H2020 ERC - Starting Grant 2020-2025

A synthetic biology approach for T cell exhaustion

Abstract: Synthetic Biology has revolutionised approaches for several scientific, industrial and medical applications. These include the development of immunotherapies based on bioengineered cells, most notably engineering of patients T cells with tumor-targeting receptors, the CAR-T cells. Cell-based immunotherapies have shown remarkable clinical success; yet, long-term benefits are hampered by dysfunction of T cells occurring following antigen chronic exposure, a process known as T cell exhaustion. Current treatments of T cell exhaustion are limited and exhibit adverse effects. Synthetic T-rEX aims to reprogram exhausted T-cells using synthetic biology circuits, to implement enhanced and more effective immune cell-based therapies. We will develop specific, self-contained genetic circuits with improved capabilities that minimise the impact on normal cell physiology; by pre-programmed integration of exhaustionspecific intracellular signals, these will rewire T cell activity and restore normal function. Circuits will be developed using a stepwise, bottom-up approach to identify exhaustion-specific inputs by RNA and microRNA-sequencing profile performed on ex vivo exhausted human CD8+ T cells. We will then design (a) synthetic promoters and (b) microRNA-regulated 5’UTR that will compute information processing to trigger output activation. Localised therapy will rely on concerted action of genetically encoded immune-checkpoint blockade and fine-tuning of epigenetic modulators that play a major role in T cell exhaustion. Finally, we will engineer T cells with sensor-actuator synthetic devices that revert exhaustion (T-rEX cells). In summary, our proposal provides a paradigm shift in the development of strategies against T cell exhaustion and a solid break-through towards enhanced natural and cell-based immunotherapy. More broadly, the proposed approach will unleash the potential of synthetic biology to the next level of therapeutic intervention.

Total budget: 1.496.250,00€

Total contribution: 1.496.250,00€

H2020 ERC - Advanced Grant 2019-2026

Synthetic photobiology for light controllable active matter

Abstract: From a Physics and Engineering standpoint, swimming bacteria are a formidable example of self-propelled micro-machines. Together with their synthetic counterpart, self-propelled colloids, they represent the “living” atoms of active matter, an exciting branch of contemporary soft matter and statistical mechanics. Differently from synthetic colloids, however, each bacterial cell contains all the molecular machinery that is required to self-replicate, sense the environment, process information and compute responses. Breaking down these biological functions into basic genetic parts has been one of the greatest triumphs of molecular biology. Today, synthetic biologists are assembling these parts into new genetic programs and exploiting bacteria as computing micro-machines. Project SYGMA will employ the synthetic biology toolkit to provide the building blocks for a light controllable active matter having reliable, reconfigurable and interactively tunable dynamical properties. We will first engineer transmembrane photoreceptors to wire RGB external light signals to cellular physical responses like speed, tumbling, growth and death rates. These genetic parts will allow the modular design of customized active particles to build active materials with unprecedented optical control capabilities. Using these new tools we will address, with experiments and theory, fundamental questions like: how fast can we drive particle density using spatiotemporal motility modulations? what is the force on a body suspended in a bath of bacteria with non uniform motility? how do physical forces contribute to morphogenesis in bacterial colonies? Finding quantitative and experimentally validated answers will eventually allow us to engineer structured illumination protocols to mold living microstructures, transport colloidal cargos by shaping active pressure, control swarms of biohybrid microcars and shape bacterial microcolonies.

Total budget: 353.388,75€

Total contribution: 353.388,75€