Biological complexity: cell competition (Introduction)

by David Turell , Friday, January 24, 2020, 00:53 (1554 days ago) @ David Turell

Normal cells act to remove unfit and aberrant cells:

https://www.scientificamerican.com/article/survival-of-the-fittest-cells/?utm_source=ne...

"an explosion of similar discoveries has revealed squabbles, fights and all-out wars playing out on the cellular level. Known as cell competition, it works a bit like natural selection between species, in that fitter cells win out over their less-fit neighbours. The phenomenon can act as quality control during an organism’s development, as a defence against precancerous cells and as a key part of maintaining organs such as the skin, intestine and heart. Cells use a variety of ways to eliminate their rivals, from kicking them out of a tissue to inducing cell suicide or even engulfing them and cannibalizing their components. The observations reveal that the development and maintenance of tissues are much more chaotic processes than previously thought. “This is a radical departure from development as a preprogrammed set of rules that run like clockwork,” says Thomas Zwaka, a stem-cell biologist at the Icahn School of Medicine at Mount Sinai in New York City.

"But questions abound as to how individual cells recognize and act on weaknesses in their neighbours. Labs have been diligently hunting for—and squabbling over—the potential markers for fitness and how they trigger competitive behaviours.

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"Myc acts as a master controller of cell growth, and Minute encodes a key component needed for synthesizing proteins—so it’s not surprising that reduced expression of those proteins makes cells less fit. But the next finding took people by surprise. A pair of papers by Johnston and Moreno showed that cells with an extra copy of normal dMyc outcompeted wild-type cells. These fitter-than-wild-type cells came to be called “supercompetitors”.

"The discovery of supercompetition emphasized that cell competition is about the relative fitness of a group of cells, says Zwaka. If one cell is falling behind, the entire group of neighbours could decide it has to go. But on the flipside, they can also sense that certain cells are better and should survive.

"Cell competition wasn’t simply about getting rid of defects; it was about survival of the fittest, with the less-fit ‘loser’ cells dying and the ‘winners’ proliferating. Importantly, competition was seen only when there was a mixture of genetically different cells, a phenomenon known as mosaicism. In this way, cell competition acts like a quality-control system, booting out undesirable cells during development.

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"But Torres’s team, led by then-postdoc Cristina Clavería, also made the striking observation that Myc expression varied naturally in mouse ESCs. Cells in the embryo with approximately half the amount of the protein compared with their neighbours were dying by apoptosis. This was one of the first studies that strongly pointed to naturally arising cell competition.

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"One big puzzle is how cells in a group sense fitness. “Maybe cells are recognizing chemical differences, or physical differences, or differences in cell-membrane composition,” says Fujita, who adds that labs have found evidence for all three.

"His filament-poking kidney-cell experiments suggest that cell–cell contact is needed. Others have seen chemical-fitness signals that seem to be short-range, travelling up to eight cell diameters. Exactly which molecules are responsible for this signalling—either secreted chemicals or physical tags—is the subject of intense debate and investigation.

"Both Johnston and Zwaka have turned up signals associated with immune surveillance. Johnston’s group identified molecules that typically call immune cells to swarm in and engulf foreign invaders and that were driving death in losers. Normal cells express low levels of these death signals at all times. But in a competitive mix, winners flooded their loser neighbours with the signal, which pushed them to kill themselves.

"Zwaka proposes that cells might assess each other’s health by sniffing out the general signals or debris that cells shed. It’s akin to smelling the steaks that your neighbour is grilling for dinner and concluding that they must be doing well.

"Or it could be as simple as seeing which flag your neighbour is flying. Moreno heads his own group now at the Champalimaud Centre for the Unknown in Lisbon, Portugal, which discovered a membrane-spanning protein called Flower. In humans, the protein can take four forms, each displaying its own characteristic structure on the outer cell surface. Two signal ‘I’m a winner’ and the other two signal ‘I’m a loser’ to nearby cells, says Moreno."

Comment: Much of this cell competition helps explain embryological formation. And I think the comments about how this works is through molecular sensing is a correct view. In the embryo much of has got to be automatic to follow the blue print in the DNA.