A Whole New Crop

A gene-altering technology from biotech Sangamo BioSciences may radically change what we eat
Jerome Peribere, the chief executive of Dow AgroSciences, has a slide show for investors. It explains how one could theoretically turn the offspring of a wild, berry-size tomato into a plant bearing full-size tomatoes just by tinkering with one gene. The sweet corn we eat for dinner would be a shriveled gray precursor called teosinte were it not for the activity of a handful of genes.

Food scientists have understood these distinctions for a decade thanks to traditional plant biotechnology research. It's what's on the next few slides that gets Peribere going: the possibility of easing world hunger by turning inedible oil crops like crambe into edible versions; tomatoes that will always taste good; crops that can survive through severe drought. These traits could be edited into a new form of the same species in a far more precise and accurate way than with the existing tricks in genetics' kit bag.

This technology, which Dow AgroSciences is moving toward the market, is called a zinc finger, a naturally occurring protein that can be used in a cell nucleus like an editor's red pencil. Zinc fingers, so named because they contain a zinc atom and are shaped like an index finger, can turn specific genes off or on or to some point in between, delete genes altogether or add new genetic material. "Within biotech," says the 54-year-old Peribere, "we believe this is one of the very disruptive technologies."

Success with the zinc finger could also give Dow AgroSciences, the crops unit of $54 billion (sales) Dow Chemical (nyse: DOW - news - people ), the second-largest chemical company in the world, a bigger share in the global agbiotech boom. Monsanto (nyse: MON - news - people )'s stock is up sevenfold since 2004 (trouncing Dow shares) thanks to its huge success selling seeds bioengineered to fight off bacteria and withstand direct application of Monsanto's own weed killer Roundup. Peribere's group, with $3.8 billion in revenue, lacks a significant presence in the genetically modified seed business. Its sales still come mostly from weed and bug killers, and in sum are less than half the sales of either Monsanto or Syngenta (nyse: SYT - news - people ). But zinc fingers, because of their precision, could give Dow a significant leg up by cutting a year or two off the six to eight years it now takes to develop a modified plant and get it past regulators.

In October 2005 Dow AgroSciences entered into an exclusive research agreement with Sangamo BioSciences (nasdaq: SGMO - news - people ), a biotech company in Richmond, California that controls most of the intellectual property around zinc finger research. It has drugs in development for ten diseases and two ongoing clinical trials, including ones for diabetic nerve injuries. Sangamo has also licensed its technology to Sigma-Aldrich (nasdaq: SIAL - news - people ), a chemicals firm, for use in discovering novel reagents for research. Amgen (nasdaq: AMGN - news - people ) and Genentech (nyse: DNA - news - people ) are also using Sangamo's zinc finger proteins to improve their manufacturing yields.

"We can target and regulate genes inside any cell in any organism," boasts Edward Lanphier, founder and chief executive of Sangamo. "This is enormously powerful science."

Dow Agro will likely sign an exclusive commercial licensing agreement with Sangamo between now and October, paying it royalties on sales of products developed using zinc finger proteins. So far Dow Agro has paid Sangamo $20 million, including a $4 million equity investment. The first fruits of the partnership aren't expected for four more years. Dow is coy about its plans, but Peribere drops hints.

"What about dramatically improving the sugar content in sugarcane?" he asks. Dow Chemical, in a separate project, already plans to make polyethylene from sugarcane ethanol in Brazil. Upping the sugar content in the cane would lead to a higher yield of ethanol per acre. A second possibility: altering specific genes to make it easier to break down the lignin in the cell walls of corn leaves and stalks, with an eye to making so-called cellulosic ethanol out of the unused part of the plants. Dow Agro biologists have already accurately inserted genetic material into specific locations in maize and rapeseed genomes using Sangamo's technology.

Use of highly targeted gene-modification tricks comes at a fortuitous time. Biologists are unearthing a trove of genomic information about plants. The rice genome was fully mapped in 2005. Corn's rough DNA blueprint was released in February, and the soybean's DNA is being mapped now. With maps in place, Dow and Sangamo's zinc fingers can be aimed directly at the genetic locations that would play the biggest role in curtailing the recent and sure to be ongoing disruptions in food and biofuels supply. "We are at the Stone Age of plant biotechnology," says Peribere. "In 25 years we are going to be laughing about what we are doing now."

Zinc fingers may also offer a way to get some genetically altered foods through regulatory approval faster than before. The European Commission and armies of environmentalists battled Monsanto nearly to a standstill over its GM seeds, but thanks to pressing global grain demand, Monsanto eventually won approval in all the world's biggest markets. The knock against Monsanto's technology was the use of foreign genes, something that Peribere says zinc fingers can avoid. When zinc fingers are used to delete genetic material, the mechanism for doing so, called a zinc finger nuclease, does not remain in the plant for more than a few days. "Our expectation is that as you are not introducing anything that stays in the ,plant, this is going to be considered non-GMO [by regulators]," Peribere told analysts in December.

That remains to be seen. Greenpeace International, a vocal opponent of genetically modified crops, is skeptical that zinc fingers can evade the GMO labeling. "It's not 100% clear, but I think that most of this would still be considered GMO because you're introducing a new gene, even if [the finger] doesn't stay in the plant," says Greenpeace International scientist Janet Cotter. Friends of the Earth Europe, another anti-GMO group, says that the Sangamo technology may well turn out to be a type of genetic modification that it would oppose.

If, that is, Sangamo crops ever make it out into the field. Zinc fingers are still unproved outside the lab. Dana Carroll, a biochemist at the University of Utah who has licensed some research to Sangamo, has run fruit fly experiments using zinc finger nucleases, in which the flies' genomes were cut in unintended places apart from the target area. Sangamo and other researchers have worked to fix some of this errant DNA editing, but Carroll says it is impossible to know if all unintended cutting has been eliminated.

Says Peribere, who was initially highly skeptical: "It's early science for some of this. It's costly. But it is disruptive. That is why we have embarked upon it."

For decades plant biologists have used brute-force methods of genetic engineering to produce biotech seeds that kill bugs and withstand herbicides. One common method was to cover small gold particles with genetic material and shoot them into the nucleus of the plant cell with a pressure gun. Where the new DNA ended up was random. It might land in the middle of an important gene and inadvertently disrupt the plant's growth.

Zinc fingers make this procedure highly targeted. Each finger is typically about 30 amino acids long, with a variable section at the tip. Sangamo scientists have engineered a library of 10,000 fingers by tinkering with the variable region, designing it so that it will seek out, recognize and bind to a specific segment of DNA for a specific gene. Sangamo scientists tether to the zinc finger a protein that contains the instructions for the targeted gene: turn on, turn off, get louder, pipe down. The finger is the homing mechanism; the tethered protein delivers the payload.

To add or delete genes, Sangamo tethers to the zinc finger the nuclease enzyme that can make a break in a specific location of DNA. Cells naturally try to repair the broken DNA, and the zinc finger nucleases use this repair system to either delete a targeted gene or integrate new DNA. "It copies and pastes the donor DNA like a Word document, right into the break, exactly where you want it," explains Philip Gregory, Sangamo's vice president of research.

Before inking the research deal with Sangamo, Dow Agro scientists evaluated other, more widely studied genetic manipulation technologies. But Dow decided none had the breadth of capability that zinc fingers do. Two better-known alternatives, antisense and rna-interference, the latter of which is being used now by Monsanto, can silence or shut down genes but cannot turn them on or make them louder. "We wanted one technology that could do it all," says Peribere.

It has taken Sangamo more than a decade to get the technology into shape. Lanphier, 52, studied biochemistry at Knox College and joined Eli Lilly (nyse: LLY - news - people )'s business planning department in the 1980s, then worked at a string of small biotechs. In 1995, while at Somatix Therapy, a Bay Area gene therapy company, he decided he wanted to start something on his own and began digging for ideas. He came across a 1991 article on zinc finger proteins published in Science by Carl Pabo, then a structural biology professor at the Massachusetts Institute of Technology. Lanphier kept digging and found that a Nobel Prize-winning British molecular biologist, Aaron Klug, had done some pioneering work on zinc fingers, as had researchers at Johns Hopkins and the Scripps Research Institute.

Lanphier licensed Klug's patents and the patents from MIT, Hopkins and Scripps. He raised $17 million in venture capital and took Sangamo public in 2000.

Well off its speculative highs earlier in the decade, Sangamo now has a $500 million market value. This biotech in a sleepy office park may hold the key to better crops, more efficient biofuels and drugs to cure the most elusive diseases. But it will be several years, at the least, before it proves itself.