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A non-eukaryotic, metakaryotic cell with large, open mouthed, bell shaped nuclei represents an important stem cell lineage in fetal/juvenile organogenesis in humans and rodents. each human bell shaped nucleus contains the diploid human DNA genome as tested by quantitative Feulgen DNA cytometry and fluorescent in situ hybridization with human pan-telomeric, pan-centromeric and chromosome specific probes. From weeks approximately 5-12 of human gestation the bell shaped nuclei are found in organ anlagen enclosed in sarcomeric tubular syncytia. Within syncytia bell shaped nuclear number increases binomially up to 16 or 32 nuclei; clusters of syncytia are regularly dispersed in organ anlagen. Syncytial bell shaped nuclei demonstrate two forms of symmetrical amitoses, facing or "kissing" bells and "stacking" bells resembling separation of two paper cups. Remarkably, DNA increase and nuclear fission occur coordinately. Importantly, syncytial bell shaped nuclei undergo asymmetrical amitoses creating organ specific ensembles of up to eight distinct closed nuclear forms, a characteristic required of a stem cell lineage. Closed nuclei emerging from bell shaped nuclei are eukaryotic as demonstrated by their subsequent increases by extra-syncytial mitoses populating the parenchyma of growing anlagen. From 9-14 weeks syncytia fragment forming single cells with bell shaped nuclei that continue to display both symmetrical and asymmetrical amitoses. These forms persist in the juvenile period and are specifically observed in bases of colonic crypts. Metakaryotic forms are found in organogenesis of humans, rats, mice and the plant Arabidopsis indicating an evolutionary origin prior to the divergence of plants and animals.

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Analysis of historical age-specific colorectal cancer rates, present day age-specific colonic adenoma prevalence and the few reports of direct measurements of genetic change in human tissues as a function of age in adults have led to a new set of hypotheses about carcinogenesis. A key observation, that the calculated rate of growth of preneoplasia is equal to the calculated growth rate of the juvenile colon, suggested that tumor initiation blocks the developmental step by which growing juvenile stem cells are transformed into or replaced by adult maintenance stem cells. In this hypothesis the slowly growing adenomatous polyps would simply be patches of highly organized juvenile tissue modified by the mechanical constraints of surrounding nongrowing adult tissue. As juvenile tissue presumably grows by net increase in stem cells creating crypts, tumor promotion could be achieved by transformation of an initiated stem cell into a fetal stem cell that would express the program of rapid net growth and differentiation into the heterogeneous cell types of fetal colonic organogenesis. (One additional interpretation of data from observations of point mutations in adult lung epithelium is that rates of genetic change in juvenile stem cells are markedly higher than in adult maintenance stem cells.) Unfortunately, the concept of a "stem cell" undergoing staged transitions in organ development and blocked or reverse transitions in carcinogenesis has lacked the physical embodiment of a cell that could be recognized, isolated, and analyzed. In an attempt to overcome this impediment we set reexamined fetal and adult colonic tissue, adenomas, and adenocarcinomas using a novel histological preparation method. Gostjeva then discovered that fetal and neoplastic tissues share a set of cells distinguished by specific nuclear morphotypes that appear to cooperate in creating the elements of the fetal organ, preneoplastic, and neoplastic lesions. In particular, microscopic examination of fetal gut at 5-7 wk gestation reveals tubular syncytia containing opened-mouthed, bell-shaped nuclei that account for some 30% of the nuclei in the protoorgan. These peculiar nuclei undergo both symmetric and asymmetric nuclear fissions, the latter creating all of the other nuclear morphotypes. These nuclear fissions are "amitotic" insofar as no general chromosome condensation is observed. Bell-shaped nuclei are rarely found in adult colonic crypt bases but are found in preneoplasia and neoplasia.

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