Programmable Microbe Therapeutics

Antibiotic-resistant infections are becoming an increasing global health concern, and new treatment alternatives to antibiotics are needed that reduce infection virulence preemptively, precisely and automatically [1]. 

To address this challenge, synthetic biology has paved the way for harnessing engineered bacteria as therapeutic "microrobotic" devices for diagnosis and eradication of infectious disease in the human body.  By "rewiring" standardized biological parts via molecular cloning desirable functionalities can be introduced within the cell. Specifically within the gut, engineered E. coli "microrobots" can be used to help fight off infections [2].  

Our research program seeks to expand on the designs of previous synthetic probiotic "microrobots" (i.e. engineered E. coli that detect and treat disease from inside the gut). 

As we move into the development of more complex therapeutic systems, the synthetic microbe should also be able to sense relevant changes in the microenvironment of the gut, such as amplification or attenuation of pathogenic signals or introduction of specific compounds administered by a doctor, and respond in a sophisticated manner. We also must consider issues of safety in introducing organisms that may be subsequently difficult to remove. 

This begs the question:  What does an ideal synthetic probiotic "microrobot" look like? Specifically, what are the design specifications for this synthetic probiotic device? What internal biological parts should be used and how should they be configured within the biomolecular circuit to obtain desired functionalities? Are there any fundamental principles that govern the biomolecular circuit design? 

 We believe that we can address these questions by applying methodologies traditionally used to design mechanical and robotic systems. 

Specifically, models play a primary role in the design of mechanical systems for the understanding of the underlying physics and to make predictions. While developing predictive models and corresponding analysis tools for the proposed synthetic probiotic device is difficult, it is important to make use of models as a central element of design and understanding.  By capturing the many interacting aspects of the system in a formal model we can ensure that we are reasoning properly about its behavior, especially in the presence of uncertainty. This will require substantial effort in building models that capture the relevant dynamics at the proper scales  as well as building an analytical framework for answering questions of biological relevance.  

Ideally the combination of experimental and computational and theoretical studies will bring us closer to a reality in which engineered therapeutic microbes will be able to accurately diagnose and effectively respond to a variety of disease states. 

[1] R. C. Allen, R. Popat, S. P. Diggle, S. P. Brown, Nature Reviews Microbiology. 12, 300–308 (2014).

[2] F. Sedlmayer, D. Aubel, M. Fussenegger, Nature Biomedical Engineering. 2, 399–415 (2018).