Cellular decision-making bias: the missing ingredient in cell functional diversity

Cell functional diversity is a significant determinant on how biological processes unfold. Most accounts of diversity involve a search for sequence or expression differences. Perhaps there are more subtle mechanisms at work. Using the metaphor of information processing and decision-making might provide a clearer view of these subtleties. Understanding adaptive and transformative processes (such as cellular reprogramming) as a series of simple decisions allows us to use a technique called cellular signal detection theory (cellular SDT) to detect potential bias in mechanisms that favor one outcome over another. We can apply method of detecting cellular reprogramming bias to cellular reprogramming and other complex molecular processes. To demonstrate scope of this method, we will critically examine differences between cell phenotypes reprogrammed to muscle fiber and neuron phenotypes. In cases where the signature of phenotypic bias is cryptic, signatures of genomic bias (pre-existing and induced) may provide an alternative. The examination of these alternates will be explored using data from a series of fibroblast cell lines before cellular reprogramming (pre-existing) and differences between fractions of cellular RNA for individual genes after drug treatment (induced). In conclusion, the usefulness and limitations of this method and associated analogies will be discussed. Introduction Reprogramming cells from one phenotype to another is a well-established technique (see Vierbuchen and Wernig, 2012). Using a small number of factors, cells can be converted to a wide variety of types, including pluripotent cells (Park et.al, 2008; Takahashi et.al, 2007), neurons (Caiazzo et.al, 2011; Vierbuchen et.al, 2010; Pang et.al, 2011, Pfisterer et.al, 2011), muscle fibers (Davis, Weintraub, and Lassar, 1987), and cardiomyocytes (Qian, 2012). While significant characterization has been done in terms of efficiencies and candidate genes for induced function (Alicea et.al, 2013; Park and Daley, 2008), less explored is the differential capacity for a single cell line to convert to different phenotypes (e.g. neuron or muscle). Are all forms of conversion equal, or are certain types of conversion easier to achieve? To better understand this question, these phenomena must be placed in the framework of more general biological mechanisms. In this paper, it will be argued that there is a clear bias towards some types of conversion over others. It will be further argued that this bias is variable across cell lines, and that this capacity is independent of priming by gene expression or the presence of precursor cells. This leads us to propose four hypotheses: the phenotypic bias (bias manifest in morphological indicators) hypothesis, the pre-existing bias (bias manifest in existing variation) hypothesis, the induced bias (bias manifest as a consequence of transformation) hypothesis, and the extrinsic bias (bias consistent with cell survivability under defined conditions).