researcher at the University of Maryland, designed an experiment that included the use of microarrays and other molecular tools to figure out how, exactly, mercury was interfering with both our nervous and immune systems. She grew cells in test tubes -- one set for mouse brain cells, another for mouse liver cells -- and exposed them to various doses of mercury so that she could see which genes were being switched on and off in the presence of the toxic metal. In the brain and the liver cells, she noticed unusual activity in the gene interleukin-6, which both responds to infection and directs the development of neurons.

"We thought we had mercury figured out," says Ellen Silbergeld, a professor of environmental health sciences at Johns Hopkins University, who collaborated with Sass on the study. Genomic tools may identify effects of other chemicals by allowing scientists to "go fishing," as Silbergeld puts it, for things they didn't know to look for.

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