Target-Directed Evolution of Mutant Transgenic Plant Cells as a Novel Source of Drugs

Most current non-peptide drugs are derived from bioactive metabolites in wild-type plants. These have mostly evolved in plant species, by mutation and natural selection over millennia, because they confer a survival advantage. A novel approach is to first transform plant cells to express a specific foreign therapeutic target protein, and then derive a mutant population of these transgenic cells by selection under conditions in which metabolites with the desired interaction with the foreign target protein confer a survival advantage. The surviving sub-population of mutants is now enriched in individual clones that overproduce known or novel metabolites with the required activity on the target. Within months, "target-directed evolution" can redirect the "bioactive metabolome" of the plant species toward a specific pharmacological phenotype. In this chapter we describe how this approach constitutes a powerful means of evolving plant secondary metabolism thus enhancing the natural capability of plant cells.