Controlling cell differentiation and cell fate through chemical means has been tried before. Its history dates back over a century to Jacques Loeb's pioneering experiments on artificial parthenogenesis in sea urchins at the Marine Biological Laboratory in Woods Hole, Massachusetts. Apart from a handful of exceptions, such as erythropoiesis-stimulating agents, certain nuclear receptor modulators and cancer differentiation therapies, reprogramming specific cell populations has remained a backwater in classical drug development. At least it did until Shinya Yamanaka's seminal finding: that a cocktail of four transcription factors—Oct3/4, Sox2, c-Myc and Klf4—was sufficient to generate pluripotent stem cells (Cell 126, 663–676, 2006). Although the transcription factors' oncogenic potential disallows them as candidates for drug or gene therapy, the discovery of their concerted action has opened up a whole new field of research. The focus is on discovering the keys to unlock the dormant biological potential residing in stem cells and progenitor cells and harness it for therapeutic purposes. “Our approach is to decode what messages [those cells] need to be rejuvenated,” says Chris Loose, co-founder and CSO of Frequency.
As scientists make inroads into cell reprogramming, many efforts converge on a small number of pathways essential for early development. These include the WNT, TGFβ, FGF and BMP pathways. “The interesting point is the fundamental biology is similar for many cell types,” says Su-Chun Zhang, professor of behavioral and neural sciences at the University of Wisconsin, Madison. How one manipulates that biology can vary. “You don't go directly for the major pathway, you go for its modulator,” says Hongjun Song, newly appointed professor of neuroscience in the Perelman School of Medicine at the University of Pennsylvania, in Philadelphia.
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