Entry Date:
August 17, 2011

Bio-Molecular Circuit Design: Retroactivity, Insulation, and Modularity

Principal Investigator Domitilla Del Vecchio


In living organisms, large networks of interactions between genes and proteins play a central role in determining the functioning of the cell. Recent technological developments have set the stage for fabricating synthetic bio-molecular networks in vivo (Synthetic Biology). This enables us to build circuitry with biological hardware to be implemented in cells to control cell behavior. While small working modules have been successfully built, larger networks composed of smaller modules are yet to be successfully fabricated: modular design, which we often take for granted in systems theory, is still not possible in bio-molecular systems. Research focuses on identifying sources of "non-modularity," which we call retroactivity, on designing systems to counteract them, and on developing a bio-molecular systems theory with retroactivity.

The property of modularity covers a fundamental role in systems engineering both for constructing systems by the composition of simple units and for predicting the behavior of a system by the behavior of its components. Such a desirable property guarantees that the input/output behavior of a component does not change upon interconnection. As it occurs in several engineering systems, such as electrical or hydraulic systems, the modularity property does not generally hold for bio-molecular systems. In this research, we formally quantify and characterize the analogous of (input/output) impedance of an electrical circuit in transcriptional gene networks. We call this analogous quantity retroactivity. We thus develop a control systems theory that takes such a retroactivity quantity directly into account in the systems description and interconnection mechanism. The problem of attenuating the retroactivity effect is formalized as a disturbance rejection problem. Accordingly, biological realizations of insulation systems are designed and then fabricated in E. coli in the Ninfa Lab.

In parallel, we work on designing ideal bio-molecular signal transmission systems that enforce unidirectional signal propagation. Cascades of covalent modification cycles, ubiquitous in natural signal transduction, are employed as fundamental building blocks. This design problem also leads to a deeper understanding of the natural engineering principles hidden in these sophisticated structures.