Genetically engineered mouse models are powerful tools in biomedical research. These specially modified mice play a foundational role in understanding the mechanisms underlying human health and disease. Their use accelerates scientific discovery, providing insights difficult to obtain otherwise. Through precise genetic alterations, these models contribute to advancements across various fields of study.
What Are Genetically Engineered Mouse Models?
Genetically engineered mouse models are laboratory mice whose DNA has been deliberately modified to study specific biological functions or mimic human conditions. These alterations can involve adding new genetic material, removing existing genes, or changing specific sequences within a gene. Mice are chosen for this research due to their genetic similarity to humans, sharing approximately 95% of their genes.
Beyond genetic resemblance, mice offer practical advantages for research. Their small size makes them manageable in laboratory settings, and their relatively short reproductive cycles allow for rapid generation of multiple generations for study. Additionally, their biology is extensively understood, providing a robust foundation for interpreting experimental results. Altering a single gene in a mouse can reveal its role in development, normal physiological processes, or disease progression.
How Are Genetically Engineered Mouse Models Created?
The creation of genetically engineered mouse models involves several techniques designed to achieve specific genetic alterations. Early methods included transgenic mice, where foreign DNA, often a human gene, is introduced into the mouse genome. This involves injecting the desired gene into a fertilized egg, which then integrates into the mouse’s chromosomes.
A more precise approach involves creating knockout mice, where a specific gene is inactivated. This is often achieved through homologous recombination using embryonic stem (ES) cells. Scientists introduce a modified gene sequence into ES cells, which then replaces the mouse’s native gene, effectively silencing it. Conversely, knock-in mice are created by inserting a specific gene sequence or replacing an existing one with a modified version, allowing researchers to study the effects of a particular mutation or the expression of a novel gene.
Further refinement led to conditional and inducible models, offering greater control over gene alterations. Conditional models allow gene modifications to occur only in specific tissues or cell types. Inducible models enable researchers to activate or deactivate a gene at a specific time, often by administering a drug or chemical. These advanced controls enhance the precision of experimental design.
The advent of CRISPR/Cas9 gene editing technology has revolutionized the creation of these models due to its precision and efficiency. CRISPR/Cas9 uses a guide RNA molecule to direct a Cas9 enzyme to a specific DNA sequence, where it can cut the DNA. This cut can then be repaired by the cell’s own machinery, either inactivating a gene or allowing for the insertion of new genetic material. This system simplifies the process of making targeted genetic changes, accelerating the development of new mouse models.
Why Are Mouse Models Essential for Medical Research?
Genetically engineered mouse models are important for understanding and combating a wide range of human diseases. In cancer research, these models help scientists investigate tumor initiation, progression, and metastasis. Researchers can introduce cancer-causing genes or remove tumor-suppressing genes in mice to mimic human cancers, allowing for the testing of new therapies and the study of drug resistance.
For neurological disorders, mouse models are developed to replicate conditions such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and autism spectrum disorders. These models allow researchers to study disease mechanisms, identify potential therapeutic targets, and evaluate new treatments. For instance, mice can be engineered to produce human amyloid-beta plaques, a hallmark of Alzheimer’s.
In the study of metabolic diseases, including diabetes, obesity, and cardiovascular conditions, mouse models provide platforms to examine gene function and metabolic pathways. Researchers can induce insulin resistance or obesity in mice to test dietary interventions or new pharmacological agents. Similarly, models of infectious diseases allow for the study of viral and bacterial infections, enabling the testing of vaccines and antiviral drugs in a controlled environment.
Mouse models are also valuable for investigating rare genetic disorders, particularly those with unknown causes or limited patient populations. By replicating specific human mutations in mice, scientists can gain insights into the disease’s pathology and identify potential treatments. Beyond specific diseases, these models serve as a platform for drug discovery and development, allowing for preclinical testing of new drugs and therapies to assess their efficacy and safety before human clinical trials.
Navigating Challenges and Advancing Mouse Model Technology
Despite their utility, genetically engineered mouse models face limitations, primarily stemming from species differences between mice and humans. Their physiological responses to diseases or drugs can sometimes differ, leading to discrepancies in research outcomes. Replicating the full complexity of multifactorial human diseases, which often involve multiple genes and environmental factors, within a single-gene mouse model can also be challenging.
Researchers are actively addressing these challenges through continuous advancements in mouse model technology. One significant development is the creation of humanized mouse models, where human cells, tissues, or entire human genes are introduced into the mouse. For example, mice can be engrafted with human immune system components to better study human-specific immune responses or infections.
The concept of personalized mouse models represents another advancement, where models are engineered to replicate specific genetic mutations found in individual patients. This approach supports developing tailored therapies, moving closer to personalized medicine. Advances in gene editing technologies, such as base editing and prime editing, further enhance precision, allowing for more subtle and complex genetic modifications.
The use of animal models in research also involves ethical considerations. Scientific institutions adhere to strict regulations and guidelines, often overseen by committees like Institutional Animal Care and Use Committees (IACUCs), to ensure the humane treatment and welfare of research animals. These guidelines emphasize minimizing pain and distress while maximizing scientific benefit, balancing research needs with ethical responsibilities.
References
Mouse Genome Sequencing Consortium. Initial sequencing and comparative analysis of the mouse genome. Nature, 420(6915):520-562, 2002.
National Human Genome Research Institute. Fact Sheet: The Mouse as a Model Organism. Accessed 2025.
Hogan, B., Beddington, R., Costantini, F., & Lacy, E. Manipulating the Mouse Embryo: A Laboratory Manual. Cold Spring Harbor Laboratory Press, 1994.
Capecchi, M. R. Gene targeting in mice: functional analysis of the mammalian genome. Harvey Lectures, 93:159-180, 1997.
Doudna, J. A., & Charpentier, E. The new frontier of genome engineering with CRISPR-Cas9. Science, 346(6213):1258096, 2014.
Frese, K. K., & Tuveson, D. A. Maximizing mouse cancer models. Nature Reviews Cancer, 7(9):645-658, 2007.
Janus, C., & Westaway, D. A. Transgenic mouse models of Alzheimer’s disease. Physiology & Behavior, 73(5):873-886, 2001.
Paolicelli, R. C., et al. Synaptic pruning by microglia is necessary for normal brain development. Science, 333(6040):1456-1458, 2011.
Seok, J., et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proceedings of the National Academy of Sciences, 110(9):3507-3512, 2013.
Shultz, L. D., et al. Humanized mice for infectious disease research. Nature Reviews Immunology, 12(11):786-798, 2012.
Anzalone, A. V., et al. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature, 576(7785):149-157, 2019.
National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals. Guide for the Care and Use of Laboratory Animals. 8th edition. National Academies Press (US), 2011.