Synthetic biology could transform chemical manufacturing

A glimpse into the future

23 June 2009 14:41  [Source: ICB]

Synthetic biology could revolutionize chemical manufacturing by simplifying the application of biotechnology

ANIMALS, PLANTS, fungi and bacteria have always been a source of carbonaceous raw materials for chemical manufacturing. But it was petroleum, owing to its low cost, that enabled the flood of innovation in commodities, plastics and specialties that made chemicals one of the most productive industries of the twentieth century.

Petrochemical-based innovation has declined over the past 30 years, with creeping commoditization driving production to lower-cost regions in Asia and the Middle East. Over this same period, however, biologists have amassed an increasingly sophisticated set of tools for harnessing the productive capacities of living organisms through genetic engineering, and they have begun to use a new term to describe their activities: synthetic biology.

One of the more ambitious objectives of synthetic biology is to build a completely synthetic organism, but its more immediate aim is to rationalize the practice of biotechnology by taking a systematic, engineering approach to the design and construction of biological systems.

A rigorous practice of this sort has largely been out of reach since scientists first transferred foreign genes into bacteria in the 1970s. In the past decade, however, researchers have sequenced the genomes of hundreds of organisms, and drawing on emerging data manipulation technologies and widespread computing power, they have developed complex models to describe the networks of molecular interaction behind the workings of cells.

Synthetic biology employs this new understanding - called "systems biology" - to design and engineer biological parts, devices and systems, and to redesign natural biological systems.

The five-stage engineering cycle is fundamental to the practice of synthetic biology. It begins with specification, when the explicit requirements of a product are described in detail. In the design stage that follows, engineers attempt to combine existing parts, devices or systems in a way that will yield a product meeting those specifications.

Standardized parts, devices and systems are key elements in the design process, according to a report on synthetic biology published in May by the UK-based Royal Academy of Engineering (RAE).

"[In] engineering, systems are normally built from standard devices, which in turn are built from standard parts," the report explains. "The standard parts and devices are all fully characterized and may be used in the design of multiple systems."

The third stage is modeling. Today, cheap computing power allows engineers of every stripe to perform detailed simulations of their designs, and it has been a particular boon to synthetic biologists, given the complexity of biological systems.

Implementation is the fourth stage. In synthetic biology, this typically involves the insertion of modified synthetic DNA into a host organism (or chassis) such as E. coli.

The last stage in the cycle, testing and validation, determines whether the specifications have been achieved. If the answer is no, then the cycle is repeated until testing and validation yield satisfactory results.

In the same way, then, that electrical engineers might design and build a radio from standard, off-the-shelf parts, synthetic biologists hope to design and build biological systems using readily available, standardized elements, which some researchers in the field call "bioparts" or "biobricks." A nonprofit organization, the BioBricks Foundation, has been established by engineers and scientists from US institutions Massachusetts Institute of Technology, Harvard University and the University of California at San Francisco to support the development of open technical standards for these biobricks and to protect open access to them.

Early achievements in this field include oddities such as bacteria that smell like bananas or blink different colors. But synthetic biology is also being applied to more practical problems.

In one of the best-known examples, US-based Amyris Biotechnologies has partnered with US-based pharma nonprofit group OneWorld Health and French pharma major Sanofi-Aventis to commercialize a fermentative process for the production of artemisinin.

A key raw material in the manufacture of malaria drugs, artemisinin is currently extracted from the sweet wormwood plant in a slow, resource-limited process. But a fermentative process originated by Jay Keasling, a professor at the US-based University of California, Berkeley, is expected to dramatically improve its availability. The philanthropic Bill and Melinda Gates Foundation has thrown its weight behind the project in the form of a $42.6m (€30.8m) grant.

Amyris is also using synthetic biology to build organisms that can be used to produce biofuels more efficiently, as are a number of other companies.

One of the leaders in this area is US-based Solazyme, which has already road-tested its diesel fuel for thousands of miles in unmodified cars, notes Harrison Dillon, president, chief technology officer and cofounder.

"We've made thousands of gallons of oil using this technology and fuels that meet the ASTM and US military standards," he says. "We're the only company in the world that's used this kind of next-generation fermentation technology to make a transportation fuel that meets these standards without having to be blended with another fuel that already meets them."

Instead of yeast or bacteria, Solazyme modifies microalgae to produce tailored triglyceride oils that can be refined into diesel fuel in the same facilities that refine petroleum.

The process is not photosynthetic. Some algae naturally produce oil more effectively when fed biomass in the dark - an adaptive mechanism that allows them to survive in the event that sunlight is blocked for extended periods. Solazyme enhances this ability or introduces it to algae that do not yet have it.

"We're very good at engineering the cells and holding them at a physiological state where they take a low-cost biomass like sugarcane and convert it into a higher-value material, this crude oil, which can be turned into anything that's made from oil," says Dillon.

Solazyme uses synthetic biology to modify the cells' ability to handle different feedstocks, as well as the structure of the oil produced.

"We think [our diesel fuel] will be at economic parity with $60-80/bbl oil in two to three years," he says. "We've dropped the cost by several decimal points since we started."

Meanwhile, the company plans to commercialize other materials produced by its algae.

"We can take the same core technology and apply it to something other than fuel when there's an advantage," Dillon points out. "Suppose you have a triglyceride oil and you need one or two chemical steps to turn it into your product. We may be able to put that catalytic activity into our cell and save the cost of those unit operations."

Dillon says Solazyme has sampled barrels of oil to most of the major oil companies, most major chemical companies, cosmetics and food companies.

"There are two reasons why they are interested," he continues. "One, because we either can or potentially can provide the oils at a lower cost than current feedstocks. The other reason is that we can provide some type of unique functionality, and that's again where synthetic biology comes in."

Some algae produce polysaccharides from biomass, instead of oils. Solazyme can use synthetic biology to modify these, as well, and some will be commercialized over the next 12 months.

US-based Verdezyne has been directing its activities at both improved ethanol fermentation and new routes to chemicals. The company expects to have its ethanol process in the pilot plant at the beginning of 2010, says Damien Perriman, vice president, business development.

"Synthetic biology tools can be used to improve the yields, reduce carbon dioxide emissions and speed up the fermentation process," he says. "These advancements would have significant impact on ethanol producers currently sitting idle."

However, he adds, the improvement of existing processes does not provide the kind of returns needed by venture-backed biotechs.

"In order to be successful, these companies need to develop their own process for a specific chemical and own a portion of that market," he says.

Perriman says that synthetic biology is ideal for developing fermentation pathways to industrial monomers, the value of which - four to five times greater than fuels - allows a producer to operate at smaller volumes and higher margins.

"As opposed to bio-based plastics, producing monomers biologically allows the chemical formulators to utilize their existing toolbox of raw materials to achieve the performance and product features their customers are asking for," he points out. "Producing bio-based monomers as petrochemical replacements also allows the chemical industry to continue to use their existing downstream assets with minimum disruption."

Verdezyne expects to have a monomer in pilot production by 2011.

Other companies doing synthetic biology include US-based LS9,Gevo and Mascoma; Netherlands-based DSM; and Denmark-based Genencor (a division of Danisco).

Synthetic biology is still a young field. But its potential to provide economical routes to unique materials could lay the foundation for another golden age of chemical innovation.

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By: Clay Boswell
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