Cheating cells are destined to fail

It took former Rice University graduate student Jennie Kuzdzal-Fick a long time to confirm it, but now she knows: Cheaters may win the battle but are destined to lose the war.

During her Ph.D. studies at Rice, the evolutionary biologist confirmed through a painstaking process that single-cell amoeba called Dicytostelium discoidium bred to cheat on their own kind ultimately end up failing to thrive in the ground-level fight for survival.

The overriding theme for Kuzdzal-Fick was the notion that even among amoeba, families thrive when they stick together. The level of relatedness among a colony of D. discoideum, aka Dicty, turns out to be an important factor in the amoeba’s ability to renew itself through successive generations.

A report on the research appears in this week’s online edition of Science. Kuzdzal-Fick, lead author of the study, worked as a research associate at the University of Texas in Austin after she graduated from Rice in 2010; co-authors are Sara Fox, who earned her doctorate at Rice in 2009, and their advisers, former Rice professors Joan Strassmann and David Queller, now at Washington University in St. Louis.

Strassmann said the study will help biologists understand the evolution of metazoans — animals (including humans) — that begin as single cells. “Our work lets us ask how crucial that single-cell bottleneck is,” she said, “and what kind of mutation rates will challenge the organization of the body.”

In this case, Strassmann said, D. discoidium are being looked at as a pseudo organism. “All along, it’s been used to look at cell processes and development, but this study really takes it in a new direction,” she said, by proving that single-cell bottlenecks are powerful stabilizers of cellular cooperation.

Dicty are ideal for evolutionary experimentation because they can be manipulated through many generations very quickly. Commonly known as cellular slime molds, or social amoebas, the single-cell organisms are found in the wild and feed on bacteria. But when the food runs out, the cells – thousands of them – come together in a single slug and begin to move toward heat and light, which will get them to a place optimum for dispersal. At their destination, the aggregate forms a fruiting body. About 20 percent of the cells sacrifice themselves for the colony as they form a stalk to support the rest, which become fertile spores that are distributed by water or other disturbances.

The new work confirms two theories: First, that experimental evolution under conditions of very low relatedness allows cheaters to arise and potentially destroy multicellular development; and second, that mutation rates alone are not high enough to threaten multicellular development.

In one experiment, the team took a single cell of D. discoideum and allowed natural mutation to occur over 31 generations of fruiting-body formation. Each generation started with a million cells, so any new mutation was unlikely to run into another like itself; the mutations’ impact on how the bearer behaved in chimera was what mattered. The evolved lines were then tested for their ability to cheat by mixing them with their highly related, lab-bred “ancestors,” which had been frozen and stored.

The thawed, reactivated amoebas were tagged with fluorescent molecules for tracking purposes and then combined in equal measure with cells from the evolved lines in nutrient-free petri dishes. The starving colonies formed fruiting bodies; subsequent analysis showed that, as predicted, the cheaters took advantage of their ancestors by forcing a greater percentage of them to become dead stalk instead of live spores.

The researchers also found that about a third of the isolated, mutated cells — the majority of a type known as obligate cheaters — were unable to produce fruiting bodies on their own. If the number of noncheaters in a colony with their ancestors rose above 50 percent, spore production dropped drastically. When nonfruiters outnumbered their more cooperative peers, the entire colony paid a high price.

“That was a surprise,” said Kuzdzal-Fick, who spent seven months cultivating her colonies at Rice. “Facultative cheaters (the other two-thirds) will cheat, but on their own they can still form a normal fruiting body and make spores.”

That’s not the case for isolated obligate cheaters. “They reproduce as long as there’s bacteria to eat, but as soon as they starve, they aggregate and die. It’s a dead end,” she said.

Such natural mutations are a threat to multicellular development, but nature’s own checks and balances seem to tilt evolution in favor of cooperation among cells.

That became clear from the earlier “mutation accumulation” experiment led by Fox. The team used a technique called single-cell bottlenecking to create conditions in which genetic drift – mutation – is maximized while selection among the resulting clones is minimized. Starting from one isolated colony of Dicty, Fox created 90 experimental lines of cells and put each through 70 single-cell bottlenecks, in which one cell is removed from a colony to start a new one and carve its own genetic path.

About 90,000 cell divisions produced some cheaters, proof of which came when they mixed the bottlenecked Dicty with their thawed ancestors, but no nonfruiters. “Our mutation accumulation experiment shows that obligate cheaters do not arise often enough to threaten clonal development,” Kuzdzal-Fick and her colleagues wrote.

The team determined nonfruiters that arise by mutation in a closely related community have little opportunity to affect the outcome, even after many generations of dividing and still not conquering. They calculated that even after 60 divisions of an amoeba population – enough to equal the mass of a great blue whale – cheaters would only amount to 0.003 percent of the total.

“It demonstrates the idea that many people have had – that single-cell bottlenecks are really important for cooperation of the type that we see in multicellular animal bodies – like ours,” Queller said. “It’s nearly universal that multicellular bodies form from a single cell. There are multiple possible explanations for that, and this is a demonstration of what we think is the most important one.”

The National Science Foundation and Wray-Todd Graduate Fellowships supported the research.

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