Researchers replicate ALS process in lab dish

A Harvard Stem Cell Institute (HSCI) research team has succeeded in deriving spinal motor neurons from human embryonic stem cells, and has then used them to replicate the Amyotrophic Lateral Sclerosis (ALS) disease process in a laboratory dish.

The researchers, led by HSCI principal faculty member Kevin Eggan, found that human motor neurons exposed to glial cells carrying a known genetic mutation associated with ALS died, while other types of neurons exposed to the disease-carrying glial cells were unaffected.

“The logical next step is to ask what the glial cells are doing to kill the motor neurons,” said Eggan, an assistant professor in Harvard’s new inter-School Department of Stem Cell and Regenerative Biology.

Eggan said that the new findings are particularly important for ALS research because they answer the field’s long-standing “murder or suicide” question. That is, do motor neurons in patients with ALS — an always-fatal, neurodegenerative condition commonly known as Lou Gehrig’s disease — die because of something inherent to the motor neurons, do they “commit suicide?” Or, are they “murdered” — is there something external killing them? This latest research strongly suggests that the motor neurons are being “murdered” by something in the glial cells carrying a mutation of the SOD1 gene.

Additionally, Eggan said, this latest study is “important for stem cell science because one of the things we’ve been promising is that these stem cells would be important for drug discovery. We’ve produced industrial quantities of these motor neurons; we’ve shown that this does work, that you can overcome the technical limitations. This is a disease process in a petri dish, and that’s what we’ve been promising.”

Finally, he said, this experiment once again proves the utility of human embryonic stem cells, and confirms the value of continuing to use them to study both normal development and disease process, particularly as there have yet to be studies demonstrating that alternative types of cells are identical in all respects to human embryonic stem cells.

In addition to replicating the disease process, Eggan, postdoctoral fellow Paolo DiGiorgio and colleagues Gabriella L. Boulting and Samuel Bobrowicz demonstrated that an inflammatory pathway plays a role in the disease process, and they found a small molecule that has at least some protective effect. Eggan noted, however, that when that same compound has been tested on ALS patients it has not slowed the disease process. “We don’t know,” he said, “whether there may be other issues there, whether there are problems involving the blood-brain barrier, or dosing levels.”

Less than six months ago, using induced pluripotent stem cell (iPS) technology, a team lead by Eggan, who in addition to his Harvard titles is a Stowers Medical Institute Investigator, produced patient-specific stem cell lines from the skin cells of ALS patients.

In spring 2007, Eggan and colleagues created an ALS model using mouse stem cells. But research findings in animal models always beg the question of whether the results will translate directly to humans. In this case, the answer to that question is a resounding “Yes!”

The publication of this latest paper in the journal Cell Stem Cell is only the second report in the literature of human stem cell work resulting in the replication of a disease process in a laboratory dish. That work, involving Fragile X Syndrome, did not involve the derivation of a specific cell type.

bd_colen@harvard.edu