Humans are sometimes challenged by the tiniest things. We continue to fail to control the spread of malaria carried by Plasmodium falciparum, the parasite responsible for the most deadly malaria disease in humans. Although malaria morbidity and mortality is difficult to establish, there are up to 515 million cases yearly, and one to two millions deaths. Disease, death, and significant economic repercussions because mosquitoes that weigh a measly 2.5 mg carry the protist in its sporozoite form until it reaches blood via a bite from the female insect. The parasite completes its lifecycle, invading the hepatocytes of the liver and the red blood cells and causing disease and/or death in its human host.
Acronym Required previously wrote about the challenge of malaria prevention and treatment in Malaria Prevention, Progress in Fits and Spurts. As that 2005 article discussed, Novartis had just revealed that it was again unable to produce the quantities of the drug that it had agreed to in its "private-public partnership" with the World Health Organization. Novartis is the sole manufacturer of the drug Coartem, an artemisin based combination therapy which has proven to be one of the most effective treatments for malaria. In 2004 the company had also fallen short of its production goals, but it had *promised* that 2005 would be different; that it was capable of meeting demand. Both years the company blamed their production failure on few initial orders and shortages of the plant quingtao, indigenous to China, from which arteminsin is derived.
Recently a group of scientists at University of California, Berkeley bioengineered yeast, Saccharomyces cerevisiae, to produce a precursor to arteminisin. The process involves the enzyme amorphadiene synthase that catalyzes the production of amorphadiene from farnesyl diphosphate (FPP). Cytochrome P450 then facilitates the next step of producing artemisinic acid. From artemisinic acid; the final step to the arteminisin compound is arguably cheaper than full synthesis of arteminisin would be. The research team says that this represents significant progress towards producing a more affordable treatment for malaria, although subsequent optimization of the process in order to produce a drug is likely 5 or 10 years away.
The researchers previously engineered E.coli to produce amorphadiene, an isoprenoid precursor to artemisinic acid, in research that was published in 2003 in the journal Nature Biotechnology; "Engineering a mevalonate pathway in Escherichia coli for production of terpenoids" (published online June 1, 2003), described here on the Berkeley press release site. At the time, the principal investigator Jay Keasling noted: "By inserting these genes into bacteria, we've given them the ability to make artemisinin quickly, efficiently and cheaply, and in an environmentally friendly way. Although E.coli replicates faster than yeast and can churn out more of the desired compounds, this next step, transformation of amorphadiene to artemisinic acid, turned out to be accomplished by cytochrome P450, a cellular membrane enzyme that functions in yeast but not E.coli. Keasling commented on the fortuitous research environment that led to the latest research:
"We reached our goal early, thanks to a number of miracles: The first gene Dae-Kyun isolated was the right one, the gene was functional in yeast, the gene's enzyme did in one step what we thought took three enzymes, and the artemisinic acid it produced didn't interfere much with the cell".
The research advances progress towards lower cost arteminisin production, which would potentially lower the cost of arteminisin combination therapy. Hopefully, this method, and/or vaccine development, or the judicious use of existing technologies, will eventually help abate malaria. As much as the spread of malaria is a scientific challenge, it is also a political and economic challenge, although arguably a more sure-fire scientific solution would ease the politics.The research is supported by multiple organizations, and UC Berkeley has issued a royalty-free license to both OneWorld Health and Amyris to develop the technology to treat malaria. Africa Malaria Day is April 25, 2006
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In addition to the article on malaria treatment progress listed above, Acronym Required also wrote about malaria vaccination development via private-public funding schemes for malaria vaccine development in Vaccine Development for Infectious Diseases. One World Health and Jay Keasling were also mentioned in a short post on Codon Devices.
