Ron Weiss just gave his talk at SB 3.0 on the application of synthetic circuits to control stem cell differentiation. Ron Weiss has already elegantly shown how synthetic circuits coupled to cell-cell communication can generate pattern forming multicellular systems (Basu et al, 2005). This previous work was performed in yeast and Ron now plans to port it to mamamlian stem cells. Pattern formation is crucial in developmental processes and the hope is that the synthetic approach will not only help to control and use stem cell differentiation and patterning but will also provide insight into the endogenous specification/differentiation mechanisms. One of the application envisioned is to develop a system regulating differentiation of pancreatic beta cells in function of cell density to enable a kind of “synthetic” homeostasis able to compensate autoimmune attacks in type I diabetes.

To achieve this type of system, cell-cell communication and control circuits regulating the necessary differentiation regulators have to be developed and optimized. Ron presented the adaptation of the AHL LuxI LuxR system (apparently with some effort…) to the mammalian system and the generation of a toggle switch with large dynamic range, which is essential to achieve the high expression levels required to trigger cellular differentiation. Finally, Ron showed the plan for a complex 22 component system (BTW what is the most complex synthetic circuit assembled so far?) that would integrate the various features necessary to achieve a homeostatic differentiation system. Ron made no mystery that setting up even simple part of thes types of circuits still require a fair amount of “tweaking” and also pointed out the importance for this project that the behavior of the synthesized circuit stays reliable within a changing cellular context of a differentiating cell. Finally, the large 22 component circuit extensively interacts with the endogenous differentiation regulatory network, adding an additional level of complexity in the design.