Opportunities and challenges in plant chemical biology.

the Center for Plant Cell Biology, Institute for Integrative Genome Biology and Department of Botany and Plant Sciences, University of California, Riverside, California, USA. e-mail: [email protected] Although resources devoted to plant biology are modest in comparison to biomedical and other areas of research, plant biologists will play a disproportionate and crucial role in the future of mankind. Basic plant biology and its application will be the major vehicle through which we will improve human health in a cost-effective manner on a global scale. Progress toward meeting the challenges facing the world—improved nutrition, increased crop yield, resistance to pests, sustainable biofuels, raw materials for industry and serious environmental problems—is being fueled by ongoing technical and intellectual advances. One area of advancement is plant genomics, which has resulted in the sequencing of the genomes of Arabidopsis thaliana, rice, poplar and many other species. More recently, the introduction of massively parallel next-generation sequencing technologies has spawned the beginnings of a revolution through metagenomic studies1 and an era of rapid access to genotypic variation between individual genomes2. Another critical, but as yet less developed, innovation has been the integration of smallmolecule approaches with plant biology. We see plant chemical biology as the application of small bioactive chemicals to interrogate dynamic cellular networks in plants. Mutational genetics has been the primary approach toward understanding such networks through the elucidation of individual gene function. However, even in plants such as Arabidopsis thaliana where there are wellestablished genetic tools, many networks have been recalcitrant to classical genetic strategies owing to a combination of gene redundancy (yielding no observable change in phenotype) and gene lethality. Plant chemical biology can address these issues by using bioactive chemicals to affect the active sites of individual protein targets or, alternatively, whole classes of protein targets in a manner that is very controllable in terms of dose and treatment time. The application of smallmolecule approaches to plant biology requires a new cadre of plant scientists who are using approaches that straddle the interface of chemistry, informatics and biology. They are poised to make important contributions by addressing the inherent challenges of multi-cellular land plants as biological systems. We will discuss some of the enormous opportunities to advance our knowledge of basic plant processes through the use of small bioactive molecules and some of the major hurdles to jump to maximize the potential of plant chemical biology. We will highlight some investigations of small-molecule structure and the identification of cognate targets, but will emphasize the ability of plant-bioactive chemicals to provide a network-level view of complex dynamic processes because this is one of the great opportunities in plant chemical biology. We also offer some suggestions for choosing resources likely to benefit the plant biology community most. Within the past decade, plant chemical biologists have begun to make important contributions to our understanding of cell wall biosynthesis, the cytoskeleton, hormone biosynthesis and signaling, gravitropism, pathogenesis, purine biosynthesis and endomembrane trafficking (reviewed in refs. 3,4). In many cases, plant phenotype–based chemical screens using cell cultures and seedlings have identified small molecules targeting these processes (reviewed in ref. 4). In other cases, important cognate gene targets have been identified5–10. Several examples below highlight the recent contributions of chemical biology in uncovering new and useful knowledge of broad potential impact.