SonoGenetics Bacterial Diagnosis and Therapeutics – SonoGT

One of the goals of Synthetic Biology is to build therapeutic bacteria that can target and treat pathologies, such as cancer, in vivo. Several such innovations are on their way: they empower the design of advanced synthetic biology to transform bacteria as therapeutic sensors and effectors in complex, physiologically relevant, biological contexts. Yet, bacterial therapeutic development is limited by the difficulty to observe the actions of bacteria in vivo and in real time. Indeed, Biological tissues are not light transparent and optical methods cannot be used to image deep inside tissues. In turn, we do not know how therapeutics bacteria behave after being injected in vivo. We cannot measure quantitatively and in real time their growth rate, their density, the expression of reporter genes and the (proper) functioning of logic based synthetic circuits as time goes. It is even harder to act on them from a distance, and recent, trendy strategies such as optogenetics are hardly usable in the context of therapeutic bacteria. Yet, being able to induce gene circuits or to control their functioning externally would greatly facilitate and amplify the potential of bacterial therapeutics. In contrast, ultrasound imaging has demonstrated its superior capacity to image deeply inside living tissues albeit at the expense of a lower spatial resolution (typically 100 µm to 1 mm). Ultrasonic waves are routinely used to explore functionally the interior of animal bodies, from the shape of organs to the circulation of fluids. Interestingly, it was recently demonstrated that bacteria producing small gas vesicles (~100 nm) could be used as contrast agent for acoustic imaging. The SonoGT project is built on this very recent breakthrough.
Here, we ambition to use “acoustic bacteria” as live reporters of the microenvironment of tumors and other complex, hard to image, ecosystems. We aim at designing bacteria that can trigger the production of gas vesicles only when and where desired thanks to specific sensing and logic based synthetic circuits. Ultrasonic imaging will then be used to “see” these cells, turned into smart, active, contrast agents for acoustic imaging. Because cells will be programmed to express gas vesicles based on the presence or absence of specific chemicals in the micro environment, it will become possible to probe the physico-chemical properties of the micro-environment deep inside biological tissues and in a non-invasive way. We will also explore how acoustic waves may be used to act on cells, building on the rare attempts done so far.

The main objectives of the SonoGT project are to (i) design bacteria that can conditionally produce Gas Vesicles in the presence of a given stimulus (ii) build a novel device to perform acoustic imaging and optical fluorescence imaging at the same time to characterize quantitatively at “high” resolution the acoustic and biological response of sonogenetic bacteria; (iii) explore several diagnosis and therapeutics proof of concepts based on sonogenetics enabled bacteria.
Sonogenetics will open a radically new way to observe, localize and activate bacterial synthetic circuits in a physiological context This is a nascent field, with fantastic possibilities for medical applications and beyond.