Joshua N. Leonard Engineering cellular systems & biomolecules for immunotherapy, synthetic biology, & biotechnology

Research Interests

The Leonard Lab is committed to enabling an emerging paradigm of design-driven medicine by integrating synthetic biology with systems biology to address pressing challenges in medicine and biotechnology. Our long-term areas of interest include (1) Mammalian Synthetic Biology:  We are pioneering the design of novel cell-based devices that can be programmed to manipulate and detect changes in human physiology. This approach promises to transform our ability to implement customizable therapeutic and diagnostic strategies, to address unmet medical needs, and ultimately to create safe, effective, and long-lasting therapeutic benefits for a wide variety of diseases. (2) Engineering Novel Biomolecular Therapies:  Recent evidence has established that all cells exchange biomolecules via lipid nanovesicles known as exosomes or extracellular vesicles (EVs). EV-mediated delivery of RNA and protein results in functional modulation of the recipient cell, which can alter disease processes in vivo and may be harnessed to deliver biomolecules for therapeutic applications. We develop methods to probe and manipulate the steps of cargo packaging into EVs and to achieve EV-mediated delivery of cargo to target cells. (3) Systems Biology of Immune Function: We seek to understand and therapeutically manipulate interactions that occur between the immune system and cancer. Tumors establish dysfunctional immunological microenvironments which pose a barrier to therapeutic intervention. We use quantitative experimental methods and computational modeling to both understand how these complex multicellular networks operate and to design therapeutic strategies that can correct dysfunctional network states. (4) Bacterial Synthetic Biology and Metabolic Engineering: In efforts to engineer microbial factories, screening and optimizing metabolic pathways remain rate-limiting steps. Metabolite-responsive biosensors may help to address these persistent challenges by enabling the monitoring of metabolite levels in individual cells and the implementation of metabolite-responsive feedback control. Given the limited pool of naturally-evolved biosensors, we are pioneering a bottom-up strategy for converting metabolite-binding proteins into metabolite-responsive transcriptional regulators.

Selected Publications

Engineering Modular Biosensors to Confer Metabolite-Responsive Regulation of Transcription. Younger AKD, Dalvie NC, Rottinghaus AG, and Leonard JN. ACS Synthetic Biology. 2017 February 17;6(2):311-325.

Rewiring human cellular input–output using modular extracellular sensors. Schwarz KA, Daringer NM, Dolberg TB, and Leonard JN. Nature Chemical Biology. 2017 February;13(2):202-209.

Engineering cell-based therapies to interface robustly with host physiology. Schwarz KA and Leonard JN. Advanced Drug Delivery Reviews. 2016 October 1;105(Part A):55-65.

A Platform for Actively Loading Cargo RNA to Elucidate Limiting Steps in EV-mediated Delivery. Hung ME and Leonard JN. Journal of Extracellular Vesicles. 2016 May 13;5:31027.

Contributions of Unique Intracellular Domains to Switchlike Biosensing by Toll-like Receptor 4. Daringer NM, Schwarz KA, and Leonard JN. Journal of Biological Chemistry. 2015 April 3;290(14):8764-8777.

View all publications by Joshua N. Leonard listed in the National Library of Medicine (PubMed). Current and former IBiS students in blue.