How iPS cells changed the world

• Megan Scudellari

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• 15 June 2016
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• Induced pluripotent stem cells were supposed to herald a medical revolution. But ten years after their discovery, they are transforming biological research instead.

Shinya Yamanaka won a Nobel prize for his work on reprogramming adult cells to an embryonic-like state.

“We have colonies.”

Shinya Yamanaka looked up in surprise at the postdoc who had spoken. “We have colonies,” Kazutoshi Takahashi said again. Yamanaka jumped from his desk and followed Takahashi to their tissue-culture room, at Kyoto University in Japan. Under a microscope, they saw tiny clusters of cells — the culmination of five years of work and an achievement that Yamanaka hadn't even been sure was possible.

Two weeks earlier, Takahashi had taken skin cells from adult mice and infected them with a virus designed to introduce 24 carefully chosen genes. Now, the cells had been transformed. They looked and behaved like embryonic stem (ES) cells — 'pluripotent' cells, with the ability to develop into skin, nerve, muscle or practically any other cell type. Yamanaka gazed at the cellular alchemy before him. “At that moment, I thought, 'This must be some kind of mistake',” he recalls. He asked Takahashi to perform the experiment again — and again. Each time, it worked.

Over the next two months, Takahashi narrowed down the genes to just four that were needed to wind back the developmental clock. In June 2006, Yamanaka presented the results to a stunned room of scientists at the annual meeting of the International Society for Stem Cell Research in Toronto, Canada. He called the cells 'ES-like cells', but would later refer to them as induced pluripotent stem cells, or iPS cells. “Many people just didn't believe it,” says Rudolf Jaenisch, a biologist at the Massachusetts Institute of Technology in Cambridge, who was in the room. But Jaenisch knew and trusted Yamanaka's work, and thought it was “ingenious”.

The cells promised to be a boon for regenerative medicine: researchers might take a person's skin, blood or other cells, reprogram them into iPS cells, and then use those to grow liver cells, neurons or whatever was needed to treat a disease. This personalized therapy would get around the risk of immune rejection, and sidestep the ethical concerns of using cells derived from embryos.

Ten years on, the goals have shifted — in part because those therapies have proved challenging to develop. The only clinical trial using iPS cells was halted in 2015 after just one person had received a treatment.

But iPS cells have made their mark in a different way. They have become an important tool for modelling and investigating human diseases, as well as for screening drugs. Improved ways of making the cells, along with gene-editing technologies, have turned iPS cells into a lab workhorse — providing an unlimited supply of once-inaccessible human tissues for research. This has been especially valuable in the fields of human development and neurological diseases, says Guo-li Ming, a neuroscientist at Johns Hopkins University in Baltimore, Maryland, who has been using iPS cells since 2006.

The field is still experiencing growing pains. As more and more labs adopt iPS cells, researchers struggle with consistency. “The greatest challenge is to get everyone on the same page with quality control,” says Jeanne Loring, a stem-cell biologist at the Scripps Research Institute in La Jolla, California. “There are still papers coming out where people have done something remarkable with one cell line, and it turns out nobody else can do it,” she says. “We've got all the technology. We just need to have people use it right.”

From skin to eyes

Six weeks after presenting their results, Yamanaka and Takahashi published¹ the identities of the genes responsible for reprogramming adult cells: Oct3/4, Sox2, Klf4 and c-Myc. Over the next year, three laboratories, including Yamanaka's, confirmed the results and improved the reprogramming method. Within another six months, Yamanaka and James Thomson at the University of Wisconsin–Madison managed to reprogram adult cells from humans. Labs around the world rushed to use the technique: by late 2009, some 300 papers on iPS cells had been published.

Many labs focused on working out what types of adult cell could be reprogrammed, and what the resulting iPS cells could be transformed into. Others sought to further improve the reprogramming recipe, initially by eliminating⁷ the need to use c-Myc, a gene with the potential to turn some cells cancerous, and later by delivering the genes without them integrating into the genome, a looming safety concern for iPS-cell-based therapies.

Another big question was how similar iPS cells really were to ES cells. Differences started to emerge. Scientists discovered that iPS cells retain an 'epigenetic memory' — a pattern of chemical marks on their DNA that reflects their original cell type. But experts argue that such changes should not affect the cells' use in therapies. “There might be some differences from ES cells, but I believe they are really not relevant,” says Jaenisch.

http://www.nature.com/news/how-ips-cells-changed-the-world-1.20079?WT.mc_id=SFB_NNEWS_1508_RHBox