Four genes can wind an adult skin cell back to an embryonic state
In 2006, two researchers in Kyoto took ordinary mouse skin cells, added four genes, and turned them into cells able to become almost any tissue in the body. Shinya Yamanaka shared a Nobel Prize for it in 2012, and named the result iPSCs with a small i, inspired by the iPod.
Pluripotent stem cells can multiply indefinitely and give rise to neurons, heart, liver and every other cell type, which makes them a dream resource for replacing tissue lost to injury or disease. The best-known kind, embryonic stem cells, requires destroying or manipulating an early embryo, which has fuelled long controversy. Induced cells sidestep that, and because they come from a patient's own tissue, transplants made from them could in principle avoid immune rejection.
Yamanaka and Kazutoshi Takahashi began with a hunch: genes that keep embryonic stem cells in their state might push adult cells back into it. They picked 24 candidate genes, delivered them into mouse fibroblasts with retroviruses, and watched for cells switching on a marker gene. Colonies appeared. Then they removed one gene at a time until only four remained, Oct4, Sox2, Klf4 and c-Myc, each necessary and together sufficient. These are now called the Yamanaka factors.
Progress came quickly. In June 2007 three teams, including Yamanaka's and groups at MIT and a Harvard-UCLA collaboration, produced improved versions that could form viable chimeric mice and pass into the germline, the gold standard of pluripotency. That November, Yamanaka's lab and James Thomson's in Wisconsin independently reprogrammed human cells. Researchers then looked for gentler starting points than a skin biopsy: cells from a single plucked hair in 2008, blood in 2010 and cells shed in urine in 2012.
Hurdles remain. The process is slow and wasteful: human cells need three to four weeks, and only about 0.01 to 0.1 percent of treated cells convert. One factor, c-Myc, is a cancer-linked gene, and a quarter of mice given c-Myc-induced cells developed lethal tumours called teratomas. Therapeutic transplants have not yet been judged safe, but the cells are already widely used to model disease and search for personalised drugs.
Source: Induced pluripotent stem cell
