Tracking the Uncertain Science of Growing Heart Cells
By NICHOLAS WADE

Published: March 14, 2005
http://www.nytimes.com/2005/03/14/health/14heart.html?th&oref=login (must register to view original article)

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."