What termites and cells have in common

A synthetic cell with life-like properties reveals fundamental principles of morphogenesis and perception

Nature is full of fascinating patterns. Plants show beautiful spiral growth, regularly arranged leaves and petals, animals impress us with their striped and dotted furs and social insects build complex nest structures. These almost perfectly arranged patterns seem to arise without a blue print, like the emergence of cellular shapes during embryonic development called morphogenesis. A team of interdisciplinary researchers led by Philippe Bastiaens, director at the Max-Planck-Institute of Molecular Physiology in Dortmund, has created a life-like proto-cell energized by chemical potential, which is capable of translating external signals into shape changes in dependence on its own self-organized morphology. With this, the team has revealed how the collective dynamics of nanometer-sized macromolecules self-organize into micrometer patterns that affect the cellular perception of shape-changing extracellular cues in our own cells. This interdependence between shape and information processing that is mediated by the deformable plasma membrane is a fundamental feature of living cells and enables them to respond to an ever changing environment in dependence on their prior experience.

Seemingly headless, thousands of termites crawl over the ground carrying and dropping sand grains. And although the termites do not have a construction plan, a regular pattern of sand pillars emerges as if from nowhere. In this termite-sand system the termites provide the energy to restructure the sand into a living, dynamic building that is in continuous coupling with an ever changing environment.

Bastiaens’s interdisciplinary group of biochemists and applied as well as theoretical physicists has now shown that a very similar situation occurs in our cells that use chemical potential as an energy source to generate dynamically maintained structures consisting of molecules instead of sand grains. The out-of-equilibrium, energized state that enables this collective behavior is a property of living matter to generate and stabilize a dynamically maintained identity in an ever changing world.

How apparent coincidence becomes form

One characteristic of self-organizing processes is random fluctuations that can be amplified by local interactions between agents. When termites make their random walks for example, they pick up and drop sand grains, which leads to fluctuations in the density of sand. However, during the reshuffling of the sand, the termites leave a pheromone scent on the sand grains that they have carried around that increases the drop chances of another loaded termite randomly passing by. This leads to a self-amplification of sand piles that depletes the free sand grains. The process of amplification and depletion leads to a regular pattern of sand pillars that forms the fundament of their nest.

This phenomenon, called stigmergy, which means ‘leaving a sign on work in progress’ was first described by the French zoologist Pierre-Paul Grassé in 1959 and explains how the indirect communication of social insects via sand leads to a collective behavior that generates dynamical structures such as sand pillars, that are organized in a regular way. The termite queen communicates with this self-organizing termite-sand system by emitting a pheromone gradient. This functions as a template to have a dynamic building being built around her that adapts to her growing size.

Molecular self-organization gets cells into shape

In order to study if the principles of the stigmergic collective behavior of the termite-sand system also apply for the self-organization of biomolecules in cellular morphogenesis, Bastiaens’s group build a synthetic cell with life-like properties by encapsulating lifeless biological building blocks within a deformable lipid membrane and put life into them by energizing the system with ATP/GTP chemical potential. This now out-of-equilibrium encapsulated system consisted of a dynamic microtubule cytoskeleton as well as a light responsive molecular signaling module that operates akin to natural morphogen signaling.

In cellular morphogenesis the emergence of new structures occurs by the deformation of the plasma membrane by dynamic rearrangements of the cytoskeleton. Extracellular morphogens guide this process by binding to receptors on the cell membrane. Information is transduced inside the cell by rebalancing intracellular phosphorylation reaction cycles. This generates intracellular chemical signaling gradients that locally promote growth of the cytoskeleton. The scientist have recreated this process by engineering a light responsive signaling system that translocates a bioengineered kinase to the membrane, which rebalances phosphorylation reaction cycles of the tubulin sequestration molecule Stathmin. They could thereby show that what actually promotes cytoskeletal growth is that these phosphorylation cycles operate like a molecular machine that continuously pumps microtubule building blocks towards the membrane.

Stigmergic principles in cellular morphogenesis

The ideas of the scientists turned out to be true as their life-like proto-cells revealed that both the cytoskeleton as well as the signaling system self-organize into different patterns by interaction with the membrane according to the same stigmergic principles as the termite-sand system. In case of the cytoskeleton, a small protrusion of the membrane formed by the local growth of a microtubule captures more microtubules, thereby amplifying the growth of the protrusion that depletes the free microtubules. In case of the signaling system, the recruitment of the kinase to the membrane results in self-amplified clusters that deplete the free kinase.

Even more, the researchers could show that indirect communication between the signaling and cytoskeletal system was mediated by the deformable membrane leading to self-organized shapes such as star-like or polar structures. They could also demonstrate that localized extracellular signaling cues operate akin to the pheromone emitting termite queen, providing a chemical template that directs the self-organizing termite-sand system to have a dynamic building being structured around her. In case of the proto-cells, the signaling gradient constrained the self-organizing solutions of the bi-directionally communicating signaling and cytoskeletal systems to reorganize the life-like cells in the direction of extracellular cues. However, this response to extracellular cues was very much dependent on the initial, self-organized shape of the proto cells, which makes their response subjective to their prior experience that shaped them.

Cellular perception emerges from the interdependence of shape and signaling

The balance of the two recursively interacting stigmergic systems turned out to determine the basal morphology of the proto-cell, for example if it had a polar or star-like shape. When basal signaling dominated over microtubule-induced membrane deformation, proto-cells exhibited star-like morphology whereas when microtubule-induced deformations dominated over signaling, the proto cells became polar. Changing the balance between the stigmergic systems by an extracellular signal can reshape a star into a polar shape but not the other way around. This shows that morphing of cells is not solely guided by an unidirectional information flow from extracellular cues, but is also determined by the morphology of the cell itself as shaped by prior events.

“Whether cells in a developing healthy or diseased tissue respond to their environment in dependence on prior experience is a big question in the field of cell and developmental biology. Our work shows, that cells do not behave like simple input-output machines but integrate previous experiences in their response to an ever changing environment. In a developing tissue the environment of cells consists of other cells and our self-organized proto-cells have the potential to establish recursive communication among them via the property of mechano-sensing that emerges from the recursive coupling between the signaling and cytoskeletal system. This could thereby enable us to investigate how recursive communication between self-organized molecular systems within cells leads to self-organized tissue formation at the higher scale”, concludes Philippe Bastiaens.

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