(6ag) Genetically Engineered Probiotics to Target and Eliminate Colorectal Cancer

I have always believed that a multidisciplinary approach to tackle complex scientific questions is critical for success, particularly in the cross-disciplinary field of biomedical science. To become a well-rounded scientist, I have made a point throughout my academic career to gain expertise in a broad array of fields. My path began as a chemical engineer modeling polymerization reactions, to a bioengineer investigating bacterial communication, to now a metabolic engineer manipulating pathways and enzymatic domains. As a principal investigator, I plan to unify my research skills towards the application of genetically engineered probiotics to treat various gastrointestinal diseases.

After my MS and time in industry, I decided to pursue a PhD in biomedical science and began investigating dynamic regulation and cell signaling under the guidance of Dr. William Bentley. Specifically, I elucidated interkingdom communication from quorum sensing (QS) molecules, clarified the mechanics of QS processing, developed quorum-quenching bacteria that could manipulate biofilms and other QS phenotypes, and established a metabolic engineering platform coordinated through QS molecules. By learning to design and develop genetic circuits towards bioengineering and biomedical applications, I established a foundation in synthetic biology, a rapidly advancing discipline that already impacts many aspects of society.

During my postdoc in Dr. Jay Keasling’s laboratory, I have sought to match my knowledge of cellular coordination and genetic circuits by learning to design and manipulate the enzymes and pathways that lead to high-value products. I was awarded the NIH National Research Service Award (NRSA) to develop an in-depth expertise in polyketide synthases (PKSs), a modular assembly-like enzyme that is responsible for the production of many pharmaceutical drugs. My work has helped to develop design principles for these enzymatic pathways, and to programmatically produce high-value chemicals in Streptomyces albus.

By marrying my graduate school expertise of dynamic regulation with my newfound knowledge in metabolic pathways, I am developing a generalizable platform to produce disease-fighting molecules, specifically cancer, in the gastrointestinal system. As a principal investigator, I seek to establish Bacillus subtilis, a probiotic and GRAS organism, as a host for the production and release of cytotoxic drugs. Through a just-in-time release mechanism, these genetically engineered probiotics will release a cancer therapeutic at the cancer site and only when sufficiently accumulated. This project not only represents a vertical advance in cancer probiotic therapy, but also provides a basis for establishing B. subtilis as a metabolic engineering chassis for the heterologous production of novel polyketides.

Teaching Interests:

Fundamentally, my motivation to teaching is to train the next generation of people to contribute to society, hopefully in science, but most importantly in the manner they choose. The philosophy behind that desire is that I am devoted to evidence-based science, and I would apply this practice to my teaching.

I believe it is important to provide context for the lesson by relating new ideas to familiar concepts. Therefore, a hallmark of my lectures would be an interactive environment, and sometimes even a ‘flipped’ classroom. As a student, I enjoyed classes where we broke up into small teams in the middle of the lecture to answer questions. It not only helped me understand better by teaching and being taught simultaneously, I found that it helped build camaraderie among fellow students, who at a large university, I would otherwise not know. As a professor, I would also plan to provide a short quiz at the end of every lecture, covering what I discussed in the prior lecture. As a teaching assistant, a professor provided these short quizzes and it enabled the lecturers and the students to identify gaps in knowledge quicker, and any broad-based gaps were identified in the following lecture. The goal is to ensure an active classroom, where questions are not treated as interruptions but as opportunities to more firmly root scientific learning.

Personally, I am fascinated at the power of synthetic and systems biology to manipulate and optimize metabolic pathways. However, a laboratory course in synthetic biology is not in most curricula of institutions, not least because of the complexity and cost. I would hope to do an in silico version of a project to create a molecule of interest. In groups, the students would select plasmid backbones, design vectors to produce gene products, manipulate promoters and ribosome binding sites, and analyze secondary regulation to identify targets to increase metabolic flux. Fundamentally, the objective of this project would be to show the cross-disciplinary nature of bioengineering to create natural products.

My diverse background in chemical and biomedical engineering enables me to explain concepts and provide context in a multidisciplinary manner to retain the interest of diverse audiences. I am comfortable teaching undergraduate courses in courses in bioengineering such as biofluids and biocomputational methods along with traditional chemical engineering topics such as chemical kinetics and thermodynamics. My foundation in these broad topics will allow me to provide a unique perspective in this interdisciplinary field.

Selected Publications (17 total, 10 first-author)

Amin Zargar, JF Barajas, R Lal, JD Keasling. "Polyketide synthases as a platform for chemical product design", AICHE Journal, (2018)

Jesus Barajas, A Zargar, B Pang, V Benites, J Gin, E Baidoo, C Petzhold, N Hillson, JD Keasling, “Biochemical Characterization of b-Amino Acid Incorporation in Fluvirucin B2 Biosynthesis”, ChemBioChem (2018).

Amin Zargar, CB Bailey, R Haushalter, CB Eiben, L Katz, JD Keasling, “Leveraging microbial biosynthetic pathways for the generation of ‘drop-in’ biofuels”, Current Opinion in Biotechnology (2017)

Amin Zargar, DN Quan, N Abutaleb, E Choi, WE Bentley, “Biocompatible capsules to control quorum sensing”, Biotechnology & Bioengineering (2016)

Amin Zargar, DN Quan, WE Bentley, “Reducing stochasticity in cell populations: rewiring quorum sensing to engineer dynamic gene expression with population-level control”, ACS Synthetic Biology (2016)

Amin Zargar, GF Payne, WE Bentley, “A ‘bioproduction breadboard’: programming, assembling and actuating cellular networks”, Current Opinion in Biotechnology (2015, journal cover) 36: p. 154-160

Amin Zargar, DN Quan, M Emamian, CY Tsao, HC Wu, CR Virgile, WE Bentley, “Rational design of ‘controller cells’ to manipulate protein and phenotype expression”, Metabolic Engineering (2015). 30: p. 61-68.

Amin Zargar, DN Quan, KK Carter, M Guo, HO Sintim, GF Payne, WE Bentley, ‘Bacterial secretions of nonpathogenic E. coli elicit inflammatory pathways: a closer investigation of interkingdom signaling”, mBio (2015). 6:2 e00025-15.