So far, stem cells have not delivered the results scientists hoped for. But excitement is still rising
The dream of medical science is to train the body to repair itself in the face of disease or trauma, and the main focus of this dream is the heart. For five years, teams of doctors around the world have been trying to coax adult stem cells, the body's innate repair kit, to regenerate damaged heart tissue after a heart attack or other coronary disease.
These efforts have generated excitement among heart specialists, despite the fact that clinical trial results have been uneven and no one is quite sure how, why, or even if, stem cell therapy works. The excitement continues to mount, despite a study released on Mar. 1 stating that one of the most widely examined methods for delivering stem cells to the heart had failed.
A team of German doctors from Technische Universitat in Munich reported on a rigorously conducted trial in the Journal of American Medical Association (JAMA). Scientists injected G-CSF, a human growth factor known to stimulate adult stem cells, within 12 hours after a heart attack.
There were 114 patients in the study, more participants than the three earlier G-CSF trials combined. Half received the treatment, and the other half were given a placebo. After six months of follow-up, the researchers discovered that G-CSF did prod a significant number of stem cells to move from the bone marrow, where they are produced, to the heart, with no serious side effects.
Nonetheless, there was no improvement in heart function, throwing doubt on the whole stem cell approach. "The answer is fairly unequivocal," says Dr. Kenneth Chien, director of the cardiovascular research center at Massachusetts General Hospital in Boston. "The stem cells did not improve function."
Unequivocal or not, the failure of the German trial has not dampened enthusiasm for heart regeneration. Several reports on stem cell research will be highlighted at the American College of Cardiology meeting in Atlanta on Mar. 11-14, and teams of doctors and biotech companies around the world are continuing their research in this area.
Most are quick to point out that their methods are fundamentally different from the German approach. If anything, the failure of G-CSF turned more attention on the many efforts to deliver stem cells directly to the heart, rather than indirectly trying to stimulate them with a growth factor.
There have been no human studies of the direct approach on the scale of the German trial, and the many smaller studies have often been contradictory. But even Chien, who considers himself a conservative when it comes to stem cell therapy, says it is one of the more exciting areas of heart research. "I don't think it should be considered a slam dunk, but I do think it is promising long-term."
Stem cell researchers, many of whom also treat patients, are driven by a huge unmet need. Some 1.1 million Americans are struck by heart attacks each year, and 4.8 million suffer from congestive heart failure, in which the heart stops pumping effectively, with 400,000 new cases diagnosed each year.
Both these conditions are caused by the destruction of heart muscle cells, and there are few effective therapies that can counteract that damage. Unlike most other tissues in the body, the heart does not regenerate itself. When damage occurs, it merely grows scar tissue, which restricts pumping even further.
Stem cells seem like an obvious solution. In an embryo, stem cells, which are undefined, can turn into any tissue in the body.
Because of restrictions and ethical concerns about the use of embryonic stem cells, however, most heart experiments involve adult stem cells extracted from the bone marrow. The pioneers in this area are Drs. James T. Willerson and Emerson C. Perin of the Texas Heart Institute at St. Luke's Hospital in Houston.
In 2000, Willerson and Perin treated 14 Brazilian patients with stem cells removed from their hip bones and directly injected with a catheter to their damaged hearts. Within two months, the patients demonstrated improved heart function, with almost double the pumping motion in those parts where the cells were injected.
When one of those patients died 11 months after treatment, of unrelated causes, the doctors discovered during an autopsy that there was clear evidence of new blood vessel formation to the heart.
The team is now conducting a U.S. trial with 25 patients, and recently won approval for another trial. "We realize that we've not identified the best stem cells, or the best method of administration," says Willerson. "We don't want to be part of the hype, but this is an exciting time."
Willerson and Perin are using the patient's own adult stem cells to avoid rejection by the body's immune system. But a small biotech in Baltimore, Osiris Therapeutics, is aiming to come up with a more universal approach by using donated mesenchymal stem cells (MSC).
These are universal to everyone, so they do not set off an immune reaction. Animal studies indicate that the MSCs are prompted by inflammatory signals to head to the site of an injury, and Osiris recently started a Food & Drug Administration-sanctioned clinical trial to test the therapy in heart attack patients.
Then there are stem cells that actually originate in the heart, discovered only two years ago. These cardiac stem cells exist in very small numbers, but doctors at Johns Hopkins School of Medicine have figured out how to harvest them by taking a small tissue sample from the heart and then growing them in culture.
The cells have not yet been tested in humans, but when injected into animals they appear to go straight to the heart and regenerate tissue, says Dr. Eduardo Marban, chief of cardiology at Johns Hopkins. "The mystery is: If these cells do work to heal the heart, how do they work?" questions Marban. "We're reading the first page of a very long book here."
Long it may be, but Marban speculates that there could be evidence of whether or not adult stem cells work in humans in a year or two. It will certainly take longer to figure out why. There are many scientists in the field who believe the stem cells may be merely "good neighbors" that are prompting the heart's own healing process to kick into high gear.
That wouldn't be such a bad discovery, says Dr. David T. Scadden, co-director of Harvard University's Stem Cell Institute. "In the short term the stem cells may be providing something that reverses damage, but that could lead to a whole new generation of studies into an off-the-shelf drug that would perform the same function." In that dreamscape, heart attack victims could just visit the pharmacy instead of the hospital.