Animal models contribute significantly to our understanding of molecular mechanisms underlying disease pathologies. However, few models predictably translate preclinical findings into what will happen in humans.
Investigational drugs are able to cure mice from many diseases, but continue to fail in clinical trials. This fact is largely attributed to poor model designs that do not sufficiently reflect the pathophysiology of disease in humans. In addition, tremendous diversity of human genetic background, co-medications, dosing, timing of treatment, and many other factors greatly influence the treatment outcome.
The new generation of animal models, described in this article, takes into consideration previous shortcomings. These models aim to reflect the human condition as closely as possible and to close the gap between translational research and the bedside.
Inbred lab mouse strains with fixed and highly reproducible genotypes are a powerful tool for genetic manipulation. Mouse embryonic stem cells are easily amenable to genetic modifications, and thousands of genetically modified mouse strains were developed in the last 20 years.
“And yet, the inbred lab strains proved to be a poor system for discovery of specific genes associated with a particular trait, such as obesity or high blood pressure,” comments Gary A. Churchill, Ph.D., professor and principal investigator, The Jackson Laboratory.
“This is a result of their limited genetic diversity and large ‘blind spots’ largely devoid of genetic variations. We cannot resolve trait association at the level of an individual gene.
“In contrast, human genome association studies map individual genes to traits with a high degree of accuracy, but this is not enough to make a conclusive disease diagnosis.
“Therefore, discovery of a genetic basis of a complex trait required a radically new genetic strategy.”
Jackson Labs is a key participant in the International Collaborative Cross (CC) project, with the goal to create new types of inbred strains based on eight parents selected from the existing laboratory and wild strains.
“CC mice demonstrate high levels of genetic diversity,” continues Dr. Churchill. “Jackson Labs used this opportunity to take CC ideas to the next level.”
The same progenitor lines served as the parent lines for the JAX Diversity Outbred (DO) Population. This unique mouse population is maintained by a carefully designed outbreeding strategy. While still not as diverse as humans, DO mice more accurately reflect human genetic architecture and may provide better insight into genetic mechanisms of human diseases.
“The DO animals proved to be an excellent tool for mapping trait-associated loci to a higher level of resolution,” says Dr. Churchill.
Using DO mice, his team mapped a cluster of genes conferring sensitivity to doxyrubicine, a common chemotherapy agent. Within the cluster, protective, susceptible and neutral alleles were identified. The Jackson lab is collaborating with the National Institute for Environmental Health and Safety to identify susceptibility genes for other environmental pollutants.
“We hope that in the future these results will support toxicology analysis of human therapeutics,” says Dr. Churchill.