S01 Survival of the Fittest Cells

"Survival of the fittest cells"

(Following post reviews an article published in Nature. This article was part of a screening test for candidature to PhD program (2020) at an Australian University. All the photographs in the post are adopted (without any change) from the original article, unless stated otherwise.)

We all have a notion of cellular functioning as being a pre-programmed clockwork activity. We do not think of cells (in multicellular prokaryotic species) as individual players. Latest findings suggest otherwise. And these findings violate the very understanding of how the cellular systems work, and the results are being seen as "radical departure" from the development. One can go through these findings below (and get amazed):

1. When a researcher "switched-on" a cancer-causing gene (Ras) in kidney cells, though he was expecting the cancerous cells to proliferate further and render the entire cell mass cancerous, to his surprise, he observed that the healthy cells 'kicked out' the cancerous cell by constantly 'poking' it through development of some sort of filaments. Biologists call this phenomenon as 'cell competition', which is already at place in maintenance of cells and tissues of skin, heart and intestine. Several researchers reported similar ways adopted by 'fit' cells to defeat 'weak' cells, like kicking out the precancerous cell from the tissue, inducing cell suicide, engulfing and 'cannibalizing' components of the 'weak' cell, etc. Although, deeper understanding of 'cell competition' may lead to development of better ways to fight cancer and combat diseases and ageing using regenerative medicine, the process by which cells recognize 'weaker' cells is yet to be understood. Several scientists are searching out for 'markers of fitness' and how they trigger competitive behaviour.

2. Researchers induced a mutation (Minute), known for slowing down growth, in fruit-fly larva amid their wild-type counterparts. They expected to find some smaller cells amid the fruit fly larvae population. To their utter surprise, they found that there were no smaller cells. Smaller cells had undergone an induced cell-death (apoptosis). This finding's important aspect was that mutated cells could grow on their own (only into smaller flies), but met with an entirely different fate when mixed with their wild-type counterparts. Another group of researchers reported that cells equipped with an extra copy of the growth controller gene outcompeted their wild-type counterparts. These 'supercompetitors' were fitter than the wild-type cells implying that it is all about relative fitness that determines the cell fate in a mixed population. The most important outcome of the these works was that the phenomenon was witnessed only when the mixture comprised genetically different members. This phenomenon is referred to as 'mosaicism'.

3. Another group of researchers created mouse embryonic stem cells with 'supercompetitor' mutation that lowered expression of a quality control protein that normally puts the break on cell division. When they put these cells into a mouse embryo, these cells quickly took over and developed into a normal mouse. Thus, cell competition could be forced into play by artificially introducing losers or winners. Another researcher reported that cells in the embryo with approximately half the amount of the protein compared with their neighbours were dying by apoptosis, pointing strongly to naturally arising cell competition.

4. A researcher introduced a concoction making cells genetically less-fit into an early stage mouse embryo (when it is single layered) and found that the genetically fit cells engulphed and cleared loser cells. When the researcher performed the same activity at later stage (when embryo is mutilayered), it was found that instead of 'killing' less-fit cells, fitter cells 'pushed' un-fit cells to the external layer and were then eliminated through differentiation. Such competition, when introduced in adult species, pointed to the conclusion that this 'cell competition' was relatively slower in adult or more differentiated stages.

Despite numerous evidences of cell competition being in play, there are several unanswered questions surrounding the phenomenon. How do cells in a group sense 'fitness'? Researchers point to plethora of mechanisms acting behind the scene, e.g., chemical differences, physical differences or differences in composition of cell membranes, etc. Findings of the experiments marked as 1 (development of filaments) suggest that contact is necessary. Some researchers have reported presence of short-range chemical signals, which in turn raises another question - which molecules are involved in signaling? Molecules calling immune cells to engulf foreign molecules have been reported to be flooding the surroundings of fit cells. Presence of membrane spanning proteins which 'display' the status of cells as being 'fit' or 'unfit' are also reported. There are several hints that the 'mosaicism' is already into play against cancer. Researchers have found many pre-cancerous mutations in the skin cells, but they rarely turn into tumours. What gives cancerous cells an edge in case of tumours is another question that needs to be answered.

Although the term 'cell competition' has been buzzing around for quite a while, a lot needs to be unearthed. How this 'competition' can be harnessed to fight diseases and ageing can be answered only when one has definitive idea on the mechanism of competition. One interesting thing to note is that the Darwinian principles which describe the macroscopic world, of super-complex individuals, also play a significant role in the microscopic world, of cells - the building blocks of macroscopic world. Competition which has its own significance in the world of organisms, also has its unique role in ensuring the wellbeing of basic units. You may truly say - "As above, so below. As within, so without." Competition in real world, sometimes, turns toxic. Are we poised to see the same in the cellular world?

⨌