December 4th, 2008

Researchers at the Salk Institute in La Jolla, California have announced two ground-breaking accomplishments: one is a demonstration of the fact that amyotrophic lateral sclerosis (ALS) can be improved with specific antioxidants, and the second is the creation of a new model of ALS which is based upon human rather than mouse tissue.
Dr. M. Carol Marchetto of the Salk Institute has created the first human ALS laboratory model ever developed, by using human embryonic stem cells. Previously, laboratory experimentation with ALS has typically been conducted with mouse models, which are only rough approximations of human ALS since the disease is caused by genetic mutations that are unique to the human genome and cannot be identically reproduced in the mouse genome. Dr. Marchetto has circumvented the problems associated with the mouse model by creating the new human model, in which she induced a genetic mutation in SOD1 (superoxide dismutase 1), the gene that instructs the body in how to manufacture the enzyme superoxide dismutase, which, among other properties, defends the body from the oxidative and inflammatory cellular damage caused by free radicals, which have long been suspected of playing a key role in motor neuron death. By studying the cellular environment of the motor neurons in this new human model, the researchers made an important discovery with astrocytes (astroglia), which are the star-shaped glial cells in the brain and spinal cord that play a number of key roles, which include providing nutrients to the nervous tissue, repairing brain tissue and supporting endothelial cells, especially in the blood-brain barrier. In a cellular environment in which ALS is present, the researchers discovered that the astrocytes are constantly bombarding the motor neurons with free radicals. The team of scientists then began testing potential drugs for their antioxidant and anti-inflammatory properties, which could possibly protect the motor neurons from the damage caused by the constant stream of free radicals. Although several pharmaceuticals were found to be prime candidates, the naturally occurring antioxidant apocynin, which is present in many plants, was identified for its ability to prevent neuronal death by blocking both the oxidation and the inflammation of the motor neuron cells. Short of figuring out how to get the astrocytes to stop secreting free radicals, the next best approach is simply to block the damage caused by the free radicals.

Until now there has only one drug approved for the treatment of ALS in the United States, namely, riluzole, which at best can only slow the progession of the disease by a month or two and does nothing to reverse the cellular damage caused by the death of the motor neurons. According to Dr. Fred Gage, professor of genetics and the principal investigator of the study, "There is an urgent need for new models of the disease that have the potential to translate into clinical trials and that could, at a minimum, be used to verify drugs and drug targets."

Many embryonic stem cell experts, including the pioneering embryologist Dr. James Thomson, have emphasized the point that the development of actual cell-based therapies from embryonic stem cells is a long and complex process, and such therapies are still at least a decade away, if not further. Meanwhile, instead of directly seeking cell-based cures, such embryonic stem cell authorities have advocated an approach that focuses on the use of embryonic stem cells for drug testing and development, and this new human model of ALS is an excellent example of precisely such an approach. Although the use of embryonic stem cells even for this purpose does not pacify the embryonic stem cell opponents, who still find the use of embryonic stem cells for drug testing to be unethical, the new ALS model nevertheless does highlight the sobering scientific reality that therapeutic cell-based cures from embryonic stem cells will not be immediately forthcoming, purely for scientific, not political, reasons. Opponents of embryonic stem cells also point out the fact that adult stem cells could just as easily be used to create new laboratory models of diseases, bioengineered from human rather than mouse tissue, while avoiding entirely the controversial ethics of embryonic stem cells as well as the numerous scientific problems and medical dangers that are inherent in embryonic stem cells, such as their ability to form the specific type of tumor known as a carcinoma, among other problems. Furthermore, laboratory models of diseases created from adult stem cells could be used not only for drug testing but also for the development of actual cell-based therapies that directly use the adult stem cells themselves for the treatment of disease and injury. In fact, such cell-based therapies have already been developed from adult stem cells, and are already in clinical use.

Although a major advantage of Dr. Marchetto's new ALS model was the fact that it was conducted on human cells, rather than in mice, she and her colleagues are now planning to test apocynin and other chemicals in mouse models of ALS to see whether or not there is any real benefit that can be measured in mouse survival.