Recent advances towards development and commercialization of plant cell culture processes for the synthesis of biomolecules

Abstract

Plant cell culture systems were initially explored for use in commercial synthesis of several high-value secondary metabolites, allowing for sustainable production that was not limited by the low yields associated with natural harvest or the high cost associated with complex chemical synthesis. Although there have been some commercial successes, most notably paclitaxel production from Taxus sp., process limitations exist with regards to low product yields and inherent production variability. A variety of strategies are being developed to overcome these limitations including elicitation, in situ product removal and metabolic engineering with single genes and transcription factors. Recently, the plant cell culture production platform has been extended to pharmaceutically active heterologous proteins. Plant systems are beneficial because they are able to produce complex proteins that are properly glycosylated, folded and assembled without the risk of contamination by toxins that are associated with mammalian or microbial production systems. Additionally, plant cell culture isolates transgenic material from the environment, allows for more controllable conditions over field-grown crops and promotes secretion of proteins to the medium, reducing downstream purification costs. Despite these benefits, the increase in cost of heterologous protein synthesis in plant cell culture as opposed to field-grown crops is significant and therefore processes must be optimized with regard to maximizing secretion and enhancing protein stability in the cell culture media. This review discusses recent advancements in plant cell culture processing technology, focusing on progress towards overcoming the problems associated with commercialization of these production systems and highlighting recent commercial successes.

Figure 1

Development of a plant cell suspension culture. Sterile explants from the whole plant (a) are plated on solid culture medium. With the correct nutrients and hormones combination, explants grow into a callus of dedifferentiated cells (b). Callus cells are transplanted into liquid media, creating a suspension culture (c), which can be scaled-up for growth and production in a controlled bioreactor (d). To avoid contamination, aseptic technique must be used to maintain the cell cultures, resulting in increased manufacturing costs.

Figure 2

Examples of the complex structures of commercially available secondary metabolites. (a) Vanillin, a food flavoring derived from V. planifolia; (b) Artemisinin, an anti-malarial compound from A. annua (c) Morphine, an analgesic from P. somniferum; (d) Camptothecin, an anti-cancer compound from C. acuminata; and (e) Paclitaxel, an anti-cancer compound from Taxus spp.