Common Ortholog Models & Their Use in Drug Development Research
An animal model is a non-human species that has been widely studied and used during research to help understand biological processes in a laboratory setting. The use of animal models as human surrogates has provided a great deal of information about physiology and disease with over 150 Nobel Prizes awarded in physiology or medicine to professionals utilizing animal models for their research.
The primary reason for the use of animal models is the evolutionary principle that all organisms share some degree of relatedness and genetic similarity. Vertebrate models in particular are useful as human surrogates in drug discovery and medical research due to their more common ancestry. Though there are many vertebrates that could be used, a few are more common in research than others.
Mice are the most popular vertebrate species in research today because of their availability, ease of handling, size, fast reproduction rate, and low cost. Biologically, mice are very similar to humans and are susceptible to many of the same diseases as humans. With a total of 49 nuclear receptors, mice are considered to be one of the best models of inherited human disease.
The mouse is also among the first mammalian species to have its genes mapped and modified to better understand genetic diseases. The ability to manipulate the mouse genome and the ease of producing “knock-in” or “knockout” mice compared to other mammalian models is what makes the mouse so widely used today. This has made mice useful in studying and modeling many different conditions, including arthritis, anxiety, aging, cancers, diabetes, obesity, heart disease, substance abuse, and Parkinson's disease.
Like mice, rats are commonly used vertebrates in research and were the first mammalian species specifically domesticated for the laboratory. Since gene editing was developed for use in mouse models first, rats have recently taken a back seat to mice. Rats have 47 nuclear receptors, and their DNA, physiology, and size allow scientists to research a variety of physiological and pathophysiological mechanisms that would not be possible in a mouse model. Because of these differences, rats are chosen over mice in studying cardiovascular and metabolic disorders, digestive system conditions, and health problems related to neurologic disease.
The zebrafish is a newer model compared to rodents but has quickly earned its place as a valuable model system that is becoming more common in research. Though not mammals, zebrafish share approximately 70 percent of genes with humans and have 73 nuclear receptor genes including all 48 human nuclear receptors. Zebrafish also have a nearly transparent body during early development, which provides unique visual access to their internal anatomy. While they’re related to humans then mice, zebrafish’s smaller size, ease of handling, lower cost, and faster reproduction rates make them a very attractive model. Zebrafish are most commonly used to study development, toxicology, specific gene function, and roles of signaling pathways.
Dogs are large animal models that are physiologically and clinically more like humans than rodents. Dogs have approximately the same number of genes as humans, most of them being close orthologs to humans. Most notably, dog models were used to understand insulin production in the body and the role of the pancreas in this process. Dogs are now used as models for studying human and veterinary diseases in aging and Alzheimer’s, cardiology, endocrinology, and long-term treatment protocols.
Although non-human primates (NHP) are the most closely related animal models to humans – with chimpanzees being the closest – they are rarely used in research and remain protected from highly invasive procedures. Non-human primates are used as models for the study of viruses such as HIV and hepatitis, and for research in neurology, behavior and cognition, genetics, and xenotransplantation.
Understanding Ortholog Differences
Studying orthologs can be informative, but care must be taken when generalizing from one organism to another. Therefore, the use of in vitro functional cell-based assays to understand a compounds function against nuclear receptors is an important step prior to in vivo trials in drug development research.
INDIGO Biosciences is a leading provider of all-inclusive cell-based nuclear receptor assays. INDIGO’s ortholog kits and services can provide researchers with the critical data they need to understand the differences in receptor functioning between orthologs, whether it be to choose the correct ortholog pre-trial or to understand off target effects post trial.