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254 18 JULY 2014 • VOL 345 ISSUE 6194 sciencemag.org SCIENCE
By Kelly Servick
In the study of cardiac regeneration, Piero Anversa is among the heavy hitters. His research into the heart’s repair mecha- nisms helped kick-start the field of cardiac cell therapy (see main story, p. 252). After more than 4 decades of research and 350 papers, he heads a lab at Harvard Medical School’s
Brigham and Women’s Hospital (BWH) in Boston that has
more than $6 million in active grant funding from the National
Institutes of Health (NIH). He is also an outspoken voice in a
field full of disagreement.
So when an ongoing BWH investigation of the lab came to
light earlier this year, Anversa’s colleagues were transfixed.
“Reactions in the field run the gamut from disbelief to vindication,” says Mark Sussman, a cardiovascular researcher at San
Diego State University in California who has collaborated with
Anversa. By Sussman’s account, Anversa’s reputation for “
pushing the envelope” and “challenging existing dogma”
has generated some criticism. Others, however, say
that the disputes run deeper—to doubts about a
cell therapy his lab has developed and about the
group’s scientific integrity. Anversa told Science he
was unable to comment during the investigation.
“People are talking about this all the time—at
every scientific meeting I go to,” says Charles
Murry, a cardiovascular pathologist at the
University of Washington, Seattle. “It’s of grave
concern to people in the field, but it’s been frustrating,” because no information is available about
BWH’s investigation. BWH would not comment
for this article, other than to say that it addresses
concerns about its researchers confidentially.
In April, however, the journal Circulation
agreed to Harvard’s request to retract a 2012 paper on which
Anversa is a corresponding author, citing “compromised” data.
The Lancet also issued an “Expression of Concern” about a 2011
paper reporting results from a clinical trial, known as SCIPIO,
on which Anversa collaborated. According to a notice from the
journal, two supplemental figures are at issue.
For some, Anversa’s status has earned him the benefit of the
doubt. “Obviously, this is very disconcerting,” says Timothy
Kamp, a cardiologist at the University of Wisconsin, Madison,
but “I would be surprised if it was an implication of a whole
career of research.”
Throughout that career, Anversa has argued that the heart
is a prolific, lifelong factory for new muscle cells. Most now
accept the view that the adult heart can regenerate muscle, but
many have sparred with Anversa over his high estimates for
the rate of this turnover, which he maintained in the retracted
Anversa’s group also pioneered a method of separating
cells with potential regenerative abilities from other cardiac
tissue based on the presence of a protein called c-kit. After
publishing evidence that these cardiac c-kit+ cells spur new
muscle growth in rodent hearts, the group collaborated in the
SCIPIO trial to inject them into patients with heart failure. In
The Lancet, the scientists reported that the therapy was safe
and showed modest ability to strengthen the heart—evidence
that many found intriguing and provocative. Roberto Bolli,
the cardiologist whose group at the University of Louisville
in Kentucky ran the SCIPIO trial, plans to test c-kit+ cells in
further clinical trials as part of the NIH-funded Cardiovascular
Cell Therapy Research Network.
But others have been unable to reproduce the dramatic effects
Anversa saw in animals, and some have questioned whether
these cells really have stem cell–like properties. In May, a group
led by Jeffery Molkentin, a molecular biologist at Cincinnati
Children’s Hospital Medical Center in Ohio,
published a paper in Nature tracing the genetic
lineage of c-kit+ cells that reside in the heart.
He concluded that although they did make new
muscle cells, the number is “astonishingly low”
and likely not enough to contribute to the repair
of damaged hearts. Still, Molkentin says that he
“believe[s] in their therapeutic potential” and that
he and Anversa have discussed collaborating.
Now, an anonymous blogger claims that
problems in the Anversa lab go beyond contro-
versial findings. In a letter published on the blog
Retraction Watch on 30 May, a former research
fellow in the Anversa lab described a lab culture
focused on protecting the c-kit+ cell hypothesis:
“[A]ll data that did not point to the ‘truth’ of
the hypothesis were considered wrong,” the person wrote. But
another former lab member offers a different perspective. “I had
a great experience,” says Federica Limana, a cardiovascular dis-
ease researcher at IRCCS San Raffaele Pisana in Rome who spent
2 years of her Ph.D. work with the group in 1999 and 2000, as
it was beginning to investigate c-kit+ cells. “In that period, there
was no such pressure” to produce any particular result, she says.
Accusations about the lab’s integrity, combined with continued silence from BWH, are deeply troubling for scientists who
have staked their research on theories that Anversa helped
pioneer. Some have criticized BWH for requesting retractions in
the midst of an investigation. “Scientific reputations and careers
hang in the balance,” Sussman says, “so everyone should wait
until all facts are clearly and fully disclosed.” ■
Top heart lab comes under fire
researchers, suggested that injecting a
patient’s bone marrow into his or her heart
might somehow enhance its ability to
pump, even if the cells did not proliferate.
Why that appeared to be happening could
be sorted out later.
One of the first trials, on 21 people with
severe heart failure in Brazil, was led by
researchers at the Texas Heart Institute. In
the 14 patients treated (seven others were
controls), they described an improvement of
left-ventricular ejection fraction—the heart’s
ability to pump blood—from 20% to 29%.
A healthy ejection fraction is 55% to 70%.
Still, the improvement was meaningful and
generated enthusiasm for further testing.
A year later, the Texas Heart Institute
announced with much fanfare that the
treatment was coming to the United States.
“A procedure that for more than a year has
been bringing South American heart failure
patients back from near-death has been
approved for testing in the Texas Medical
Center,” a press release declared. The release
quoted one of the trial leaders effusing about
the treatment: “These people in Brazil were
reborn,” the cardiologist said.