Team:William and Mary/Background
Background
Motivation
A fundamental goal of synthetic biology is to be able to effectively interface with natural systems. No matter where you look, from synthetic organs to the production of biomaterials, synthetic systems are constantly closely interacting with the biological systems they serve. This means that synthetic systems must share in the capabilities and principles of their natural counterparts.
However, when it comes to signal processing, synthetic biology lacks a in a crucial way: there is no existing system that can decode dynamic information. In nature, countless systems rely on decoding dynamic inputs (giving different outputs depending on how the signal is encoded). Take, for instance, the p53 tumor suppressor gene. Depending on the type of DNA damage the cell undergoes, p53 will be activated in a transient or sustained manner. These two inputs lead to vastly different outputs: cell death or apoptosis.ADD FIGURE OF TRANSIENT V SUSTAINED
Until synthetic systems can similarly decode dynamic signaling, biologists will be unable to meaningfully interact with p53 and other dynamic biological systems.To address this problem, our team set out to create a circuit that can decode time-based inputs, opening up the field to more applied research in signal processing.
The IFFL
In nature, a great number of systems that decode dynamic information have a similar genetic architecture: the incoherent feedforward loop (IFFL). IFFLs code for a protein and its inhibitor.
Figure 1: Schematic of an Incoherent Feed Forward Loop architecture. An activator (green) activates the production of a reporter/output (purple) as well as an inhibitor of the reporter (blue).
Based on abstract mathematical modeling, IFFLs are predicted to be temporal distinguishers, meaning their output is different depending on how the input was delivered. When subjected to a continuous input, the output is expected to be a pulse. When subjected to a pulsatile input, we expect to see a stepwise output. (cite plos)
The p53 tumor suppressor gene mentioned earlier is built on an IFFL motif, as are many other relevant systems, such as ERK in determining cell fates. Clearly, IFFLs play a unique and critical role in biology, so bringing their decoding abilities into SynBio could offer boundless research opportunities.
Our Project
Our team created an IFFL mathematical model tuned specifically to our system. Based on our modeling, we designed and constructed various IFFL circuits. We then investigated how these circuits responded to varying temporal inputs. Our results can be found here: link.
By researching the dynamics of genetic circuits, we are opening the doors to new possibilities in synthetic biology relating to dynamic signaling, thus broadening the ability of synthetic biologists to interact with natural systems. Through building and characterizing a diverse set of IFFL circuits, we have given every iGEM team access to the unique abilities of this genetic motif. We hope that teams will continue with our foray into the advancing field of dynamics within SynBio.