The problem is that nature offers no known examples of micro­örganisms that can ferment sugars into the types of hydro­carbons useful for fuel. So synthetic biologists have to start from scratch. They identify promising metabolic reactions in other organisms and insert the corresponding genes into E. coli or yeast, recombining metabolic pathways until they yield the desired products.

At LS9 in San Carlos, CA, researchers are turning E. coli into a hydrocarbon producer by reëngineering its fatty-acid metabolism (see “Better Biofuels,” Forward, July/August 2007). Stephen del ­Cardayré, LS9’s vice president of research and development, says the company decided to focus on fatty acids because organisms naturally produce them in abundance, as a way of storing energy. “We wanted to take advantage of a pathway that [naturally] makes a lot of stuff,” del Cardayré says. “Just grab your middle.” Del ­Cardayré and his coworkers use many of the existing pathways in E. coli’s fatty-acid metabolism but divert them near the end of the metabolic cycle. Since fatty acids consist of a hydrocarbon chain with a carboxyl group, it is relatively straightforward to make the hydrocarbon fuels. “Think of it as a highway,” says del Cardayré. “Near the end of the highway, we add a detour, a pathway we designed and stuck there, so the fatty acids have a better place to go. We pull them off and chemically change them, using this new synthetic pathway that takes them to products that we want.”

Amyris, too, is taking the synthetic-biology approach, but instead of tweaking fatty-acid metabolism, it is working on pathways that produce isoprenoids, a large class of natural compounds. So far, however, both LS9 and Amyris are making their biofuels a few liters at a time. And while the companies have ambitious schedules for commercializing their technologies–both claim that their processes will be ready by 2010–improving the yield and the speed of their reactions remains a critical challenge. “It’s where most of the biological work is going on,” says Renninger. “We still have a little way to go, and that little way is very important.”

If eventually commercialized, the hydrocarbon biofuels made by LS9 and Amyris could overcome many of the economic disadvantages of ethanol. Unlike ethanol, hydrocarbons separate from water during the production process, so no energy-­intensive distillation step is necessary. And hydrocarbon biofuels could be shipped in existing petroleum pipelines. “It’s all about cost,” says Robert Walsh, president of LS9. But a critical factor will be the price of feedstock, he says. “We want dirt-cheap sugars.”

Indeed, the synthetic-biology startups face the same problem that established ethanol producers do: corn is not an inexpensive source of biofuels. “The next generation [of feedstock] will be cellulosic,” says John Melo, CEO of Amyris. “But we are not sure which cellulosic technology will emerge as the winner.” Whichever technology prevails, Melo says, Amyris expects to be able to “bolt it” onto its fermentation process, giving the company the advantages of both cheap cellulosic feedstocks and practical hydrocarbon fuels.

For now, though, the lack of an alternative to corn is driving Amyris right out of the country. The company, which plans to retro­fit existing ethanol plants so that they can make hydrocarbons, will initially work with Brazilian biofuel facilities that are using sugar­cane as a feedstock. Given the price of corn and the amount of energy needed to produce it, Melo says, Brazilian cane offers the most “viable, sustainable” way to make biofuels today.

No Choice
Even in a Silicon Valley culture that reveres successful venture capitalists, Vinod Khosla has a special place of honor. A cofounder of Sun Microsystems in the early 1980s, Khosla later joined the venture capital firm Kleiner Perkins Caufield and Byers, where in the late 1990s and early 2000s he gained a reputation for ignoring the dot-com excitement in favor of a series of esoteric startups in the far less glamorous field of optical networking. When several of the startups sold for billions of dollars to large companies gearing up their infrastructure for the Internet boom, Khosla became, in the words of one overheated headline of the time, “The No. 1 VC on the Planet.”