A matter of decades ago, the idea of turning a humble skin cell into a live, firing nerve cell would have seemed impossible; perhaps deemed the result of reading too many science fiction novels. Yet in a paper published earlier this year in PNAS, an international collaboration of researchers has done exactly this — essentially ‘reprogramming’ skin cells and changing them on a fundamental level into nerve cells (Bilican et al. 2012 PMCID: PMC3326463).
Fly, fish and mouse models are commonly used in research; however, they can only give insight as to what might be happening in humans. As experimentation can’t be performed on the latter, researchers are continuously looking for humanized models to study certain human diseases.
Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease, which causes motor neuron death and muscle wasting. This gives way to paralysis and eventual breathing difficulties that are ultimately fatal. Animal models have been heavily used in order for researchers to understand this devastating disease. However an international group of scientists (including Sir Ian Wilmut of Dolly the sheep fame) have managed to create human motor neurons that successfully mimic ALS from the skin cells of patients with the disease.
In proof-of-principle experiments the researchers selected skin cells from a 56-year old male ALS sufferer carrying the TDP-43 mutation for their motor neuron cell candidates. TDP-43 accumulation and aggregation in motor neurons is a pathological hallmark of inherited and non-inherited forms of ALS, and can be caused by a mutation in the TARDBP gene. The Proteintech TARDBP antibody can be used to bind to N-terminal TDP-43 to visualize or detect TDP-43 aggregation. (In the PNAS paper, the researchers used this antibody for all TDP-43 Western blotting experiments.)
The researchers next used retroviral gene transduction to insert reprogramming factors into the TDP-43 mutation-carrying skin cells to transform them into cells known as induced pluripotent stem cells (iPS cells). iPS cells can be manipulated to differentiate into any cell in the body, and these particular iPS cells were used to generate motor neurons.
The resulting human-derived motor neurons successfully mimicked ALS, matching ALS motor neurons for TDP-43 protein levels and survival. Furthermore, and most promisingly, the researchers concluded this motor neuron model could be used to screen potential new drugs for ALS treatment. A large number of potential ALS drugs fail clinical trials in humans, despite showing promising results in animal models. This novel human motor neuron model could eliminate unnecessary clinical trials that are ultimately destined to fail. This model could screen pre-clinical ALS drugs and improve the likelihood of their success and efficacy in humans. Potentially, this was one of the biggest discoveries in the ALS field in 2012.