Grant: Discovery Grants Program - Individual

Plantshave remarkable attributes for being able to perform complex and biologicallyinnovative biochemistry that generates a diversity of colors, fragrances, aromasand biologically active organic molecules. While the majority of the molecules produced arenot directly essential for survival, many may play key roles in plantadaptation to the biotic and abiotic environment. The unique biologicalactivities of this chemical diversity have provided medicinal and diseasepreventing molecules that have been used by humanity to prevent/cure manydevastating diseases. The monoterpenoid indole alkaloids (MIAs) makeup the largest and most diverse class of compounds that are characteristicallyfound within many members of the Apocynaceae (4700 species), the Loganiaceae(600 species) and the Rubiaceae ( 10,000 species) plant families. Thecomplexity of MIA chemistry is matched by their remarkably diverse effects onliving organisms that has led to their use as drugs for preventing malaria(quinine) and for treating neurological disorders (reserpine), cancer(camptothecin, vinblastine and vincristine), as vasodilators (yohimbine), asanti-inflammatories for gout treatments (colchicine) and as potential analgesics and novel painkillers (conolidine) in human beings. Over the past 25 years my laboratoryhas made many key discoveries about the biosynthesis ofanti-cancer MIAs of the Madagascar periwinkle ( Catharanthus roseus ) that have been used in chemotherapy treatmentsover the past 45 years. The genetic resources and biochemical knowledge derivedfrom these discoveries arepresently being exploited to enhance the production of valuable medicinalcompounds in C. roseus or through synthetic biology experiments in other organisms including yeast or in microbialfactories. The production of MIA pharmaceuticals in recombinant organismscreates unique opportunities for less expensive manufacturing of existing MIA drugsand for generating new and unique medicines not available from natural sources. The initial discoveries made in this model plant have also greatly improved the tools available for gene discovery of other MIA pathways found in Nature and for learning about theecological roles that MIAs play in plant fitness and adaptations to their environment.