Genetically modified (GM) mice are a cornerstone of modern biomedical research, offering a significant ability to study biological processes and diseases. Their genetic material, or DNA, is intentionally altered in a laboratory. By introducing, deleting, or modifying specific genes, scientists create living models that offer insights into complex biological systems. The use of GM mice has greatly advanced our understanding of health and disease, enabling discoveries not possible through other methods.
What is a Genetically Modified Mouse?
A genetically modified mouse is a mouse (Mus musculus) whose genome has been intentionally altered using genetic engineering techniques. Unlike natural genetic variations, these changes are precise and deliberate. Scientists introduce, delete, or modify specific genes for research. For example, a “knockout mouse” has a specific gene inactivated, while a “knock-in mouse” has a new gene inserted or an existing gene modified.
These modifications mimic human conditions or investigate gene function. A humanized mouse, for instance, might carry human leukocyte antigen genes to study immune system responses. This creates a living system to study how specific genetic changes affect an organism’s biology, allowing researchers to observe disease progression or gene function in a controlled environment.
How Genetically Modified Mice Are Created
Creating genetically modified mice involves several techniques. One early method is pronuclear injection, where DNA is directly injected into a fertilized mouse egg’s pronucleus. This DNA can randomly integrate into the mouse’s genome, creating a “transgenic” mouse that expresses a new or modified gene. This method can result in unpredictable gene expression.
Another technique uses embryonic stem (ES) cell technology for more precise gene targeting. Genetic modifications are introduced into ES cells, often through homologous recombination, allowing for targeted gene disruptions or replacements. These modified ES cells are then injected into early-stage mouse embryos (blastocysts), which are implanted into surrogate mothers. The resulting offspring, called chimeras, can transmit the modification to their progeny.
More recently, gene-editing tools like CRISPR/Cas9 have improved the process, offering increased efficiency and speed. This system uses a guide RNA to direct the Cas9 enzyme to a specific genomic location, creating a double-strand break in the DNA. Scientists can then introduce, delete, or modify genes at this precise location, often by co-injecting Cas9 mRNA and guide RNA into fertilized mouse embryos. CRISPR/Cas9 can generate various modifications, including gene knockouts and knock-ins, typically in a matter of weeks.
Research and Medical Applications
Genetically modified mice are powerful models in scientific research and medical applications, significantly advancing our understanding of human health. They are frequently used to mimic human diseases, providing a platform to study disease progression and identify genetic causes. For example, GM mice model conditions like cancer, Alzheimer’s disease, diabetes, and cystic fibrosis, allowing researchers to observe how genetic changes manifest in a living system. This enables investigation of disease mechanisms and testing of therapeutic interventions.
Beyond disease modeling, GM mice are also instrumental in understanding individual gene functions. By activating, deactivating, or altering genes, scientists observe their roles in normal physiological processes, such as growth and development. This contributes to foundational biological knowledge, which in turn informs strategies for addressing various health challenges. The ability to manipulate specific genes provides insights into how genes are regulated and how they interact within the body.
GM mice also play a role in drug development and vaccine testing. They can be engineered to express human proteins or immune system components, making them relevant models for evaluating drug efficacy and safety. During the COVID-19 pandemic, GM mice expressing the human ACE2 protein, the entry receptor for SARS-CoV-2, became invaluable for studying infection and testing vaccine candidates. This accelerates preclinical testing, allowing researchers to assess immune response and protective effects of new treatments before human trials.
Ethical Considerations and Animal Welfare
The use of genetically modified mice in research raises ethical considerations and animal welfare concerns. Altering an animal’s genetic makeup prompts discussions about the moral implications and potential for unintended consequences. Researchers must weigh scientific benefits against potential suffering or adverse effects.
GM animals, even with the same genetic alteration, can exhibit phenotypes that negatively impact their well-being. For example, a modification modeling a disease might cause unexpected pain or health issues. Therefore, newly created GM animals require close monitoring for health or behavioral abnormalities to mitigate welfare concerns.
To address these issues, strict regulations and guidelines ensure humane treatment. Institutional Animal Care and Use Committees (IACUCs) provide oversight, reviewing and approving research protocols. These committees ensure researchers adhere to principles:
Reduction (using the minimum number of animals)
Refinement (minimizing pain and distress through improved practices)
Replacement (using non-animal alternatives when possible)
These measures balance scientific advancement with the duty to provide appropriate care and minimize discomfort for GM mice.