The Gatekeeper 

What if scientists devised a strategy to tackle some of the world's most notorious diseases, but just one company held all the patents?

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."

That may be good news for the company, but some academics complain that Sangamo has created a bottleneck. One group of zinc finger researchers has even banded together to combat the firm's information dominance. A 2005 article in Nature Biotechnology dubbed Sangamo "the zinc finger nuclease monopoly," noting that it's hard for anyone else in the field to move without Sangamo's cooperation. Should these therapeutics come to market, the article concludes, "Sangamo has the equivalent of three hotels on a purple swath of Park Place." (Park Place is actually blue in Monopoly, but you get the idea.)

Sangamo's dominance not only leaves one entity as the primary financial gatekeeper of how this new technology will develop, but it also raises profound ethical questions. "Like most current biomedical research, there is a fuzzy line between public good and private interest that these researchers try to straddle," Reynolds said. "How do you balance those interests?"

Zinc fingers have been with us since time immemorial, but it wasn't until 1986 that Sir Aaron Klug discovered them at the Laboratory of Molecular Biology in Cambridge. In the early '90s, Carl Pabo at the Massachusetts Institute of Technology first described their structure and showed that they could be engineered to turn genes on or off. Lanphier, who has spent his entire career working at Bay Area biotech companies, recognized their promise and set about buying up both scientists' intellectual property rights, also acquiring Klug's company, Gendaq, in 2001. When the Human Genome Project finished up in 2003, laying bare the entire code of how our bodies are constructed, it provided, as Sangamo communications director Dr. Elizabeth Wolffe puts it, "an embarrassment of targets" for additional research.

Borrowing a name that had once belonged to his great-grandfather's business — the Sangamo Electric Company, based in Sangamon County, Illinois — Lanphier set up shop in a low-slung laboratory in a nondescript office park. While some biotech companies have lavished their funds on glass and steel edifices well stocked with Eames executive chairs, Sangamo's office is an ode to austerity, despite the $58 million in current assets the company had on hand as of its last quarterly report. The primary office decorations are large posters illustrating various genetic processes, and plaques from its many patent awards. The CEO's window looks out toward the railroad tracks. There's no fancy cafeteria, just a roomful of vending machines.

That's in keeping with the company's public image — not too flashy, financed by a few initial waves of venture capital, an IPO in 2000, and supplemental funding from the government and advocacy groups such as the Michael J. Fox Foundation and the Juvenile Diabetes Research Foundation. "We don't have a very high profile," Lanphier said. "We sit over here in Point Richmond and don't wave our hands a whole lot, but I think the work we're doing is some of the most interesting science that is going on anywhere in the world."

Genes are the templates from which all of the proteins needed to run our bodies are built. Often in genetic disorders, a defective gene is either producing too much or too little of a necessary protein. That flaw disrupts a cascade of chemical processes needed to make the body function normally. Friedmann, of the American Society of Gene Therapy, compares such defects to cracks in a dam that is leaking and flooding everything downstream. Pharmaceuticals treat symptoms, but don't undo this initial genetic damage. "Almost all treatment of disease until now has assumed that we'll leave the dam in place leaking, leave the underlying metabolic and genetic defect in place, but we'll sort of try to just clear up the mess downstream," Friedmann said. "Gene therapy is based on the concept that you fix what is broken."

Repairing the gene itself, at least in theory, is a more elegant, definitive, and less expensive solution, because ideally it could replace a lifetime on drugs with a one-time procedure. Sangamo's basic concept is relatively simple. Think of your DNA as a long chain of letters that spells out your genetic code. Each zinc finger can match up, and then bind with, a three-letter sequence. Put together a protein made of six zinc fingers, and that combination will be long enough that you can guarantee it's a match for only one spot on the human genome. The synthetic protein can then shuttle in the DNA repair tools that will actually fix the gene.

What you get, said Dr. Philip Gregory, Sangamo's vice president of research, is an "extremely scalpel-like" method of gene transfer, as opposed to the more scattershot previous approaches, which he compared to trying to fix a flat tire by haphazardly firing a barrage of wheels at your car. Maybe one flies into the wheel well, but more likely it shows up in the backseat or lands someplace truly disruptive, such as in the engine block, destroying the car. "What we do is we actually turn up with a puncture repair kit," Gregory said. "Our approach is to fix the puncture, the mutation, but after that there is no evidence that we were here."

That's the theory, anyway. In reality, all of Sangamo's products are still in testing, and will be for several years. But the company's product pipeline provides a tantalizing peek at what zinc fingers could do.

The concept that has advanced farthest through Sangamo's pipeline is a treatment for nerve damage caused by diabetes. This damage is irreversible and affects about half of diabetics, generally starting as numbness or tingling in the feet or legs and potentially leading to a total loss of sensation. As a result, sores on the feet can go unnoticed, become infected, and necessitate amputation — diabetes is the leading cause of lower-limb amputation. "There is no successful treatment of diabetic neuropathy," Gregory said. "All that's given today are painkillers or antidepressants to treat the symptoms of this diabetes complication and not the complication itself."

Sangamo's solution is to slow the nerve damage by stimulating production of a natural nerve-protecting agent. In the current clinical trial, patients are injected in the legs with a solution that is absorbed into their muscle cells. The zinc fingers turn on the gene that makes the needed nerve protectant. Nobody is sure how often dosing would need to be repeated — right now they're testing injections every two months — but it would certainly be less frequent than dosing for antidepressants and painkillers, which need to be taken daily.

Sangamo also is looking into using zinc fingers to activate the gene that makes a neural growth factor that may improve motor function in Parkinson's patients. Genes can be turned off for therapeutic effect as well; Sangamo is investigating gene repression as a way to modulate nerve pain.

In addition to turning genes on and off, zinc fingers can be used to modify or replace them. The most compelling test case Sangamo has for this approach is HIV. Some people are born with a natural resistance to the virus — even if you put their immune cells in a Petri dish and bombarded them with HIV, they still wouldn't become infected. To infect a cell, the virus must bind to a site on it called the CCR5 receptor, and people with natural immunity are missing one or both copies of the corresponding CCR5 gene. People totally lacking the gene never become HIV positive; people with one copy can become infected, but their progression to full-blown AIDS is dramatically slowed because the virus cannot easily spread through their bodies and bind to other cells. (One intriguing, although disputed, theory is that people with this HIV-resistant blood are descended from survivors of Europe's bubonic plague, which also may have spared people without this gene.)

Since it seems people are not harmed by lacking this gene, and in fact are better off without it, pharmaceutical companies have tried with varying degrees of success to develop drugs that would block these CCR5 receptors and keep the virus from entering. But Sangamo's approach is to disable or "delete" the gene altogether. Zinc fingers could bring in enzymes that slice the DNA apart, activating a natural, albeit error-prone, resealing process.

Think of the DNA sequence as a cassette tape with a recorded message, Wolffe says. Now imagine that you've cut a section out of the tape, spliced the ends back together, and tried to play it again. "All of the sudden you've got a blip in the middle of it," she says. "You can't actually hear what all was said — you're missing a word or two." With this DNA message disrupted, the cell no longer has the code for CCR5 receptors — and there's nothing left for HIV to bind to.

Eventually, the company hopes to harness this mechanism as a vaccine for people without HIV. But initially, Gregory said, this kind of therapy would be an intensive process for HIV-positive patients, in which T-cells would be removed, treated outside of the body, and then returned to the bloodstream. "What it would do is limit viral load and it would also prevent opportunistic infection," Gregory said. Sangamo expects to start human clinical trials for this therapy later this year.

While possibilities suggested by the HIV and diabetes examples are profound, Sangamo execs are quick to point out the limitations of zinc fingers. They're best used for conditions in which treating a small amount of tissue can provoke a profound therapeutic effect, not diseases involving huge numbers of cells all over the body, like metastatic cancer. At this stage, they're also limited to treating so-called monogenic diseases — those caused by one malfunctioning gene, rather than the interplay of several. Since trials in people have been small-scale, there is still much to learn about how well these therapies will be received by the body, how long they might produce positive effects, and if there will be any surprise complications.

Nobody yet knows how much such therapies will cost if they do eventually come to market, or how available they will be to the world's poorest citizens, who are disproportionately affected by diseases like HIV. Then again, muses Friedman, "What else is new? New technologies are never distributed in what you and I might think of as an equitable or fair way, where the distribution is directed at those who need it most. Sadly, that is not the way our world spins."

Concerns about boundaries and ethical use have been leveled at the entire field of gene modification. As genetic manipulation gets more accurate and market demand pushes biotech companies to provide a wider and wider variety of applications for the technology, Sangamo, by virtue of being a principle patent holder, will influence how that research progresses.

So far, most researchers looking into human genetic modification have been looking for therapies for serious diseases, most of which have no other cure. But like any other method of gene transfer, zinc finger technology could theoretically be used to modify any gene, and that leaves the door open to enhancement — modifying the human genome to make a person, say, more athletic. As Jesse Reynolds from the Center for Genetics and Society points out, the line between what is medical therapy and what is enhancement, or between what is a disability and what is just a difference, can get blurry. "To pick at one gray area, is obesity a disease?" he asks. How about dwarfism or deafness or male pattern baldness — if we had a choice, should we try to eliminate them? Watchdogs worry that biotech companies will follow the lead of the pharmaceutical and surgical industries, which have medicalized many complaints that would have once been considered cosmetic. (Think your breasts are too small? You have micromastia! Not happy in the bedroom? Try Viagra!)

If such thinking already creeps too close to eugenics for some critics, it could cross the line altogether when it comes to the final frontier in gene therapy — the germ line. Our bodies are made up of two kinds of cells: the germ cells, which are sperm and ova, and somatic cells, which are everything else. Some have called germ cells "immortal cells," because they carry the genetic code of our ancestors, which we pass along to our children. Somatic cells, on the other hand, die when we do. So far, all gene transfer therapies focus only on treating adult somatic cells. Should a gene therapy treatment go terribly wrong, the damage is limited to that one patient — future generations remain unaffected. But tamper with the germ line, and you tamper with the process that has built humans into what we are.

"Heritable genetic modification is one of the most profound lines we could choose to cross," Reynolds said. "Any modification to the inheritable genes would affect all of the descendants of that person or baby. It would unleash, at the least, an enormous experiment, and also cross the line where humans have decided to take control of evolution."

Still, you can imagine some rather sympathetic scenarios in which people would seek out therapy that would affect their germ cells. For example, prospective parents with a family history of a severe genetic disorder might want to avoid passing it to their children. But you also can imagine some distinctly unpleasant ones, especially if you factor in the possibility of genetic enhancement. What's to stop pushy parents from trying to give their children a social advantage by making sure that they're, say, tall? Or smart, muscular ... or fair-skinned and blue-eyed? The ability to select traits like this could reinforce all of the social divisions that are based on people's appearance, and potentially set up new divisions between the those whose families can afford "better genes" and those who can't.

Well aware of these ethical issues, Lanphier said he intends to hold the line against enhancement. "What we are doing is focusing on serious medical diseases, and have no interest nor inclination to look at areas that aren't serious medical diseases," he said. As for the germ line, he said, "It's a line that we wouldn't cross and others like us would not cross."

At least in humans, that is. It's a line that many genetic engineers, including those at Sangamo, crossed long ago with plants. In 2005, Sangamo inked a deal with Dow AgroSciences to help develop genetically modified crops. Sangamo's role is to provide the zinc fingers and leave their ultimate applications up to Dow, but likely uses might include increasing crops' vitamin content; boosting resistance to drought, salt, or herbicides; or possibly making them more useful as biofuels.

Traits such as those Dow is believed to be interested in are all intended to be heritable. And because so-called "elite" crops often have more than one gene change made to them, a priority for researchers is to make sure that these modifications not only all show up in each subsequent generation, but in the right place on the genome. That's where zinc finger technology would come in.

"Dow AgroSciences has recognized the potential importance of precision in gene targeting since the late 1990s," said Dr. Bill Kleschick, the company's Global Discovery R&D Leader. The current collaboration, he said, grew from a small proof-of-concept study in 2004 that demonstrated the potential of zinc fingers for targeting specific genes. Although Kleschick declined to elaborate on how Dow envisions applying this technology, citing the ongoing nature of research, he said the partnership is going well: "We continue to be very excited about the potential of this technology."

Working with plants entails a different set of ethics than human research does. "If you kill 99 percent of your experiment, in agriculture, it's not a moral dilemma," Reynolds noted. Nevertheless, genetically modified organisms have engendered tremendous worldwide opposition from people concerned about a host of other repercussions. Some activists worry that such plants will cross-pollinate with native plants in a sort of "genetic pollution" that gives them an evolutionary edge and ultimately creates superweeds or undermines biodiversity. (A homogeneous population is vulnerable to being wiped out by a single disease.) Some object to what they see as an effort by biotech companies to patent and then economically control the production of staple crops. Others have grave moral reservations about transgenic crops — those in which genes from one species are imported into another, for example, the insertion of a gene from soil bacterium Bacillus thuringiensis, which is toxic to some insects, into crops as a pesticide.

As with human medical research, there are worries that inserted material will wind up in the wrong part of the genome, accidentally interrupting or activating other genes, and perhaps causing dangerous side effects, such as food allergies. Even if the gene is inserted correctly, critics say, given that genes may have more than one function or may interact with other genes, modifying one may cause unintended consequences later.

Lanphier and Wolffe say that Sangamo's methods may mitigate at least the last two complaints. "A lot of the time, what they are concerned about is inserting foreign DNA into a plant," Lanphier said. "This is a way of regulating the plant's own genes versus putting something new in." The company said that the precision of its gene insertion technology also should allay fears about changes accidentally being made to the wrong part of the genome. "We believe that we can go in and place the gene wherever you want it," Wolffe said. "You could identify a safe harbor location where you could put a gene in without interrupting another important gene or without interfering with another function or turning some weird and wonderful gene on."

Do critics of genetically modified foods think zinc fingers will allay any of their concerns? Well, no one could say. The Express contacted a half dozen Bay Area scientists, watchdog groups, and other experts, and most of them just referred us to one another, saying they didn't yet know enough about this new science to venture an opinion.

Just as Sangamo's patents give it clout over how the technology develops, they also make it the gatekeeper of who develops it.

The tension between the desire to harness all available brainpower to study a potentially life-saving technology and the desire to play things close to the vest to maximize profits for shareholders is a common one in biotech, and companies like Sangamo have a cautious alliance with the academic world. Although Sangamo has about eighty collaborations with academic institutions, these collaborators often have zinc fingers shipped to them but are not given information about how to make them or refine them for maximum effectiveness — Sangamo considers that information the key to the kingdom.

While academics are free to research domains in which Sangamo dominates the intellectual property rights, they cannot commercialize their results without a license from Sangamo, Wolffe said. Additionally, as the Nature Biotechnology article noted, despite some pressure to make its zinc finger library "open source," Sangamo has not done so.

For good reason, Wolffe said — zinc fingers are hard to make and even harder to optimize, they're the fruit of years of labor, and at the end of the day, the company wants to make money for its shareholders, not give away the store. "I think some of the academic researchers would like us to hand over our libraries, but that's a bit like saying Merck is holding back small molecule [drug] research because they don't make their libraries available," Wolffe said.

In fact, companies have an incentive to hang on to their intellectual property for as long as possible, considering that it can take nearly a decade, as well as millions of research dollars, to develop a single product, and even then FDA approval is not guaranteed. The New York Times recently highlighted the strange fate of Berkeley's Xoma, one of the nation's oldest biotech firms, which, despite never bringing a drug to market, has remained afloat since 1981 by collaborating with bigger companies that need access to its proprietary technology for making antibodies. Companies that can find ways of generating revenue even while their test therapies are still in the development pipeline may stand a better chance of surviving in the notoriously hit-or-miss biotech world.

Dr. Carlos Barbas of the Scripps Research Institute, once a member of Sangamo's advisory board and one of the researchers whose work was acquired to found the company, split with Sangamo several years ago over disagreements about what it should keep proprietary. Today, he's one of its chief critics.

"I think they're distorting the complexity of the technology, making people think in order to use it they have to go through them," he said. "But a number of academic groups are trying to break that myth and show it's something that can be accessible without having to go through them."

Barbas, for example, launched a Web site that allows researchers to type in the sequence of a gene they're interested in, and get back what is essentially the recipe for a zinc finger that would target it. A handful of other researchers, some of them frustrated after failed attempts to collaborate with Sangamo, banded together as the Zinc Finger Consortium to pool knowledge and resources. Two of the consortium's founders did not respond to repeated requests for interviews, but one of them, Harvard's Dr. Keith Joung, explained the organization's purpose to Science magazine: "My interest is not to circumvent Sangamo's patents. I just want to make the technology available, easy to use, efficient, and robust."

Barbas believes that both Sangamo and healthcare consumers would benefit if the company opened up a little — after all, a 75-person company can't tackle every disease in the world, particularly the rarer ones with a smaller potential patient base. He also believes that what he calls the "high ticket price" of working with Sangamo has driven researchers to apply their efforts to competing technologies instead — particularly a gene repression technique known as RNA interference, or RNAi, that is becoming the hot new thing in biotech. "I believe Sangamo has crippled their [own] advances by keeping the technology in-house," Barbas said. "It also spurs the development of this other approach, RNAi, because researchers were not provided with any easy way into zinc fingers and they simply turned to another technology. As a consequence, RNAi is advancing far faster into the clinic than zinc fingers have."

While RNAi can't do everything zinc fingers can, Sangamo execs are well aware that the ease with which researchers can get the materials they need has both increased its buzz and given more researchers experience using it — things they'd like to have, too. "It would be in our own best interest to get the technology out there," Wolffe agrees. "At this state it's too complicated for it to be general usage, but we are seriously investigating ways to make it more user-friendly and get it out there."

The push may come, in fact, from the Dow AgroSciences agreement, which gives Dow the right to option the products of its research for an exclusive commercial license. If that should happen, Sangamo would have to find a way to share some of its secrets. It already has been preparing for that eventuality by improving the speed and automation of zinc finger production, so that it can be handed over more easily. "We will come to some agreement, whatever makes commercial sense, so that the making of zinc finger proteins is not a bottleneck," Wolffe promises. And indeed, Wolffe agrees that such a small company will need collaborators in order to expand the number of diseases it can investigate. It also will need partners to help get its current test products through the final, much larger, stages of clinical testing.

The next few years should be make-or-break ones for zinc finger therapeutics, as more of Sangamo's research moves from the lab to human trials. In addition to the HIV and diabetes-related treatments, Sangamo is considering its possibilities for cancer, Parkinson's, peripheral artery disease, X-SCID, and sickle cell anemia.

If the history of gene therapy is anything to go on, Friedmann warns, zinc finger therapeutics won't turn up in your local doctor's office anytime soon — there are still many kinks to be worked out. "Delivery will be difficult, efficiency will be difficult, and the body will try very hard to figure out ways to get around the manipulation that is being performed, so there will be a lot of surprises and no quick cures," he said. But he's quick to add that the field is eagerly watching: "This technology is really enticing because it's really the first time one begins to get a glimmer of how to correct the gene," he said.

As for Sangamo's top exec, it's hard for him to talk about the future without sounding a little giddy. "If we are successful, it will be the creation of the first new medical platform in the post-genomic era," Lanphier said. "If that doesn't get you excited, nothing will."


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