By Erin Sherbert
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Like test tubes or litmus paper, it's easy to go through a lot of gene chips while doing an experiment. But unlike test tubes, gene chips are incredibly expensive -- as much as $2,000 for a single commercially manufactured slide. "If I want to look at only 100 tumors, we're talking hundreds of thousands of dollars," Jeffrey says. "That's costly enough to prohibit research." After all, the typical annual budget of an academic researcher may be only $100,000.
Yet the chips are vital, and Jeffrey must have them. So for only about a hundred dollars each, she makes her own. With a homemade robot, two full-time microarray technicians spend their days stamping out gene chips for Jeffrey's tumor experiments. The robot uses tiny metal printing tips that are first dipped in separate liquid solutions of standard genes obtained in bulk from various labs. These already-known genes are then dabbed on the glass plate to create spots measured in mere microns. This is repeated until 24,000 spots representing as many individual genes fill the chip.
What Jeffrey can do with the gene chip is where the magic starts.
After the tumor from Jean Christ's breast is removed, it is ground up and its RNA is isolated. RNA is the carrier of genetic information produced from DNA, which determines how a cell will behave. Jeffrey marks the RNA with a red dye. At the same time, a controlled reference sample made of cancerous RNA from other tumors is marked with a green dye. Both mixtures are then washed over the standard gene chip. A chemical reaction called hybridization happens, and genetic material that is similar from both mixtures will stick to corresponding genes already on the chip.
The chip is then scanned by a laser that fluoresces in red and green light. On a computer screen, Jeffrey can view all 24,000 genes in color. Red dots tell Jeffrey which genes were active in Christ's tumor. Green dots represent the reference sample. A yellow dot means the gene was common in both samples. A black dot indicates the gene wasn't active in either.
This is called gene expression. From the genes that she knows were already on the standard chip, Jeffrey can figure out which genes were active in Christ's tumor by looking at where the red and yellow dots appear. These colors tell her which genes she needs to examine in order to figure out what makes Christ's tumor work. By repeating this process with hundreds of tumors, Jeffrey hopes to find patterns and begin to unravel the mysteries of cancer.
"This is different from how science is normally done," she says. "It's almost like we're in a hunting expedition, looking for genes we didn't know about or wouldn't have looked at in the first place. By speeding up the process, the microarray lets us do it."
Paradoxically, the gene chip seems almost too simple a tool to tackle such a complex problem, but researchers like Jeffrey are realizing this could be the "Eureka!" that defines medical research in the 21st century. "It's just a glass slide, but it's an incredible and amazing technique. What would've taken us years to discover without it, we can now find in just a few days. It is a powerful tool that is the future of genetic research," she says. "I hope Pat Brown wins the Noble Prize for this."
Patrick Brown is the Stanford biochemist who is widely credited as one of the early creators of the glass slide Dr. Jeffrey finds so incredible. But before any prizes are handed out, there will be plenty of legal wrangling over just who did what in the process of developing the gene chip.
In the decade since the first patents were issued on the most rudimentary models of gene chips, scores of scientists have begun creating equipment that can read lots of genes at one time. Believing the analogy that someone can patent a Ford or a Chevy, but not the concept of the car itself, they've raced to find the best way to put genes on a chip. The profit potential is astronomical. Industry experts believe the value of the worldwide gene chip market could reach $1 billion by 2005. So a number of biotech companies are working feverishly to develop their own methods, or spending large sums to buy new ideas from enterprising scientists, in hopes of producing a best-seller chip.
And to protect their products, the companies have been filing patents -- and contesting them -- every step of the way, creating great confusion in the courts as they accuse each other of infringing on their respective turf. The seemingly endless litigation has resulted in questions over who will ultimately control the gene chip. Could one biotech company eventually be in a position to claim an all-encompassing patent on gene chips -- regardless of how they are made?
The uncertainty over what the courts will decide means research has slowed. Some companies are nervous about launching new product lines before a ruling is made, which has limited choice and helped keep prices high. Many academic researchers eager to use gene chip technology simply can't afford it. Other scientists are afraid to begin research, lest the company manufacturing the gene chip system they choose loses its patent case and goes out of business, leaving their labs stuck with the biotech equivalent of Beta format videotapes.