Developing plant synthetic biology platforms to elucidate the role of natural products

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Project Summary and Abstract Candidate and Environment During my graduate career at UC Berkeley, I became interested in the evolution and engineering of metabolic pathways, primarily relating to photosynthesis. It was through this work that I became familiar with the field of synthetic biology and integrated it into my graduate work through engineering synthetic carbon fixation pathways to improve photosynthetic yield and the synthesis of phylogenetically predicted enzymes that existed hundreds of millions of years ago. Excited about the prospects of synthetic biology in plants, I received a Life Sciences Research Foundation postdoctoral fellowship and joined Dr. Dominique Loqué's lab at the Joint BioEnergy Institute and Lawrence Berkeley National Laboratory, where I have focused on developing plant synthetic biology tools to facilitate metabolic engineering in plants. Although I have spent my postdoctoral career focused on tool development, I am interested in the application of these technologies to engineer novel natural product biosynthetic pathways with unique biological functions. My long- term career goals involve the development of synthetic biology tools and platforms for enabling basic discovery and translational research involving plant natural products and metabolic engineering. My diverse research experiences provide a strong foundation to attain this goal. Although I have spent much of my career focusing on primary carbon metabolism and photosynthesis, I have not yet had any training in secondary metabolism and elucidation of natural product biosynthetic pathways. Thus, my immediate goal is to obtain training from the K99/R00 award under the guidance of experts in the field to successfully bridge my interests in synthetic biology and plant natural products and ultimately transition to an independent faculty position. My mentoring team is composed of experts in disparate yet complementary fields, allowing me to receive training in their respective niches and organically build my own independent research program. I will be co-mentored by Dr. Dominique Loqué (Lawrence Berkeley National Lab/UC Berkeley), an expert in plant synthetic biology, Dr. Elizabeth Sattely (Stanford), a leading expert in plant secondary metabolism, and Dr. Jay Keasling (Lawrence Berkeley National Lab/UC Berkeley), a pioneer in microbial synthetic biology and metabolic engineering. I will receive further training and guidance form Dr. Justin Sonnenburg (Stanford) as a collaborator and expert studying the role of small molecules on the intestinal microbiota. I will have regular one-on-one meetings with my advisory committee to ensure that I stay on track with my career development and research progress to obtain an independent faculty position. The proximity between both Berkeley and Stanford will enable me to take advantage of the excellent academic environment of both institutions, providing opportunities to meet visiting scholars, attend seminars, and take courses from experts in the field. Furthermore, leading experts in the field of synthetic biology and plant biology are members of both universities, providing opportunities to receive guidance and input on research from other distinguished faculty. I will take advantage of seminars and workshops on career and professional development offered by both schools. The combination of mentorship and professional training between Berkeley and Stanford will provide the training needed to establish my own unique interdisciplinary research program merging synthetic biology and plant secondary metabolism. Research Plants produce a wealth of natural products that have wide-ranging effects on human nutrition, disease, and overall wellbeing. However, because of the complexities of many of these specialized metabolites, we have been limited in our ability to study the effects of individual phytochemicals on human health. Recently, the nascent field of synthetic biology has provided the means to dissect biological systems into their individual components, enabling scientists to reverse engineer and reconstruct their biochemical makeup. This approach has largely been limited to simple organisms (e.g., E. coli and yeast); however, plants provide a unique platform to leverage synthetic biology. My research focuses on introducing design and engineering principles to rationally manipulate plant metabolism in order to investigate the biosynthesis and physiological roles of plant natural products. Edible cruciferous plants (e.g., broccoli, bok choy) have been implicated in cancer prevention, stemming from their diversity of indole glucosinolate derivatives. However, because of the vast diversity of bioactive compounds produced in cruciferous plants, it is challenging to tease apart and pinpoint the specific molecules that may be responsible for a trait as complex as cancer prevention. As a result, many studies have resulted in conflicting findings and tenuous links between glucosinolates and their claimed nutritional benefits. Engineering specific target molecules into novel hosts with no basal biological activity may provide insight and help clarify their role in human health at a molecular level. The development of plant synthetic biology platforms to produce and deliver specific concentrations of target plant natural products will enable future studies to more quantitatively study the claimed benefits and effects of glucosinolates on human health.