In 1999, French investigators undertook a daring experiment. Their patients were eleven children with a devastating immune system disorder called X-SCID, popularly known as "bubble boy" disease. Born with a genetic defect related to the development of certain types of white blood cells, the children were vulnerable to severe, chronic infections and would probably have died young. The experiment was an attempt at a new solution gene therapy. Doctors inserted properly functioning genes into the children's own dysfunctional sequences. At first, it worked wonderfully: nine of the eleven children developed normally functioning immune systems. But within a few years, three had developed leukemia. What had gone wrong?
As it turned out, it was not enough to insert the good genes it also mattered where they landed. In three of the eleven cases, the new gene's location triggered another gene, an event that led to the leukemia. It was a horrific example of how imprecise targeting could have catastrophic real-world results. In response to the French experiment, the US Food and Drug Administration placed a temporary "clinical hold" on similar gene therapy trials here.
Although gene therapy burned bright with promise back in the 1990s, its reputation has since fizzled. "In the early days of gene therapy, it looked like it was going to be quite easy, and it turned out not to be so," said Dr. Theodore Friedmann, president of the American Society of Gene Therapy. The field was in some ways the victim of its own hype, which underestimated the difficulty of the task at hand and set up unrealistic expectations about how quickly these treatments would turn up in doctors' offices. The field confronts a host of safety issues hinted at by the French trials and also the 1999 death of Jesse Gelsinger, an American teenager with a rare metabolic disorder whose experimental treatment led to multiple organ failure. Similar concerns about bio-engineered crops have also fueled a global backlash against genetically modified foods what if inserted genes turned up at unexpected locations in the sequence, causing nasty surprises? Meanwhile, biotech companies spent millions of dollars chasing approaches that failed, and the industry has had very few successes to point to indeed, some insist the phrase "gene therapy" is a misnomer, since there are no actual therapies yet on the market.
Now, researchers at a low-profile but well-financed Richmond biotech firm, Sangamo BioSciences, think they have a method for taking the guesswork out of gene therapy and overcoming at least some of the objections of the anti-GMO crowd. The company's goal is no less grand than to create therapies for some of the most debilitating diseases on the planet: cancer, Parkinson's, complications from diabetes, even infectious diseases like HIV.
Company officials believe that they can so accurately modify the human genome that what they will be doing, essentially, is molecular surgery. "Sangamo is the only company that has technology that allows us to build drugs at the DNA level, the most basic level of life, the way cells are programmed," said founder and CEO Edward Lanphier. "It is an incredibly cool and powerful science."
Lanphier isn't the only one excited about the company's technology. Wired called it the "killer app for gene therapy." The more staid Nature hailed it as "a considerable step toward a successful genetic-engineering approach to treating human disease." Friedmann said what Sangamo's approach "begins to promise is kind of the Holy Grail of the field the potential for going into a cell, fixing it, and coming out again without leaving any footprints."
Although Sangamo's most advanced therapeutics are still midway through clinical testing and have yet to face the FDA approval process, the company has created buzz in the business worlds. Its stock is rated as a "Buy" or "Strong Buy" by all seven analysts who cover it, according to the investment research firm Thomson First Call.
The technology that Sangamo is banking on is called a zinc finger, and your body, right now, is full of them. Zinc fingers are the DNA-binding portions of many naturally occurring proteins, and they can be engineered in the lab to stick to precise locations on the genome. Sangamo researchers believe they can insert them into genes without accidentally interrupting or activating neighboring genes. All sorts of DNA repair tools can be fused to zinc fingers materials that can activate, repress, delete, add to, or even correct a misbehaving gene. The zinc finger can ferry these tools to exactly where they're needed, and let them get to work. When the job is done, the zinc finger dissolves away into the body, leaving nothing behind.
Even bioscience watchdogs like the Oakland-based Center for Genetics and Society agree that the technology holds incredible promise. "I think it's pretty cool," said Jesse Reynolds, the center's program director for biotechnology in the public interest. "It's a new paradigm of medicine."
But any technology that allows mankind to tinker with the building blocks of life also raises serious ethical issues: What disorders should we use it to treat? How far should we take it? Who gets to use it?
At the moment, the answer to that last question is, pretty much, just Sangamo. After founding the company in 1995, Lanphier worked vigorously to secure its patent dominance. He licensed and acquired patent rights from the four most prominent researchers in the field and added them to Sangamo's scientific advisory board. The publicly traded company now has assembled a formidable patent estate: fifty US patents with another 82 pending, as well as 91 foreign patents with another 108 pending. "Other groups that want to have a commercial interest in this would have to have access to our patents in order to raise money, in order to sell a product," Lanphier said. "As such, no other companies have been able to start up around this, and no other companies are able to use the technology without working with us."
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