Metabolic Engineering: Beyond Recombinant DNA

Release Date:
Alisa Zapp Machalek, NIGMS
(301) 496-7301

Selective breeding gave us seedless bananas. Genetic engineering gave us Flavr Savr tomatoes. Now a new field, metabolic engineering, promises such extraordinary advances as vaccines from plants and plastic from bacteria.

Metabolic engineering was the focus of a one-day workshop on Mar. 22 sponsored by the National Institute of General Medical Sciences (NIGMS). The workshop's eight-member panel consisted of university and industry scientists with backgrounds in such diverse fields as enzymology, molecular genetics, chemical engineering, and organic synthesis.

The panelists discussed how metabolic engineering combines techniques from all these disciplines to control product synthesis in bacteria, animal cells in culture, or plants.

"The goal of metabolic engineering is to manipulate cell metabolism purposefully to produce a valuable product," said NIGMS' Dr. Warren Jones, one of the workshop organizers. "By linking together a number of biosynthetic steps, you can start with a cheap material--glucose is very popular--and come out with something more complex and more valuable." Metabolic engineers are already working out how to produce new antibiotics, food additives, and industrial chemicals.

"In a global sense, this is not different from what genetic engineers have been doing for years with proteins," Jones said. "Like genetic engineers, metabolic engineers insert foreign genes into an organism to promote synthesis of desired products. But with metabolic engineering the focus is on small molecules that range in size from catechol [a precursor to vanilla that has only 14 atoms] to molecules 10 to 20 times larger, like antibiotics and taxol [an anti-cancer drug]."

Because even small molecules frequently require many steps to synthesize intracellularly, metabolic engineering is more complex than most genetic engineering, Jones said. "To get an antibiotic like avermectin, there are more than 35 chemical steps involved," he said. "And each step has at least one enzyme and at least one gene associated with it."

Because metabolic engineering is so involved, the technology will most likely be used to obtain high-value products that cannot be easily produced using other techniques, the panelists acknowledged. The value of metabolically engineered products, however, is judged by more than monetary standards. In addition to making some items more cheaply--such as silk from soybeans--metabolic engineering offers the hope of producing medical and industrial compounds that are purer, have fewer hazardous byproducts, or are unobtainable by traditional methods.

For example, according to a paper published in Chemistry in Britain ( March 1995: 206 - 210) by Dr. John Frost, one of the panel members, E. coli bacteria can be engineered to produce adipic acid, a component of nylon. Adipic acid is currently produced industrially from benzene, a known carcinogen and air pollutant. The manufacture of adipic acid accounts for about 10 percent of the annual increase in atmospheric nitrous oxide, a compound that destroys stratospheric ozone, has been implicated in global warming, and is a respiratory irritant. Frost's engineered bacteria use glucose as a starting material and do not synthesize any environmental pollutants.

But don't count on an immediate surge of metabolically engineered adipic acid. Although bacterial production would be cleaner and "greener" than the current industrial process, metabolically engineered adipic acid must also be able to compete in the global market. With words like "profit margin" and "market forces," the panelists made it clear that metabolic engineering is as much about economics as it is about science.

And, all too frequently, insufficient science is as much of a barrier to advances in metabolic engineering as are market concerns. Currently, scientists know too little about the metabolism of common model organisms and next to nothing about the metabolism of many other, potentially useful, organisms, according to the panelists. Progress in metabolic engineering depends on understanding enzymatic reactions and regulatory mechanisms well enough to manipulate them to synthesize new products.

That's where NIGMS comes in. The workshop opened with an explanation of why NIGMS, an institute that primarily funds basic research, would be interested in an area so driven by market forces.

"We don't have a direct interest in production, but we have a very vested interest in understanding metabolism," said Dr. Jim Anderson, who helped organize the workshop. "From NIGMS' point of view, we're in business to understand fundamental life processes. You don't get much more fundamental than understanding the basic metabolism that underlies all forms of life. And the fact that this understanding is also 'commercializable' is a bonus."