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Hysteresis in a synthetic mammalian gene network Kramer, B.P. and Fussenegger, M. 2005. Hysteresis in a synthetic mammalian gene network. Proc. Natl. Acad. Sci. 102: 9517-9522. Overview In 2005, the lab of Martin Fussenegger (at the Federal Institute of Technology in Zurich, Switzerland) published a paper on the construction a hysteretic switch in mammalian cells. This research can be viewed as an extension of the toggle switch that was constructed in the lab of J.J. Collins 5 years earlier. While the toggle switch construct was able to respond to two separate inputs in different ways, the hysteretic system can respond to a single input in different ways depending on the history of the cell. Using an autoregulatory positive feedback design, this system is a step in the direction of constructing a permanent memory circuit, which will be the topic of the next example paper. This work is also significant because of the use of a mammalian cell chassis, in which it is substantially more complicated to implement a genetic network than it is in E. coli. What is Hysteresis? Figure 1: A graphical depiction of hysteresis. "A system with hysteresis exhibits path-dependence, or 'rate-independent memory'. Consider a deterministic system with no hysteresis and no dynamics. In that case, we can predict the output of the system at some instant in time, given only the input to the system at that instant. If the system has hysteresis, then this is not the case; we can't predict the output without looking at the history of the input. In order to predict the output, we must look at the path that the input followed before it reached its current value. A system with hysteresis has memory" (Wikipedia). In Figure 1 on the right, hysteresis in demonstrated graphically. The arrows indicate the direction of movement from one state to another. For a system that exists in the low output state initially (red line), a relatively high level of input is required to induce a change to a high system output. For a system that exists in the high state initially (blue line), a relatively low level of input is required to induce a change to a low system output. In other words, more extreme amounts of input are required to move out of a state than are required to move into a state (meaning that the system resists a change of state). Specific Biological Design Figure 2 below shows the specific biological design that was used to construct a hysteretic gene network in mammalian cells. Figure 2: Biological design of a hysteretic switch in mammalian cells. Mathematical Modeling Results Conclusions