Organiser's Note: The presenter of this talk withheld their permission for video to be published.

The combined activity of three transcription factors can reprogram adult cells into embryonic stem-like cells with the potential to form most of the cell types in the human body. However, the transgenic methods used to deliver reprogramming factors have raised concerns regarding the future utility of the resulting stem cells in regenerative medicine. These uncertainties could be overcome if each transgenic factor were replaced with a small molecule that either directly activated its expression from the somatic genome or in some way compensated for its activity. To this end, we have used high-content chemical screening to search for small molecules that can replace the transgenic factors in reprogramming. We have identified chemicals that can specifically replace each factor individually without compromising reprogramming efficiency. In addition, we have determined that some of these molecules function by increasing the expression of the transcription factors they replace, whereas others work through an alternative mechanism. One molecule replaces Sox2 by inhibiting Tgf-b signaling in a stable, trapped intermediate cell type that forms during the process. We find that this inhibition promotes the completion of reprogramming by inducing the transcription of Nanog, and that Nanog expression functionally bypasses the requirement for Sox2 in reprogramming. These results demonstrate that small molecules can replace the reprogramming transcription factors through specific perturbation of signaling pathways and that reprogramming can proceed through multiple routes.