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An affordable antimalarial.

In a blend of new and old, a plant-derived drug called artemisinin that the ancient Chinese used to treat fever is now being used effectively against drug-resistant malaria. When derived from the plant Artemisia annua, artemisinin costs about $1.50 per adult dose--unaffordable in much of Africa, where most malaria deaths occur. But while naturally derived artemisinin is too costly for many malaria sufferers in developing nations, an elaborate genetic engineering project may offer hope for a more affordable artemisinin-based therapy.

According to the World Health Organization, malaria kills more than 1 million annually. The malaria parasite Plasmodium falciparum has evolved resistance to older medicines, and artemisinin and its derivatives are considered essential to fighting the disease.

In April 2003, the volunteer medical group Medecins Sans Frontieres asked international donors to promote "rapid implementation of artemisinin-based combination therapy (ACT), a proven treatment that is being promoted by the World Health Organization." ACT works by pairing artemisinin with traditional antimalarials that act by other mechanisms.

In a project reported in the July 2003 Nature Biotechnology, Berkeley professor of chemical engineering Jay Keasling and colleagues inserted 10 genes into the common bacterium Escherichia coli, creating a microbe that makes amorphadiene, an artemisinin precursor that is easily converted to the drug. The transferred genes convert a chemical commonly found in E coli, acetyl co-enzyme A, into amorphadiene. Instead of enhancing the E. coli genes that normally produce amorphadiene, the substitute pathway becomes a second, much larger source of amorphadiene.

One key to success has been balancing the multistep biosynthesis of amorphadiene in the bacteria, says Keasling. Some intermediate compounds in the synthesis, including isopentanyl pyrophosphate (IPP), are toxic to E. call at high concentrations. It's critical to carefully balance the genes that synthesize and utilize IPP to ensure that IPP is quickly converted to amorphadiene before it kills the E. coli, Keasling adds.

The transformed E. coli produce about a gram of precursor--enough for one adult dose of treatment--per liter of solution. By fine-tuning the bacteria and perhaps adding more genes, Keasling hopes to reach 50 grams per liter. "If we were to get some high, but reasonable, yields, we could be producing one treatment for twelve cents," he says.

The report is "a landmark paper," says Jorg Bohlmann, an assistant professor in the Biotechnology Laboratory at the University of British Columbia. Instead of transferring just one gene, he says, Keasling moved enough genes to create an entire new metabolic pathway in E. coil, thereby of raising the yield of the drug precursor. Plants, he notes, are quite variable in their production of specific chemicals. "If the plant has the best production at a certain stage of development, or in a certain part of the tissue, or under certain environmental conditions ... Keasling can now control the conditions of production in E. coli" to maximize yield.

The transformed bacteria may be useful against other diseases besides malaria, says Keasling. Artemisinin is one of roughly 50,000 isoprenoid chemicals that have evolved to fight pathogens and parasites in plants, microbes, and some marine organisms. Other isoprenoids include the flavoring menthol, carotenoids (useful for combating ultraviolet damage), and Taxol (an anticancer agent derived from the Pacific yew).

Keasling says the engineered E. coli could be further transformed to produce other isoprenoid chemicals: "A company could tweak the bacteria a bit, add any number of plant genes involved in the chemical of interest, and get pretty much any isoprenoid."
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Title Annotation:Enviromental Medicine
Author:Tenenbaum, David J.
Publication:Environmental Health Perspectives
Date:Jan 1, 2004
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