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

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Abstract

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.

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Notes

  1. PubMed is a database of primarily biomedical sciences research articles. It is maintained by the US National Library of Medicine at http://www.ncbi.nlm.nih.gov/pubmed/.

  2. The initial procedure of creating induced pluripotent stem cells was carried out by Shinya Yamanaka’s laboratory at Kyoto University in 2006 (see Takahashi and Yamanaka 2006). The procedure required the introduction of four factors to adult fibroblast cells, which were cultured in conditions usually used to grow embryonic stem cells. These cells were eventually shown to be capable of contributing to all cells of the murine embryo. The protocol for creating mouse induced pluripotent cells is around 1–2 weeks, and is relatively inefficient.

  3. Several techniques are described in Obokata et al. (2014a) for stressing the cells. These include: treating cells in a low-pH (pH 5.7) solution for 25 min at 37 °C; titrating cells through narrow pipettes (50 um) for 20 min; heating the cells to 42 °C for 20 min; nutrient deprivation for three weeks; growing in high calcium (2 mM) media for 2 days; and creating pores in the cell membrane by treating cells with streptolysine O for 2 h. It was the acid treatment that was the most successful method.

  4. It is currently understood that the stem cell environment is important for maintaining cells as stem cells, and inducing differentiation. For example, mechanical (such as cell adherence to other cells or extracellular matrix, for instance) and chemical (exposure to extracellular ‘factors’) cues can affect cell division and differentiation. This function works in tandem with expression of certain genes.

  5. These are tissues such as the placenta, that are required by the foetus for development but do not form part of the body. These cells are referred to as ‘totipotent’.

  6. ‘Demethylation’ is a process that changes the molecular structure of DNA. This occurs normally, and can occur across the entire genome (for example, in paternal DNA immediately following fertilisation) or in a specific region of DNA. Demethylation (and its opposite counterpart, methylation) is part of a cell’s mechanism to influence which genes are ‘turned on’ and which are ‘turned off’. (For a detailed review, see Chen and Riggs 2011.)

  7. PubPeer is a website that involves an online community of scientists, giving them a platform to discuss scientific articles. Authors are encouraged to join discussions of their research papers.

  8. In this instance, Obokata had carried out PCR and had run gels to check the results of the PCR. Instead of showing that these gels were run at different times (by including two separate images), Obokata had edited the gel images to appear as though the results were produced at the same time (i.e. there was one gel showing the results of a PCR that occurred on one occasion). This was considered to be misleading.

  9. Senior author Teruhiko Wakayama claimed that he gave Obokata these raw results, and may not have been clear about them when he passed them on. Wakayama was also keen to highlight the pressure Obokata was under to complete the manuscripts and get the STAP work published; perhaps her misuse of the images were genuine mistakes.

  10. A condition of publishing work in Nature, as of May 2013, is that “authors are required to make materials, data and associated protocols promptly available to others without undue qualifications” (Nature Publishing Group 2014b).

  11. In early October 2014, The Wall Street Journal reported that Waseda University, where Obokata obtained her doctorate, had threatened to strip Obokata of her PhD; she has been given twelve months to correct her thesis under supervision. Only if she fulfils the university’s requirements will Obokata be allowed to retain her qualification (Martin 2014).

  12. In the middle of June 2014, Nature News published a report highlighting exactly how the cells were genetically dissimilar (Cyranoski 2014b). The cells Obokata claimed to be STAP cells had a genetic signature of no other cells at the Center for Developmental Biology at RIKEN. There was a suggestion that the cells presented as STAP cells were probably embryonic stem cells (see also Cyranoski 2014a).

  13. In Japan, Obokata’s overnight celebrity status was aided by her quirks, again separating her from the stereotypical middle-aged male scientist. For example, she had placed ‘Moomin’ cartoon stickers on her laboratory equipment, and claimed that she didn’t often wear a laboratory coat, but a traditional Japanese apron made for her by her grandmother.

  14. This included the head of the RIKEN investigation committee, Shunsuke Ishii. Ishii was suspected of splicing images in figures in a very similar fashion to Obokata; Ishii claimed that this method was considered acceptable ten years ago (when the paper in question was published). Ishii resigned on 25 April, stating that his position would complicate the current investigation of Obokata’s work.

  15. The RNA sequencing (RNA-seq) Endo describes looks specifically for expression levels of certain genes and the frequency of alleles in the cell population tested.

  16. The manuscript originally sent to Science had Wakayama as a co-author, but not Sasai.

  17. For example, according to the University of Tromsø Pro Rector for Research and Development Curt Rice, peer-review is a “sacred cow” of scientific research (Rice 2013).

  18. For example, see Zuckerman (1984), Hardwig (1991), Jasny et al. (2011), Crocker and Cooper (2011), Koole and Lakens (2012), Chambers and Sumner (2012).

  19. For example, also considering peer-review and refereeing (unfortunately without highlighting the difference between the two), Broad and Wade (1982) suggest that replication is the third line of defence and “most exacting test” for potentially fraudulent claims (p 17, 62).

  20. In some cases, deliberate omissions may be made in order to prevent replication of an experiment. For example, Resnik (1998) highlights the case of chemists Stanley Pons and Martin Fleischmann; when they believed they had found a method for successful cold fusion, Pons and Fleischmann had financial incentives for being vague about their methods. Robert Proctor (2008) has also pointed out the importance of ‘institutional amnesia’ for those working in the military, law, or government for example (p 10). Peter Galison (2008) goes a step further, suggesting that secrecy may even be a threat to democracy. Stepping back from such ambitious claims, Frederick Grinnell (1992) has suggested that science does not necessarily require secrecy, but ‘discretion’; secrecy would likely bring scientific progress to a standstill, but discretion is seen as necessary. Priority is of particular importance in the current scientific climate, and appropriate discretion can be the difference between getting funded or not (p 123).

  21. Writing for a special issue of Science, Jennifer Couzin-Frankel has described a situation whereby a researcher was struggling to replicate the findings of a study published in a highly-regarded journal. The researcher, whilst at a conference, had the opportunity to talk to the author of the paper, and quizzed him about the experiment. Nonchalantly, the author replied that they too had repeated the experiment many times, but the described result only occurred once. Since that was the interesting result, this is the one published (Couzin-Frankel 2013).

  22. There are often few methodological details noted in original research articles, particularly in high impact journals such as Nature, where space is often at a premium. Small nuances of protocols may not be reported explicitly, and this is (currently) normal practice. Usually, if contacted, a laboratory is willing to share more detailed protocols or offer a visit, to allow others to replicate methods.

  23. It perhaps took almost two months for Vacanti to publicise the more detailed protocol, as an initial interview on 2 February suggested that the original research article (Obokata et al. 2014b) was essentially a ‘how-to’ of creating STAP cells.

  24. The retraction notice in Der Pathologe for Huss, Xiao, and Hiemberg states that neither Heimberg nor Xiao had given their consent for publication, “whose existence they were not aware of”. Huss et al. (2008, p 289).

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Acknowledgments

A shorter version of this paper was presented at the Centre for Ethics, Law, and the Life Sciences (CELLS), Durham University, in June 2014. I would like to thank CELLS members, and in particular Prof A-H Maehle, for their comments, and to the anonymous reviewers for their helpful suggestions.

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  1. Department of Philosophy, Durham University, 50 Old Elvet, Durham, DH1 3HN, UK

    Cheryl Lancaster

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  1. Cheryl Lancaster
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Correspondence to Cheryl Lancaster.

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Lancaster, C. The Acid Test for Biological Science: STAP Cells, Trust, and Replication. Sci Eng Ethics 22, 147–167 (2016). https://doi.org/10.1007/s11948-015-9628-2

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