Tracking the Uncertain Science of Growing Heart Cells
By NICHOLAS WADE
Published: March 14, 2005
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In April 2001, researchers from the New York Medical College and the
National Institutes of Health announced electrifying news for heart surgeons
and their patients: stem cells from bone marrow, injected into the damaged
hearts of mice, had morphed into the special cardiac muscle cells that the
body cannot replace after a heart attack.
The researchers held out the hope that the procedure could be applied to
people, too. The findings underlined a basic premise of stem cell therapy,
that it will work before the cells and their elaborate control systems are
fully understood - just put stem cells in the right place in the body, and
they will do the rest.
But four years later, the treatment has yet to demonstrate whether it will
fulfill its promise. And it has touched off a sharp difference of views
among clinical doctors as to whether the therapy is ready to be taken to
Ten human trials of the marrow-to-heart approach have been completed in
clinics around the world, all but one with positive results. But the overall
degree of improvement in the patients' heart function has been modest. At
the same time, the original research that provided the rationale for many of
the trials has come under severe criticism from scientists who have tried
without success to reproduce it.
The approach, if it works, would be a leading example of regenerative
medicine, the idea that the best way to repair the body is not with strong
drugs or the surgeon's scalpel but with the body's own system of cells and
signaling molecules. Regenerative medicine should work, in principle, on the
host of diseases that result as aging organs and tissues fail to maintain
the vigor of youth.
The difficulties of the marrow-to-heart therapy do not dash the hopes for
regenerative medicine or imply failure for the stem cell research financing
set up by states like California and New Jersey. But they do suggest that
successful stem cell treatments, whether with adult cells or ones derived
from embryos, may require many years to come to fruition.
The bone marrow stem cell technique, devised by Dr. Donald Orlic of the
National Institutes of Health and Dr. Piero Anversa of New York Medical
College in Valhalla, N.Y., was taken up with such alacrity because it
promised to address a desperate medical need and seemed reasonably safe,
given that patients were to be injected with their own cells. Patients are
now being recruited for at least two trials in the United States, one at the
Texas Heart Institute in Houston and a second at the Caritas St. Elizabeth's
Medical Center in Boston and two other sites.
The Houston trial, led by Dr. James T. Willerson and Dr. Emerson C. Perin,
follows from a test in Dr. Perin's native Brazil. Though Brazilian
regulators would allow only the sickest patients to be enrolled, Dr. Perin
said, there was "significant evidence" that the treatment worked. Before
receiving injections of their bone marrow stem cells, most of the patients
were bedridden or too sick to walk without effort. But after treatment, he
said, "some patients were jogging on the beach, one climbed eight flights of
stairs, and one, who had gone home to live with his mother, reopened his
On the strength of these results, the Food and Drug Administration allowed
the Texas Heart Institute to start recruiting patients for a similar trial.
So far 13 patients with end-stage coronary disease have been treated, and
all are doing well. "We are thrilled by what we have seen," Dr. Willerson
said of the two trials.
At the St. Elizabeth's Medical Center, Dr. Douglas W. Losordo has started
recruiting patients and is also impressed with the results so far.
"There are dramatic examples of patients' going from being bedbound to
living normal lives," Dr. Losordo said. Although the study is blind, meaning
he does not know which patients were treated and which are serving as
controls, the group as a whole is doing better. One patient who has left the
study - the rules allow patients showing no response to be withdrawn after
six months - turned out to be in the untreated group.
But though clinicians say they are encouraged, researchers are considerably
more skeptical. At least two separate laboratories, at Stanford University
and at the University of Washington in Seattle, reported last year that they
had been unable to repeat the Orlic-Anversa experiment. Bone marrow stem
cells, these researchers found, did not turn into heart tissue. The few that
lodged in the heart turned into blood cells in the usual way. The Stanford
researchers, who included Dr. Irving Weissman, a leading expert on the
blood's stem cells, warned that until the science underlying the clinical
trials was better understood, "these studies are premature and may in fact
place a group of sick patients at risk."
Clinicians have paid little heed to this apparent setback, arguing that
there is an urgent need to try anything that is safe and might do good,
regardless of whether its mechanism of action is fully understood.
"The basic-science guys don't see patients that are going to die, but I have
to look them in the face every day," Dr. Perin said. "It's ludicrous to say
we must understand the molecular mechanisms before we can try anything."
Dr. Losordo said, "My patients and I have finite lifespans, and adult stem
cells to me are an answer that is available in the very near term."
Clinicians say they have established that the technique is safe - some 200
patients have now been treated worldwide without adverse effect - and that
the results so far are worth pursuing. But individual cases, however
striking, count less than overall statistics. Most studies so far show a 5
percent to 10 percent improvement in heart function. While not great, that
is not discouraging, either, given that most of the patients were very sick
to begin with.
A degree of improvement this mild could be caused by some unintended aspect
of the treatment. Just the act of injecting the heart can cause local
inflammation, leading perhaps to better circulation in the inflamed area.
While that possibility has not been ruled out, the clinicians are convinced
that something in the potent mix of bone marrow stem cells is causing the
results they see. Dr. Helmut Drexler, leader of a clinical trial in Hannover,
Germany, said last year that if the bone marrow stem cells were failing to
convert into heart cells themselves, as the critics assert, perhaps the
cells were secreting hormones that prompted a beneficial response from the
heart's own cells.
Clinicians like the Texas and Tufts teams carry out their own laboratory
research and are hoping to discover which of the several different kinds of
stem cells in the bone marrow is the most effective. Dr. Losordo and his
colleague Dr. Young-sup Yoon reported this year that they had isolated a
special kind of bone marrow stem cell that in laboratory tests can morph
into each of the three kinds of cells that build the heart. This or some
other specific stem cell could be a better agent to inject than crude bone
marrow extracts, but the clinicians have not yet agreed on a better
Meanwhile, basic researchers are trying to figure out the natural role of
stem cells in maintaining the heart. Dr. Anversa has long championed the
belief that the heart does possess the ability to generate new muscle cells,
despite its apparent inability to do so after a heart attack. Four years ago
he described evidence that the heart's muscle cells can divide,
contradicting the dogma that no new heart cells are created after birth.
But if the heart does possess stem cells, their role seems confined to
slowly replacing the heart's muscle cells throughout life, and does not
include emergency repairs after a heart attack.
"You are not supposed to live long enough to get a heart attack," said Dr.
Kenneth Chien, a research cardiologist at the University of California, San
The bone marrow may be a source of stem cells for repairing organs in
crisis, including the heart. Even if so, this system, too, fails to operate
Some researchers say they think the stem cell system itself may age and lose
its effectiveness in older people. If so, it could be futile to treat
elderly patients with their own stem cells, sharply limiting the
possibilities of the new therapy.
"In older individuals, perhaps the regenerative capacity of the stem cell
pool is compromised," said Dr. Mark Sussman of San Diego State University.
Dr. Sussman hopes to enhance the cells' vigor by lengthening their
telomeres, segments of DNA that shorten each time a cell divides and limit
how often it can do so.
A quite different approach is being explored by Dr. Silviu Itescu of
Columbia University. In Dr. Itescu's view, not only may a patient's own bone
marrow cells be compromised by age, but bone marrow transplants are far too
expensive for a commonly required operation. That argues for finding a
generic source of younger cells that can be used to treat any patient.
Four years ago, Dr. Itescu and his colleagues found a bone marrow stem cell
that caused proliferation in the heart of the tiniest blood vessels, known
as capillaries. Though that seemed promising at the time, Dr. Itescu did not
proceed to clinical trials, saying the improvement was too small. He says he
has now found a more promising type of bone marrow stem cell that increases
the arterioles, blood vessels one size up from capillaries.
Meanwhile, Dr. Anversa has repeated his original experiment with the same
results as before. In an article in the journal Circulation Research, he
suggested that his critics had failed to follow his procedure correctly and
suffered from "emotional disbelief" - fighting words for a scientific
article - that bone marrow cells were capable of morphing into heart cells.
He believes that the new bone marrow stem cells discovered by the Tufts team
may be the source of the new cells he sees in damaged hearts.
Some researchers say the clinicians, by using a crude extract of bone marrow
cells, will find it hard to figure out which kind of stem cell, if any, is
having the beneficial effect. "We are spending a lot of time on clinical
trials that are unlikely to give us definitive answers because the science
has not caught up yet," Dr. Itescu said.
But the researchers acknowledge they cannot yet advise the clinicians which
kind of stem cell is the best candidate for heart repair. "The literature is
replete with contradictions that have generated widespread confusion," Dr.
Orlic said. Dr. Sussman called the situation a "quagmire."
Perhaps not surprising, the two groups have differing views about the likely
time scale for bone marrow stem cells to become standard therapy for ailing
"There is mounting evidence that these cells have therapeutic potency," Dr.
Losordo said. "In the near term, within three to five years, this therapy
will be available to treat a large population of patients with a very common
But researchers fear that the clinicians, in their desire to offer something
immediately to patients who have run out of options, are being too hasty.
"Let's find the right cell first," Dr. Chien said. The clinicians complain
that will take years, he said, adding: "They are right. It will take years."