Making anti-malarials from yeast: Jay Keasling and synthetic biology

Guest blog by  Shah R. Ali, an MD candidate at Stanford Medical School.

Malaria  is getting a cutting-edge, first world scientific treatment at the hands of synthetic biologist Jay Keasling.

The most effective antimalarial currently in use is artemisinin, which is effective against the Plasmodium falciparum species (the most lethal malaria-causing species), including multidrug-resistant forms. However, most of the available artemisinin is extracted from the Artemisia annua plant, and supplies depend on the yield and cultivation-related factors. Chemical synthetic options are being explored, but their potential costs are not lower than for extraction of the active ingredient from plants. Dr. Keasling’s synthetic biology approach to re-engineer yeast to synthesize a key artemisinin precursor is estimated to reduce the cost of artemisinin-based combination therapies by 30-60%.

Dr. Keasling recently spoke at Stanford Medical School as part of the “Access and Delivery of Essential Medicines” lecture series about the story of artemisinin. At the beginning of his talk, he surprised audience members by talking about computer parts. He used this example to make his point that “we often take for granted the standardization that is so important for engineering disciplines.” Standardization of various biological components is one of the major goals of synthetic biology. After providing the background of the field, he said, “we thought…we could engineer a chemical factory inside a microbe to produce [artemisinin].”

The premise is deceptively simple: since we know the metabolic pathway to synthesize the drug in A. annua, we should be able to put it into another easily-cultured organism to churn out the compound at high quantities. Dr. Keasling did just this: his team tested some steps in E. coli then moved onto S. cerevisiae, into which they engineered 1) a mevalonate pathway engineered to increase yield of farnesyl pyrophosphate, 2) the amorphadiene synthase gene, and 3) a novel cytochrome P450 monooxygenase. The modified yeast metabolizes simple sugars to artemisinic acid, a nontoxic precursor to artemisinin. This genetically engineered yeast strain could prove a boon for malaria patients worldwide. The work was funded by the Bill and Melinda Gates Foundation, which gave Dr. Keasling (UC-Berkeley), Amyris Biotechnologies, and the Institute for OneWorld Health $43 million for this project.

Amyris Biotechnologies optimized culturing conditions and the chemical process for scale-up, and Sanofi-Aventis has partnered with these groups and obtained a license to produce the drug on a large scale and sell it cheaper than the farmed artemisinin. Furthermore, Sanofi currently produces several antimalarial compounds and has distribution networks in the developing world, and their partnership with the Keasling team should enable access to the infected individuals who need the drug.  The Institute for OneWorld Health will support global access to the drug through public policy. The synthetic version of the drug is projected to cost a fraction of its current retail value, and thereby make it more affordable in resource-poor settings.

I think the reason that yeast-derived artemisinin has captured the attention of the media is that its story is compelling: a world-class researcher used cutting-edge science to produce a drug for the developing world, while collaborating with a start-up (Amyris), a non-profit drug-development company (Institute for OneWorld Health), and a for-profit pharmaceutical company (Sanofi-Aventis), and using the equipment and manpower of one of the premier research universities in the world (UC-Berkeley) and funds from the BMGF. This unique collaboration is all the more exciting given that the project actually worked in the laboratory, and many organizations and groups of people optimistically look forward to the translation of this benchtop discovery to the bedsides of infected individuals in the developing world. It remains to be seen whether such a scenario is, like a good experiment, replicable, but I hope that similar attempts will be made in the future that follow this paradigm. After all, Dr. Keasling did stress the importance of standardization.

Access and Delivery of Essential Medicines is a Stanford elective that aims to increase attention to diseases particularly concerning to the developing world at the medical school. The majority of talks, including Dr. Keasling’s, are recorded and made available to the public at www.adem.stanford.edu/talks.

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