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Better Drug-Producing Bacteria

A synthetically engineered strain of E. coli, stripped of non-essential parts, could boost the bug’s industrial power.

Leaner, meaner bacteria could provide safer and more efficient ways to make hard-to-manufacture biological products, including vaccines and DNA-based pharmaceuticals. In a paper published online in Science last week, researchers described how they used synthetic biology techniques to remove large, unnecessary chunks of the genome from Escherichia coli, a type of bacteria commonly used for research and industrial purposes. The resulting bacteria could grow just as well as their unedited counterparts and could produce some biological products more efficiently.

The findings show that genomes can be restructured on a large scale without harming the organism. That achievement points to the great promise of the emerging field of synthetic biology – the attempt to design and rebuild organisms to perform specific functions. “It’s a great achievement,” says George Church, a geneticist at Harvard Medical School in Boston. “It makes people think about redoing genomes to make them do what you want it to do. It gives one hope that these sorts of things are possible.”

Bacterial genomes change rapidly – they have genetic elements that allow bits of DNA to move around the genome or to be swapped between other bacteria and viruses. This mechanism allows the bugs to adapt to different environments, such as high iron conditions, but it also means the bacteria hang on to genes that are unnecessary when grown in the lab.

To make the streamlined strain, researchers at the University of Wisconsin-Madison compared the genomes of different strains of bacteria to determine which genes were crucial for the organism’s survival and which the bug could do without. They then removed these elements from the E. coli genetic code, making a smaller and more stable version of the bacteria. The new slimmed-down strain has about 15 percent less DNA. Scientists ultimately hope to remove another 5 percent.

One such disposable gene was the bug’s swimming apparatus, which requires a lot of energy to make and manipulate. The extra genes “use up energy resources that could be better spent making a protein or whatever the product is,” says Frederick Blattner, the geneticist who led the project. As a proof of principle, Blattner and colleagues showed that the new strain could produce a particular protein used in vaccines more efficiently than the common lab strain.

The bacteria could ultimately provide a better way to create DNA-based therapeutics, such as gene therapy. The idea of a reduced genome “is attractive from a safety and manufacturing point of view,” says David Schoenhaut, director of technology affairs at Nucleonics, a biotech company based in Horsham, PA. For example, because the gene-swapping elements have been removed from the bacteria, the DNA region coding for the drug is unlikely to be inadvertently altered, which is an important safety concern.

Schoenhaut’s company is developing a treatment for Hepatitis C based on RNA interference, a molecular technology used to silence specific genes. But the way the drug is made – via replication of DNA segments in bacteria – means it’s difficult to grow with high fidelity in bacteria. “We want the lowest potential for mutation, and [Blattner’s] strains provide that,” says Schoenhaut. “I think his approach of making bacteria safer and more streamline will be important in making the next phase therapeutics.”

Blattner has founded a company, Scarab Genomics, based in Madison, WI, to develop and market the stripped-down bugs. Harvard’s Church says he thinks academics are unlikely to adopt the bacteria if they are costly or require licenses that claim future commercial rights. Academic scientists can buy the bugs with no license for some research, but need a license for commercial research or production, says Blattner.

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