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Artemisinin, a potent antimalarial drug derived from the wormwood plant (left), is too costly for widespread use in poor countries. Researchers hope to provide an affordable source of artemisinin by turning Escherichia coli (right) into microbial factories that pump out the drug.

Original Contribution
February 16, 2005

Collaboration Hopes Microbe Factories Can Supply Key Antimalaria Drug

JAMA. 2005;293(7):783-789. doi:10.1001/jama.293.7.785

Curing a disease in developing countries takes more than designing an effective medicine because pharmaceutical companies have little incentive to produce a drug that will not turn a large profit. But a recent collaboration of three California organizations—a nonprofit institute, a biotech company, and a university—could help change that paradigm.

A $42.6 million grant from the Bill and Melinda Gates Foundation will help the Institute for OneWorld Health, in San Francisco; Amyris Biotechnologies Inc, in Albany, Calif; and the University of California at Berkeley apply a breakthrough technology to the production of the antimalarial drug artemisinin for developing countries. Scientists at the University of California at Berkeley will conduct the necessary research and development, OneWorld Health will work to clear regulatory hurdles, and Amyris will scale up production of the drug. And all three organizations will come out ahead.


Artemisinin is not a new wonder drug. The chemical has been around for more than a 1000 years, extracted from the wormwood plant Artemisia annua and used as an ancient Chinese herbal medicine. It destroys the malaria parasite by releasing free radicals that attack the cell membrane of the parasite in the presence of high iron concentration, as found in the blood.

But there are several problems with it. First, it costs about $2.40 per cure, which is twice the amount infectious disease officials deem a reasonable cost for developing countries. In addition, cultivating the plant and stockpiling artemisinin are not easy tasks, particularly because A annua grows only in certain regions of China and Southeast Asia.

“Growing of the crop and extraction are really subject to all of the caveats of crop harvest,” said Jack Newman, PhD, founding scientist of Amyris. “So, for example, if you get a hurricane through an area that decimates your crop . . . that’s the end of your drug for that year,” he explained.

Growing crops for drug production can also be difficult in countries that may withhold resources to drive up prices. Such was the case recently when the World Health Organization deemed a combination drug therapy including an artemisinin derivative as the preferred treatment for malaria in countries where the disease is resistant to conventional treatments. As a result, the price of the wormwood plant in Asia increased dramatically. A better option is needed if artemisinin is going to have a significant effect on malaria, a disease that causes more than 300 million acute illnesses and at least 1 million deaths each year, most in Africa.


The pioneering technology that could solve these problems involves inserting plant genes into Escherichia coli to fashion microbial factories that pump out the lifesaving drug. About a dozen enzymatic steps are involved in the production of artemisinin, and Jay Keasling, PhD, at the University of California at Berkeley has unveiled these and is in the process of expressing the relevant genes in E coli. “The intermediates haven’t been completely mapped out yet, but we know where we are and we know where we need to be,” said Keasling. “The chemistry is fairly straightforward.”

Once all of the genes involved have been inserted into E coli, production of artemisinin can go full speed ahead. “In the past, if you were to just take a gene out of a plant and put it into a microbe, you would get sort of a trickle of products coming out. But with this whole new pathway, it’s really more like a fire hose,” said Newman. He added that Amyris will speed up production even more “by tinkering inside the microbe genetically to get it to produce more per cell and by using your standard tricks of the trade in scale-up of fermentation.”

Many other complicated molecules could be made in this way as well. Artemisinin is a terpenoid, a class of the isoprenoid family of chemicals. Isoprenoids are used to make a wide variety of products, including medicines and additives. Inserting genes from the isoprenoid biosynthetic pathway into E coli enables scientists to synthesize various precursors, which can be converted to any isoprenoid product. These include anticancer drugs such as taxol, nutraceuticals such as carotenoids, as well as vitamins and perfumes.

In addition, using microbial factories to make products is a more efficient and environmentally friendly technique than traditional synthetic chemistry procedures. “You’re doing things inside the cell rather than using solvents and things like that,” said Keasling. “And you can do in one step in biology what would take you maybe five steps in chemistry.”


Replacing plants with microbes is not enough to make artemisinin affordable for developing companies, but in this latest collaboration, all of the organizations involved have vowed to not take a profit from artemisinin. And that promise could be just what is necessary to make affordability a reality.

There are plenty of benefits to go around for the University of California at Berkeley, OneWorld Health, and Amyris, though. Berkeley obtains funding to use for academic research, OneWorld Health is able to do work that fulfills its humanitarian mission, and Amyris receives support to perfect a technology that it can use for the development of other products.

“My partners and I are very much committed to taking no profit on the antimalarial, but there’s also quite a few other drugs and products that can be made with this process,” said Newman.

OneWorld Health is on board because it is interested in finding a way to decrease costs of medicines for developing countries. “There are new biotechnology processes that could make medicines that are already in the market be produced much more efficiently and much more affordably,” said Katherine Woo, PhD, director of scientific affairs. “Artemisinin is not new, but there really have been barriers to its widespread application because of cost. So we looked into ways to help in that regard, and this technology just kind of popped out from ones that we looked at,” she said.

Woo hopes other collaborations will arise due to this project. “This is really an example that we want to use to entice other biotech companies, or other entrepreneurs with new technologies, to think to develop the technology both for the developed world and the developing world at the same time,” she said.

For Keasling, the collaboration is a perfect opportunity to move his research forward. “It made sense to be working with a small biotech company to translate what we discover in the lab into something that might be usable, and then to work with a nonprofit pharmaceutical that really specializes in getting drugs to these people who need them,” said Keasling.

Despite excitement over the potential of this technology and the collaborative effort to fight malaria, it will take years before any potential applications are made.

“The timeline for my lab is to get everything out of the lab within a 3-year period,” said Keasling. “We’re going to try to shorten this timeline as much as we can, but there’s some really basic research that has to be done.”

And although artemisinin is the most common herbal product used for malaria treatment outside of the United States, it has not been approved by the Food and Drug Administration or the European Medical Agency. OneWorld Health will conduct a series of toxicology studies and perform the regulatory work required by United States and other agencies that will allow the microbe-derived drug to be substituted for the plant-derived product. The organization will also conduct toxicology studies to determine the safest artemisinin derivatives, adhering to Food and Drug Administration standards.

Keasling sees great promise for the broader field of synthetic biology, in which scientists design biologically inspired products to address problems that cannot be solved using naturally occurring entities. He foresees a time when synthetic biology will be used to produce novel enzymes and materials for a wide variety of applications, from treating patients, to cleaning up toxic sites, to neutralizing chemical and biological poisons.