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Celebrate Diversity

And who couldn’t use a better molecule? Analysts say the market for directed evolution stretches wide, including medicine and agriculture in addition to the chemicals industry. “This is no fad,” says David Molowa, a biotech analyst at Chase Manhattan in New York. “I think this technology is very real, and it’s already generating new products.” This list today includes a potential new catalyst for penicillin production, developed by Maxygen and now in commercial development at Dutch conglomerate DSM, and a fat-stain-removing enzyme from Novo Nordisk called Lipoprime, already on the market.

Indeed, the $2 billion industrial enzyme market is a logical niche for directed evolution, says Carolyn Fritz, global director of industrial biotechnology for Dow Chemical. Fewer than 30 enzymes generate more than 90 percent of industrial enzyme sales. That’s not for lack of trying on the part of the chemical companies to make new ones. The problem is that most enzymes fizzle under harsh, real-world conditions. Manufacturers could use new enzymes to make everything from paper to ethanol, low-cholesterol cooking oils and blue jeans. “We have a lot of different customers who could use better enzymes,” Fritz says.

To bring those enzymes to life, Dow has partnered with another biotech firm, San Diego-based Diversa, which has a different take on directed evolution from Maxygen. Rather than starting with a few different versions of a gene and shuffling the DNA, Diversa researchers typically begin with one gene and then introduce a multitude of mutations.

This technique generates maximum diversity in the pool of new candidate proteins. Indeed, using a procedure called “gene-site saturation mutagenesis,” Diversa researchers can try each of the 20 possible amino acids in each position along the protein chain-in less than two weeks. “It’s a numbers game,” says Dan Robertson, head of enzyme technology at Diversa, a game the company hopes will yield hardier and more effective proteins.

Diversa researchers stack the odds in their favor by choosing unusual genes as starting points. The company has hired far-flung scientists to collect microbes from extreme locations-the gut of a bug from the Costa Rican jungle, an industrial dump site or the rotting skin of a submerged whale carcass. By harvesting DNA from bacteria on that dead whale, Diversa scientists collect the raw genes for enzymes that naturally break down polymers or fats in nasty environments. “If we need a high-temperature enzyme to work under an alkaline pH, we go looking for places that already have those kinds of conditions,” explains Diversa CEO Jay Short. “We discover enzymes that are optimal in those settings, and then we can use directed evolution to push favored traits even further.”

Short says Diversa hopes to spread its discoveries around, selling improved proteins for everything from animal feed to human medicine. “I think directed-evolution tools are going to be very important for evolving human therapeutics-increasing a drug’s binding affinity or its half-life, or lowering the dosages necessary for it to work,” Short says.

Diversa isn’t the only evolutionary firm sizing up the $300 billion worldwide pharmaceuticals market. After working on enzymes for the oil industry, Enchira Biotechnology of The Woodlands, Texas, is moving toward crafting antibiotics and drugs that fight cancer, says Peter Policastro, company president. San Diego’s Applied Molecular Evolution is packing an extra punch into existing drugs by changing their protein structures, evolving more powerful medicines. Currently, AME is partnering with Gaithersburg, Md.’s MedImmune to churn out second-generation versions of several MedImmune drugs.

For now, Chase Manhattan’s Molowa says that directed-evolution firms will continue to sell themselves as technology-platform providers, partnering with industry giants that promise dollars and distribution. In addition to its deal with Novo Nordisk, Maxygen has forged collaborations with DuPont subsidiary Pioneer Hi-Bred, AstraZeneca and others-and has “proof-of-principle collaborations” with Abbott, Pfizer and Novartis under way. Diversa has joined forces not only with Dow, but with Novartis and Rhone-Poulenc, among others, as well. Eventually, Molowa adds, look for firms like Maxygen and Diversa to roll out their own products.

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