The data for all three Cooperative mechanisms show a spread of the trajectories corresponding to the order in the mechanism. This makes intuitive sense, because the cooperative models have a strongly preferred ordering of events. The results also reveal information about limiting kinetic aspects. The plot of the Cooperative 1 Slow Step model shows what the limiting step is. The large difference between the red and 
green line shows that the probability of observing reprogramming dramatically increases once H3K27 methylation is lost, the slow step. This is in contrast to the negligible change observed after we observe loss of DNA methylation. The theme that slow steps can be revealed in reprogramming trajectories is also apparent in the Independent 1 Slow Step model. While there is no order for this model, all successful reprogramming pathways must traverse a slow step that is essential �C to lose H3K27 methylation. This corresponds to a modest acceleration in reprogramming trajectories once they have accomplished the slow step. Thus, a separation of scales may result from a slow step whether or not there is obligate ordering in the pathway. Figure 6C shows a slow step that tends to happen late because it is slow but not because the biochemistry requires that it occur after other epigenetic changes. Figure 6B, C, and E correspond to cases where the ordering is essentially obligate due to the modeled biochemistry. The common assumption that late events are required to occur after some early event is not always appropriate and may lead to incorrect conclusions, such as that it is not worth speeding up a late event when, in fact, it is. Cinoxacin Finally, from this data it is also possible to understand some of the biological principles that might give rise to the proposed views of elite or stochastic iPSC generation. For example, in Figure 6D, the state cells are in is an important determinant of reprogramming time. Cells that have already lost H3K27 methylation have an approximately 80% probability of reprogramming within 15 days; for cells that retain H3K27 methylated the probability drops to 15%. Cells that have lost H3K27 methylation could thus be construed as an elite subpopulation that is closer to reprogramming. Similarly, Figure 6E cells that lost DNA methylation have a 50% probability of reprogramming at around 30 days, whereas for the cells at the initial state 50% requires almost double that time. These results show that one way that elite-type results can be explained is by the existence of subpopulations of cells that overcome one of the low probability reactions on the way to reprogramming earlier than others. Regarding these last observations, one key point is that all the cells in these simulations start with the same initial conditions, yet, at any given time after induction, some will have had that reaction happen and some not. Therefore, stochastic processes acted upon a population that was homogeneous at time of induction and created a subgroup that can be said to have elite-like properties. The same results are obtained when cellular populations are already heterogeneous at the time of induction as shown in the next section. The work described up to this point in the paper reports on simulations that all began from the same uninduced starting point. Stochastic variation led to differences in simulated behavior across a population of initially identical cells. Even with such variation, key features of the kinetic pathway leading to full induction produced distinguishing features in the overall reprogramming dynamics of the populations. In this section we Ginsenoside-Ro examine how preexisting variation of uninduced cells can affect reprogramming dynamics.