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categories: ["genetics", "longevity"]categories: ["genetics", "longevity"]tags: ["reprogramming", "stem cells", "transcription factors", "epigenetics", "pluripotency"]tags: ["reprogramming", "stem cells", "transcription factors", "epigenetics", "pluripotency"]summary: "The four transcription factors Oct4, Sox2, Klf4 and c-Myc, which together convert a differentiated cell into an induced pluripotent stem cell."summary: "The four transcription factors Oct4, Sox2, Klf4 and c-Myc, which together convert a differentiated cell into an induced pluripotent stem cell."updated: "2026-07-27"updated: "2026-10-29"humanEvidence: "Human cells have been reprogrammed to iPSCs since 2007 and clinical-grade lines are made routinely; no partial-reprogramming therapy using these factors has entered human testing with published results."humanEvidence: "Human cells have been reprogrammed to iPSCs since 2007 and clinical-grade lines are made routinely; no partial-reprogramming therapy using these factors has entered human testing with published results."access: "A research reagent: the factors are used daily in laboratories and in clinical-grade iPSC manufacturing, and are not available as a treatment in any country."access: "A research reagent: the factors are used daily in laboratories and in clinical-grade iPSC manufacturing, and are not available as a treatment in any country."reversibility: "irreversible"reversibility: "irreversible"lines 44–50 → 44–5029 unchanged lines not shown
Oct4, encoded by *POU5F1*, is the core pluripotency regulator; it is expressed in the early embryo and in embryonic stem cells, and no reprogramming cocktail has reliably dispensed with it or a close functional substitute. Sox2 binds cooperatively with Oct4 at composite motifs and helps activate the pluripotency network. Klf4 supports self-renewal, suppresses apoptosis in cells being pushed out of their identity, and cooperates with the other two at enhancers. c-Myc is not a pluripotency factor at all: it is a broadly acting driver of proliferation and chromatin opening, and it raises reprogramming efficiency largely by making the genome more permissive.Oct4, encoded by *POU5F1*, is the core pluripotency regulator; it is expressed in the early embryo and in embryonic stem cells, and no reprogramming cocktail has reliably dispensed with it or a close functional substitute. Sox2 binds cooperatively with Oct4 at composite motifs and helps activate the pluripotency network. Klf4 supports self-renewal, suppresses apoptosis in cells being pushed out of their identity, and cooperates with the other two at enhancers. c-Myc is not a pluripotency factor at all: it is a broadly acting driver of proliferation and chromatin opening, and it raises reprogramming efficiency largely by making the genome more permissive. Two of the four, Klf4 and c-Myc, are proto-oncogenes. That fact shapes everything downstream, from tumour incidence in early chimeric mice to the design of every proposed therapeutic use.Two of the four, Klf4 and c-Myc, are proto-oncogenes. That shapes the work downstream: tumours appeared in early chimeric mice, and every proposed therapeutic use is designed around the risk. ## How reprogramming proceeds## How reprogramming proceeds lines 62–69 → 62–7111 unchanged lines not shown
Because c-Myc is the most oncogenic member, its removal was pursued immediately. Reprogramming with Oct4, Sox2 and Klf4 alone works at lower efficiency and produced chimeric mice with fewer tumours.[^nakagawa2008] The three-factor combination, written OSK, is now the default in rejuvenation research, including the optic nerve work central to [[partial-reprogramming]].Because c-Myc is the most oncogenic member, its removal was pursued immediately. Reprogramming with Oct4, Sox2 and Klf4 alone works at lower efficiency and produced chimeric mice with fewer tumours.[^nakagawa2008] The three-factor combination, written OSK, is now the default in rejuvenation research, including the optic nerve work central to [[partial-reprogramming]]. Other substitutions have been mapped extensively. Nanog, Lin28, Glis1, Esrrb and various small molecules can replace or supplement individual factors. Chemical reprogramming dispenses with transgenes entirely: cocktails of small molecules produced mouse pluripotent cells in 2013 and human ones in 2022, at the cost of long, finicky protocols.[^guan2022] A parallel line of work skips pluripotency altogether and uses lineage-specific transcription factors to convert one somatic cell type directly into another, a strategy that avoids the tumour risk by never passing through a pluripotent state. Companies such as [[newlimit]] apply the same logic to aging, screening transcription-factor combinations for youthful gene expression within a fixed cell identity rather than for pluripotency. [[retro-biosciences]] has instead worked on the canonical factors themselves, reporting computationally designed variants of SOX2 and KLF4 intended to raise reprogramming efficiency; that claim was announced through press coverage rather than a peer-reviewed paper and has not been independently replicated. A third approach, [[epigenome-editing]], targets specific loci with catalytically dead Cas9 fused to methylation-writing or -erasing domains, trading the breadth of transcription-factor reprogramming for site-level control.Other substitutions have been mapped extensively. Nanog, Lin28, Glis1, Esrrb and various small molecules can replace or supplement individual factors. Chemical reprogramming dispenses with transgenes entirely: cocktails of small molecules produced mouse pluripotent cells in 2013 and human ones in 2022, at the cost of long, finicky protocols.[^guan2022] A parallel line of work skips pluripotency altogether and uses lineage-specific transcription factors to convert one somatic cell type directly into another, a strategy that avoids the tumour risk by never passing through a pluripotent state. Companies such as [[newlimit]] apply the same logic to aging, screening transcription-factor combinations for youthful gene expression within a fixed cell identity rather than for pluripotency. [[retro-biosciences]] has instead worked on the canonical factors themselves, reporting computationally designed variants of SOX2 and KLF4 intended to raise reprogramming efficiency; that claim was announced through press coverage rather than a peer-reviewed paper and has not been independently replicated. A third approach, [[epigenome-editing]], targets specific loci with catalytically dead Cas9 fused to methylation-writing or -erasing domains, trading the breadth of transcription-factor reprogramming for site-level control. ## Delivery## Delivery The original retroviral vectors integrate into the genome, which makes derived lines unsuitable for clinical use. The field moved through adenovirus, piggyBac transposons, episomal plasmids, Sendai virus, and synthetic modified mRNA, the last of which leaves no genetic footprint at all.[^warren2010] Sendai virus and episomal plasmids dominate routine iPSC derivation as of 2026.The original retroviral vectors integrate into the genome, which makes derived lines unsuitable for clinical use. The field moved through adenovirus, piggyBac transposons, episomal plasmids, Sendai virus, and synthetic modified mRNA, the last of which leaves no genetic footprint at all.[^warren2010] Sendai virus and episomal plasmids dominate routine iPSC derivation as of 2026.lines 83–89 → 85–9113 unchanged lines not shown
As a laboratory reagent the four factors are settled technology, used daily to make patient-derived cells for disease modelling, drug screening, [[organoids]], [[tissue-engineering]] and cell therapy. Well-funded programmes at [[altos-labs]] and elsewhere are betting that the same molecules can be turned into medicines rather than reagents.As a laboratory reagent the four factors are settled technology, used daily to make patient-derived cells for disease modelling, drug screening, [[organoids]], [[tissue-engineering]] and cell therapy. Well-funded programmes at [[altos-labs]] and elsewhere are betting that the same molecules can be turned into medicines rather than reagents. As a therapeutic input they remain unproven. The open question is not whether the factors can reset a cell but whether the reset can be stopped at a chosen point, in a chosen tissue, in a living person, without producing a tumour or a cell that has forgotten its job.As a therapeutic input they remain unproven. That the factors can reset a cell is not in doubt. The open question is whether the reset can be stopped at a chosen point, in a chosen tissue, in a living person, without producing a tumour or a cell that has forgotten its job. ## See also## See also removed, struck through added, underlinedLine numbers count the serialised markdown of each revision, frontmatter included.
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