Green Pharmaceuticals: Renewable Production of Natural Product Cancer Drugs

Natural products have traditionally played a major role as drug leads, particularly as chemotherapeutics where almost two-thirds of small molecule cancer therapies developed over the past three decades were of natural product origin. However, supply issues, particularly with complex chemicals that can only be derived from slow growing or rare plants, have resulted in a steady decline in the exploration and commercialization of these natural cancer killers. In vitro plant cell culture technology represents an alternative production method which could be used for renewable supply of these invaluable products. By inducing plant cells to dedifferentiate, they can be grown in liquid suspension cultures and scaled up in reactors similar to those used in other large scale industrial fermentation processes, while leveraging the plant’s native machinery to produce the metabolites of interest. The primary limitations facing widespread commercial application of this technology are low and variable drug product yields. In particular, plant cells tend to aggregate, which affects the metabolism of individual cells and also the properties of the bioprocess a whole. We take an integrated, multi-scale approach to engineer our Taxus suspension cultures for the production of the anti-cancer drug paclitaxel (Taxol). For example, we have analyzed gene expression in cultures with different levels of paclitaxel production; we have found heterogeneity in the paclitaxel content of individual cells; we have developed methods to characterize populations of these cells in aggregates; and we have used mathematical models to describe and predict bioprocess behavior. Our work provides critical insight on how to develop sustainable processes for the supply of these medicines, and demonstrates the importance of an integrated, interdisciplinary approach to realizing the potential of plant cell culture technology.