Drug Discovery
scientific justification and performance for the model in question above any other consideration. Although all B6 mice look very similar, they are far from carbon copies, and the B6 substrains produced and sold by different vendors can and do perform very differently. The choice and source of B6 substrains is critically important and should be a top priority when establishing and validating research models.
The microbiome and B6 model performance
While genetic variation between B6 substrains has been acknowledged for some time, there is a grow- ing appreciation for how the microbiome affects the performance of B6 models. The microbiome encompasses the entire population of all micro- organisms (bacteria, fungi, etc) that inhabit the body, and modern research has shown that the microbiome can have major impacts on health and disease. Differences in the microbiome in B6 mice can have an equal, if not greater, impact on model performance as compared to genetic influences. The effect of the microbiome has been shown in a wide variety of research models, including infec- tious disease, immunological disorders, oncology, diabetes (Type 1 and Type 2), obesity and neuro- logic disorders (eg, autism, Parkinson’s and depres- sion), to name a few. The microbiome is also sus- pected to be one of the most impactful variables contributing to irreproducibility in animal models. Unfortunately, in this relatively new field there are no standard approaches to address the microbiome in B6 models and relatively few options available for researchers to control for its effects or harness its potential.
The animal vendor industry does not typically provide options to buy B6 mice with a known microbiome, but rather relies on the exclusion of specific pathogenic organisms. While excluding a pathogen can be straightforward, controlling the overall microbiome of a mouse is challenging. The microbiome of a B6 mouse is determined by a number of key factors: environmental exposure (from housing location and other mice), husbandry conditions, diet and water. Typically, B6 mice pro- duced in a single location will tend to have similar microbiomes, compared to those produced in other locations, even if all other factors are tightly con- trolled. For example, B6 mice ordered from differ- ent vendors, and even different production loca- tions from the same vendor, can possess very differ- ent microbiomes. A general recommendation is to obtain B6 mice from specific locations (ie, barrier facilities) when validating a model to select for a
Drug Discovery World Fall 2017
microbiome profile that is optimal and then to exclusively source from that location throughout the life of the study.
Although there are few options for researchers to select a specific B6 microbiome, one option is to select mice that carry specific commensal (ie, non- pathogenic) organisms that are known to affect model performance. One such example is an organism known as segmented filamentous bacte- ria (SFB). SFB lives in the mouse gut, where it reg- ulates immune system development, and has been shown to affect the performance of immunology, diabetes and obesity models. Only one vendor, Taconic Biosciences, reports on the presence or absence of this important organism and provides options to obtain B6 mice with or without SFB. Other strategies to control the microbiome in B6 models are still in their infancy, but the recognition of this important factor will hopefully lead to bet- ter microbiome options for researchers.
Considerations for selecting B6 mice Selecting an appropriate B6 and using it to its fullest potential is challenging, yet critical for the successful completion of any research project. Unlike many other tools and consumables in the biomedical industry, there is no standard B6 and there are few established criteria to monitor perfor- mance. A pipette, for instance, will either deliver liquids with accuracy and precision, or it will not. Either way, this can be determined empirically, and there are set criteria for evaluating one pipette ver- sus another. As another example, chemicals are sold as known molecular entities at specified levels of purity. There is a reasonable expectation that one chemical compound will work just as well as another, given that same level of purity. In contrast, the biological basis of B6 mice is complex and messy. Unlike the pipette, there is no easy way to establish equivalency between differ- ent B6 mice. Unlike the purity of a chemical com- pound, there is no way to know and quantify all the genetic, environmental and microbiome factors that would affect model performance. Instead, B6 models should be selected for a given application based on validation studies that consider all the variables that affect performance, including sub- strain, vendor source and microbiome.
The B6 toolbox: reshaping possibilities, enabling discovery Other than humans, more is known about the B6 genome than any other mammal. The B6 genome was first sequenced in 2002, and this knowledge has helped the B6 become the standard strain not
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