Japanese stem cell scientist Haruko Obokata was the first author of two papers that appeared in the journal Nature earlier this year that described the derivation of pluripotent stem cells from mature cells without the use of genetic manipulation. Instead, these cells were subjected to environmental stresses such as physical pressure or exposure to acid that, according to these papers, caused the cells to express genes associated with pluripotency. Culturing of these cells led to the derivation of pluripotent stem cells lines. Thus were born STAP or stimulus-triggered acquisition of pluripotency cells. Needless to say, these results were hailed as a remarkable advance in stem cell biology.
Unfortunately, as soon as the papers were published, several high-level laboratories tried to recapitulate these results and universally failed. Even more troubling were some of the inconsistencies that came to the forefront in the published papers that the reviews had apparently missed or were ignored by the journal. The RIKEN center where this work was done even launched an internal investigation that concluded that Dr. Obokata was guilty of scientific misconduct. Obokata gave approval to formally retract her Nature papers. However, the RIKEN Center gave Obokata and her colleagues until the end of November to prove that she could reproduce STAP cell derivation.
Now the jury is in – Obokata has been unable to replicate her results. In the original experiments, Obokata used a gene fusion that caused the cells to glow green if they expressed genes related to pluripotency. In her replication of her original experiments, Obokata produced such green glowing cells when she subjected to environmental stresses. However, this is only a preliminary test that only involved a few such cells. More rigorous tests that were conducted, however, failed. In this case, Obokata’s stressed adult cells were introduced into a mouse embryo to see whether they could contribute to the development of various tissues during animal development. Obokata’s stressed cells, however, were unable to integrate into the developing embryos. Since this is the ultimate test for pluripotency, and since these cells were not able to pass this test, it seems virtually certain that Obokata’s original results were completely bogus.
With her signature conclusions in tatters, Obokata has resigned from the RIKEN center. In a very emotional resignation letter, Obokata wrote she could not “find words enough to apologize… for troubling so many people at RIKEN and other places.” The RIKEN president, Ryoji Noyori, wrote in an accompanying statement that Dr. Obokata had been subjected to horrible psychological stress as a result of this affair. Noyori added that he accepted her resignation to hopefully save her from suffering further from a severe “mental burden.” One the co-authors of the STAP papers, Japanese stem cell scientist Yoshiki Sasai, committed suicide a few weeks after the retraction of the paper.
Hopefully, RIKEN and the other scientists who were involved in this venture move on and continue with the business of pushing back the frontiers of science. It is entirely possible that intentional fraud was involved, but ultimately, we will never know. For now, it is clear that sloppiness and a lack of skepticism about one’s own results contributed to this fiasco. I think most people simply want to put this whole sordid event behind them. However, there are pointed lessons to be learned and we will be better investigators if we learn them.
For one, peer review is not omnipotent. Post-publication review is important and will continue to be important. Secondly, journals need to be willing to solicit outside opinions to ensure the quality of high-level publications. Third, the majority of scientists publish in journals that most people will never read. Their work is not glamorous, but instead document tedious, high-quality, detailed, scientific research. The majority of such work will never appear in Nature or Science or Cell, but that’s alright because good solid research is still good solid research regardless of where it appears. It is really too bad that the push for high-visibility publications can cause people to publish too quickly before results have been properly vetted. The STAP episode might be a reminder for journals to take greater care with the review of original research.