Over the past decade, the long-held view of bacteria as pathogens has been transformed by microbiome data revealing an astounding prevalence of microbes within the human body. These bacteria exist not only in well- known regions such as the intestines, but also in a multitude of tissue types including tumors. Given this prevalence, microbes represent a natural platform for the development of diagnostics and therapies engineered to sense their environment and deliver drugs to tumors. Current & Mentored Research: Our preliminary results have shown that oral delivery of probiotic bacteria can colonize colorectal liver metastases and enzymatically cleave an injected substrate that can be detected in the urine (Danino et al., Science Translational Medicine, in revision). Building upon this result to improve sensitivity and specificity, we will engineer a gene circuit to lyse at a threshold population density within the tumor environment and release a urine diagnostic peptide. Circuit parameters will be predicted by mathematical modeling, characterized by microfluidic measurements, and experimentally tuned by genetic copy number and ribosome binding strengths to optimize for detection of the diagnostic peptide in mouse models. Independent Phase Research: Following initial characterization of the engineered diagnostic circuit, we will assess colonization in more realistic orthotopic and genetically engineered mouse models of colorectal cancer. We will determine earliest stages at which bacteria colonization occurs and simultaneously measure diagnostic peptide concentrations in the urine. We will target our probiotics with tumor-homing peptides, express pro- apoptotic peptides as therapeutics, and monitor progression of tumors as a function of time. Altogether, the programmable probiotic platform will allow for more sophisticated microbial diagnostics and therapeutics for cancer and establish an engineering framework for in vivo applications for synthetic biology.
As advances toward clinical applications of synthetic biology continue, one major challenge is bridging the scales from computational modeling and in vitro characterization to clinically relevant paradigms of diagnosis and treatment. Here, we will design and engineer a probiotic that senses tumor environments and lyses itself, releasing a urine-detectable peptide as well as therapeutics in the tumor.
| Chien, Tiffany; Doshi, Anjali; Danino, Tal (2017) Advances in bacterial cancer therapies using synthetic biology. Curr Opin Syst Biol 5:1-8 |
| Din, M Omar; Danino, Tal; Prindle, Arthur et al. (2016) Synchronized cycles of bacterial lysis for in vivo delivery. Nature 536:81-85 |
