EFRI-MIKS: Control of Signaling and Function by Design with Spatially Pre-Structured Microbial Communities

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1137089IsmagilovThis project aims to develop a rigorous engineering framework to enhance understanding of interspeciesand interkingdom signaling in order to enable building of "microbiome in a pill" particles preciselyengineered, spatially structured microbial communities encapsulated in a biocompatible material toultimately prevent and treat human diseases associated with dysbiosis (microbial imbalance). Thisengineering framework will enable prediction and control of interspecies signaling and interactions both invitro and in vivo by solving four challenges: Goal 1 (MIKS1a): Use computational methods to predict, fora given desired function, which specific microbes are needed and which spatial structures are required toachieve that function. Goal 2 (MIKS1b and MIKS2): Develop in vitro microfluidic technologies andassociated design principles to understand signaling by rapidly characterizing and measuring the impactof spatial structure on the complex molecular interactions that underlie signaling, and host cells? responseto signaling. Goal 3 (MIKS2 and MIKS3): Develop and test design principles for the scale up of spatiallypre-structured microbial communities, discovered and characterized in Goals 1 and 2, to enableproduction of engineered functional communities in gram quantities needed for in vivo testing. Goal 4(MIKS2 and MIKS3): By using communities produced in Goal 3, and by gavaging them into germ-freeand gnotobiotic mice, measure in vivo the function of the community and the host's response, and iteratewith Goals 1-3 to develop a set of design rules that enable rational engineering of spatially pre-structured"microbiome in a pill" particles that predictably function in vivo in a mammalian gut.Intellectual Merit: The importance of multi-species and inter-kingdom systems and their signaling iswidely appreciated but general engineering approaches for control of such systems are urgently needed.This project proposes that signaling and interactions can be precisely engineered via a biomimeticapproach control of spatial structure. This is a potentially transformative shift in understanding howsignaling, metabolic exchange, and function of communities are controlled. The mammalian microbiomeis an excellent test system because it contains a diverse number of species interacting with one anotherand the host. This work will lay the foundation for a new engineering paradigm, a "microbiome in a pill",and establish design principles for controlling signaling and metabolic exchange within the community,between the community and competitors, and between the community and the host. Engineeringcommunities with spatial structure may close important gaps in understanding the mechanisms ofdysbiosis and manipulating communities affected by dysbiosis, ultimately leading to more effectiveprophylactics and treatments for human disease. The assembled team is well-qualified to carry out theproposed work: The PI has expertise in microfluidic technology development, and analysis and modelingof complex networks in biological contexts. Co-PIs Meyer and Henry are experts in automated annotationof metagenomic datasets and in using these annotations to create and analyze genome-scale metabolicmodels. Co-PIs Chervonsky and Mazmanian are experts in the use of germ-free and gnotobiotic animalmodels to understand the impact of microbiota in the mammalian gut on the host immune system.Broader Impact: Ultimately, the simple yet precisely engineered "microbiome in a pill" communitiesdesigned in this work could dramatically improve quality of life and reduce healthcare costs by modulatingdysbiosis in the context of conditions affecting millions of Americans: IBD, infections, diabetes,autoimmune conditions, and obesity. This approach may pioneer new solutions for problems wheregenetically modified microorganisms are not acceptable or feasible. The design rules for buildingfunctional microbial communities developed here should have broad impact outside of human health, withthe potential to address numerous issues facing society today, including environmental contaminants,climate, and food and fuel production, which are all strongly impacted by the function of microbialcommunities. The project will provide education, training, and mentoring for graduate and undergraduatestudents and postdoctoral scholars, enhanced by the PI's excellent track record in mentoring students.This project will also provide researchers with numerous tools to study and use microbial communities forspecific functions. Co-PIs Meyer and Henry have extensive track records in disseminating computationalmethods and tools, and the PI has an excellent track record of disseminating knowledge via high-impactpublications and partnerships with industry. This project will support public outreach through REELScience, hands-on science for K-12 curriculum development through CalTech Classroom Connection,and research training for teachers and high school students through the Summer Research Connection.