Brigham researcher facing new questions after retraction

Two days after a heart research paper was retracted, questions have been raised about a stem cell study overseen by the same prominent Brigham and Women’s Hospital cardiovascular researcher.

In an “expression of concern” posted online Thursday night, editors of the British medical journal The Lancet said Harvard Medical School had notified them of an ongoing investigation examining the “integrity of certain data” used in two sets of images of cells in a 2011 paper overseen by Dr. Piero Anversa at the Brigham.

Both Anversa’s 2011 paper and a separate 2012 study that was withdrawn from the journal Circulation earlier this week examined the regenerative capacity of the heart, in an effort to harness cardiac stem cells to repair damaged or diseased heart muscle.

“This notice of concern, coupled with the recent retraction, is extremely troubling because of the large number of clinical trials inspired by reports from this group, the many desperate patients potentially affected, and the large amount of federal and private money that has been diverted from other areas of promising research to pursue these ideas,” Dr. Jonathan Epstein, a professor of cardiovascular research at the University of Pennsylvania Perelman School of Medicine, wrote in an e-mail.

Neither of the journals has been specific about who is at fault or what the nature of the problems are, but the papers come from the laboratory of an extremely influential and controversial figure in the high-profile field of cardiac stem cells.

Anversa, according to the National Institutes of Health website, was the principal investigator on grants totaling $57 million since 2000.

He has published hundreds of scientific articles over his long career. Clinical trials have been launched based on research insights from his laboratory, though pointed questions have been raised about the validity of some of his findings by other scientists.

Anversa said in an e-mail to the Globe Friday that he is “fully cooperating” with the investigation being conducted by Harvard and the Brigham “and cannot comment on it due to its ongoing nature.” He added that he still believes the basic findings of the two papers are correct.

An “expression of concern” is issued when a journal learns of potential problems with a paper but is awaiting more information before deciding whether to correct or retract the study.

“It alerts our readers to the fact the investigation is going on,” a Lancet spokeswoman said Friday. The notice said the investigation into the paper “is likely to take several months” and concerns images of cells published in an online supplement that were generated in a Brigham laboratory.

“As far as we are aware, the investigation is confined to the work completed at BWH,” the editors wrote.

The Lancet study described an early-stage clinical trial, led by Dr. Roberto Bolli of the University of Louisville. Adult stem cells were isolated from tissue taken from heart failure patients and later infused back into their hearts. The paper, which was a continuation of work by Anversa’s laboratory that had shown such cells could repair heart muscle in animals, reported improvements in some measures of heart function in people.

“I continue to believe that the data show improved heart performance in most patients who participated in the study,” Anversa wrote in his e-mail.

According to the paper’s description of the study’s methods, portions of the patients’ hearts were surgically removed at Jewish Hospital in Louisville and shipped to the Brigham, where the stem cells were isolated and processed to greatly expand the number of cells. They were then returned to Louisville to be used in patients.

“I am of course as anxious as anyone else to see the results of the ongoing investigation by the BWH,” Bolli wrote in an e-mail Friday. “The data in question were generated by Dr. Anversa’s lab independently of us in Louisville; we in Louisville have nothing to do with the issues cited in the Expression of Concern.”

A University of Louisville Health Sciences Center spokeswoman said that the potential problems do not affect the positive results of the clinical trial and that there have been no adverse events ascribed to the therapy in any patients, either during the trial or over two years of follow-up.

“Dr. Bolli firmly believes that the clinical findings for the work conducted in Louisville are entirely correct and valid,” Jill Scoggins wrote in an e-mail.

The Harvard and Brigham investigation has already revealed “compromised” data in the 2012 paper in the journal Circulation, which described rapid turnover of cells in the heart and was also overseen by Anversa. That paper was retracted Tuesday.

A third stem cell study, which was overseen by a different Brigham researcher, has also been challenged, in a separate controversy that has drawn international headlines. That high-profile paper’s lead author was accused of fraud last week by the Japanese research institute where she works. Dr. Charles Vacanti, the Brigham anesthesiologist who supervised the research while she was in Boston, has not been implicated.

A spokeswoman for the Brigham said that the hospital could not answer specific questions about the investigation into Anversa’s research, but added that she was not aware of any other papers that would be affected.

At least one other journal has said it has been in contact with Harvard regarding work from the laboratory. In 2011, Anversa and colleagues published a paper in the New England Journal of Medicine that identified stem cells that could give rise to many different cells in the lung, which other scientists viewed with skepticism.

“It’s standard protocol for scientific publishers to contact research institutions directly when questions are raised about their researcher’s work,” New England Journal spokeswoman Jennifer Zeis wrote in an e-mail. “We have been in contact with Harvard Medical School regarding the May 2011 NEJM article on lung stem cells. We will cooperate with whatever they decide.”

Outside researchers have said that they hope that the investigation will extend to Anversa’s other research, helping to clarify what to make of the rest of his large body of work.

“I’d say it’s really a pity that somebody has disturbed a field that could have been really good, but now that there’s so much skepticism about his particular studies that people have become almost unnecessarily cynical about it,” said Christine Mummery, a professor of developmental biology at the Leiden University Medical Center in the Netherlands. “He did accelerate a field; he did bring it into the clinic. That would never have started without his initial work, but it just went wobbly at some point, for whatever reason, that the consistency of the data doesn’t stand up to scrutiny.”