A university investigation says a pre-eminent paper contains "significantly flawed"
By Stephen Pincock | February 26, 2007
One of the most high profile -- and controversial -- papers in the adult stem cell field has been called into further question this month after a university investigation raised concerns about the methods used to identify the cell population.
In a 2002 Nature paper Catherine Verfaillie and colleagues reported that cells derived from mouse bone marrow, which they called multipotent adult progenitor cells (MAPCs), seemed able to differentiate into "most, if not all, somatic cell types." The paper, which triggered international headlines, claimed that multipotent adult progenitor cells could be an ideal source for stem cell therapy.
But the results proved difficult to replicate, and scientists have been debating the paper since its release. "It was very controversial because it has been so difficult to pin down what the cells exactly were, and how they were able to differentiate so widely," said Perry Bartlett, Foundation Chair in Molecular Neuroscience at the University of Queensland, Australia.
In recent weeks, it emerged that the University of Minnesota has conducted an inquiry into the study after questions about some of its data were raised by a reporter for New Scientist magazine. Verfaillie ran the university's stem cell center from 1999-2006.
The university's investigation concluded that the paper contained "significantly flawed" data, and the paper's conclusions are "potentially incorrect." Verfaillie and other stem cell researchers argue, however, that the inaccuracies have no effect on the report's conclusions.
The review was triggered after New Scientist's San Francisco bureau chief Peter Aldhous discovered that some of the data in the Nature paper had also appeared, albeit labeled differently, in the journal Experimental Hematology.
He and colleagues contacted Verfaillie about the errors in the first half of last year, and in June she and her colleagues published a correction in the second journal explaining that it was a simple mistake.
"The error occurred in part because the two papers were under review simultaneously, and at the time of submission of the Experimental Hematology paper, the Nature paper was not yet accepted. Although we changed the references in the proofs to include the Nature paper, we omitted to correct the legend," the correction said.
Verfaillie could not be reached by telephone, but told The Scientist in an Email that Aldhous had been concerned about the quality of a fluorescence-activated cell sorter (FACS) plot in the Nature paper, and some plots in the Experimental Hematology paper. Specifically, the control IgG staining for different specific antibodies in those plots was not as identical as it should have been, considering the IgG subtype was the same, she explained.
Tim Mulcahy, vice president for research at the University of Minnesota, told The Scientist that the university asked two experts in flow cytometry to review the data, and they found "technical flaws with the paper," but said they didn't have the background to determine if the problems affected the results. The university then contacted three stem cell experts, and two agreed to review the data. One reviewer said the flawed data wouldn't affect the findings, and the other said the flaws might "weaken the conclusions," Mulcahy noted. He said the university decided to release the information to allow the scientific community to debate the impact of the panel's findings. The university is not releasing the names of the stem cell experts who reviewed the data.
Mulcahy added that Verfaillie asked the university to investigate the findings, and has been very helpful. "This was all done with her consensus and her willing cooperation."
The outside experts agreed with Aldhous that the antigenic markers used to define the MAPCs were in question, Verfaillie said -- "as do I," she added. But these concerns don't affect the results, she noted. "As MAPCs were - and still are - not defined on the basis of a phenotype, but based on functional criteria, I believe therefore that the conclusions of the papers are still correct. Obviously that is up to the scientific community to decide."
The current debate is over a "minor point," said Diane Krause, a stem cell researcher at Yale University. The concerns about the Nature paper focus on the "antigenic profile of these cells, and not what they can do," she told The Scientist. "I certainly believe Catherine," Krause added. "I think she's got the highest amount of integrity."
Indeed, researcher Mark Clements, from Westminster University in London, UK, has had some success replicating Verfaillie's results with human cells. "The inaccuracies in Catherine's papers do cast a shadow over her work," he told The Scientist, "but I do believe the underlying premise is valid."
Clements said the errors in the paper raise questions about the definition of MAPCs in terms of cell markers, but agreed that the overall premise of the paper is intact. "Our experience of the human cells tells us that the main problem with them is that they're so fastidious to grow," he said. This would explain why other labs and indeed Catherine's lab have had difficulties replicating this work, Clements said.
Thomas Braun from the Max Planck Institute for Heart and Lung Research in Germany told The Scientist he thinks the explanation for the duplication of the figures was adequate. "Things like that happen although it is always hard to understand why such errors are not recognized at an earlier stage," he said.
Still, Braun said he remains skeptical about the claims made in the original paper. "I think it was clearly exaggerated what she published," he said in a phone interview. "I think it's clear that the cells have the capacity to respond to certain stimuli with some plasticity, but the proposition that they can contribute functionally to all cell types in the developing organism is not supported in the data."
He commented in a follow-up Email that it is true that there is no single definitive marker for MAPC and that these cells are defined functionally. "But this is exactly the point. Prof. Verfaillie claimed to define MAPC by 'proving' a contribution to normal tissue development and a differentiation of MAPC into functional cells in vivo. The evidence for such a contribution is -- in my opinion -- rather poor."
Alison McCook contributed reporting to this article.
Links within this article
Y. Jiang, et al, "Pluripotency of mesenchymal stem cells derived from adult marrow." Nature, 2002;418:41-49.
D. Bruce, "Stem cells to the fore again," The Scientist, June 21, 2002.
P. Aldhous, "Flawed stem cell data withdrawn," New Scientist, Feb 15, 2007.
University of Minnesota Stem Cell Institute
Y. Jiang, et al, "Multipotent progenitor cells can be isolated from postnatal murine bone marrow, muscle, and brain," Experimental Hematology, 2002 Aug;30(8):896-904.