ALS is the first major neurodegenerative target of clinical trials using neural stem-cell grafts. the center of public attention during a New York Academy of Sciences conference held in New York City in the early 1980s.1Since then, the field has gone through a number of experimental and conceptual shifts, including, most notably, the appreciation of the widespread activation of cell-death programs written in the genome of all vertebrate animals suffering from neurological disease; the discovery, in the 1990s, of a host of naturally occurring molecules (peptides), termed trophic factors, that modulate or suppress these cell-death programs in mammalian organisms; and the reemergence, in the early 2000s, of cell therapies using neural stem cells after disappointments in early clinical trials with trophic peptides (seefigure). Physique courtesy of Vassilis Koliatsos and Leyan Xu Scientists introduced stem-cell therapies as interventions that work presumably without directly interfering with cell-death programs. They were designed to replace dying or dysfunctional neurons regardless of the mechanism of neuronal demise. Still, it is possible that these therapies best contribution is the local manufacture and release of trophic peptides, as well as the delivery of these peptides to sick nerve cells with greater accuracy and in larger quantities than would be possible with conventional injections of trophic peptides into muscle or under the skin. In lieu of intramuscular or subcutaneous injections, neural stem cells can differentiate into neurons and transfer trophic peptides to other neurons via synapses. This is a great way to give trophic treatment that no one would have thought possible ten years ago. In the 1990s, scientists identified more than five different trophic peptides that promote the survival and function of motor neurons. This discovery inspired optimism in the ALS research field. By 2000, however, researchers had deemed several clinical trials unsuccessful or unsafe, and any future optimism was thwarted by the prevailing view that this spinal cord, lacking cells and signals that promote regeneration in adult humans, may not be an ideal environment for new growth. Three years ago, it came as a pleasant surprise HSPC150 when investigators discovered that neural stem cellsprecursor cells that can divide only a few occasions and then give rise to mature cells of the nervous system, such as neurons and gliacan successfully survive and differentiate into mature neurons when injected into the adult spinal cord.2The observation that such newly differentiated neurons make contacts with motor neurons in the host spinal cordincluding motor neurons of animals with a genetic form of ALS that greatly resembles the human diseasewas the first demonstration that motor circuits can be reconstituted with the help of stem cells, at least to a limited degree.3In addition, scientists found that grafts of neural stem cells in the spinal cord help relieve paralysis and improve the overall survival of rats and mice with genetic forms of ALS. This spurred new enthusiasm for the concern of clinical trials in humans.4,5 Everything that goes into isolating, culturing, and grafting neural stem cellsindeed, all types of stem cellsaffects the therapeutic outcome. Where and how you pick the initial cells, how you grow them, what chemical and other treatments you expose them to before grafting, how many you graft, and how exactly you Salermide graft them: All these factors are relevant to the outcome.6Our recent success in preclinical therapeutics with neural stem cells in models of ALS,4,5which led to the clinical trial described in Dr. Glass article, may have well been the result of initially isolating these Salermide stem cells from the spinal cord. Cells isolated in such a fashion have positional and other cues that optimize their maturation when we restore them to their environment of origin. The endowment of these cells with positional and other cues might also have hampered their potential to form tumors, as occurs with neural precursors derived from human embryonic stem cells. The fact Salermide that these spinally derived stem cells were cultured in monolayer (they were not allowed to Salermide form three-dimensional structures.