Authors retract already-corrected Nature malaria paper
Nature is retracting a 2010 paper by a team from Princeton and Drexel on the workings of Plasmodium falciparum, which causes malaria in people. How that came about seems to have been a winding road.
The article — a research letter — titled “Branched tricarboxylic acid metabolism in Plasmodium falciparum,” came from the Princeton lab of Manuel Llinás. It purported to find that:
… tricarboxylic acid metabolism in the human malaria parasite Plasmodium falciparum is largely disconnected from glycolysis and is organized along a fundamentally different architecture from the canonical textbook pathway. We find that this pathway is not cyclic, but rather is a branched structure in which the major carbon sources are the amino acids glutamate and glutamine. As a consequence of this branched architecture, several reactions must run in the reverse of the standard direction, thereby generating two-carbon units in the form of acetyl-coenzyme A. We further show that glutamine-derived acetyl-coenzyme A is used for histone acetylation, whereas glucose-derived acetyl-coenzyme A is used to acetylate amino sugars. Thus, the parasite has evolved two independent production mechanisms for acetyl-coenzyme A with different biological functions. These results significantly clarify our understanding of the Plasmodium metabolic network and highlight the ability of altered variants of central carbon metabolism to arise in response to unique environments.
That clarity soon clouded over. In January 2011, the group issued the following correction:
The samples used for histone proteomics described in this Letter were inadvertently switched, such that the U-13C-glucose and U-13C-15N-glutamine data were inverted. The plots in Fig. 2b and the spectra in Supplementary Fig. 3 have been modified to reflect this. The corrected results demonstrate that 13C-labelling of histone acetyl groups occurs only in cells grown on 13C-glucose and not on 13C-glutamine. Therefore, glucose is the primary source of the acetyl units used for both amino sugar biosynthesis and nuclear protein acetylation. Although U-13C-15N-glutamine does give rise to labelled acetyl-CoA, its localization and function remain unclear. The model presented in Fig. 4 has been modified to reflect these facts, which do not alter the paper’s main conclusions about TCA cycle architecture. The corrected Figs 2b and 4 are shown below. The authors apologize for this error.
Now comes the retraction, which calls the whole thing off, although not before the article was cited 65 times, according to Thomson Scientific’s Web of Knowledge:
We retract this Letter, which reported both reductive and oxidative tricarboxylic acid (TCA) metabolism in Plasmodium falciparum parasites (‘branched TCA metabolism’). The data for metabolic labelling of TCA intermediates remain reliable, but we have come to realize that the interpretation presented is incorrect. Although there is both reductive and oxidative TCA cycle flux in P. falciparum-infected red blood cell (RBC) cultures (as we reported), new data from the Llinás and Vaidya groups (manuscript in preparation) suggests that the reductive flux occurs primarily in the RBCs and not in the parasite itself. Specifically, we have used new enrichment strategies for the parasitized RBCs that enhance our ability to measure P. falciparum-infected RBC metabolic activity without excessive interference from surrounding uninfected RBCs. On feeding 13C5 glutamine, we measured both 13C2-succinate and 13C4-succinate in the infected RBCs, demonstrating that TCA metabolism in blood-stage P. falciparum is not branched but primarily oxidative (cyclic).
As it happens, there’s more news from Nature. The journal/publisher has announced new steps to “improve transparency and reproducibility” — the crux of which appears to be a checklist. According to a press release:
New measures to improve the consistency and quality of reporting in the life sciences research published in Nature and the Nature Research journals are being introduced. An Editorial [which RW readers ought to take a look at] in Nature highlights the problems that result from publishers exerting insufficient scrutiny and failing to publish enough information for other researchers to assess the reliability of results. It also announces measures to improve procedures at the Nature journals, including systematically ensuring the reporting of key methodological details, increasing the space given to methods sections and examining statistics more closely.
Central to the initiative is a checklist that will prompt authors to disclose technical and statistical information in their submissions and encourage referees to consider aspects important for research reproducibility. It focuses on a small number of often-incompletely reported elements of experimental and analytical design that are crucial to the interpretation of research results; it also consolidates several existing policies about data deposition and presentation. In addition, the Nature journals will employ statisticians as consultants on certain papers, abolish length restrictions on methods sections and encourage authors to provide data underlying figures in papers.
The editorial concludes that “tackling these issues is a long-term endeavour that will require the commitment of funders, institutions, researchers and publishers” and urges others to “do whatever they can to improve research reproducibility”.
Reproducibility, of course, is an important and growing concern in science, with projects such as the Reproducibility Initiative and the Open Science Framework launching recently. We’ll of course keep an eye on Nature‘s efforts.