One Step Closer to the Bedside:
The Basics Bolster Stem Cell Therapy

Mahendra Rao nudges stem cells into becoming neurons.

“Cleveland’s studies, and ones like them, tell us there’s more hope for stem cells as a therapy than we’d thought,” says Center geneticist Mahendra Rao. First, we’re finding that motor neurons take a long time to die, Rao explains. “And that could buy us time for a therapy to take hold.” Second, the studies suggest that surrounding ailing neural cells with healthy cells keeps them whole even longer. “The idea is that we wouldn’t have to replace every cell that’s damaged. Restoring maybe 10 percent new cells would give a bigger bang for your buck.”

Add to that a report by Center advisor Thomas Jessell, a Columbia University biologist, and the possibilities of stem cells as therapy grow stronger. Jessell, like Rao, works with ES, or embryonic stem cells—those with the potential to become any cell type. Recently, Jessell became the first to coax mouse ES cells into becoming motor neurons.

And that’s made Rao’s pulse quicken. “We’ve been following that route with human ES cells,” he says, “and so far, we feel we’re on track for developing the sort of replacement cells you’d need for neurodegenerative disease.” From the human stem cells, his team’s been able to culture healthy quantities of glial cells—motor neurons’ neighbors—and, apparently, motor neurons as well. His version of the latter carry the same identifying proteins as motor neurons. They send impulses and secrete the right nerve transmitters; they’re stable; they don’t appear to mutate. Like motor neurons, they synapse with other nerve cells.

Stem cell-generated motor neurons have the right stuff.

“But we’re not home free,” says Rao. His team’s cautious because they have yet to see if the cells behave properly—that they migrate where they should and make right connections—when transplanted. Right now, they’re implanting various human ES offshoots in rats with spinal cord injuries. “This is our grunt work” he explains. “You have to do these studies before you can move to the next stage, that of putting all this into practice in the clinic. There’s no getting around the nuts and bolts.”

Stem cells may also hasten therapy in another way that Rao expects to catch on fast. Their ability to provide large numbers of nervous system cells in cultures is “a huge plus” for testing drugs and pinning down how they work, not to mention advancing ideas on ALS biology. “Animal models, of course, have drawbacks for predicting human therapies. We only have a few human nervous system cell cultures because it’s hard to get such tissue and even harder to grow it,” says Rao.

“You can’t just put nerve cells in a lab dish and test ‘em. But with ES cells, we can make our own cell lines and test drugs. We can work in genes that we think might protect cells or improve their resistance to ALS and see what happens.

I have no doubt that these cultures will change the face of ALS research.”

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With approaches to ALS therapy, progress seems to move one step forward and a half step back.