In the early 2000s, the malaria parasite Plasmodium falciparum developed resistance to the commonly used antimalarial drug chloroquine. In response, the World Health Organization declared that the treatment of choice should combine the plant-derived drug artemisinin with other antimalarials.
The cocktail made a difference: Deaths from the disease — which every year strikes some 219 million people, mostly children — have declined by more than 25 percent since 2000. However, consistent supplies of artemisinin, which is derived from the sweet wormwood plant, are subject to the whims of weather and other growing conditions.
Now, a new synthetic biology technique that produces artemisinin in a vat may act as a buffer against potential supply crises.
The journey from sweet wormwood seed to harvest to finished drug is slow. Farmers in China, where most of the crop is grown, plant early in the year and harvest in late summer. The plants must then be processed to extract artemisinin, which is sent to a drug company to formulate combination therapies. This process takes an average of 18 months, and that long lead time has sparked price fluctuations that cause supply crunches. In 2007, for example, the price swung from $200 to $1,100 per kilogram.
Searching for an alternative, University of California, Berkeley, bioengineer Jay Keasling began developing new ways to genetically modify yeast to produce the substance. “Our goal is to stabilize the supply of artemisinin and get the lowest possible price,” says Keasling.
Instead of changing one gene at a time, as is done with traditional genetic engineering, he invented ways to make large-scale changes to the yeast’s metabolic pathways so that it produces artemisinic acid, which can be easily converted to artemisinin. This method is considered “semi-synthetic” because the acid production stage is a natural process.
The drug company Sanofi bought the license to Keasling’s technology and announced it was beginning production in April. It expected to produce 35 tons of the drug artemisinin in 2013, ramping up to between 50 and 60 tons per year by 2014 — an amount that the company says will be enough for 80 million to 150 million therapies.
Simply replacing natural supplies with synthetic alternatives could be a tempting quick fix. But manufacturers cannot produce enough semi-synthetic drug to completely replace the natural product, says Malcolm Cutler, technical adviser to the WHO-funded nonprofit Assured Artemisinin Supply System initiative.
Putting too much of the new compound on the market too soon could further intensify price instability, he says, and that could make the drug supply even less predictable. “If we mess this up we could be losing lives,” he warns. Cutler says semi-synthetic artemisinin should help ensure access to the crucial drug and would be a significant victory against malaria.