Yeast engineered to manufacture a precursor of an important malaria drug could ultimately provide a much cheaper and more efficient way to make the life-saving compound.

Malaria can be effectively treated, but the therapies are too expensive for many in poor countries – one to three million people worldwide die from the disease each year. Artemisinin combination therapies, for example, can combat drug-resistant strains of the infection; but the drugs used in those therapies cost $2.40 per treatment and are in limited supply. (Artemisinin is made from an extract of the sweet wormwood tree, which produces the chemical only under certain growth conditions.)

Jay Keasling and colleagues at the University of California, Berkeley, are working to alleviate this shortage. Using a combination of synthetic biology and metabolic engineering, the researchers have overhauled the biochemical pathways in yeast to generate large quantities of artemisinic acid, a precursor of the drug artemisinin.

Their work illustrates the great potential of synthetic biology – a fledging field in which researchers engineer novel biological “parts” into organisms. “It a big piece of work, a high water mark of success,” says Drew Endy, a synthetic biologist at MIT. “They had to upregulate the production of precursors, drop in new chemical pathways, and adapt proteins from other organisms. They are doing a lot of different things and getting it all to work together. It shows yeast metabolism is sufficiently hackable to let something like this succeed.”

Plants and microbes naturally make small quantities of artemisinin precursors, called terpenoids. In previous research, Keasling and his colleagues engineered bacteria to boost their production of terpenoids and convert the compounds into a molecule found later in the pathway for artemisinin synthesis (see TR10 2005.)

In the paper, published today in the journal Nature, the researchers transferred the entire process to yeast, where it would be more efficient, and engineered the yeast to complete the last few steps of the synthesis process to create artemisinic acid. Other scientists have shown that artemisinic acid can easily be converted into artemisinin with a few easy chemical reactions.

“[Their] work is unique because they are able to engineer entire pathways to produce precursors for an anti-malarial drug in relatively high quantities,” says James Collins, a biomedical engineer at Boston University. Some other drugs are made in microorganisms, such as bacteria engineered to produce human insulin; however, these bacteria were engineered by changing a single gene.

The finding is among the first pharmaceutical successes for metabolic engineering – the redesigning of an organism’s metabolic pathways to produce a specific compound. Metabolic engineering is more complex than traditional genetic engineering, because it requires the coordination of many different reactions, says Gregory Stephanopoulos, a chemical engineer at MIT. “The product is a property of the overall network of reactions, not the outcome of a single reaction or a single gene,” he says. 

According to Keasling, the team carefully considered the efficiency of every step in the pathway, in order to keep the production costs as low as possible. One of the most crucial modifications was blocking a pathway for making a cholesterol–like substance. This pathway uses the same precursors as artemisinin, and would therefore divert some of the organism’s drug-making capabilities. “We turned down that pathway so the yeast made just enough of the [cholesterol-like molecule] to live,” says Keasling. “That increased the yield tenfold.”

Scientists still need to make the process 50 to 100 times more efficient to lower the price enough so that those in poor countries can afford the treatment (estimated at about 22 cents a dose). Keasling projects that it will take another year and a half to achieve this level of efficiency.

Eventually, the yeast will be cultivated in bioreactors, to make huge amounts of the drug precursor. In 2004, Keasling won a $42.6 million grant from the Bill and Melinda Gates Foundation to develop the technology for pharmaceutical use. The grant will support Amyris Biotechnologies, a company founded by Keasling and colleagues to ramp up the technology for industrial-scale production, as well as the nonprofit pharmaceutical company, OneWorld Health, which will work on regulatory approval for the drug.

Keasling also plans to produce other drugs using some of the same technologies developed to make artemisinic acid. His next project will be the anti-HIV drug prostratin, which also comes from a plant.