Throughout human history, there has been an extensive reliance on herbs (and their extracts) as sources of medicine, and such dependence still stands today. Indeed, a significant number of blockbuster drugs, ranging from quinine extracted from Cinchona and Remijia spp. for malaria treatments to paclitaxelfrom pacific yew (Taxus brevifolia) for tumor suppression, are still being extracted from plants rather than using chemical synthesis approaches. This is mainly for two reasons: cost and complexity of synthesis. In some other cases, herbal extracts are used to obtain drug precursors for following chemical synthesis into the final compound (semi-synthetics) such as most of the opioids, which all share the same precursor morphine from opium poppy (Papaver somniferum) to seek balance between planting and synthesis cost.
However, in some cases, little consensus can be found between herbal sources and synthetic sources. One specific example is the anti-cancer drug etoposide (Brand name: Etopophos). This semi-synthetic drug requires podophyllotoxin as its precursor before subsequent chemical modifications can be made to obtain the final compound. However, the precursor podophyllotoxin is originally extracted from the plant Himalayan mayapple (Podophyllum hexandrum), which only grow within the premise of Himachal Pradesh, northern India due to the special climate and soil condition there. This makes the source material to be extremely rare and difficult to obtain. Although recent extractions uses more commonly-found American mayapple (Podophyllum peltatum), this plant nevertheless still grows very slow, and a usable colony would require several years of cultivation. What is worse, podophyllotoxin is only synthesized by the plant when it is under stress such as being wounded and tedious manual wounding has to be applied to the plant before harvest. In all, the supply of podophyllotoxin is always in duress and acted as the bottom-neck factor of etoposide manufacturing.
A recent research article published in Science, performed by the Sattely group of Stanford University in Palo Alto, California, has provided an alternative approach to the podophyllotoxin supply problem by the means of synthetic biology. The Sattely group compared the differential gene expression profile in pre-wounding and post-wounding Himalayan mayapple leaves, and screened out 31 genes as potential candidates that may participate in podophyllotoxin biosynthesis. They then transferred such 31 genes in different combinations into the fast-growing lab plant, tobacco (Nicotiana benthamiana), and finally pinned down a group of 10 enzyme-coding genes that allow the plant to produce (-)-4’–desmethyl-epipodophyllotoxin, which is not only a direct precursor to etoposide, but also has demonstrated anti-cancer potential on its own. Their results mean that, through the application of synthetic biology and using lab tobacco as a bioreactor, now etoposide precursors can be extracted from fast-growing, low-maintenance lab tobacco, which is expected to provide an abundant supply of this precursor compound if commercialized.
Interested in learning more about synthetic biology and applications in food, pharma, fuels, and chemicals? Join our next webinar on October 15th 2015, Disrupting Tomorrow: Applications in Synthetic Biology
References:
Six enzymes from mayapple that complete the biosynthetic pathway to the etoposide aglycone, Warren Lau and Elizabeth S. Sattely, Science 11 September 2015: 1224-1228.
Fighting cancer while saving the mayapple, Sarah E. O’Connor, Science 11 September 2015: 1167-1168
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