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Anything plants can grow鈥� (Image: Good Wives and Warriors)

Our best antimalarial drug comes from a plant, but now modified microbes are brewing it in a factory. Synthetic biology has got real 鈥� and food may be next

A REVOLUTION is brewing in Bulgaria 鈥� quite literally. In vats similar to those used to ferment beer, genetically modified yeast is churning out tonnes of a molecule that can easily be turned into the most potent antimalarial drug on the market today, artemisinin.

Before the brewing began, all of the world鈥檚 artemisinin came from a Chinese plant called sweet wormwood. The supply of farmed artemisinin has been erratic, and shortfalls have sometimes put lives at risk. The yeast in Bulgaria is supposed to guarantee a plentiful, cheap supply, helping the fight against a terrible disease that blights the lives of hundreds of millions.

It is no surprise, then, that yeast-grown artemisinin is being hailed as a triumph for synthetic biology 鈥� the engineering of living organisms to do everything from making drugs to mopping up pollution. Here, say those in the field, is proof that this young science is starting to deliver on its promise.

Except the story isn鈥檛 that simple. The problems with the artemisinin supply have largely been ironed out already. The yeast-grown artemisinin could actually trigger a shortfall in the next year or two rather than prevent one. What鈥檚 more, it turns out that it would have been quicker and cheaper to make synthetic artemisinin with conventional methods.

So is this really the dawn of a new era? Or are the yeast in Bulgaria a one-off vanity project that will lead nowhere? The answer could soon be arriving on your dinner plate.

The artemisinin story starts in 1967, when Chairman Mao launched a project to find an effective antimalarial to help the communist forces in the Vietnam war. A researcher called Tu Youyou began testing traditional Chinese fever remedies and hit the jackpot with sweet wormwood.

When the active ingredient was unveiled to the rest of the world in 1979, the reaction was sceptical: artemisinin looked too unstable to qualify as a wonder drug. 鈥淚t was the first natural product found that contained this unusual oxygen-oxygen endoperoxide bond,鈥� says , a chemist at Indiana University in Bloomington.

Its Chinese origins didn鈥檛 help either. The drug didn鈥檛 become widely available until 1999, when launched a pill form containing artemisinin and another antimalarial. Combining drugs like this makes it much harder for the malaria parasite to evolve resistance.

Meanwhile, at the University of California, Berkeley, had set out to prove that microbes could be turned into chemical factories. His team had decided to start with isoprenoids, a large family of commercially useful molecules found in plants and animals 鈥� but which to chose? 鈥淭hen one day, one of my students showed me a paper on artemisinin,鈥� says Keasling. 鈥淲e thought, gosh 鈥� this is something we could make.鈥�

Soaring demand

That鈥檚 because artemisinin can be derived from another chemical called amorphadiene, which just happens to be an isoprenoid. Keasling鈥檚 team homed in on the genetic machinery needed to produce amorphadiene in yeast, and transferred it to E. coli 鈥� a much-studied bacterium that is easy to work with.

It was pioneering work. While conventional genetic engineering involves tweaking one or two genes, Keasling had to transfer half a dozen. And he took the approach championed by synthetic biologists: trying to develop a module, or 鈥渂iobrick鈥�, for making amorphadiene that could be plugged into organisms other than E. coli.

By 2003 . Their timing was impeccable. In 2001, the . Its , from 600,000 treatments in 2002 to 5 million in 2004, leading to . A number of companies came sniffing at Keasling鈥檚 door.

But Keasling鈥檚 work was far from finished. Converting amorphadiene into artemisinin is complicated and expensive so the team wanted to engineer the bacteria to perform most of this tricky step themselves. This meant finding the necessary genes in sweet wormwood, and then transferring them into the bacteria.

鈥淚 explained to the pharmaceutical companies that it would take money to find those genes and get them working in the microbes, and the conversation just stopped,鈥� says Keasling. By this time, Novartis had agreed to sell its farm-sourced artemisinin therapy at essentially the cost-of-production price 鈥� the right thing to do and good PR too, Keasling says. But with no prospect of a profit, companies weren鈥檛 prepared to stump up any money for research.

The came to the rescue. The foundation pumped $42 million into the gene hunt, which was carried out by a start-up company, , founded by Keasling and his colleagues.

Progress was rapid. It turned out that just one enzyme was involved and, as luck would have it, it was the first enzyme his team isolated from the plant. There was one stumbling block: the enzyme wouldn鈥檛 work in bacteria. Because of the biobrick approach, though, it wasn鈥檛 too difficult to switch microbes. Keasling鈥檚 team took what they had developed in E. coli, added the new sweet wormwood gene and plugged it into brewer鈥檚 yeast. By 2006, their yeast , which is easily turned into artemisinin.

Yields were still low, but promising enough to encourage Paris-based pharma giant Sanofi to license the yeast in 2008 and help boost the efficiency. Last year the numbers finally added up, and from yeast. The company produced 35 tonnes of artemisinin last year 鈥� a third of the entire world production. It plans to make 50 to 60 tonnes this year: enough to treat between 80 and 150 million people.

Synthetic biologists have nothing but praise for Keasling鈥檚 decade-long quest to give the world a new source of artemisinin. It is hailed as the great success story of the field. 鈥淲hat鈥檚 more inspiring than trying to benefit that many people on the planet?鈥� says , a synthetic biologist with biotech firm Biodesic of Seattle. 鈥淚t鈥檚 almost like the Apollo project 鈥� it鈥檚 going to get kids into science and technology.鈥�

鈥淲hat could be more inspiring? It鈥檚 almost like the Apollo project鈥�

of Stanford University sees another benefit. 鈥淭he artemisinin project is most useful because it reminded people that biology is not just a science but also a technology for making stuff,鈥� he says.

Outside the field, though, not everyone is convinced. Keasling says the plan is to use brewing as a backup supply in case of shortfalls in farmed artemisinin, but of ETC Group, a technology watchdog based in Montreal, Canada, says the technology is the wrong approach to the shortfall problem. By 2007, farmers were producing too much artemisinin and the price plummeted. This volatility led to largely successful efforts to ensure the farm supply matched demand, such as the . Thomas says ventures like this are the best way to safeguard the supply of the drug.

Farmers fearful for future

The danger now is that farmers worried that the yeast will trigger a drop in the selling price of farmed artemisinin will switch to other crops 鈥� a possibility highlighted by the A2S2 in its . If the Bulgarian brewery then fails to keep up with global demand, there could be shortages. With farmers already concerned about their futures, it didn鈥檛 help when Keasling that yeast-grown artemisinin could replace the entire world supply, not merely supplement it, Thomas says. 鈥淭hat sent real shock waves through the farming industry.鈥�

But if in the long term the cost of artemisinin falls and stays low, Keasling could fairly claim success. 鈥淎t the end of the day this isn鈥檛 about us trying to protect the farmers,鈥� says Malcolm Cutler, formerly managing director of A2S2. 鈥淲e鈥檙e all striving to get these therapies out there at the lowest price.鈥�

And if yeast-grown artemisinin does completely replace farm supplies, there could be a benefit. In many countries artemisinin is still sold on its own rather than as part of a combination, encouraging artemisinin-resistant malaria to emerge and spread. Yeast-derived artemisinin won鈥檛 be sold to monotherapy makers, Keasling says.

So while synthetic artemisinin is almost certainly bad news for the tens of thousands of sweet wormwood farmers, it鈥檚 hard to see it as anything other than good news for the hundreds of millions of people with malaria. But was synthetic biology the best tool for producing the drug?

Yes, say some, because molecules like artemisinin are too complex to be chemically synthesised in a cost-effective way. Yet when Silas Cook read as much in a WHO publication, he immediately set about disproving the statement. In 2012, just 18 months and $100,000 later, . 鈥淚n terms of R&D, it鈥檚 a relative bargain,鈥� he says.

Cook鈥檚 method may never be used for mass production now, but had the Bill & Melinda Gates Foundation funded this kind of approach back in 2003, synthetic artemisinin production might have begun years earlier. That casts yeast-grown artemisinin in a rather different light: more an expensive and time-consuming diversion than the unmitigated triumph trumpeted at synthetic biology meetings.

Of course, pioneering a whole new approach is always going to be difficult and expensive. But it is by no means clear that biosynthesis is going to 鈥渞evolutionise the way we treat and prevent diseases鈥�, as . It isn鈥檛 even on the radar for pharmaceutical companies, says Phil Baran, a chemist at the Scripps Research Institute in La Jolla, California. Yeast-derived artemisinin looks more like a one-off than the dawn of a new age of growing drugs cheaply in microbes.

But outside the drug industry the story is very different. The food industry, with its long experience of brewing, is particularly interested. A whole range of valuable chemicals currently extracted from plants, from fragrances to flavourings to food additives, could soon be grown in engineered organisms such as yeast. In fact, you may already be consuming a few such chemicals.

For instance, valencene is a citrus flavour and aroma usually extracted from Valencia oranges. Two companies, Allylix of California and Isobionics of the Netherlands, have quietly been brewing it since 2010. In the European Union, the brewed version is regarded as a natural product by regulators and . It is being sold worldwide for use in beverages and perfumes, says Toine Janssen of Isobionics.

Next up could be vanilla flavouring. It is a rather surprising example because the vast majority of vanilla flavouring, often sold as vanilla essence, is manufactured chemically from wood or coal. The key ingredient is a complex molecule called vanillin 鈥� one of the main flavours found in genuine vanilla extract made from the dried seed pods of the vanilla orchid. The seed pods are very labour-intensive to produce, making natural vanilla the world鈥檚 second most expensive spice.

Now the Swiss-based firm Evolva has modified yeast to produce vanillin. It says taste tests have confirmed that its yeast-grown version is preferable to other synthetic vanillin. 鈥淧etrochemically derived vanillin has notes that a sophisticated palette can identify,鈥� says Neil Goldsmith, head of Evolva.

Evolva hopes to sell its yeast-grown vanillin at a premium compared with the petrochemical variety. Being able to label it as 鈥渘atural鈥� will help. But the imminent introduction of 鈥渟ynbio vanilla鈥� has caught the attention of anti-GM groups such as .

One fear is that synbio versions of chemicals currently extracted from crops such as vetiver and patchouli, and from rubber and coconut trees, will put farmers out of work. 鈥淚n time, millions of tropical farmers may be kicked out of the way by this,鈥� says Thomas. 鈥淭hat鈥檚 the bigger problem.鈥�

Goldsmith insists this won鈥檛 happen. 鈥淚t鈥檚 really about giving people an alternative to the material coming out of chemical factories,鈥� he says. That is the case for Evolva鈥檚 vanillin. But some other microbe-grown products will compete with farm-derived products.

In a sense these arguments show how far synthetic biology has come. Just a few years ago . Now it is seen as a threat to some existing products. And although Keasling鈥檚 artemisinin work led to the perhaps mistaken belief that synthetic biology will revolutionise medicine, the technology is still poised to feed into most of our lives. 鈥淭en years from now, the world is going to look profoundly different,鈥� says Carlson.

Leader: 鈥�Synthetic biology can supplement traditional farmers鈥�

This article appeared in print under the headline 鈥淎nything plants can grow鈥︹��