December 2011

Synthetic biology: edging toward the clinic

“Conventional genetic engineering often refers to cutting and pasting genes from one place to another without fine control over how the genes are regulated or a clear understanding of all the detailed molecular mechanisms,” explains Timothy K. Lu at the Massachusetts Institute of Technology. “Synthetic biology puts a lot more emphasis on separating out components into individual modules and functions,” such as understanding how to quantitatively control translation and transcription rates. In addition, synthetic biologists don’t want to pursue the one-time genetic engineering of an organism but want “to build a set of tools that will allow you to do many types of modifications, regardless of your end application, much more rapidly, quantifiably and predictably,” says Lu.

First indications of clinical applications
Regardless of whether you call it synthetic biology or improved genetic engineering, the field has begun to make some headway in clinical applications, such as using engineered microorganisms for cost-effective, timely and robust drug production. An example is artemisinin, an anti-malarial drug whose extraction from the Chinese sweet wormwood plant is inefficient and expensive. Given that every year, malaria infects 300 million to 500 million people and causes 1 million to 2 million deaths, mostly in the developing world, cheaper and more readily available sources of artemisinin-type drugs are urgently needed.

Jay D. Keasling’s laboratory at the Lawrence Berkeley National Laboratory and the University of California, Berkeley, armed with a $42.5-million grant from the Bill and Melinda Gates Foundation, engineered Saccharomyces cerevisiae to produce artemisinic acid, which is readily converted into artemisinin by chemical means. To engineer the yeast, the researchers first created a new metabolic pathway in the microorganism. Next, they placed bacterial and wormwood genes in the yeast genome so that the products of those genes interacted in the new metabolic pathway to produce a precursor to artemisinic acid. The researchers also then added in the wormwood cytochrome P450 gene so the this precursor would be converted to artemisinic acid.

The researchers estimated their method could produce the drug for 25 cents per treatment. The conventional approach of extracting artemisinin from the plant costs about $2. This year, Sanofi-Aventis licensed the technology to optimize it and scale it up. The company hopes to have synthetic artemisinin in the supply chain by 2013.

A more complicated application of synthetic biology involves engineering biological components to work inside a mammal. In the dairy and livestock industries, farmers struggle to determine when a cow is ready to be impregnated, which they do by observing the cow’s behavior. But even if they correctly guess when a cow is ovulating, artificially inseminating the cow with sperm from a plastic tube has only a 40 percent success rate.

Earlier this year, Martin Fussenegger’s group at the Swiss Federal Institute of Technology (ETH) in Zurich developed a capsule made from cellulose polymers (3). Into the capsule they placed sperm and engineered mammalian cells that detected luteinizing hormone (the ovulation signal) and produced cellulase in response. The capsule works like this: A farmer tracks an animal’s 21-day ovulation cycle and notes when ovulation is most likely to start. The capsule keeps the sperm fresh for three days, so a vet inserts the capsule into the cow’s uterus a day or two before ovulation. When luteinizing hormone surges through a the cow, the engineered cells inside the capsule detect it and initiate the expression of cellulases. The cellulases degrade the capsule and release the sperm. In the first trial run carried out in Switzerland, Fussenegger says the device had a 100 percent success rate.

Other efforts to develop clinical therapeutics are still in the laboratory testing phase. For example, researchers are looking to exploit the commensal bacteria that reside in the gut. “There are a number of things these bacteria normally do daily in the intestine that we just haven’t tapped into,” says March. “There is no reason why we couldn’t engineer them to act on the behalf of their host rather than just on their own behalf.”

March’s team has manipulated commensal bacteria to treat cholera. Vibrio cholerae, the bacterium that causes the infection, populates the upper intestine and reaches a certain density after which it stops making its colonization proteins. It then exits the body by diarrhea, causing life-threatening dehydration in victims. March’s team decided to beat V. cholerae at its own game by getting a probiotic Escherichia coli strain to produce the signature quorum-sensing V. cholerae proteins. “If [E. coli bacteria] were making the signal and a V. cholerae bacterium came in, it would think other V. cholerae were already there. It wouldn’t attach,” says March. The investigators were successful in getting the method to work in a mouse model last year (4).

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