Pharmaceutical manufacturers are always chasing the twin goals of greater efficiency and reduced costs, regardless of whether the economy is doing well or badly. Each of these goals can be elusive, and achieving both at once even more so. That’s why news about a promising method for producing paclitaxel caught my attention.
Taxol, a therapeutic used to treat certain cancers, originally had to be isolated from the yew tree, in which it had been discovered. Pure chemical synthesis of the compound is possible, but requires a complex series of steps and results in low yields. Current commercial synthesis involves the chemical modification of a compound extracted from plants—less costly and offering higher yields than the previous two methods, but far from ideal.
In the new work, however, Blaine Pfeifer of the Department of Chemical and Biological Engineering at Tufts University and colleagues at MIT and in the Chemical and Pharmaceutical Engineering Program, Singapore–MIT Alliance have discovered a way to produce the drug in a genetically engineered strain of Escherichia coli. The team described their method in the Oct. 1, 2010 issue of Science. Their “multivariate-modular approach” to the drug’s synthesis is unique in that it engineers the bacterium to implement part of a metabolic pathway and not merely produce a single compound, which is how most transgenic organisms function. Furthermore, the authors have successfully gotten a bacterium to recreate a plant-based metabolic pathway.
The group produced 1 g of taxadiene, the first committed paclitaxel intermediate, in a 1-L bioreactor containing the bacterium. This yield represents roughly a thousandfold increase over that of earlier synthesis using E coli.
The engineered pathway first creates an important intermediate within E. coli in what they’re referring to as the upstream synthesis, and then converts that to the final product in the downstream portion of the pathway. The authors combined various promoters (i.e., the gene’s on switch) and gene copy-numbers to modulate diverse expression levels of upstream and downstream pathways of taxadiene synthesis.
Although this method is not yet ready for commercial production, it seems to represent a potential quantum leap in taxadiene yields. The method also could prove to be the cost-effective means of producing paclitaxel that manufacturers have been seeking. Pfeifer’s paper encourages me that science and elbow grease together can help solve some of the industry’s difficult problems. Ingenuity like this could help the industry, its employees, and the consumers that rely on its medicines.