that an intrinsic program was established to maintain the newly adopted neuronal identity. The overall efficiency of generating human iN cells with four factors (2–4%) was about 10-fold lower than that of mouse with just three factors (compare to (Vierbuchen et al., 2010)). The observed species differences in the iN cell reprogramming may appear unexpected in light of the robustness of generating human iPS cells. However, upon closer inspection, the two different human reprogramming paradigms do share many similarities. The drop in human iPS cell reprogramming efficiency as compared to mouse is of a similar magnitude, especially when taking into account that only a small fraction of plated fibroblasts and only a small subset of these cells’ progenies are forming iPS cells. Similarly, it takes much longer for iPS cell-like colonies appear with human versus mouse fibroblasts. Thus, human cells in general appear to be less plastic and have a higher epigenetic “hurdle” for reprogramming to both iN and iPS cells. Finally, human ES cell-derived neurons require similar amounts of time to develop synaptic competence as human iN cells (Johnson et al., 2007; Wu et al., 2007). Thus, long maturation time may be an inherent property of human cells, which
