Biological feedback and cell migration

Human-made vehicles consist of a vast array of mechanical and electronic components, which serve as both actuators and sensors. Control systems for these machines are designed to integrate and process information from these sensors to regulate the actuation of the system using feedback loops.

On the other hand, natural biological systems are not designed, but evolution has led to the development of similar feedback systems that connect cellular sensors to cellular actuators. These basic principles operate across a wide range of biological systems, but one system in which they are particularly evident and well-studied is cell migration.

White blood cells in the body are professional and rapid migrators. To reach sites of injury and infection, they must integrate internal and external information to polarize and orient their "engines" of movement in one direction. They do this by employing positive and negative feedback loops that increase and decrease signaling levels at different locations around the cell.

The positive feedback loop drives the activation of "front" signals at different locations around the cell. This system is connected to molecular sensors on the plasma membrane that allow the cells to detect single molecules shed by bacteria and dying cells. The positive feedback loop makes cells extremely sensitive to these signals, but it can also lead to a runaway process. If the signal always self-amplifies, the system becomes saturated after encountering even a single bacterium-indicating molecule. To balance this positive feedback, cells have connected it to a negative feedback system.

The negative feedback system uniformly decreases "front" signals anywhere they might pop up in the cell. Work from the Weiner lab (Houk, 2012) suggests that this global negative feedback signal is closely tied to a mechanical property in cells, such as tension, rather than another molecular signal. This enables distant sites of positive feedback to compete with each other, resulting in a winner-take-all system.

However, the two-component model tends to "lock" into place and become insensitive to new information (left simulation below). This problem can be resolved by adding a local inhibitor to the model (right simulation below). The addition of a local inhibitor ensures that the system remains responsive to new information and does not become stuck in a single configuration.

Overall, understanding the basic principles of feedback systems in natural biological systems, such as cell migration, can provide insights into the evolved "design" of these systems and help us understand what happens when these designs fail and cause disease.