The National Institutes of Health will pause human testing of an experimental stem cell therapy for heart failure while a board charged with overseeing patient safety reviews the taxpayer-funded trial, in light of emerging questions about the scientific foundation for the treatment.
Outside physicians and scientists have been publicly calling for the trial to be suspended since news earlier this month that a years-long Harvard investigation uncovered “false and/or fabricated data” in 31 scientific papers from the laboratory of Piero Anversa, a researcher whose blockbuster findings raised hope there were stem cells in the heart that could repair damaged muscle. Anversa is not directly involved in the trial, but the heart stem cells he identified are being injected into the hearts of some of the patients.
The decision to temporarily pause the trial came “out of an abundance of caution,” said David Goff, director of the Division of Cardiovascular Sciences at the National Heart, Lung and Blood Institute, who said the trial’s scientific rationale is largely based on animal studies not conducted by Anversa.
Goff said the board charged with overseeing the safety and integrity of the trial was convened last week and NIH leadership made the decision to pause the trial, which has enrolled 125 of 144 patients, to allow a thorough review.
“Our commitment, first and foremost, is to patient safety. We haven’t seen any safety signals related to the cell treatment, but we can’t do any of our research without the partnership of our participants, and we make a commitment to our participants that their safety is our highest priority,” Goff said. The pause will allow the board to examine the trial and “assure that it continues to meet the highest levels of adherence to participant safety and scientific integrity.”
Outside scientists have said the scientific underpinnings of the trial must be weighed against the risks of medical research. One patient died early in the trial when their heart was perforated while cells were being harvested to create stem cells, highlighting the inherent risks to vulnerable patients.
“I think this is a reasonable and prudent step,” said Charles Murry, director of the Institute for Stem Cell and Regenerative Medicine at the University of Washington, who has been studying a different approach to repair the heart — growing heart muscle cells from embryonic stem cells.
Anversa did not immediately respond to questions about the trial. He repeatedly said the problems discovered in his lab came solely from a longtime colleague, whom he collaborated with closely for at least a quarter of a century. He has said the results from his laboratory still stand.
The heart stem cells Anversa and colleagues first identified as having regenerative potential are being used in the CONCERT-HF trial, which will test whether those cells alone or in combination with others can improve heart function.
NIH officials have said Anversa’s work did not directly inspire the trial, because the theory about how the heart stem cells may have beneficial effects has changed since his initial studies — and are supported by research in other laboratories.
“We were aware of some of the controversies,” said Victor Dzau, the former chair of the committee that reviewed the initial trial protocol. “Patient safety is No. 1 — as long as you can make sure there is [patient] consent and patient safety, the issue is we need to know if this whole area is worth pursuing or not.”
Many researchers have watched with growing frustration and disappointment as powerful figures in the field have continued to advance the idea these cells work to regenerate the heart, even as other laboratories have revealed problems with the initial research. Experts recounted how compelling Anversa’s ideas were initially, especially for cardiologists and scientists eager for treatments for patients with desperate need for a therapy.
“No matter how jaded you were, you couldn’t help but think this was a fantastic answer,” said Jil Tardiff, a cardiologist at the University of Arizona College of Medicine. “We used to joke the person who figures this one out gets a Nobel Prize … and makes one of the biggest impacts on cardiovascular health, ever.”
But very quickly, outside researchers began to poke holes in research from Anversa’s laboratory. Murry recalled presenting research at an American Heart Association meeting and a Keystone Symposium in 2001 and 2002 that undermined one of Anversa’s initial findings that showed bone marrow cells could regenerate the heart.
In a story that has become somewhat legendary among heart researchers, called the “Pavarotti session” by some, Murry presented negative evidence that challenged Anversa’s work in the two meetings. Murry recalled explaining that processing images of cells with Photoshop could explain the disparate results from his lab and Anversa’s.
According to Murry, on those two occasions Anversa or a collaborator stood up to respond to the data — by suggesting Murry was not enough of a scientific virtuoso — saying not everyone could sing like the famed tenors Luciano Pavarotti or Plácido Domingo. Several other researchers also recalled the interaction.
Anversa did not immediately respond to questions about those conferences.
Murry’s work was one of two papers eventually published in the journal Nature that showed bone marrow cells did not regenerate the heart, as Anversa had found. Anversa’s lab began to focus on a population of heart stem cells, called c-kit-positive cells, that could regrow muscle tissue.
“The results that they showed were really quite amazing to many of us, from the perspective of being developmental biologists or cardiac physiologists. We didn’t understand how things could be possible; they didn’t present a mechanism, and it just seemed to be just really extraordinary — and extraordinary claims require extraordinary proof,” said Benoit Bruneau, a cardiovascular disease researcher at the Gladstone Institutes.
More recently, other researchers have shown those c-kit heart stem cells do not turn into heart muscle. But other researchers have injected those cells into animal hearts and observed an improvement in heart function, leading to a new theory that the cells secrete molecules that help regenerate the heart.
Because Anversa’s work had such influence, researchers think it is right to take stock of the science.
“I think it’s obviously the responsible thing to do, to pause and reevaluate the scientific basis for a clinical trial like this, and to really carefully ask the question — is there still a good scientific basis for it,” said Richard T. Lee, a stem cell biologist at Harvard. “I won’t make that judgment, but I think it’s quite obvious, you can’t do trials on patients when there is a question about the basis.”
Beyond the trial, scientists hope a reexamination of the field will help them understand how these ideas about heart repair became so dominant despite questions about how they work. Anversa received more than $59 million in taxpayer-funded research support, and many in the field say his opinions carried significant weight.
“The field was ripe for something new for these patients we all took care of and had nothing else. They’re desperate and miserable, and their lives are bad — it’s awful. It became, who cares how it works — it just does,” Tardiff said. “We need to learn from this, or we’re going to do it again.”