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Plant natural products from cultured multipotent cells

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- Susan Roberts & Martin Kolewe, Nature Biotechnology 28 , 1175–1176 (2010) doi:10.1038/nbt1110-1175

Natural products from plants have an important place in the history of pharmaceuticals as a rich source of leads and drugs1. Yet research into natural products has declined steadily over the past two decades, eclipsed by high-throughput screening and combinatorial chemistry and by uncertainties regarding the feasibility of large-scale manufacture2.

 In this issue, Lee et al.3 show that these concerns might be overcome by culturing cambial meristematic cells (CMCs), multipotent plant cells that give rise to the vascular tissues xylem and phloem. From a commercial perspective, CMCs could supersede existing plant cell culture methods for generating natural products.

Owing to their structural complexity, most natural products cannot be produced on an industrial scale by chemical synthesis. Extraction from plants is often not feasible as the plants can be rare or slow growing. These supply issues came to national attention in the United States during development of the anticancer drug paclitaxel (Taxol) in the early 1990s, when legislation was enacted to protect the pacific yew (Taxus brevifolia) from overharvesting and to mandate exploration of alternative sources of paclitaxel. One solution that emerged was culture of dedifferentiated cells (DDCs) from various Taxus species, and after extensive research efforts involving media optimization, metabolic engineering and process engineering in both academic and industrial laboratories, Phyton Biotech, a DFB Pharmaceuticals company, received US Food and Drug Administration approval to produce Taxol for Bristol-Myers Squibb by plant cell culture4.

Nonetheless, this method of producing natural products has several limitations, including the slow growth rates of dedifferentiated plant cells, their aggregation (which complicates scale-up to bioreactors), low yields of secondary metabolites, and above all, variability in these properties5. Another alternative is microbial hosts engineered to express plant metabolic pathways. For example, Escherichia coli was recently engineered to express the first 2 out of the putative 19 steps of the dedicated paclitaxel biosynthetic pathway6. However, many complex plant secondary biosynthetic pathways are not fully defined, and it is unlikely that this strategy will ensure a reliable and cost-effective supply of natural products such as paclitaxel in the near future. Currently, the best options involve a combination of approaches. Notable examples include production of the anti-malarial agent artemisinin by expression of a precursor in a microbial host followed by synthetic chemistry7, and a partial solution for paclitaxel that involves sustainable harvest of Taxus needles, extraction of a precursor and synthetic chemistry. In many situations, however, such as natural products derived from slow-growing plants and having complex, undefined biosynthetic pathways, plant cell culture will remain the most viable option.

The work of Lee et al.3 marks an important departure from traditional plant cell culture. Instead of culturing heterogeneous mixtures of dedifferentiated cells, they isolated cells derived from vascular cambium and propagated them in solution. When exposed to the appropriate ratio of growth regulators, explants from most plant organs can be induced to dedifferentiate to form so-called callus cultures, which can be transferred to liquid media and disaggregated into single cells (Fig. 1). The resulting suspension cultures are amenable to bioprocessing technologies used for large-scale mammalian and microbial cultures. However, the starting cell population from the plant organ is a mixture of specialized cell types, which vary in cell cycle participation8 and other properties, and the cell types that remain after extended culture in the dedifferentiated state are also probably heterogeneous, contributing to the instability of many culture properties.

Figure 1: Suspension cultures of CMCs provide an attractive alternative to cultures of DDCs for the production of plant natural products.
A reliable, cost-effective supply of natural products for use as pharmaceuticals, fragrances, dyes and insecticides remains a major challenge for many systems. Plant cell tissue culture has been limited by inconsistent performance and the economic constraints associated with slow growth and low product yield. Compared with mammalian cell culture, plant cell culture has required batch times of months rather than weeks and has reached product titers of mg/l rather than g/l. Additional problems include cell aggregation, susceptibility to shearing, variability in growth and profusion of necrotic cells. CMCs appear to enhance cell culture performance in all of these areas, and notably do not require selection of specific cells and aggregates for consistent growth over repeated subcultures, thereby minimizing maintenance requirements.

These improvements yield cell cultures that are substantially closer to mammalian cell cultures with regard to large-scale process considerations. CMC-based strategies should therefore facilitate the development of economically viable plant cell tissue culture processes for many natural products.