Stem Cells for ALS

Does anyone need more proof that stem cells are not going to serve as universal repair kits for Alzheimer’s disease, Parkinson’s disease, Lou Gehrig’s disease and spinal cord injury any time soon? Here is what counts as a big breakthrough in stem-cell research these days: producing cells that can then be studied for clues to what drugs will work against a particular disease.

I don’t mean to be cynical. Scientists today are announcing what is truly a milestone: they have taken skin cells from two elderly women—ages 82 and 89—who have Lou Gehrig’s disease, or amyotrophic lateral sclerosis (ALS), and used a technique that was announced less than a year ago to make the cells go backward in time, so to speak, and become embryonic stem cells. The researchers then made the stem cells morph into spinal motor neurons, the very ones that die in ALS. It’s a milestone because earlier studies had generated these induced stem cells from healthy donors, but no one knew if it would work on cells from elderly patients with a serious genetic disease.

So kudos all around. But the achievement is not, as the press release puts it, “an important step toward the goal of using induced pluripotent stem cells . . . to treat disease”—except if the step is small and the goal is decades away.

Just to recap what scientists led by Kevin Eggan of the Harvard Stem Cell Institute and Christopher Henderson of Columbia are reporting online today in Science. They started with skin cells from the two women, who had an inherited form of ALS in which one gene is mutated (this mutation is the cause of only about 2 to 5 percent of ALS cases, however, something to keep in mind). They then followed the recipe discovered last year, introducing four genes into the skin cells to “reprogram” them, essentially causing the cells to revert to embryonic stem-cell status. They then bathed the "pluripotent" cells in a stew of molecules that caused them to morph into motor neurons. Voila: motor neurons with the exact same genetic make-up as the women.

Not too long ago, that possibility was hailed as a technique for producing “patient-specific cells” that could then be returned to the patient to cure what ailed her. But think about it. The cells carry the same mutation that causes these women’s ALS in the first place. Transplanting them into the women would be like putting a cirrhotic liver into an alcoholic whose own liver was kaput.

Sure, maybe the cells could be used to generate genetically-matched healthy neurons to replace the diseased ones. But in a press conference, the scientists were quite clear about the more likely next step. “Because the cells contain the genes that produced the disease [in these women],” Eggan said, “you can study them in a Petri dish.” Henderson added, “we don’t understand the disease process, and that is preventing us from developing cures. But we now have in a culture dish cells with the same genetic make-up as the ALS patients in the very cells that are affected by the disease. We’ll see if they degenerate and die faster than normal cells, and will try to understand the mechanism of the degeneration process, since it is the mechanism that is the key to a cure, and will test chemical compounds that might stop the degeneration.”

That may sound like something that should have been done before, but in fact it has been impossible to isolate the diseased motor neurons from ALS patients, of which there are about 30,000 in the United States. With a limitless supply of those neurons thanks to the iPS technique, scientists can both study the disease process and try everything they can think of to stop it.

Eggan had originally hoped to produce patient-specific stem cells using human eggs, in the process called therapeutic cloning, or somatic-cell nuclear transfer. In this technique, scientists remove all the genetic material from the ovum and replace it with the DNA from the skin cell of a patient. The fertilized ovum undergoes several cell divisions, yielding stem cells that the scientists then extract and induce to differentiate into the motor neurons they want to study.

But despite blanketing the Boston area with ads asking women to donate, he had no takers: women were eager to help, but when they learned that Massachusetts law prohibits the scientists from compensating them in any way—not for lost time at work, not for transportation—they had second thoughts. Women can, of course, be paid thousands of dollars for donating eggs to infertile couples. “Over the last two years we’ve done everything we could within the law to recruit women to donate ova,” Eggan said. “We were never able to recruit enough donors because we were legally prevented from providing the same sort of compensation that these women would receive for donating their ova for in vitro fertilization.”

In another sign of how crazy the politics of stem-cell research have become, the Harvard/Columbia research was financed by the New York Stem Cell Foundation and Project ALS—no government money allowed.