POPPY DISRUPTION

Currently, the sole source of opiates such as the analgesic morphine, the cough-suppressant codeine, the vasodilator papaverine and the drug precursor thebaine is the poppy Papaver somniferum. Due to the complexity of the chemical reactions involved, commercial-scale synthesis of these molecules is not feasible by traditional means. Thus, the global supply of these medically essential compounds is subject to the vicissitudes of climate, crop pathogens and international trade—to say nothing of the potential for diversion to illicit use as opium or refined heroin. (Worldwide, illegal cultivation of the flowers dwarfs legitimate production by greater than tenfold.)

Christina Smolke envisions a novel alternative. Marshaling the tools of synthetic biology to reprogram common baker’s yeast, she hopes to manufacture various opioid drugs from sugars in industrial-sized fermentation vats. As far-fetched as it may sound, in the past decade Smolke, an associate professor of bio-engineering, has made significant progress toward that goal.

In the first phase of the project, she and a Caltech collaborator successfully modified the microorganism to produce an intermediate product in the opiate biosynthetic pathway. Now, with Stanford colleagues Kate Thodey, a postdoctoral scholar, and Stephanie Galanie, MS ’13, a doctoral student, Smolke has altered yeast, using genes from P. somniferum, to turn thebaine into morphine and codeine. They further demonstrated that the addition of a gene from a bacterium that feeds on dead poppy stalks facilitated the conversion of thebaine into oxycodone and hydrocodone—semi-synthetic drugs sold under the brand names OxyContin and Vicodin.

“We are now very close to replicating the entire opioid production process in a way that eliminates the need to grow poppies, allowing us to reliably manufacture essential medicines while mitigating the potential for diversion to illegal use,” says Smolke. However, she acknowledges that it may take several more years to combine the two innovations in a single strain of yeast, fine-tune the process to optimize yield, and scale it up. Ultimately, though, she estimates that a 260-gallon vat could produce as much morphine as a 2.5-acre poppy field.