ABOUT THE SCIENCE
This project is focused on increasing and stabilizing the supply of artemisinin to reduce the cost of life-saving artemisinin-based combination therapies (ACTs) by lowering the production cost of artemisinin derivatives. To do this we are using a new technology, synthetic biology, to produce artemisinin, a natural compound traditionally extracted from Artemisia annua, or the sweet wormwood plant. The project team has developed a semisynthetic artemisinin production system, into which the genes from A. annua are being transferred. The microbes will produce artemisinic acid, a precursor to artemisinin, during a standard semi-synthetic fermentation process. Artemisinic acid is then chemically converted to artemisinin using a novel chemistry process. The resulting production method is unique and powerful in that it will be able to reliably produce pure artemisinin, which can then be chemically converted into one or more of its derivatives for incorporation into ACTs, in large quantities at an affordable cost.

The Process for the Production of Artemisinin. Using synthetic biology, the metabolism of Escherichia coli (E. coli) is engineered to produce artemisinic acid, a precursor to the important antimalarial artemisinin. Starting from acetyl-CoA, an abundant product of E. coli central metabolism, the bacteria produce, in turn, mevalonate, farnesyl pyrophosphate (FPP), amorphadiene and finally, artemisinic acid. The artemisinic acid is released from the bacteria and purified from the culture media. The artemisinic acid is then chemically converted to artemisinin. Once the artemisinin is produced, it must be further chemically converted into a derivative such as artesunate or artemether, which is then integrated into ACTs. The production process to make semisynthetic artemisinin is expected to take weeks rather than the months required to grow and extract botanically-derived artemisinin.

Synthetic Biology

Synthetic biology is a cutting-edge field of research that combines science and engineering in order to design and build novel biological systems or to re-design existing systems for useful purposes. In this case, the project team is using synthetic biology to insert genes from the plant A. annua into E. coli, a bacterium. Professor Jay Keasling’s laboratory in the Center for Synthetic Biology at the University of California, Berkeley has completed the synthetic biological process to produce artemisinic acid, a precursor to artemisinin. Berkeley scientists have discovered the metabolic pathway in the wormwood plant and identified the genes required to make artemisinic acid. Using synthetic biology, they inserted this pathway into microorganisms to manufacture copious amounts of the precursor. Scientists at Amyris are collaborating with the Center for Synthetic Biology to optimize this semi-synthetic artemisinin strain for commercial production. More information on synthetic biology can be found here.

Fermentation

Fermentation refers to the bulk growth of microorganisms such as E. coli in a culture medium containing nutrients. The organisms break down these nutrients using metabolic processes that produce various compounds utilized by the cell. Fermentation has been used for decades to produce foods and beverages, as well as important chemicals and medicines, such as some antibiotics and protein-based pharmaceuticals. In this project, the Keasling lab and Amyris have developed inexpensive processes to begin the scale-up process of fermentation to produce artemisinic acid. In this case the cells produce artemisinic acid as a product of their metabolism, which they release into the culture medium. The artemisinic acid can then be extracted from the medium and purified.

Chemistry