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The Cheater Phenotype

10/07/2013
Caitlin Smith

Scientists have spent considerable effort studying how cells work cooperatively, an essential step in the evolution of multicellular organisms. Now, new research suggests that the real question is "What prevents cells from going rogue?" Learn more...


Ancient cells somehow figured out how to cooperate with one another to create the first multicellular organisms. Now, after centuries of evolution, cells work together in diverse tissues with common functions—except for when they don’t. Cells that form tumors serve only themselves at the expense of the organism, and little is known about why these cells go rogue.

Colonies of social microorganisms, such as single-celled Dictyostelium discoideum, often include cells that “cheat” when competing with their neighbors, but until now there has been little evidence that such selfish behavior occurs in multicellular organisms during embryogenesis. Writing in Science (1), Thomas Zwaka, professor of developmental and regenerative medicine at the Icahn School of Medicine at Mount Sinai, and his colleagues present data suggesting that multicellular organisms have evolved genetic mechanisms to discourage a cell from outcompeting its neighbors for limited resources and thus compromising the fitness of the organism.

“More broadly, our findings provide a different lens through which to view interactions that have been described explicitly in terms of competition, winners and losers, cheating and selfish genes,” said Zwaka.

After identifying mammalian iPS cells in culture that carried genetic mutations enabling them to outcompete control cells, the authors wondered whether conditions during embryogenesis were more stringent, possibly limiting the cheaters’ abilities to supersede control cells. To test this hypothesis, Zwaka and colleagues made an embryonic stem cell line for each putative cheater mutation, with the potential cheater gene knocked down and tagged with green fluorescent protein (GFP). They also made mock knockdown control cells tagged with red fluorescent protein (RFP).

The researchers injected an equal number of mutant and control cells into blastocysts, which they implanted in mice and let develop for 11 days. After harvesting the implanted tissue, they used PCR to assess the relative contributions of cheater and control cells to the embryo.

In some cases, the tissue was composed only of the cheater cells. Other embryos showed more moderate cheating, containing 60%-75% cheater cells. And some mutant cells showed little or no cheater contribution to the embryonic tissue. Cells with cheater phenotypes also contributed disproportionately to tumors during a teratoma differentiation assay.

Zwaka believes that Darwin’s theory of evolution framed as competition for survival has shaped the questions that scientists tend to ask. “It has not been as fashionable to ask questions such as ‘Why are selfish genes so often cooperative?’ or ‘How have selfish genes evolved to produce complex, highly interdependent systems?’” said Zwaka. To investigate this, his group used microarray analysis to compare the expression of genes in cheater and control cells.

The researchers found that cheater cells all expressed a similar network of genes, including p53, Top1, other genes involved in apoptosis and differentiation, and genes associated with cell cooperation. The authors suggested that these changes increased the ability of cheater cells to colonize embryonic niches.

“These studies situate mammalian development in the larger matrix of evolutionary cooperation and identify a genetic network that safeguards the embryo against competitive behavior,” said Zwaka. He hopes that understanding how the gene network fosters cell cooperation will shed light on how to treat a lapse in cooperation, such as the development of tumors due to the overgrowth of rogue cells.

Reference

Dejosez et al. 2013. “Safeguards for cell cooperation in mammalian embryogenesis shown by genome-wide cheater screen.” Science doi: 10.1126/science.1241628