Genes Without Frontiers

The so-called gene chip could revolutionize the way we treat cancer patients. That is, if biotech firms don't keep it out of doctors' hands.

Dr. Stefanie Jeffrey must remove the tumor growing inside Jean Christ's left breast before it metastasizes, spreading cancerous cells through her bloodstream.

The lump Christ first felt with her fingers measures barely 2 centimeters on a mammogram. The X-ray shows only a tiny white dot sitting close to her nipple, but Christ will sacrifice her entire breast in order to rid her body of the potentially lethal mass. She has chosen to have a radical mastectomy. Though she could have had a less invasive surgery, which would have removed only the tumor -- a procedure known as a lumpectomy -- she would have had to follow this up with a series of highly toxic treatments to kill any stray cells left behind that could cause the cancer to return.

At 78, Christ still likes to dance with her husband. She's afraid getting sick from the side effects of chemotherapy or radiation will jeopardize her active lifestyle and the enjoyment of her remaining years. So she has decided she can do without her breast if that's what it takes to have peace of mind.

Stanford's Dr. Patrick Brown
Anthony Pidgeon
Stanford's Dr. Patrick Brown
Dr. Stefanie Jeffrey.
Anthony Pidgeon
Dr. Stefanie Jeffrey.
Leveling the Playing Field: Joe DeRisi prepares a gene chip for scanning.
Anthony Pidgeon
Leveling the Playing Field: Joe DeRisi prepares a gene chip for scanning.
Space Age Medical Research: The chip's dots each represent a human gene.
Space Age Medical Research: The chip's dots each represent a human gene.
Brew Your Own: Instructions to build a microarray robot are posted at http://cmgm.stanford.edu/pbrown.
Anthony Pidgeon
Brew Your Own: Instructions to build a microarray robot are posted at http://cmgm.stanford.edu/pbrown.

Jeffrey, Christ's surgeon, wishes her patients didn't have to make these all-or-nothing choices. And soon, she hopes, they won't. Jeffrey is the chief of breast surgery at Stanford Medical Center, where she is attempting to find better ways to combat breast tumors by researching what makes them work. Why do some spread, and not others? Are there more reliable ways than chemotherapy to stop migrating tumors?

The results of Jeffrey's research, which may end up saving women's lives, are dependent on a new invention called the gene chip. At the moment, Jeffrey makes her own gene chips using a cost-effective homemade robot. But a legal battle over rights to the gene chip could ultimately place her and other medical researchers in the position of having to purchase expensive equipment and services from private companies. A patent dispute among several of these companies -- most notably Silicon Valley biotechnology leaders Affymetrix and Incyte -- is the most recent example of the way private corporations are seeking to control the technology used to study today's hottest medical research subject: human DNA.

If Jeffrey can compare tumors that spread with those that don't, she will be able to see patterns that could determine whether patients like Christ need chemotherapy or not. As it is, all tumors are treated as metastasizing suspects because it is impossible to tell which are which. Jeffrey hopes to change that -- by reading genes. Until now, gene reading has been an arduous, labor-intensive process. Though there are an estimated 80,000 or more genes in the human genome, the most powerful scientific instruments could look at only a few at a time. And every person, and tumor, is unique. Sheer numbers have kept what is sure to be life-saving genetic research out of reach.

But the gene chip has changed that.

The chip allows researchers to read tens -- even hundreds -- of thousands of genes simultaneously, catapulting the study of genetics from the equivalent of the horse and buggy era to the space age in an instant. And obviously, with cures for cancer and other lethal diseases potentially on the line, anyone who can claim rights to the chip stands to make a lot of money. But exactly who thought up the gene chip, who made it work, and who made it better -- and when -- is disputed. The confusion has resulted in a long list of unresolved court battles among the Silicon Valley biotech companies that want to market and sell the chip.

Jeffrey is ignoring the lawsuits. Using the gene chip, she figures it will take her less than five years of gene reading to begin learning which breast tumors are prone to spread, and less than 10 years to develop more effective drug therapies. Within a generation, it may even become possible to predict whether a woman will get breast cancer at all. She believes the research is too vital to be sidelined by a prolonged patent dispute.

Fortunately for Jeffrey and for her patients, so does the group of scientists showing academic researchers how to build homemade gene chips at a fraction of what it would cost to buy them commercially. These Bay Area biochemists were early pioneers of the same gene chip technology now being fought over in the patent courts. For researchers like Jeffrey, the gene chip system widely known as "home brew" has become a welcome and effective way to move scientific progress beyond the control of lawyers and profiteers.

Still in the surgical scrubs she wore during Jean Christ's mastectomy, Dr. Jeffrey walks through the Stanford Medical Center complex to the school's genetics department in her trademark bright pink shoes. She special-ordered her surgical clogs in the color that represents breast cancer awareness. "But I didn't know they would be fluorescent," she says. At the gene lab, Jeffrey checks on the progress of her breast cancer study. There, Stanford scientists are using the home brew gene chips to analyze her growing stock of tumors.

Jeffrey holds up a 1-by-3-inch glass slide to the light. She can see, when squinting, that there are thousands of dots arranged in tiny rows. Twenty-four thousand dots to be exact. Each dot is an individual gene, and together they make a gene chip. "A microarray," Jeffrey corrects. "Gene chip" is the sexy term marketers like to use. The chip itself is not unique, apart from the idea and technology behind it. It simply holds 24,000 known genes in one convenient place. All gene chips are the same, standard boilerplates on which to do comparison experiments with the unknown genes of a tumor.

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.

Patrick Brown, though, has helped many scientists circumvent the problems inherent in depending on commercial technology. With "blast ahead" as his motto, Brown has been instrumental in spreading the home brew technology that Jeffrey and countless other researchers now use.

Brown created a successful microarray system in the early 1990s with the help of two graduate students -- one from Stanford's engineering department and the other from his biochemistry lab. Brown and Dari Shalon, the engineer, are credited with inventing the technology. Joe DeRisi, a student working in Brown's lab, did a lot to help make it work.

Interested in mapping genes, Brown was frustrated that there was no practical way to read them. He had a simple design in mind, so he set out to find someone on campus who could help him build it. Most of the engineers at Stanford scoffed when Brown explained his concept: a robot with "fountain pens" that would dot DNA onto a glass slide. "This is an academic institution and you don't get ahead here doing something so rudimentary," Brown says. "Everyone wanted to do something incredibly complicated and expensive."

But Shalon was eager enough to try Brown's idea that he left the engineering department, joined Brown's lab, and began pursuing a Ph.D. in biotechnology engineering. "Right away he asked me if this was something he could start a company with," Brown says. "I knew it was something with a lot of commercial potential, which is how I was able to persuade Dari to take it on. But it never occurred to me just how big it would become. Dari has a very good quality that is underappreciated here -- pragmatism."

Indeed, as soon as the technology was viable, Shalon left the project and founded his own company, Synteni. There, he spent a few years perfecting the gene chip system on his own before selling Synteni to Incyte -- one of Silicon Valley's largest biotech firms -- for $90 million. Now, at 34, Shalon is back in academia as the new director of Harvard's Center for Genomics Research.

But when Shalon sold his company to Incyte in December 1997, the transaction sparked a patent dispute that pitted the biotech industry's biggest players against each other. Santa Clara-based biotech powerhouse Affymetrix, which had been collaborating with Palo Alto's Incyte on aspects of gene chip technology, immediately sued Incyte when the latter acquired Shalon's company. Affymetrix was developing its own, much more advanced, version of the gene chip. But Brown and Shalon's spotting system remained more popular among scientists, who claimed it was more versatile -- and certainly cheaper -- than Affymetrix's photolithographic method. "Many scientists say the Affymetrix technology is not well-suited for them," says Alex Ward, a Silicon Valley biotech analyst. "They agree Affymetrix can make very dense chips, but it's not good for everything. You don't need a Ferrari to commute down Highway 101."

Incyte's system had its drawbacks, too. Instead of selling gene chips, Incyte acted as a job shop: Scientists would drop off their gene expression experiments and pick up the processed results later. While some customers enjoyed the convenience of not having to buy a microarray system, others preferred to have control over their work. "It's like taking your film to be developed at Walgreens, except you don't get to take the pictures," Ward says. "A lot of scientists don't like that. They want to be hands-on with their own experiments."

Still, Incyte's foray into the business threatened Affymetrix's share of the market. In suing Incyte, Affymetrix claimed infringement by asserting that its patents covered all gene chips of a certain density -- no matter how they were made.

Incyte cried foul. "Affymetrix claims it owns the field," says Incyte lawyer Teresa Corbin. "They're trying to shut out everyone else for things they didn't think of in the first place."

In fact, Stanford's Brown says the intellectual his- tory of microarrays goes back years before he or Affymetrix began doing anything in the field. The idea of reading lots of genes at once is not new, he says, and there are plenty of ways in which it can be done. "There are many subtle as well as obvious differences between the technologies Affymetrix and my lab developed, and in the visions we had for their applications," Brown says. "So the question of what's patentable is really a difficult one."

Affymetrix is already widely known as the undisputed industry leader in gene chips. And the aggressiveness with which Affymetrix has pursued patent litigation -- not only against Incyte, but against companies like Hyseq and Oxford Gene Technology -- demonstrates its determination to continue dominating the market, says Los Angeles-based biotech analyst Alan Auerbach. "Affymetrix is going for the full monty. They're trying to patent anything they can because they want everything," he says. "They have a real crack legal staff that's going after any and all competitors. If the people at Incyte are smart, they will be figuring out ways other than the microarray to make money."

Incyte, too, has been on the offensive, countersuing Affymetrix, as well as getting into its own patent disputes with other smaller biotech companies like Gene Logic. However, Incyte was dealt a blow when the U.S. Patent and Trademark Office ruled in favor of Affymetrix last September, in a broad interpretation that took many patent experts by surprise. "A lot of people feel the normal patent standards that should have been applied in this case may not have been applied to Affymetrix," says Peter Dehlinger, a Palo Alto patent lawyer who served the biotech industry for 20 years.

The final decision will be rendered by the Northern California District Court later this year. Affymetrix is confident its rights to the gene chip will be established -- something that would mean the company effectively owns a vast new area of medical research. "Our patents are very fundamental to the gene chip. If we're successful in enforcing them, it will have significant ramification in the marketplace," says Affymetrix lawyer William Anthony. "If we win, it will be game over for Incyte."

But Dehlinger believes the court may not rule in Affymetrix's favor. "If it looks like one company has so much dominance that it's slowing everyone else down, that the patent system is starting to impede science, I believe the PTO will shift its policy -- if people raise enough ruckus."

When Affymetrix began its campaign of litigation, Brown's lab only intensified its "blast ahead" efforts: Worried that scientists would have limited access to the technology, Brown handed it out for free.

"We're just leveling the playing ground with the big boys by distributing the technology more evenly," says Joe DeRisi, the student who stepped up to help Brown complete the gene chip when Shalon left. "It's not fair for people to be victimized by corporate profit schemes when they can easily build the technology themselves."

So DeRisi has posted step-by-step instructions for making gene chips on the Internet. The "M-Guide" promises that, using mostly store-bought materials, anyone can assemble his or her own microarray-making robot for about $30,000. The methods are remarkably simple. "It's a no-brainer," DeRisi says. "You can do this in your garage, even if you don't have a science background."

In addition to the Web site, DeRisi and Brown have personally taught other researchers their techniques. Last November, they ran a workshop at the Cold Spring Harbor Laboratory in New York at which 16 scientists spent two weeks learning how to make and use microarrays.

"The whole purpose is to enable and empower researchers and stimulate innovation," DeRisi says. "If researchers don't have access to microarrays, or can't afford them, how else will they make discoveries?"

Though Brown shares credit with Shalon in one Stanford-owned microarray patent, Brown has no financial stake in his invention. And as instrumental as he was in making the technology work, DeRisi doesn't stand to profit from it either. "If I were resentful, I think I would just quit academics and join a biotech company to make the big bucks, or start my own company," says DeRisi, who is now a fellow in biochemistry at UCSF, where his latest focus has been on using microarray research to combat malaria. "What are the companies working on, anyway?" he wonders. "With all the money they put into Viagra, we could have a cure for malaria by now. Millions die from malaria, but most of those people aren't rich. I'm doing stuff the pharmaceutical companies won't touch. We'll see who does better good."

Brown, too, believes the only worthy goal of scientific research is to benefit the public. "There are lots of peripheral things about being a scientist that can be a pain in the ass, like dealing with all the academic politics and having to apply for grants," Brown says. "Cynics will find this corny, but the bottom line is we are charged with a responsibility of trying to make the world a better place by helping people with science."

Brown admits he is on a "minor crusade" to change the way scientific information is shared. "I would always like to make a discovery public before a company can patent it," he says. "It rubs me the wrong way that people can own information and restrict its use, especially when companies try to commercialize it."

He doesn't regret passing up the chance to be a multimillionaire. "I think it's good for my kids that we don't have a lot of money," Brown says. "We're already doing very well. We have enough money to live in a condo in Palo Alto. How much more do we need?"

In May, at a Washington, D.C., ceremony, Brown will be awarded the prestigious National Academy of Sciences award in molecular biology. He will re-ceive a medal and $20,000 for his "intellectual leadership in ... the development of a reliable and accessible DNA microarray system."

But any mention of the Nobel Prize makes Brown uneasy, especially upon hearing Dr. Jeffrey's hope that he will win it. "If you print that, I'll just die," he says. "That kind of recognition is pure politics. It can put too much emphasis on the individual, and can taint the scientific community." The only award he seems proud of is a certificate taped on his office door. Presented by his staff, it proclaims: "Perfect Attendance Award (between 3:48-4:17pm) Feb. 30, 1999." Brown is notoriously late for everything, his assistant jokes.

Stanford Department of Genetics Chairman David Botstein -- Brown's boss -- was so impressed with Brown's work that he suggested they team up to make gene chips available to any Stanford researcher who needs them, such as Jeffrey with her breast tumor study. Brown and Botstein set up a microarray production facility, with Botstein agreeing to handle the bureaucratic part of the endeavor. "There's been a lot of lip service to how studying genes will revolutionize the way we do and think about science, but very few have done anything on the ground," Botstein says. "This business of DNA chips has been soured considerably by the restrictive behavior of the companies engaged in it. Pat has fought hard and effectively to disseminate the technology, which was a very laudable impulse on his part."

But there is now some question over whether the home brew scientists work-ing with Brown's technology will be at risk of being sued by biotech companies once the gene chip patent disputes are settled. In fact, a recent study of the microarray market by Silicon Valley consulting group Frost & Sullivan concluded that besides the ongoing intellectual property battles, competition from home brews will be a key restraint to future profits. "It's a threat for sure, and a concern the companies have," says study author Alex Ward.

While patent lawyers say the home brew scientists could technically be infringing by using a patented method, it is unclear if biotech companies will go after individual scientists. Brown doesn't think so: "There is such a symbiotic relationship between these companies and academic researchers," he says. "They would be shooting themselves in the foot by being so heavy-handed."

Botstein isn't so sure. "I wouldn't say it is impossible. Companies will sue you tomorrow if they think you are trying to profit," he says. "Already, some companies want you to pay royalties not only on the technology, but on what you discover using the technology. I think it's outrageous and I've argued strenuously against it. Bill Gates doesn't expect royalties on the novel you've written using his software."

Still, Botstein isn't worried someone will try to shut down his and Brown's microarray lab. "So far these patent issues have just been a lot of noise and furor," he says. "Unless they come with the marshal and say, 'Don't do that,' why should we care?"

Getting the gene chip into scientists' hands, he believes, may advance medicine in completely new directions. "Since we don't know exactly where we are going, this is research in search of a hypothesis," he says. "We feel like Lewis and Clark, when Jefferson said, 'Go forth and tell us what's out there.'"

Brown, meanwhile, is just happy that in spite of the lawsuits, it's science as usual, with home brew technology ensuring new research won't be stalled.

"I think the answer most real scientists would give to the question of what's really original, and useful, and non-obvious, is sufficiently different from the answer that lawyers would give," he says. "It's almost as if these patent battles take place in some strange parallel universe. I know it's important on some level, but I find it extremely boring."

Last week, Patrick Brown, David Botstein, and others published their first important study proving that a look at global gene expression patterns will be a major help to scientists struggling to understand cancer. Using the microarray to examine B-cell lymphoma, they were able to find that there are two different kinds of tumor, with very different prognoses, which had previously been diagnosed and treated as a single disease. "It validates the concept," Botstein says.

The outcome is good news for Dr. Jeffrey, who's using the gene chip to analyze tumors in her breast cancer study. Now she expects the data she's gathering from Jean Christ's tumor and others will ultimately mean something. And not just for breast cancer: Stanford urologic surgeon Jim Brooks has teamed with Jeffrey to work on a prostate cancer portion of the tumor gene study.

But with the ability to see more than 20,000 genes in each tumor at one time, the amount of data becomes exponentially more difficult to digest. Jeffrey's goal is to study 1,000 tumors, which means she will have to look at and compare more than 20 million genes. "And from that we have to make some sense," she says. "We don't even know what all the genes do yet."

So, as the patent lawsuit between Affymetrix and Incyte moves ponderously toward the courts, Brown and his colleagues have enlisted the help of mathematicians and statisticians to develop computer software that will effectively analyze what the gene chip finds. Botstein predicts it won't be long before the microarrays in the Stanford lab alone will have gathered a terabyte of information. For comparison, he likes to point out, the entire Internet contains 100 terabytes.

And whether or not the eventual winner of the patent dispute decides to start suing researchers, the issue seems completely trivial to the home brew scientists caught up in the excitement of new discoveries. "When I see people like Dr. Jeffrey doing good science, it makes us feel like our goals are being accomplished," DeRisi says. "We could care less what happens to those companies."

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