Almost weekly in the news there is an article about a new scientific breakthrough and how animal models were instrumental in making this discovery.
Case in point, just this week a paper was published showing that a single session of a gene therapy cures Sanfilippo Syndrome A in animal models. [Sanfilippo Syndrome A is tragic and fatal neurodegenerative disease, diagnosed early in childhood and is fatal by the time adolescence is reached].
In order to understand human biology and disease, and potentially identify treatments and cures, the scientific community has come to rely heavily on living systems that can be experimentally manipulated. Animal models include mice, rats, zebrafish, fruit flies, and more.
How are animal models of human disease made?
One way is to use radiation and chemicals to cause random mutations in organisms that are then screened for physiological changes, usually in a high-throughput assay. Large-scale mutation screens such as this are useful in smaller organisms, like yeast and zebrafish. This approach can lead to the discovery of previously unknown disease pathways.
Instead of screening for disease-causing mutations, specific mutations that are known to be linked to disease can be introduced to an animal’s genome. For gain of function studies, this can be accomplished by direct microinjection of the gene into the pronucleus of a fertilized egg. For loss of function (knockout) studies, transgenic animals are generated with the help of embryonic stem (ES) cells. Homologous recombination eliminates the gene’s function through a double-crossover event. These engineered stem cells are then injected into early-stage blastocysts.
An international collaborative effort is currently underway to knockout every one of the 20,000 mouse genes in mouse ES cells, paving the way for a complete library of knockout mice to study the function of any desired gene. More than 18,000 genes have been knocked out of ES cells, and there are nearly 2,500 knockout mice in the International Mouse Knockout Consortium library. Having a complete library of knockout mouse ES cells available will maintain the mouse’s dominance as an animal model. Even with this nearly complete library of mouse ES knockouts, a large investment of time (and money) is still required to understand the biological function of each gene. To that end, the NIH has committed at least $110 million to the International Mouse Phenotype Consortium, which aims to do just that.
For those not married to mouse models, zebrafish are a good alternative animal model to study the effects of gene knockdown. Morpholinos, short oligomers that target the RNA of interest, are injected directly into the zebrafish embryo. The morpholino blocks or reduces translation, and the result is gene knockdown that is usually apparent within 3-5 days. This alternative knockdown model allows for rapid screening of candidate genes in an animal model, with significantly less investment than the typical mouse model.
 Haurigot, V., et al., (2013) Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy. J Clin Invest. doi:10.1172/JCI66778.
 International Mouse Knockout Consortium. Progress listed on their homepage. Statistic cited from July 2013.
 E. Dolgin (2011) Mouse library set to be a knockout. Nature 474, 262-263 (2011) doi:10.1038/474262a
 Bill, BR et al. (2009) A primer for morpholino use in zebrafish. Zebrafish. March; 6(1): 69–77. doi: 10.1089/zeb.2008.0555