Triggering a pathway designed to sense viral infection can help boost generation of induced pluripotent stem cells (iPSCs), suggesting that the viruses used by many reprogramming methods influence the fate of the cell. The new research, published today (October 25) in Cell, suggests that targeting the pathway without using viruses could avoid the risk that the viruses’ genetic material will integrate into the genome and cause the cell to become cancerous—a common concern for iPSC therapies.

“This is something everyone else missed before,” said Gioacchino Natoli, an experimental oncologist at the European Institute of Oncology in Italy who was not involved in the study. An innate immune response to the viral vector is clearly needed for reprogramming, and “stimulating this leads to reprogrammed cells without exogenous DNA being integrated,” he added.

Six years ago, Shinya Yamanaka identified four key transcription factors, that, when transduced into cells using a viral vector, caused cells to de-differentiate into a stem-cell-like state, capable of generating a multiplicity of human tissues. He shared this year’s Nobel Prize in Medicine for the achievement, which has already made significant contributions to biomedical research. But there was a major hurdle on the path to clinical use: the strategy relies on a retrovirus that can integrate into host genomes, sometimes activating an oncogene that could render the cell cancerous. Injecting such cells as therapies thus raised concerns about the risk of patients developing tumors.

Hoping to devise a non-integrative carrier for Yamanka’s reprogramming factors, John Cooke, who studies vascular regeneration at Stanford University and colleagues created cell-permeant peptides (CPPs)—the transcription factors attached to an 11-amino–acid-long protein tag that allows them to pass through the cell membrane. But using CPPs to reprogram fibroblasts turned out to be a hundred times less efficient than using retroviral vectors. Compared to virally-transduced cells, CPP-programmed cells also expressed critical pluripotency target genes several days later and at much lower levels.