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ALS Worldwide
October 05, 2015

Human Neuronal Cells VS. Animal Models for Drug Development and Neurotoxicity Testing

Two important papers were recently published from scientists at the University of Wisconsin, where stem cell technology was pioneered almost two decades ago. The results presented likely represent a new paradigm for how to study human neural cells in 3-dimensional “scaffolds” so that drugs can be tested for effectiveness in diseases like ALS, or toxicity to nerve cells, without having to use experimental animals.

One of the goals as presented in the first paper was to develop a cell culture system to evaluate accurately the toxicity of chemicals on human neural cells (neurons and glia). To accomplish this, the investigators developed a growth system consisting of an inert polymer substrate (polyethylene glycol) containing chemical modifications, such that when it was mixed with other chemicals and exposed to UV light, it would polymerize into a semi-solid matrix. By including some peptides in the mix, the scaffolds were made to be “tissue friendly”. Human neural stem cells and human neurons grew well in this 3D scaffold, connecting with each other and becoming electrically active. The scientists then exposed the neurons to a panel of chemicals with no known toxicity or a panel of chemicals known to be variably neurotoxic. After exposure, the cell responses of the neurons in the 3D scaffolds were assayed using modern “next generation” sequencing technology. Armed with this data on cell responses to each chemical, the scientists then used “machine learning”, which is a computer technique by which the computer “learns” the molecular signature of which chemical is toxic and which is benign. Using this approach, they achieved >90% accuracy in showing which individual chemical was toxic to neurons.

In the second paper, another group from the same institution used their new 3D scaffolds to show that human neurons grown in their scaffold showed biochemical evidence of toxicity to botulism toxin ~2 weeks before neurons grown in typical 2-dimensional culture plates showed the same toxicity. Also, neural stem cells (that can be turned into neurons or glia (astrocytes)) would become mostly glia if grown in 2D plates but would become mostly neurons if grown in the 3D scaffold. Thus, their 3D scaffold system holds many advantages for producing and studying human neurons in culture.

What might these findings mean for developing ALS therapeutics? We can now make neural stem cells from fibroblasts (skin cells) or mononuclear cells (from blood) of ALS or CTL persons. These neural stem cells divide and can be propagated in culture. Based on these two recent papers, and the work of many other investigators, it is becoming clear that for several reasons it is better to grow these cells in 3D scaffolds than in traditional 2D culture plates. Drugs can be screened for neuron survival-promoting effects using machine learning, or screened for toxicity using the same 3D culture system. All of this takes place without use of animals, which are expensive, time consuming for generating results, controversial as to utility for being therapeutic models of neurodegenerative diseases, and ethically problematic for some.

Papers

  1. Schwartz MP, Hou Z, Propson NE, Zhang J, Engstrom CJ, Costa VS, Jiang P, Nguyen BK, Bolin JM, Daly W, Wang Y, Stewart R, Page CD, Murphy WL, Thomson JA. Human pluripotent stem cell-derived neural constructs for predicting neural toxicity. Proc Natl Acad Sci U S A. 2015 Sep 21.
  2. Pellett S, Schwartz MP, Tepp WH, Josephson R, Scherf JM, Pier CL, Thomson JA, Murphy WL, Johnson EA. Human Induced Pluripotent Stem Cell Derived Neuronal Cells Cultured on Chemically-Defined Hydrogels for Sensitive In Vitro Detection of Botulinum Neurotoxin. Sci Rep. 2015 Sep 28;5