The Evolution & Medicine Review

In his 1987 book, “The Evolution of Individuality,” Leo Buss addressed a fundamental biological question: “How could individual multicellular animals (known as metazoans), like sea anemones, insects, frogs, and humans arise?”  Buss focused on a key challenge confronting any multicellular animal with differentiated cell types performing different functions: the potential conflict between selection on the whole organism and selection on the cells that constitute the organism (or on the whole genome and the individual genes that constitute the genome).   A new study (Dejosez et al., Sciencexpress, 2013) explores this issue by using a genome-wide screen to identify genes that favor cell cooperation and discourage so-called “cheater” cells that through genetic or epigenetic variation outcompete wild-type cells in the developing embryo.

Dejosez et al. transfected a library of small inhibitory hairpin RNA molecules into murine induced pluripotent stem cells (iPSCs) and then subjected these cells to mutagenesis and several rounds of growth, development in the form of embryoid body differentiation, and reacquisition of pluripotency.  The rationale was that cell clones in which genes critical to constraining cheater cells were expressed at subnormal levels due to the hairpin RNAs would constitute greater proportions of embryonic tissues in the products of embryonic day 3.5 blastocysts eleven days after implantation into pseudopregnant mice.

By this approach, two genes, p53 and Top1, appeared to be most critical to enforcing cellular cooperation and preventing cell variants from dominating the developing embryo.  When the expression of these two genes was reduced by experimental manipulations, cells with the decreased p53 and Top1 expression levels possessed a substantial advantage under differentiation conditions (but not under undifferentiated conditions).  Numerous other genes, knockdown of which was associated with the “cheater” phenotype, were functionally connected to p53, Top1, or both.

While complete loss of p53 is associated with abnormal development (incomplete closure of the neural tube) in some cases  and deletion of Top1 is associated with nonviability, cells expressing these same genes at reduced levels can apparently support normal development as assessed by the present methods.  Consequently, I am led to wonder if somatic mutations in other genes that can reduce the expression of either p53 orTop1, or otherwise antagonize the functions of the corresponding gene products, arise in murine development.  If such mutations, or epigenetic variations that yield comparable effects, are not seen, it is fair to wonder why.

This study suggests that biologists and biomedical scientists have the tools necessary to begin elucidating key mechanisms that permit metazoans to exist.  Dejosez et al. also argue that gaining insights into how cells coordinate their activities may yield new strategies of value in manipulating various types of stem cells and in managing malignancy.  These results also illustrate how intense competition can result in a measure of cooperation and simultaneously generate the potential for conflicting selection forces at different levels of organizational complexity.

Acknowledgments.  I wish to thank Peter Harte for alerting me to this article.


Buss, Leo. The Evolution of Individuality. Princeton University Press, Princeton, New Jersey, 1987.

Dejosez M, Ura H, Brandt VL, Zwaka TP. Safeguards for cell cooperation in mouse embryogenesis shown by genome-wide cheater screen. Science. 2013 Sep 27;341(6153):1511-4. doi: 10.1126/science.1241628. Epub 2013 Sep 12. PubMed PMID: 24030493.