Stimulus-triggered Acquisition Of Pluripotency Research Articles

When the research is not reproducible: the importance of author-initiated and institution-driven responses and investigations

ABSTRACTImportant and potentially useful findings in the sciences are under more intense public scrutiny now more than ever. Other researchers in the field dive into replicating and expanding the findings while the media swamps the community and the public with peripheral reporting and analyses. How should authors and the hosting/funding institutions respond when other workers in the field could not reproduce or replicate their published results? To illustrate the importance of author-initiated and institution-driven investigations in response to outcries of research irreproducibility, I draw on comparisons between three recent and well-publicized cases in the life sciences: betatrophin, Stimulus-Triggered Acquisition of Pluripotency (STAP) cells, and Natronobacterium gregoryi Argonaute (NgAgo). Swift, transparent responses and investigations facilitate activation of the self-correcting mechanism of science and are likely also critical in preserving the community’s resources, public trust, and the reputation of the institutions and individuals concerned. Operational guidelines for “author and institutional responses” towards external reports of irreproducibility should therefore be in place for all research intensive institutions.

The Case of Inferred Doability: An Analysis of the Socio-institutional Background of the STAP Cell Scandal

On 28 January 2014, Haruko Obokata and her colleagues held a press conference regarding their new method of producing stem cells. The cells, named STAP (stimulus-triggered acquisition of pluripotency) cells, were of considerable interest not only for stem cell scientists but also for the wider society in Japan because both its government and citizens enjoyed the international reputation earned for the country by Shinya Yamanaka’s earlier success in developing a novel technique of cell reprogramming. However, it was soon pointed out that the data in the research article seemed fabricated and was hence suggested that their claims lacked scientific credibility. What was initially considered another triumph of Japanese stem cell research thus resulted in a major national scandal. Instead of seeing this case merely as one of scientific misconduct, this article examines it as a window into the local culture of stem cell research and argues that the socio-institutional background of Obokata’s work incited the researchers involved to infer doability of STAP cell research. The problem with this inference surfaced after those who did not share the culture challenged the robustness of her work, suggesting some cultures of science may be more vulnerable to scientific misconduct than others.

Research Misconduct in Japan and How It Is Covered by the Media

Cases of research misconduct (fabrication, falsification, and plagiarism) have been increasing worldwide, including in Japan. In particular, since 2006, many cases of research misconduct have been reported in Japan, and these cases have also been covered by the media. The 2014 case of the withdrawal of articles on STAP cells followed a rare course in which research misconduct became a full-blown social phenomenon. In recent years, even the University of Tokyo has experienced reported cases of research misconduct. In this report, I would like to introduce some representative cases of research misconduct in the field of life sciences over the past decade. These examples include studies conducted at Osaka University Graduate School of Medicine (2006), Osaka University Graduate School of Frontier Bioscience (2006), Ryukyu University School of Medicine (2010), Toho University School of Medicine (2012), The University of Tokyo Institute of Molecular and Cellular Biosciences (2013), and several cases outside of Japan. I will discuss what researchers should do to reduce the incidence of research misconduct. In addition, I will discuss how these cases were covered by the media, because the public's impression of research misconduct is formed by media coverage.

Research Misconduct in the Age of Open Science: The Case of STAP Stem Cells

In early 2014, Dr Haruko Obokata and her co-authors caused a global media storm by publishing two scientific papers in Nature on stem cells. The papers proposed a surprisingly simple new method called stimulus-triggered acquisition of pluripotency (STAP) to generate pluripotent stem cells for research purposes in a fast and inexpensive way. To the dismay of many, both papers were retracted within six months of their release due to data fabrication and falsification. The rise and fall of the STAP research illustrates the impacts of open science practices of quality control and validation on new scientific claims. In the STAP case, collective action generated through two online forums—the Knoepfler Lab Stem Cell Blog and PubPeer—exposed not only data manipulation in the two papers but also the irreproducibility of the purported new cellular reprogramming method. The case brings to the fore the tentative possibilities as well as potential pitfalls of ‘accelerated virtual witnessing’ through crowdsourced post-publication peer reviews that value accessibility and inclusiveness. Indeed, it calls for empirically grounded discussion on the ongoing reconfiguration of the shared system of values and norms or the moral economy of science.

Public Response to Scientific Misconduct: Assessing Changes in Public Sentiment Toward the Stimulus-Triggered Acquisition of Pluripotency (STAP) Cell Case via Twitter.

BackgroundIn this age of social media, any news—good or bad—has the potential to spread in unpredictable ways. Changes in public sentiment have the potential to either drive or limit investment in publicly funded activities, such as scientific research. As a result, understanding the ways in which reported cases of scientific misconduct shape public sentiment is becoming increasingly essential—for researchers and institutions, as well as for policy makers and funders. In this study, we thus set out to assess and define the patterns according to which public sentiment may change in response to reported cases of scientific misconduct. This study focuses on the public response to the events involved in a recent case of major scientific misconduct that occurred in 2014 in Japan—stimulus-triggered acquisition of pluripotency (STAP) cell case.ObjectivesThe aims of this study were to determine (1) the patterns according to which public sentiment changes in response to scientific misconduct; (2) whether such measures vary significantly, coincident with major timeline events; and (3) whether the changes observed mirror the response patterns reported in the literature with respect to other classes of events, such as entertainment news and disaster reports.MethodsThe recent STAP cell scandal is used as a test case. Changes in the volume and polarity of discussion were assessed using a sampling of case-related Twitter data, published between January 28, 2014 and March 15, 2015. Rapidminer was used for text processing and the popular bag-of-words algorithm, SentiWordNet, was used in Rapidminer to calculate sentiment for each sample Tweet. Relative volume and sentiment was then assessed overall, month-to-month, and with respect to individual entities.ResultsDespite the ostensibly negative subject, average sentiment over the observed period tended to be neutral (−0.04); however, a notable downward trend (y=−0.01 x +0.09; R ²=.45) was observed month-to-month. Notably polarized tweets accounted for less than one-third of sampled discussion: 17.49% (1656/9467) negative and 12.59% positive (1192/9467). Significant polarization was found in only 4 out of the 15 months covered, with significant variation month-to-month (P<.001). Significant increases in polarization tended to coincide with increased discussion volume surrounding major events (P<.001).ConclusionsThese results suggest that public opinion toward scientific research may be subject to the same sensationalist dynamics driving public opinion in other, consumer-oriented topics. The patterns in public response observed here, with respect to the STAP cell case, were found to be consistent with those observed in the literature with respect to other classes of news-worthy events on Twitter. Discussion was found to become strongly polarized only during times of increased public attention, and such increases tended to be driven primarily by negative reporting and reactionary commentary.

Scientific Misconduct and Social Media: Role of Twitter in the Stimulus Triggered Acquisition of Pluripotency Cells Scandal.

BackgroundThe academic scandal on a study on stimulus‑triggered acquisition of pluripotency (STAP) cells in Japan in 2014 involved suspicions of scientific misconduct by the lead author of the study after the paper had been reviewed on a peer‑review website. This study investigated the discussions on STAP cells on Twitter and content of newspaper articles in an attempt to assess the role of social compared with traditional media in scientific peer review.ObjectiveThis study examined Twitter utilization in scientific peer review on STAP cells misconduct.MethodsSearches for tweets and newspaper articles containing the term “STAP cells” were carried out through Twitter’s search engine and Nikkei Telecom database, respectively. The search period was from January 1 to July 1, 2014. The nouns appearing in the “top tweets” and newspaper articles were extracted through a morphological analysis, and their frequency of appearance and changes over time were investigated.ResultsThe total numbers of top tweets and newspaper articles containing the term were 134,958 and 1646, respectively. Negative words concerning STAP cells began to appear on Twitter by February 9-15, 2014, or 3 weeks after Obokata presented a paper on STAP cells. The number of negative words in newspaper articles gradually increased beginning in the week of March 12-18, 2014. A total of 1000 tweets were randomly selected, and they were found to contain STAP-related opinions (43.3%, 433/1000), links to news sites and other sources (41.4%, 414/1000), false scientific or medical claims (8.9%, 89/1000), and topics unrelated to STAP (6.4%, 64/1000).ConclusionsThe discussion on scientific misconduct during the STAP cells scandal took place at an earlier stage on Twitter than in newspapers, a traditional medium.

Analysis of KOBE Biomedical Innovation Cluster based on Michael Porter Strategy

Kobe city at Hyogo prefecture in Japan suffered the Kobe earthquake in 1995, which caused economic losses of 6.9 trillion yen and human casualties of 4,600 within Kobe city. Kobe Biomedical Cluster was put RD 2. Clinical trial support; 3. Clinical application for regeneration medical technology. Issues are the lack of trust in RIKEN due to the IPS cell affair in Japan, in which one researcher plagiarized research of STAP cells. Riken had to change its name. It was unknown to healthy adults. The degree of community penetration of K supercomputer is low on a world scale and even less for engineers, which can utilize K supercomputer. Then, this research applies them into Diamond Flame of Michel Porter (Cho) and the BCG model and Product Market Matrix (Iizawa), which find improvement strategies in the big picture. Result of Product Market Matrix (Iizawa) is as follow. KBIC was located at diversification because the new advanced technology is unique and regeneration medicine is an outstanding market. Result of BCG model (Iizawa) is that market growth rate is high because people have easy access to related medical agencies within 5 minutes. KBIC wasn't known outside of healthcare practitioners. KBIC should shift its market worldwide. Its methods are to introduce medical tourism and information for coming through competitive society.

Results of an attempt to reproduce the STAP phenomenon.

In 2014, Obokata and colleagues reported their observation of a novel cell reprogramming phenomenon they named 'stimulus-triggered acquisition of pluripotency' (STAP). The most conclusive evidence for the pluripotency of so-called STAP cells was the purported ability of such cells to contribute to chimera formation. Here, I report the results of an attempt by Haruko Obokata to replicate the phenomenon under the supervision of the Scientific Validity Examination Team of RIKEN. In this follow-up study, putative STAP cells prepared by Haruko Obokata were injected into 1051 embryos, of which 591 were recovered. However, the injected cells made no significant contribution in any of the embryos that developed.

Results of an attempt to reproduce the STAP phenomenon

In 2014, Obokata and colleagues reported their observation of a novel cell reprogramming phenomenon they named ‘stimulus-triggered acquisition of pluripotency’ (STAP). The most conclusive evidence for the pluripotency of so-called STAP cells was the purported ability of such cells to contribute to chimera formation. Here, I report the results of an attempt by Haruko Obokata to replicate the phenomenon under the supervision of the Scientific Validity Examination Team of RIKEN. In this follow-up study, putative STAP cells prepared by Haruko Obokata were injected into 1051 embryos, of which 591 were recovered. However, the injected cells made no significant contribution in any of the embryos that developed.

A Comparative Analysis : Focusing on Korean Media’s Coverage of STAP Cell Research Fabrication Issue

A Comparative Analysis : Focusing on Korean Media’s Coverage of STAP Cell Research Fabrication Issue

Investigation of the cellular reprogramming phenomenon referred to as stimulus-triggered acquisition of pluripotency (STAP).

In January 2014, it was reported that strong external stimuli, such as a transient low-pH stressor, was capable of inducing the reprogramming of mammalian somatic cells, resulting in the generation of pluripotent cells. This cellular reprograming event was designated ‘stimulus-triggered acquisition of pluripotency’ (STAP) by the authors of these reports. However, after multiple instances of scientific misconduct in the handling and presentation of the data were brought to light, both reports were retracted. To investigate the actual scientific significance of the purported STAP phenomenon, we sought to repeat the original experiments based on the methods presented in the retracted manuscripts and other relevant information. As a result, we have concluded that the STAP phenomenon as described in the original studies is not reproducible.

Results of an attempt to reproduce the STAP phenomenon.

In 2014, Obokata and colleagues reported their observation of a novel cell reprogramming phenomenon they named 'stimulus-triggered acquisition of pluripotency' (STAP). The most conclusive evidence for the pluripotency of so-called STAP cells was the purported ability of such cells to contribute to chimera formation. Here, I report the results of an attempt by Haruko Obokata to replicate the phenomenon under the supervision of the Scientific Validity Examination Team of RIKEN. In this follow-up study, putative STAP cells prepared by Haruko Obokata were injected into 1051 embryos, of which 591 were recovered. However, the injected cells made no significant contribution in any tissue in any of the embryos that developed.

Web 2.0 and academic debate: Social media challenges traditions in scientific publishing.

Web 2.0 and academic debate: Social media challenges traditions in scientific publishing.

The Acid Test for Biological Science: STAP Cells, Trust, and Replication.

In January 2014, a letter and original research article were published in Nature describing a process whereby somatic mouse cells could be converted into stem cells by subjecting them to stress. These "stimulus-triggered acquisition of pluripotency" (STAP) cells were shown to be capable of contributing to all cell types of a developing embryo, and extra-embryonic tissues. The lead author of the publications, Haruko Obokata, became an overnight celebrity in Japan, where she was dubbed the new face of Japanese science. However, in the weeks that followed publication of the research, issues arose. Other laboratories and researchers (including authors on the original papers) found that they were unable to replicate Obokata et al.'s work. Closer scrutiny of the papers by the scientific community also suggested that there was manipulation of images that had been published, and Obokata was accused of misconduct. Those who should have been supervising her work (also her co-authors on the publications) were also heavily criticised. The STAP cell saga of 2014 is used as an example to highlight the importance of trust and replication in twenty-first century biological science. The role of trust in the scientific community is highlighted, and the effects on interactions between science and the public examined. Similarly, this essay aims to highlight the importance of replication, and how this is understood by researchers, the media, and the public. The expected behaviour of scientists in the twenty-first century is now more closely scrutinised.

When science does not improve human knowledge and progress: the STAP cells’ case

When science does not improve human knowledge and progress: the STAP cells’ case

Questions linger over stress-induced stem cells

Investigation confirms STAP cells were contaminated, but mystery still surrounds original results.

Quality control method for RNA-seq using single nucleotide polymorphism allele frequency.

RNA sequencing (RNA-seq) provides information not only about the level of expression of individual genes but also about genomic sequences of host cells. When we use transcriptome data with whole-genome single nucleotide polymorphism (SNP) variant information, the allele frequency can show the genetic composition of the cell population and/or chromosomal aberrations. Here, I show how SNPs in mRNAs can be used to evaluate RNA-seq experiments by focusing on RNA-seq data based on a recently retracted paper on stimulus-triggered acquisition of pluripotency (STAP) cells. The analysis indicated that different types of cells and chromosomal abnormalities might have been erroneously included in the dataset. This re-evaluation showed that observing allele frequencies could help in assessing the quality of samples during a study and with retrospective evaluation of experimental quality.

Stress and pluripotency.

Stress and pluripotency.

Genes &amp; cells: Controversial stem cell papers retracted: Mistakes, misconduct lead to questions about STAP cells

Science NewsVolume 186, Issue 2 p. 7-7 News Genes & cells: Controversial stem cell papers retracted: Mistakes, misconduct lead to questions about STAP cells Tina Hesman Saey, Tina Hesman SaeySearch for more papers by this author Tina Hesman Saey, Tina Hesman SaeySearch for more papers by this author First published: 25 July 2014 https://doi.org/10.1002/scin.2014.5591860204Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume186, Issue226 July 2014Pages 7-7 RelatedInformation

Retraction Note: Bidirectional developmental potential in reprogrammed cells with acquired pluripotency

One of two papers describing a reprogramming phenomenon called stimulus-triggered acquisition of pluripotency (STAP) — in STAP, lineage-committed adult somatic cells are reprogrammed to pluripotency by transient exposure to low-pH treatment, and extensive analysis of the molecular features and developmental potential of STAP cells indicates that they represent a unique state of pluripotency. The fates of the somatic cells that form the bulk of the mammalian body are thought to be largely determined by the time the cellular differentiation processes of development have been completed. Reprogramming in response to environmental stress has been observed in plants but not so far in mammalian cells. Now two manuscripts by Haruko Obokata and colleagues describe an unexpected reprogramming phenomenon, which the authors call stimulus-triggered acquisition of pluripotency (STAP). In STAP, mouse somatic cells such as CD45+ haematopoietic cells are reprogrammed to pluripotency by transient exposure to low pH. Extensive analysis of the molecular features and developmental potential of STAP cells suggests that they represent a unique state of pluripotency — and provide an alternative source of pluripotent cells to the use of transcription factors, as has become routine for induced pluripotent stem cell production. We recently discovered an unexpected phenomenon of somatic cell reprogramming into pluripotent cells by exposure to sublethal stimuli, which we call stimulus-triggered acquisition of pluripotency (STAP)1. This reprogramming does not require nuclear transfer2,3 or genetic manipulation4. Here we report that reprogrammed STAP cells, unlike embryonic stem (ES) cells, can contribute to both embryonic and placental tissues, as seen in a blastocyst injection assay. Mouse STAP cells lose the ability to contribute to the placenta as well as trophoblast marker expression on converting into ES-like stem cells by treatment with adrenocorticotropic hormone (ACTH) and leukaemia inhibitory factor (LIF). In contrast, when cultured with Fgf4, STAP cells give rise to proliferative stem cells with enhanced trophoblastic characteristics. Notably, unlike conventional trophoblast stem cells, the Fgf4-induced stem cells from STAP cells contribute to both embryonic and placental tissues in vivo and transform into ES-like cells when cultured with LIF-containing medium. Taken together, the developmental potential of STAP cells, shown by chimaera formation and in vitro cell conversion, indicates that they represent a unique state of pluripotency.