Cell communication is complex. A quick look at a cell biology textbook will show multiple components within a cell interacting with one another and producing complex outcomes at precise times. In addition, each of the millions of cells in an organism can move and divide, which in turn alters its interaction with its neighbor. In our research, we aimed to simplify these processes and thereby reveal fundamental, basic processes that are most important when one cell communicates with another. To do this, we used the principles of synthetic biology to build from the ground up our own cell-signaling pathway, whereby contact between proteins on the surface of cells directly leads to the expression of a transcriptional response. This system is an engineered form of the Notch signal transduction system, called “synthetic Notch.” The advantage of the system is that the signal protein, the receptor, and the GFP response gene are all that is required to produce a functioning synthetic signaling pathway. There is no crosstalk between different pathways or complex set of feedback loops that make understanding native signal transduction such a headache.

The cover of the January 7 issue of Biophysical Journal shows such a synthetic pathway in action within developing Drosophila wing tissue. The blue marks the signal protein on the surface of a population of sending cells. They induce the expression of the green fluorescent protein (GFP) transcriptional output where they meet the red receptor protein on the surface of a population of receiving cells. Images like this immediately raised the question of why, if our synthetic system depended on contact between a sending and receiving cell, did red receptor cells far away from the sending cells produce a GFP output? We also noticed that the amount of GFP that each responding cell produced varied enormously. Thus, our simple engineered system was producing a pattern of response that defied our expectations. To solve the puzzle, we developed a computational model of the signaling. Despite the complexities of real wing epithelial tissue and the dynamics of cell division, we found that we could replicate the patterns that we observed in the animal by using a computational model in which the key features were just the length of the contact between cells and the simulated growth and division of cells. The minimal model immediately suggested why the patterns that we observed were not those that we intuitively expected and highlighted important fundamental principles that govern this sort of contact-mediated cell communication. Our approach will probably be important in the future because the ability to predict precisely where and when a custom-made signaling pathway can produce a response will be a critical part of future therapeutics that use such tools to combat disease, repair injury, or regenerate tissues. More details are available at langridgelab.com and Malmi-Kakkada’s webpage at biologicalphysics.org.

— Jonathan E. Dawson, Abby Bryant, Breana Walton, Simran Bhikot, Shawn Macon, Amber Ajamu-Johnson, Trevor Jordan, Paul D. Langridge, and Abdul N. Malmi-Kakkada