Novel Method of Creating Stem Cells: Too Good To Be True?

by Dalton Banh

Bathe mature cells in mild acid for half an hour and what do you get? Pluripotent stem cells.

That was the shocking discovery made in late January 2014, when researchers at the RIKEN Center for Developmental Biology in Japan and their collaborators published a pair of papers in the prominent scientific journal Nature. The two studies, titled “Stimulus-triggered fate conversion of somatic cells into pluripotency” and “Bidirectional developmental potential in reprogrammed cells with acquired pluripotency,” gained substantial attention from both the media and the scientific community and was hailed as a major breakthrough in stem cell research.

In the papers, lead author Haruko Okobata and her colleagues described a novel and efficient method for creating pluripotent stem cells by exposing mature cells to a stress stimulus, such as low pH. They termed their method STAP, or “stimulus-triggered acquisition of pluripotency.”In their experiments, the scientists soaked mouse white blood cells in a weak acid bath for 30 minutes and demonstrated that these STAP cells were indeed pluripotent by injecting the cells into a normal mouse embryo and documenting their differentiation into multiple cell types.

“It’s just a wonderful result; it’s almost like alchemy,” said Douglas Melton to The Boston Globe upon hearing of the announcement. Melton is the co-director of the Harvard Stem Cell Institute and was not involved in either of the studies.

The findings of the two studies are groundbreaking because STAP can utilize an individual’s own mature cells and therefore bypasses the problem of host rejection during regenerative therapy. In addition, STAP does not involve the introduction of genetic material into cells, nor the destruction of embryos—both approaches that historically invoke ethical disputes.

However, in a surprising turn of events, the validity of this astounding finding is now been seriously questioned, in part because no other research group has been able to create STAP cells by replicating the apparently simple methods described by the original papers.

In early March, Okobata and two other co-authors at RIKEN published a detailed technical protocol in response to the failure of other researchers in generating STAP cells. However, this protocol noted many restrictions for the types and age of cells and conditions that could be used, which is inconsistent with the original papers’ claims which illustrated the STAP method as straight-forward, efficient, and could be used to convert multiple cell types into STAP cells.

In addition, due to intense scrutiny by the scientific community, there have also been allegations that several images in the paper have been doctored, or duplicated from Okobata’s own Ph.D. dissertation at Waseda University from 2011, which did not involve STAP cells. Furthermore, the dissertation itself has also been brought into question regarding proper citation and whole sections being plagiarized.

RIKEN has launched its own internal investigation to determine if there was scientific misconduct or a breach of research ethics by reviewing the studies and questioning the scientists involved. As of this article’s writing, the RIKEN investigation is still ongoing and no conclusion has been reached.

Several of the researchers involved have provided public statements about their thoughts on the STAP controversy.

Teruhiko Wakayama, a senior co-author currently at the University of Yamanashi, called for the retraction of the papers until external research groups could confirm the data.

“It’s better to retract it once and submit it again after making sure that data are all correct and it won’t be criticized by anyone.” Wakayama reportedly received STAP cells from Okobata to use in the mice experiments but was not involved in creating the STAP cells.

Charles Vacanti, a senior co-author at Harvard Medical School and one of Obokata’s dissertation advisors, however, has opposed retraction of the paper. Obokata reportedly performed her first STAP experiments as a visiting graduate student in Vacanti’s laboratory.

In a recent interview with The Wall Street Journal, Vacanti said: “Some mistakes were made, but they don’t affect the conclusions…based on the information I have, I see no reason to why these papers should be retracted.”

Okobata, however, has kept a low profile and has not released any public statement to date.

Whether or not STAP is a genuine cellular reprogramming strategy has yet to be revealed and will currently remain a mystery. But if any of these allegations turn out to be true, there will be certainly be serious repercussions for the authors involved and the validity of the studies will be discredited until they can be replicated by another research group.

Paul Knoepfler, a stem cell researcher at UC Davis, runs an active blog (see: http://www.ipscell.com/) where guest bloggers can post their thoughts as the truth unfolds. This blog has been an active source of opinions from both researchers in the field and lay-people on the STAP debacle.

Robert J. Geller, a seismologist in Japan, articulates the importance of this controversy on Knoepfler’s blog: “I’m an outsider to the stem cell field, but this mess impacts public trust and support for every field of science in Japan. The longer it’s allowed to drag on the worse the ultimate impact will be. So it’s in the interest of every scientist in Japan that Riken, Nature, Waseda, and other institutions fully and transparently identify the problems and take appropriate actions.”

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