The study of genetics provides insights into how traits are inherited and how biological processes function. Mice have emerged as a model organism, allowing scientists to explore complex genetic mechanisms in a living system. Their genetic makeup and biological similarities to humans make them a tool for understanding normal biological processes and the origins of various diseases. This reliance on mouse models has shaped advancements in biological and medical research, helping address health challenges.
Why Mice are Chosen for Genetic Research
Mice are used in genetic research due to practical and biological advantages. Their close genetic relationship to humans is a primary reason; approximately 95% of mouse genes have counterparts in the human genome, with protein-coding regions showing about 85% identity on average. Mice also share many anatomical and physiological features with humans, including similar organ systems and immune responses.
Another factor is their rapid reproductive cycle and short generation time. Female mice can reach sexual maturity as early as five to six weeks of age and have a gestation period of roughly 19 to 21 days. This allows researchers to study multiple generations quickly, observing inherited traits and long-term effects of genetic modifications. A single female mouse can produce five to ten pups per litter and may have up to 15 litters per year.
Beyond their biological attributes, mice are also convenient for laboratory settings. Their small size makes them easy to house and care for, and they can be maintained in large numbers, which reduces research costs. This combination of genetic similarity, rapid breeding, and manageable husbandry has established mice as the predominant mammalian model for genetic and biomedical research over the past century.
Modifying Mouse Genes
Researchers employ various techniques to manipulate the mouse genome, to investigate gene function and disease mechanisms. One common approach involves creating “knockout” mice, where an existing gene is inactivated or removed. This is achieved by disrupting the gene with an artificial piece of DNA, allowing observation of resulting changes in behavior or physiology to infer the gene’s normal role. Such models have been important in understanding genes whose functions were previously unknown.
Conversely, “knock-in” mice are generated by introducing specific gene sequences or mutations into a specific location within the mouse genome. This technique can be used to simulate human genetic diseases, introduce reporter genes to track gene expression, or replace mouse genes with their human counterparts to create “humanized” models. For instance, a point mutation can be introduced to study how subtle genetic alterations affect protein function.
“Transgenic” mice are another category, involving the insertion of foreign DNA (a “transgene”) into the mouse’s genome. This method allows for the addition of new genetic information or the overexpression of existing genes. While older methods like pronuclear injection led to random integration, modern techniques, including those that use homologous recombination in embryonic stem cells, offer more targeted approaches.
An advancement in gene editing technology is the CRISPR-Cas9 system. This tool allows for precise and efficient modifications to the mouse genome. CRISPR-Cas9 utilizes a guide RNA to direct the Cas9 enzyme to a specific genomic site, where it creates a double-strand break in the DNA. This break can then be repaired by the cell in a way that inactivates a gene (creating a knockout) or incorporates new DNA (creating a knock-in), accelerating the development of customized mouse models.
Unlocking Human Health Discoveries
Mouse models have been important in advancing our understanding of human diseases and biological processes. In cancer research, genetically engineered mouse models (GEMMs) provide systems to study tumor initiation, progression, and metastasis. Researchers use these models to investigate the roles of specific oncogenes (cancer-promoting genes) and tumor suppressor genes, such as the p53 gene, which when inactivated in mice, increases cancer susceptibility. Mouse models have also identified how different genetic mutations, like those in Kras, drive lung cancer.
In the context of Alzheimer’s disease, transgenic mouse models have been developed to mimic pathological features, particularly the accumulation of beta-amyloid plaques. These models often involve the overexpression of mutated human genes like amyloid precursor protein (APP) and presenilin 1 (PS1), which are associated with familial forms of the disease. While current mouse models may not fully replicate all aspects of human Alzheimer’s, they offer insights into amyloid toxicity and the biological underpinnings of the disease. Recent efforts aim to create mouse strains genetically susceptible to late-onset Alzheimer’s by introducing multiple human genetic factors associated with it.
Mouse models have also provided insights into diabetes and obesity. The non-obese diabetic (NOD) mouse, for example, spontaneously develops type 1 diabetes, making it a model for studying the genetic and immunological factors involved in this autoimmune condition. For type 2 diabetes and obesity, models like the ob/ob and db/db mice, which have mutations in the leptin gene or its receptor, exhibit early-onset obesity and insulin resistance, mimicking human metabolic syndrome. Diet-induced obesity (DIO) models, often using C57BL/6J mice fed high-fat diets, replicate human obesity and its associated metabolic dysregulations.
Mouse models have contributed to understanding cardiovascular diseases. Researchers use models like the transverse aortic constriction (TAC) model to induce cardiac hypertrophy and heart failure, to study underlying mechanisms of heart adaptations to stress. Genetically modified mice, such as those deficient in apolipoprotein E (apoE-/- mice) or low-density lipoprotein receptor (LDLR-/- mice), are used to study atherosclerosis and the development of arterial lesions. These models, despite some physiological differences in heart rate and calcium cycling compared to humans, remain useful for dissecting the molecular basis of heart conditions.
From Mouse Models to Medical Advances
The insights gained from mouse genetics translate into medical advancements, in preclinical drug testing and identifying therapeutic targets. Mouse models are used to assess the efficacy and safety of new drugs before human clinical trials. Over 70% of new cancer drugs are initially tested in mouse models. This helps researchers identify the most promising drug candidates and reduce the risk of adverse reactions in humans.
Mouse models also play a role in validating therapeutic targets. By observing the effects of gene modulation in mice, scientists can determine if a particular gene product is a target for drug intervention. For instance, humanized mouse models, where a mouse gene is replaced with its human counterpart, allow for the testing of human-specific therapies, such as antibody-based drugs, that might not interact with mouse proteins. A humanized mouse model was developed to test a novel dopamine receptor D1 potentiator for Parkinson’s disease, targeting the human protein.
Beyond drug testing, mouse genetics aids development of new treatments and diagnostic tools. Studies in mice have led to an understanding of disease mechanisms, leading to targeted therapies. For example, the breast cancer drug Herceptin, a monoclonal antibody, was informed by mouse studies that targeted the HER2 protein. Advances in mouse modeling, including the ability to test multiple antibodies simultaneously in a single mouse, are accelerating the drug development pipeline and reducing the number of animals required for preclinical studies.