Tracking the Uncertain Science of Growing Heart Cells

From: Bill (xxx_at_yy.zz)
Date: 03/14/05 

Date: Mon, 14 Mar 2005 20:23:29 GMT

Previous reports were more encouraging, though this still looks like it has
some promise. From NYT.

Bill

__________________________

Tracking the Uncertain Science of Growing Heart Cells
By NICHOLAS WADE

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 people.

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 business."

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 candidate.

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
Diego.

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 when
needed.

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
hearts.

"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
disease."

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."

Relevant Pages