Team:HZAU-China/Application

Application

Multiple functions integration

Multiple functions integration is the general goal we want to achieve. As the number of system components grows, it becomes increasingly difficult to coordinate component inputs and outputs to produce the overall desired behavior. For this reason, we increase the complexity of the system by reusing the exist parts instead of addition of new parts. Our design allows the cells to run different functions at different time and it will not give extra burden to cells when a function is unnecessary.

Organism development

Many researches understand what orchestrates epigenomic changes by Waddington’s model of epigenetic determination of development (Fig. 1) (Mohammad and Baylin, 2010). From a dynamic view, the organism development is like jumping among different attractors. Once the cell falls into a stable steady state, it will be very hard to jump out. Many motifs in developmental network like mutual inhibition and double-positive feedback loop exhibit irreversibility unless the environment has a big change. If the gene circuit that decides the cell fate were rewirable, we could easily reprogram the cell.

Figure 1. Depiction of potential cell signaling in Waddington's model of epigenetic determination of development.

Living therapeutics

The tumor suppressor p53 can induce cell cycle arrest or apoptosis according to degree of DNA damage. It was reported that p53 and its downstream targets applied an oscillation mode to repair DNA damage and chose a bistability mode to trigger apoptosis once the damage cannot be fixed by oscillation mode (Zhang et al., 2011). These functions were achieved by a very complex systems (Fig. 2).

Figure 2. A complex mechanism described in previous study.

In our design, we can achieve these functions by using only three genes and rewiring their regulatory pathway. We can construct an oscillation into the therapeutic bacterium that colonizes a niche in the human microbiome to maintain homeostasis. And once the the equilibrium is broken, the oscillation will be rewired to be a switch used for next decision.

Environment improvement

Some environment projects in synthetic biology utilize an event trigger to keep expressing some special proteins to tackle the environmental problem. These systems often contain a positive feedback loop module that can memorize the received signal and activate the downstream functional protein. After the problem is handled, we don’t need the positive feedback module anymore, but it is difficult to stop this module. In this case, we can rewire the system rather than kill all these meritorious cells. The positive feedback module can be rewired to be a negative feedback module, which is used to maintain the lower steady state or control the population of the engineered cells. Once the environmental problem recurs, it can be rewired into a positive feedback one again.

References

Mohammad, H. P., & Baylin, S. B. (2010). Linking cell signaling and the epigenetic machinery. Nature biotechnology, 28(10), 1033-1038.

Zhang, X. P., Liu, F., & Wang, W. (2011). Two-phase dynamics of p53 in the DNA damage response. Proceedings of the National Academy of Sciences,108(22), 8990-8995.