A simpler twist of fate.

Until the day it dies, a cell that has become a skin cell remains a skin cell — or so scientists used to think. Over the past decade, it has become clear that cellular identity is not written in stone but can be rewritten by activating specific genetic programs. Today, the field of regenerative medicine faces a question: should this rewriting take the conventional route, in which mature cells are first converted back into stem cells, or, where feasible, a more direct approach? ‘Terminally differentiated’ is a term that sums up the old way of thinking — that skin, muscle or other mature cells cannot be coaxed to adopt a drastically different fate. That idea began to falter a decade ago, when cell biologist Shinya Yamanaka of Kyoto University in Japan showed that a handful of genes could transform adult fibroblast (connective tissue) cells into induced pluripotent stem (iPS) cells. Like embryonic stem cells, iPS cells can develop into any cell type, a property called pluri potency. They can also be produced in unlimited quantities, unlike embryonic stem cells, which must be harvested from human embryos and therefore come with considerable political baggage. Just a few years after Yamanaka’s discovery — which earned him a share of the 2012 Nobel Prize in Physiology or Medicine — researchers began uncovering shortcuts for switching cell types that they called ‘direct reprogramming’. Mature cells of one kind could be coaxed to directly become another, with no pluripotent middleman. Researchers have learned how to turn skin cells into neurons or heart cells, and stomach cells into insulin-producing pancreatic β-cells. “It’s amazing to watch the cells change right before your eyes,” says Benedikt Berninger of the Johannes Gutenberg University of Mainz in Germany, who uses direct reprogramming to generate neurons. Research into direct reprogramming is more preliminary than work on iPS cells, but it is stirring excitement in regenerative medicine. Directly reprogrammed cells might be safer than cells that pass through a pluripotent state, because the latter share with tumour cells a capacity for extensive proliferation — making them potentially cancer-causing Trojan horses. Clinical interventions based on iPS cells must be done carefully to ensure that no pluripotent cells are transplanted along with the fully mature cells. “There’s a risk that you could lose control of these cells and that they start proliferating uncontrollably after transplantation,” says Malin Parmar, a neurobiologist at Lund University in Sweden who hopes to use direct reprogramming to reverse the loss of neurons in people with Parkinson’s disease. The green heart muscle cells are ‘natural’. The orange ones were fibroblasts that have been directly reprogrammed to become heart muscle cells. C O U R TE SY O F TH E G LA D ST O N E IN ST IT U TE S