Trials of the Heart

Adult human stem cells may offer the opportunity to use one of biomedical science's most promising technologies without the ethical dilemmas of embryonic cells.

Christopher Thomas Scott(cscott@the-scientist.com)
Jul 3, 2005
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Adult human stem cells may offer the opportunity to use one of biomedical science's most promising technologies without the ethical dilemmas of embryonic cells. But whether the cells' plasticity-or ability to ignore germ-line heritage and differentiate into therapeutically useful tissues-warrants clinical application at this stage remains controversial.

"We're still debating it," says Amy Wagers, Harvard Medical School investigator and plasticity critic. "It's too early to tell which way things will fall." Biologists generally agree that even the most potent adult stem cells can't approach the therapeutic power of embryonic stem cells. Nevertheless, at least a dozen clinical trials based on adult-cell plasticity have commenced in patients with serious heart disease – prematurely, some contend.

REVERSING FATE

In embryonic development, cells form three germ layers: ectoderm, mesoderm, or endoderm. Generally, biologists considered cell differentiation overwhelmingly unidirectional and progressively restrictive. A cell fated to make neurons could not make blood cells; a...

CHANGING STORIES

By early 2004, many of the original claims of stem cell switching had been refuted. Early results couldn't be repeated and experimental design was called into question. Several papers indicated that adult stem cells had not changed into, but rather fused with organ cells. Two labs attempted to repeat experiments showing blood-heart plasticity in mice and primates, but failed.34

In a follow-up study, Wagers, along with Stanford's Leora Balsam, Robert Robbins, and HSC pioneer Irving Weissman, injected highly purified populations of genetically tagged HSCs into the heart muscle of 23 mice. The transplanted cells did not increase the survival rate in mice, did not typically persist in the heart muscle more than 30 days, and did not produce the signature proteins of heart cells.5 They did notice slightly improved pumping efficiency, however.

It's important to note that the bone marrow-heart trials have been conducted safely, and the clinical effect, while small, is significant. Despite this, many basic scientists say the clinicians moved too swiftly. Transplanting mixed populations of cells, they say, leaves the mechanisms of the therapy locked in a black box. "It is important to do as much basic research as we can before going to clinical trials," says Johns Hopkins University professor Saul Sharkis. "We still don't completely understand the mechanisms of stem cell repair."

Wagers worries about declaring victory too early. "If we consider a 6% improvement in cardiac function a success, then we've left behind an opportunity to understand why this is happening and aim for a 60% improvement." Clinicians bristle when told that they should slow down. Joshua Hare, principal investigator for the Johns Hopkins trial says, "It's unethical to wait. We won't fully understand the mechanism until we do the clinical research. That's what evidence-based medicine is all about."

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