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December 02, 2010

The Future of Metabolic Engineering – Designer Molecules, Cells and Microorganisms

Metabolic engineering - the practice of altering genes and metabolic pathways within a cell or microorganism – could one day be used to mass-produce biofuels, pharmaceuticals and other chemical products from inexpensive and renewable starting materials. (Image by Flavio Robles, Berkeley Lab Public Affairs)

In a paper published in the journal Science titled “Manufacturing molecules through metabolic engineering,” Jay Keasling discusses the potential of metabolic engineering – one of the principal techniques of modern biotechnology – for the microbial production of many of the chemicals that are currently derived from non-renewable resources or limited natural resources. Examples include, among a great many other possibilities, the replacement of gasoline and other transportation fuels with clean, green and renewable biofuels.

Keasling is the chief executive officer for the Joint BioEnergy Institute, a U.S. Department of Energy (DOE) bioenergy research center. He also holds joint appointments with the Lawrence Berkeley National Laboratory (Berkeley Lab), where he oversees that institute’s biosciences research programs, and the University of California (UC), Berkeley, where he serves as director of the Synthetic Biology Engineering Research Center, and is the Hubbard Howe Jr. Distinguished Professor of Biochemical Engineering.



“In any future, metabolic engineering will soon rival and potentially eclipse synthetic organic chemistry,” Keasling says.

Keasling cites the production of active pharmaceutical ingredients as one area where metabolic engineering enjoys a distinct advantage over synthetic organic chemistry. This includes three specific classes of chemicals – alkaloids, which are primarily derived from plants; polyketides and non-ribosomal peptides, which are produced by various bacteria and fungi; and isoprenoids, which also are typically produced by microbes.

“Many of these natural products are too complex to be chemically synthesized and yet have a value that justifies the cost of developing a genetically engineered microorganism,” Keasling says. “The cost of starting materials is generally a small fraction of the complete cost of these products, and relatively little starting material is necessary so availability is not an issue.”

Keasling also says that metabolic engineering could provide a valuable alternative means of producing variations of terpenes, the hydrocarbon compounds common to the resins of conifers, in a form that could yield pharmaceuticals that are more effective for the treatment of human disease than the forms that nature has provided.

Perhaps the ripest targets of opportunity for future metabolic engineering efforts are petroleum-based bulk chemical products, including gasoline and other fuels, polymers and solvents. Because such products can be inexpensively catalyzed from petroleum, microbial production has until now been rare, but with fluctuating oil prices, dwindling resources and other considerations, the situation, Keasling says, has changed.

“It is now possible to consider production of these inexpensive bulk chemicals from low-cost starting materials, such as starch, sucrose, or cellulosic biomass with a microbial catalyst,” he says. “The key to producing these bulk chemicals in metabolically-engineered cells will be our ability to make the exact molecule needed for existing products rather than something ‘similar but green’ that will require extensive product testing before it can be used.”

n his Science paper, Keasling discusses the formidable roadblocks that stand in the way of a future in which microorganisms and molecules can be tailor-made through metabolic engineering, including the need for “debugging routines” that can find and fix errors in engineered cells. However, he is convinced these roadblocks can and will be overcome.

“One can even envision a day when cell manufacturing is done by different companies, each specializing in certain aspects of the synthesis, with one company constructing the chromosome, one company building the membrane and cell wall bag, and one company filling this bag with the basic molecules needed to boot up the cell.”

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