Frustrated at the turn

The Weizmann Institute scientist and his research partners developed a computer model that explains the collective movement of cells

When group members have difficulty reaching a common decision, and each pulls in a different direction, the result can be frustration and inaction. Sometimes out of the frustration a compromise is born that rescues the group from the impasse and leads it on a new path that none of the members aimed for. It sounds like a social parable, but these are new findings on cell migration by an international team of scientists, including Prof. Nir Gov from the Department of Chemical and Biological Physics at the Weizmann Institute of Science. The study was recently published in the scientific journal Science Advances.

Similar to how fish or birds migrate in flocks in coordinated patterns, cells in our bodies also migrate in "flocks" and produce migratory patterns. Cell migration in the body is part of natural development, for example in the fetus, or is intended for "routine maintenance" purposes, such as wound healing, but may also characterize disease states, such as the formation of cancer metastases. Observations in vitro of a certain type of migrating cells - cancer cells of the immune system - revealed that when they advance in a group (cluster of cells) they move in three distinct patterns: "running" forward in a certain direction, rotational movement of the group around an axis or random and uncoordinated movement during which The group is almost not progressing. "The transitions between the different patterns seem to be completely random. 40% of the time the cells 'run' forward, about a quarter of the time they move in circles - and the rest of the time they move randomly," explains Prof. Gov. "Observations of schools of fish revealed three similar patterns: swimming together in one direction, circular movement or random movement. However, in fish, the transition between the states occurred as a result of a collision with an obstacle, for example the wall of the aquarium, while the cells in the observation apparently changed patterns spontaneously."

To understand why the cells move between the different states and under what circumstances, the scientists created a computer model in which each cell is a unit with a specific direction that tries to match the direction of its movement to the average of the cells around it. This model yielded two possible migration patterns - a state of order and "running" forward or disorder and random movement, but not rotational movement. The transitions between the different patterns were affected by the noise levels in the model - above a certain noise level the cells could not be coordinated and moved randomly. "A cell is a noisy creature. Random processes inside the cell cause it to sometimes move a little to the right, sometimes a little to the left, but never in the same direction all the time," says Prof. Gov and adds: "After we ran the model, we asked ourselves why we didn't succeed also predict the rotational movement".

To this end, the scientists created a new model in which the system is not uniform: the cells in the outer shell of the group have a higher mobility capacity than the cells in the core. In this model the noise level may be too high to allow the core cells to be coordinated, but low enough so that the outer cells are in an orderly state and 'want' to run forward. The gap created in this system between the outer and inner cells creates a state of frustration. Says Prof. Gov: "If the outer cells were 'alone in the world' they would 'run forward', but they are 'stuck' with the inner cells in the backlog. If the outer cells fail to push the core cells forward, And the whole group is frustrated, the second best option in terms of the shell cells is to move in rounds - this way they maintain a high mobility and also a certain degree of coordination with the cells next to them. They run in a circle, And the core cells are carried after them."

The decision of the scientists to produce a difference in the model between the cells in the outer shell and the core cells was not arbitrary. It is known that the motility of cells decreases as they are surrounded by neighbors. For example, cells that together produce tissue - are not supposed to move anywhere; However, as soon as there is an empty space around them - for example when a wound is opened - their mobility increases. Therefore, the scientists assumed that the cells in the outer shell are more mobile, since they are not surrounded by neighbors on all sides.

The scientists focused their research on cancer cells, but the working assumption is that the findings are valid for cell migration in general. The research is the result of a collaboration between physicists and biologists and was led by research student Kathryn Copenhagen from Prof. Ajay Gopinathan's group from the University of California, Merced.

"Collective movement models usually assume a uniform behavior of individuals. In this study we saw that as soon as the system is not uniform, new behaviors are formed - even when the rules of the system remain in place. One of the mechanisms that can produce new behavior is 'frustration,'" concludes Prof. Nir Gov , a physicist who studies the collective movement of living things. "Animals that move in groups, can see their group members, or sense them in other ways, process the information in their minds - and choose a desired course of action. But cells, unlike fish or birds, do not 'see', and do not have a 'brain' that can process information So how do they adapt to their neighbors? We took this ability for granted. Future studies may also crack the molecular mechanisms that make it possible for cells wander in 'bands'".