{{Use mdy dates|date=August 2022}} {{short description|Proposed method of generating pluripotent stem cells}} '''Stimulus-triggered acquisition of pluripotency''' ('''STAP''') was a proposed method of generating pluripotent stem cells by subjecting ordinary cells to certain types of stress, such as the application of a bacterial toxin, submersion in a weak acid, or physical trauma.<ref name='natnews'>{{cite news | first = David | last = Cyranoski | title = Acid bath offers easy path to stem cells | date = January 29, 2014 | publisher = Nature Publishing Group | url = http://www.nature.com/news/acid-bath-offers-easy-path-to-stem-cells-1.14600 | work = Nature News | accessdate = January 30, 2014}}</ref><ref name='bbc'>{{cite news | first = James |last = Gallagher | title = Stem cell 'major discovery' claimed | date = January 29, 2014 | url =https://www.bbc.co.uk/news/health-25917270 | work = BBC News | accessdate = January 31, 2014}}</ref> The technique gained prominence in January 2014 when research by Haruko Obokata et al. was published in ''Nature''. Over the following months, all scientists who tried to duplicate her results failed, and suspicion arose that Obokata's results were due to error or fraud. An investigation by her employer, RIKEN, was launched. On April 1, 2014, RIKEN concluded that Obokata had falsified data to obtain her results.<ref name=falsified>{{cite news|title=Obokata falsified data in STAP papers: probe|date=April 1, 2014|url=http://www.japantimes.co.jp/news/2014/04/01/national/obokata-falsified-data-in-stap-papers-probe/|work=The Japan Times|first1=Masaaki|last1=Kameda|first2=Tomoko|last2=Otake|accessdate=April 2, 2014}}</ref> On June 4, 2014, Obokata agreed to retract the papers.<ref name=retract>{{cite news|title=Japan researcher agrees to withdraw disputed stem cell paper|author=Elaine Lies|url=https://www.reuters.com/article/us-japan-stemcells-researcher-idUSKBN0EF0SO20140604|newspaper=Reuters|date=June 4, 2014|accessdate=June 4, 2014}}</ref> On August 5, 2014, Yoshiki Sasai—Obokata's supervisor at RIKEN and one of the coauthors on the STAP cell papers—was found dead at a RIKEN facility after an apparent suicide by hanging.<ref name=Suicide>{{cite news|title=STAP paper co-author Sasai commits suicide|url=http://www.japantimes.co.jp/news/2014/08/05/national/embattled-stap-study-co-author-dies-after-apparent-suicide-bid/|accessdate=August 5, 2014|work=The Japan Times}}</ref>

STAP would have been a radically simpler method of stem cell generation than previously researched methods as it requires neither nuclear transfer nor the introduction of transcription factors.<ref name="STAP Nature Paper">{{cite journal|last=Obokata|first=Haruko|title=Stimulus-triggered fate conversion of somatic cells into pluripotency|journal=Nature|date=January 30, 2014|volume=505|issue=7485|pages=641–647|doi=10.1038/nature12968|pmid=24476887|s2cid=4463394 |display-authors=etal}}{{Retracted|doi=10.1038/nature13598|pmid=24990753|http://retractionwatch.com/2014/07/02/stap-stem-cell-papers-officially-retracted-as-nature-argues-peer-review-couldnt-have-detected-fatal-problems/ ''Retraction Watch''|http://retractionwatch.com/2015/10/12/nature-no-plans-to-change-wording-of-stap-retractions/ ''Retraction Watch''|http://retractionwatch.com/2014/03/10/co-author-of-controversial-acid-stap-stem-cell-papers-in-nature-requests-retraction-report/ ''Retraction Watch''|intentional=yes}}</ref>

==Overview== Haruko Obokata claimed that STAP cells were produced by exposing CD45<sup>+</sup> murine spleen cells to certain stresses including an acidic medium with a pH of 5.7 for half an hour.<ref name="STAP Nature Paper" /><ref name=Aaacccid2014>{{cite web | last = NHS Choices| authorlink = National Health Service (England) | title = Breakthrough in stem cell creation using acid bath - What did the research involve?| quote = They put them in a weak acid solution (pH 5.7) for 30 minutes at 37°C, and then put them into petri dishes and grew them at normal pH.| publisher = nhs.co.uk | date = January 30, 2014 | url = http://www.nhs.uk/news/2014/01January/Pages/Breakthrough-in-stem-cell-creation-using-acid-bath.aspx| accessdate = February 6, 2014 }}</ref> Following this treatment, the cells were verified to be pluripotent by observing increasing levels of Oct-4 (a transcription factor expressed in embryonic stem cells) over the following week using an Oct4-GFP transgene.<ref name="STAP Nature Paper" /><ref name='newsci'>{{cite news | first = Helen | last = Thomson | title = Stem cell power unleashed after 30 minute dip in acid | date = January 29, 2014 | url =https://www.newscientist.com/article/mg22129542.500-stem-cell-power-unleashed-after-30-minute-dip-in-acid.html | work = New Scientist | accessdate = January 31, 2014}}</ref> On average only 25% of cells survived the acid treatment, but over 50% of those that survived converted to Oct4-GFP<sup>+</sup>CD45<sup>−</sup> pluripotent cells.<ref name='STAP Nature Paper' /> The researchers also claimed that treatment with bacterial toxins or physical stress were conducive to the acquisition of pluripotent markers.<ref name=natnews /> STAP cells injected into mouse embryos grew into a variety of tissues and organs found throughout the body. According to the researchers, the chimaeric mice "[appeared] to be healthy, fertile, and normal" after one-to-two years of observation.<ref name='guard' /> Additionally, these mice produced healthy offspring, thereby demonstrating germline transmission which is "a strict criterion for pluripotency as well as genetic and epigenetic normality."<ref name="STAP Nature Paper" />

STAP cells were supposedly able to differentiate into placental cells, meaning they would be more potent than embryonic stem cells or induced pluripotent stem cells (iPS).<ref name='natnews' /> It was not clear why ordinary cells do not convert into stem cells when subjected to similar stimuli under ordinary conditions, such as acidity in the body; Obokata et al. suggested that ''in vivo'' inhibitory mechanisms may block conversion to pluripotency.<ref name="STAP Nature Paper" /> In February 2014, Charles Vacanti and Koji Kojima (Harvard researchers originally involved in the discovery and publication of STAP) claimed to have preliminary results of STAP cells generated from human fibroblasts, but concomitantly cautioned that these preliminary results require further analysis and validation.<ref name="STAP Human Tissue NS Article">{{cite web|last=Thomson|first=Helen|title=Extraordinary stem cell method tested in human tissue|url=https://www.newscientist.com/article/dn25004-extraordinary-stem-cell-method-tested-in-human-tissue.html#.UxnFXvmwLMp|work=New Scientist|accessdate=March 7, 2014}}</ref>

==History== In the early 2000s, Charles Vacanti and Martin Vacanti conducted studies that led them to the idea that stem cells—spore-like cells—could be spontaneously recovered from ordinary tissues that are stressed via mechanical injury or increased acidity.<ref name=Vacanti20140209>{{cite web | last = Connor | first = Steve | title = Exclusive: The miracle cure - scientists turn human skin into stem cells | quote = | publisher = independent.co.uk | date = February 9, 2014 | url = https://www.independent.co.uk/news/science/exclusive-the-miracle-cure--scientists-turn-human-skin-into-stem-cells-9117102.html| accessdate = February 9, 2014 }}</ref>

The technique for producing STAP cells was subsequently studied by Obokata at the Brigham and Women's Hospital (BWH), while she was studying as a post doc under Charles Vacanti, and then at the RIKEN Center for Developmental Biology in Japan.<ref>{{cite web | first = Kerry | last = Grens |title=New Method for Reprogramming Cells |date=January 29, 2014 |publisher=The Scientist |url=http://www.the-scientist.com/?articles.view/articleNo/39025/title/New-Method-for-Reprogramming-Cells/}}</ref><ref>{{cite news |title=STAP cell pioneer nearly gave up on her research |date=January 30, 2014 |publisher=The Asahi Shimbun |url=http://ajw.asahi.com/article/behind_news/AJ201401300073 |archiveurl=https://archive.today/20140130205546/http://ajw.asahi.com/article/behind_news/AJ201401300073 |archivedate=January 30, 2014 |url-status=dead }}</ref> In 2008, while working at Harvard Medical School, she verified at the request of Charles Vacanti that some of the cultured cells she was working with shrank to the size of stem cells after being mechanically injured in a capillary tube.<ref name='natnews' /><ref name='guard' /> She went on as directed, to test the effects of various stimuli on cells. After modifying the technique, Obokata was able to show that white blood cells from newborn mice could be transformed into cells that behaved much like stem cells. She repeated the experiment with other cell types including brain, skin, and muscle cells with the same result.<ref name='guard' />

Initially Obokata's findings were met with skepticism, even among her coworkers. "Everyone said it was an artefact&nbsp;– there were some really hard days", she recalled.<ref name='natnews' /> The manuscript describing the work was rejected multiple times before its eventual publication as an article (together with a shorter jointly-written "letter") within the journal ''Nature''.<ref name='guard'>{{cite news | first = Ian | last = Sample | title = Simple way to make stem cells in half an hour hailed as major discovery | date = January 29, 2014 | url = https://www.theguardian.com/science/2014/jan/29/make-stem-cells-major-discovery-acid-technique | work = The Guardian | accessdate = January 31, 2014}}</ref> A series of experiments, first turning a mouse embryo green by fluorescently tagging STAP cells, then videotaping the transformation of T-cells into pluripotent cells, finally convinced skeptics that the results were real.<ref name='natnews' />

===Investigation into disputed claims=== In the months after the two ''Nature'' papers <ref name='guard'/> were released, all scientists who tried to duplicate Obokata's results failed and suspicion arose that her results were due to error or fraud. An investigation into alleged irregularities was launched by RIKEN on February 15, 2014. The allegations questioned the use of seemingly duplicated images in the papers, and reported failure to reproduce her results in other prominent stem-cell laboratories. ''Nature'' also announced that they were investigating. Several stem-cell scientists defended Obokata or reserved their opinion while the investigation was ongoing.<ref>{{cite journal | last1 = Cyranoski | first1 = David | title = Acid-bath stem-cell study under investigation | date = February 17, 2014 | doi = 10.1038/nature.2014.14738 | url = http://www.nature.com/news/acid-bath-stem-cell-study-under-investigation-1.14738 | journal = Nature | s2cid = 87071842 | accessdate = February 20, 2014 }}</ref> To address the problem of reproducibility in other laboratories, Obokata published some technical 'tips' on the protocols on March 5 while promising that the detailed procedure would be published in due course.<ref>Haruko Obokata, Yoshiki Sasai and Hitoshi Niwa (March 2014). [http://www.nature.com/protocolexchange/protocols/3013 Essential technical tips for STAP cell conversion culture from somatic cells]. Nature Protocols Discussion Forum</ref>

On March 11, Teruhiko Wakayama, one of Obokata's coauthors, urged all the researchers involved to withdraw the articles, citing many "questionable points".<ref>{{cite news|title=Prof. wants STAP findings withdrawn|url=http://www.the-japan-news.com/news/article/0001109178|newspaper=The Yomiuri Shimbun|date=March 11, 2014|accessdate=March 17, 2014|url-status=dead|archiveurl=https://web.archive.org/web/20140317012922/http://the-japan-news.com/news/article/0001109178|archivedate=March 17, 2014}}</ref> Charles Vacanti said he opposed their retraction and posted a "revised protocol" for creating STAP cells on his own website, which was taken down after he resigned his BWH post.<ref>Charles A Vacanti (2014)[https://web.archive.org/web/20151009073931/https://research.bwhanesthesia.org/research-groups/cterm/stap-cell-protocol PROTOCOL FOR GENERATING STAP CELLS FROM MATURE SOMATIC CELLS]. Center for Tissue Engineering & Regenerative Medicine.</ref>

On March 14, RIKEN released an interim report of the investigation. Out of the six items being investigated, the committee concluded that there was inappropriate handling of data on two items, but did not judge the mishandling as research misconduct.<ref>{{cite web|url= http://www.riken.jp/en/pr/press/2014/20140314_1/|title=Interim report on the investigation of the Obokata et al. articles|author=Press Release|publisher=RIKEN|date=March 14, 2014|accessdate=March 17, 2014}}</ref> On April 1, RIKEN concluded that Obokata had engaged in "research misconduct", falsifying data on two occasions. The co-authors were cleared of misconduct, but bore "grave responsibility" for not verifying the data themselves. RIKEN also announced that an internal group had been established to verify whether the ‘stimulus-triggered acquisition of pluripotency’ is reproducible.<ref>{{cite web|url=http://www.riken.jp/en/pr/press/2014/20140401_2/|title=Report on STAP Cell Research Paper Investigation|author=Press Release|publisher=RIKEN|date=April 1, 2014|accessdate=June 2, 2014}}</ref> Obokata maintained her innocence and said she would appeal the decision.<ref name="falsified" /> On June 4, 2014, Obokata agreed to retract both the article and the "letter".<ref name="retract"/> The article was officially retracted on July 2, 2014. An article analyzing the controversy concluded that while issues of image manipulation, duplication and plagiarism were potentially detectable, the reviewers could not have concluded that the article was the product of academic misconduct prior to acceptance.<ref>{{cite journal|last1=Cyranoski|first1=David|title=Research integrity: Cell-induced stress|journal=Nature|year=2014|volume=511|issue=7508|pages=140–3|doi=10.1038/511140a|pmid=25008506|doi-access=free|bibcode=2014Natur.511..140C }}</ref>

In the wake of the controversy, some commentators argued the scandal reflected broader problems with research oversight at RIKEN and in Japanese science generally.<ref>Otake, Tomoko, "[http://www.japantimes.co.jp/news/2014/04/20/national/stapgate-shows-japan-must-get-back-to-basics-in-science/#.U1WkzMKRVZI ‘STAPgate’ shows Japan must get back to basics in science]", ''Japan Times'', April 21, 2014</ref><ref>Schreiber, Mark, "[http://www.japantimes.co.jp/news/2014/07/05/national/media-national/ongoing-obokata-story-seeks-scandal/#.U7qcsY2KB9A Ongoing Obokata story seeks out scandal]", ''Japan Times'', July 5, 2014, p. 19</ref>

RIKEN commissioned a team of scientists to attempt to verify Obokata's original results and asked Obokata to participate in the effort. On August 5, 2014, Obokata's supervisor and co-author of the original paper, Yoshiki Sasai, was discovered dead by apparent suicide by hanging in a building at the RIKEN facility in Kobe, Japan.<ref>Kyodo News, "[http://www.japantimes.co.jp/news/2014/08/05/national/embattled-stap-study-co-author-dies-after-apparent-suicide-bid/#.U-IWe40cR9A STAP paper co-author Sasai commits suicide]", ''Japan Times'', August 6, 2014, p. 1</ref> On September 24, 2015, the RIKEN scientists reported that Obokata's STAP cells came from embryonic stem cell contamination,<ref name="KonnoKasukawa2015">{{cite journal|last1=Konno|first1=Daijiro|last2=Kasukawa|first2=Takeya|last3=Hashimoto|first3=Kosuke|last4=Itoh|first4=Takehiko|last5=Suetsugu|first5=Taeko|last6=Miura|first6=Ikuo|last7=Wakana|first7=Shigeharu|last8=Carninci|first8=Piero|last9=Matsuzaki|first9=Fumio|title=STAP cells are derived from ES cells|journal=Nature|volume=525|issue=7570|year=2015|pages=E4–E5|issn=0028-0836|doi=10.1038/nature15366|pmid=26399834|bibcode=2015Natur.525E...4K |s2cid=4471867 }}</ref> while on the same day, research groups who had attempted to reproduce the STAP protocol jointly reported that they had found it irreproducible.<ref name="De Los AngelesFerrari2015">{{cite journal|last1=De Los Angeles|first1=Alejandro|last2=Ferrari|first2=Francesco|last3=Fujiwara|first3=Yuko|last4=Mathieu|first4=Ronald|last5=Lee|first5=Soohyun|last6=Lee|first6=Semin|last7=Tu|first7=Ho-Chou|last8=Ross|first8=Samantha|last9=Chou|first9=Stephanie|last10=Nguyen|first10=Minh|last11=Wu|first11=Zhaoting|last12=Theunissen|first12=Thorold W.|last13=Powell|first13=Benjamin E.|last14=Imsoonthornruksa|first14=Sumeth|last15=Chen|first15=Jiekai|last16=Borkent|first16=Marti|last17=Krupalnik|first17=Vladislav|last18=Lujan|first18=Ernesto|last19=Wernig|first19=Marius|last20=Hanna|first20=Jacob H.|last21=Hochedlinger|first21=Konrad|last22=Pei|first22=Duanqing|last23=Jaenisch|first23=Rudolf|last24=Deng|first24=Hongkui|last25=Orkin|first25=Stuart H.|last26=Park|first26=Peter J.|last27=Daley|first27=George Q.|title=Failure to replicate the STAP cell phenomenon|journal=Nature|volume=525|issue=7570|year=2015|pages=E6–E9|issn=0028-0836|doi=10.1038/nature15513|pmid=26399835|bibcode=2015Natur.525E...6D |s2cid=4458211 }}</ref><ref>{{cite journal|title=STAP revisited|journal=Nature|volume=525|issue=7570|year=2015|pages=426|issn=0028-0836|doi=10.1038/525426a|pmid=26399791|doi-access=free|bibcode=2015Natur.525..426. }}</ref>

==Implications== If the findings had proven to be valid, stimulus-triggered pluripotency cells could have been generated more easily and efficiently than by existing iPS techniques.<ref name='natnews' /> Adapted to human tissue, the technique could have led to cheap and simple procedures to create patient-specific stem cells. Stem-cell researcher Dusko Ilic of King's College London called STAP cells "a major scientific discovery that will be opening a new era in stem-cell biology".<ref name='guard' /> Shinya Yamanaka, a pioneer of iPS research, called the findings "important to understand nuclear reprogramming&nbsp;... [and] a new approach to generate iPS-like cells".<ref name='natnews' /> The idea that STAP cells can form placental tissue meant they could have made cloning considerably easier by bypassing the need for a donor egg and ''in vitro'' cultivation.<ref name='natnews' />

One previous way of creating stem cells has been via genetic manipulation of adult cells into iPS cells. Progress on iPS-based therapies has been slow due to regulatory hurdles surrounding genetic manipulation.<ref name='guard' /> Additionally, iPS techniques have an observed efficiency of around 1%, significantly lower than the claimed efficiency of STAP.<ref name='natnews' />

==See also== *Induced stem cells *Muse cell *Stem cell controversy *Masayuki Yamato

==References== {{reflist|2}}

==Further reading== *{{cite journal|last1=Baumann|first1=Kim|title=Stem cells: Reprogramming with low pH|journal=Nature Reviews Molecular Cell Biology|volume=15|issue=3|year=2014|pages=149|issn=1471-0072|doi=10.1038/nrm3754|pmid=24518367|doi-access=free}} *{{cite journal|last1=Obokata|first1=Haruko|last2=Sasai|first2=Yoshiki|last3=Niwa|first3=Hitoshi|last4=Kadota|first4=Mitsutaka|last5=Andrabi|first5=Munazah|last6=Takata|first6=Nozomu|last7=Tokoro|first7=Mikiko|last8=Terashita|first8=Yukari|last9=Yonemura|first9=Shigenobu|last10=Vacanti|first10=Charles A.|last11=Wakayama|first11=Teruhiko|title=Bidirectional developmental potential in reprogrammed cells with acquired pluripotency|journal=Nature|date=January 29, 2014|volume=505|issue=7485|pages=676–687|doi=10.1038/nature12969|pmid=24476891|bibcode=2014Natur.505..676O |s2cid=54564044 }}{{Retracted|doi=10.1038/nature13599|pmid=24990752|http://retractionwatch.com/2014/05/28/obokata-agrees-to-retract-one-of-two-stap-stem-cell-papers-in-nature-reports/ ''Retraction Watch''|http://retractionwatch.com/2014/07/02/stap-stem-cell-papers-officially-retracted-as-nature-argues-peer-review-couldnt-have-detected-fatal-problems/ ''Retraction Watch''|http://retractionwatch.com/2015/10/12/nature-no-plans-to-change-wording-of-stap-retractions/ ''Retraction Watch''|http://retractionwatch.com/2014/03/10/co-author-of-controversial-acid-stap-stem-cell-papers-in-nature-requests-retraction-report/ ''Retraction Watch''|intentional=yes}} *[http://www.riken.jp/en/pr/topics/2014/20140306_1/ Update on the STAP cell papers]. March 6, 2014 *{{cite journal|title=The rise and fall of STAP|journal=Nature|url=http://www.nature.com/news/stap-1.15332}} *{{cite magazine|title=The Stress Test|magazine=The New Yorker|url=http://www.newyorker.com/magazine/2016/02/29/the-stem-cell-scandal}}

==External links== *[https://stap-hope-page.com/ STAP HOPE PAGE] {{Webarchive|url=https://web.archive.org/web/20160331060038/https://stap-hope-page.com/ |date=March 31, 2016 }} by Haruko Obokata, March 25, 2016 *[http://www.riken.jp/en/pr/topics/2014/20140130_1/ Stress turns ordinary cells pluripotent] News release at RIKEN with videos.

Category:Stem cells Category:Induced stem cells Category:Medical controversies Category:Discovery and invention controversies Category:Hoaxes in science Category:Riken Category:2014 in biotechnology Category:Hoaxes in Japan