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The Twisted Path to Pluripotency
Jeffrey M. Perkel, Ph.D.
BioTechniques, Vol. 56, No. 4, April 2014, pp. 167–169
Full Text (PDF)

On Jan. 29, 2014, the scientific community was stunned by the news that, with a simple 30-minute dip in acid, mouse pluripotent stem cells could be efficiently generated from adult precursor cells. (1,2) If reproduced and extended to human cells, the findings, detailed in a pair of papers in the journal Nature, promise to be a game changer for stem cell therapeutics, as they offer inducible pluripotent stem cell-like flexibility with none of the concomitant technical difficulty.

“The result is ‘shocking,’ ‘astounding,’ ‘revolutionary,’ and ‘weird,’ said scientists not accustomed to using such exuberant words to describe research findings,” wrote Carolyn Johnson in the Boston Globe. (3)

But within days, excitement over what the researchers called STAP (stimulus-triggered acquisition of pluripotency) cells moved to dismay amid reports of difficulty in reproducing the method and allegations of scientific misconduct.

Paul Knoepfler, associate professor of cell biology and human anatomy at the University of California, Davis, was one of the first to publicly express skepticism. Comparing the so-called “acid bath” strategy to pickling, he wrote, “It'd be like putting your cucumber in vinegar to make a pickle and instead finding the cucumber had changed into a living, swimming goldfish in the jar.” (4)

“My gut feeling was that it was too good to be true,” Knoepfler tells BioTechniques. And he wasn't alone. Conversations with stem cell colleagues convinced Knoepfler that many others were also skeptical, but wary of going public. And yet researchers were still trying, and failing, to repeat the results, wasting precious time and resources.

Testing the limits

Knoepfler wasn't among those researchers repeating STAP experiments—he had adopted a wait-and-see approach. But motivated by the buzz he was hearing, he did set up a “crowd-sourcing an open question?” (5)

Spurred by claims that the findings were irreproducible, the STAP research team, led by first-author Haruko Obokata of the RIKEN Center for Developmental Biology (CDB) in Japan, did publish a more detailed, amended protocol in March. (6) Still, other questions emerged in the meantime, including allegations of plagiarism, image duplication, and image manipulation. As of this writing, the RIKEN CDB is conducting an internal investigation, as is Nature. (RIKEN released its preliminary findings March 14. Its interim report concluded “that there had been inappropriate handling of data for two of the [six] items under investigation, but the circumstances were not judged to constitute research misconduct.”) (7)

At least one author has called for the papers to be retracted, and that may well happen before this column appears in print. But Charles Vacanti, senior author on one of the papers, is standing by the findings. He wrote in a statement to BioTechniques, “I firmly believe that the questions and concerns raised about our STAP cell paper published in Nature do not affect our findings or conclusions.”

Anyone who has followed the stem cell field is keenly aware the subject is no stranger to scientific controversy. Most famously, South Korean researcher Woo Suk Hwang and colleagues announced in 2004 and 2005 the creation of cloned human embryonic stem cells by somatic cell nuclear transfer, the same technique used to create Dolly the sheep, only to have those claims debunked the following year. While it's unclear how the current story will play out, given the speed with which events are unfolding, BioTechniques decided to investigate the steps used in validating new stem cell findings, to see just what it means to demonstrate pluripotency.

A question of validation

In 2006, Shinya Yamanaka dramatically changed the field of stem cell research when he announced the development of induced pluripotent stem (iPS) cells in mice. (8) Prior to Yamanaka's discovery, the only source of pluripotent human stem cells was the human embryo, a source fraught with moral and legal complications. Yamanaka's approach offered a way to create individualized stem cells without embryos, simply by introducing four transcription factors into adult cells.

Marius Wernig was a postdoctoral researcher with Rudolf Jaenisch at MIT when Yamanaka's paper appeared. He was pursuing the same research problem: looking for factors that could transform adult cells into embryonic-like plurip otent cells. “We and probably a couple labs had, just like Shinya, envisioned that the oocyte must contain reprogramming factors,” explains Wernig. “Actually, we knew ES cells must have them, too.” But Yamanaka beat them to the punch.

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