A discredited stem cell technique, long in its death throes, has finally been laid to rest. And just to be sure it will never discomfort us with any zombie-like stirrings, a group of scientists representing seven international laboratories and led by researchers at Harvard Medical School and Boston Children's Hospital has published a collection of papers that may constitute the last word on stimulus-triggered acquisition of pluripotency (STAP).
These papers, which appeared September 23 and 24 in Nature, were accompanied by an editorial seconding the idea that STAP, already in the grave, needed to have the dirt above it tramped down. The editorial acknowledged that the original STAP papers, which appeared in early 2014 and purported to have shown that acid baths and other stresses could drive cells to novel pluripotent states, have already been retracted. Nonetheless, the Nature editorial observed that the wording of the STAP retraction notices had left open the possibility that the phenomenon was genuine. The retraction, in fact, read as follows: “Multiple errors impair the credibility of the study as a whole and we are unable to say without doubt whether the STAP-SC phenomenon is real.”
Intent on setting the scientific record straight, Nature has posted two Brief Communications about the STAP retraction (“Failure to replicate the STAP cell phenomenon”; “STAP cells are derived from ES cells”) and a Review about confirming cell provenance (“Hallmarks of pluripotency”). The Brief Communications, asserted Nature, “clearly establish” that the STAP stem cell phenomenon is not real. The Review, Nature added, is intended to “offer guidance from the community to help researchers, editors, and reviewers to decide how best to evaluate future claims as well as how to view those already published in the scientific literature.”
In the investigations described by the Brief Communications, earnest attempts to replicate STAP failed. These attempts included experiments conducted in the lab where STAP was first developed, as well as analyses of publicly available genomic sequence data with newly developed bioinformatics algorithms.
“Neonatal cells treated with two STAP protocols exhibited artefactual autofluoresence rather than bona fide reactivation of an Oct4 and green fluorescent protein transgene reporter, did not reactivate pluripotency markers toward embryonic stem (ES)-cell-like levels, and failed to generate teratomas or chimaerize blastocysts,” indicated the “Failure to Replicate” paper. “Re-analysis of the original RNA sequencing and chromatin immunoprecipitation sequencing data identified discrepancies in the sex and genetic composition of parental donor cells and converted stem cells, and revealed a STAP-derived cell line to be a mixture containing trophoblast stem cells.”
The “STAP cells are derived from ES cells” paper included data that had been presented to an external investigative committee convened by RIKEN, the institute from which the original STAP papers emerged. “We report the results of a whole-genome sequencing investigation of STAP-related samples kept mainly at the RIKEN Center for Developmental Biology,” the article stated. “We show that all purported STAP stem-cell lines were contaminated with ES cells, and that chimeric mice and teratomas supposedly derived from STAP cells instead show ES cell contribution.”
And so the STAP story—which started with too-good-to-be-true findings and nagging doubts, proceeded to investigations and findings of scientific misconduct, and culminated in retractions and even the reorganization of a RIKEN institute—may finally be nearing its epilogue. For this part of the story, we turn to the Review article, which described functional and molecular hallmarks of pluripotent stem cells, proposed a checklist for their evaluation, and illustrated how forensic genomics can validate their provenance.
“For lasting scientific impact, claims of reprogramming and altered states of pluripotency should be broadly applicable to more than one experimental model and be independently replicated by multiple laboratories,” the Review concluded. “Before publication, we encourage that researchers claiming landmark reprogramming advances first demonstrate replication by independent laboratories and incorporate forensic genomic analyses to confirm appropriate cell provenance. Science is ultimately a self-correcting process where the scientific community plays a crucial and collective role.”