A genetically modified mouse or genetically engineered mouse model (GEMM) is a mouse (''Mus musculus'') that has had its

genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding g ...

altered through the use of genetic engineering techniques. Genetically modified mice are commonly used for research or as animal models of human diseases, and are also used for research on genes. Together with

patient-derived xenograft Patient derived xenografts (PDX) are models of cancer where the tissue or cells from a patient's tumor are implanted into an immunodeficient or humanized mouse. PDX models are used to create an environment that allows for the natural growth of cance ...

s (PDXs), GEMMs are the most common ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

'' models in

cancer research Cancer research is research into cancer to identify causes and develop strategies for prevention, diagnosis, treatment, and cure. Cancer research ranges from epidemiology, molecular bioscience to the performance of clinical trials to evaluate and ...

. Both approaches are considered complementary and may be used to recapitulate different aspects of disease. GEMMs are also of great interest for

drug development Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for re ...

, as they facilitate target validation and the study of response, resistance, toxicity and

pharmacodynamics Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms ...

History

In 1974 Beatrice Mintz and

Rudolf Jaenisch Rudolf Jaenisch (born April 22, 1942) is a Professor of Biology at MIT and a founding member of the Whitehead Institute for Biomedical Research. He is a pioneer of transgenic science, in which an animal’s genetic makeup is altered. Jaenisch ...

created the first genetically modified animal by inserting a DNA virus into an early-stage mouse embryo and showing that the inserted genes were present in every cell. However, the mice did not pass the

transgene A transgene is a gene that has been transferred naturally, or by any of a number of genetic engineering techniques, from one organism to another. The introduction of a transgene, in a process known as transgenesis, has the potential to change th ...

to their offspring, and the impact and applicability of this experiment were, therefore, limited. In 1981 the laboratories of

Frank Ruddle Francis Hugh Ruddle (1929–2013) was an American cell and developmental biologist who was the Sterling Professor at Yale University. Ruddle was an early visionary of the Human Genome Project and created the first genetically modified mouse. He ...

from

Yale University Yale University is a Private university, private research university in New Haven, Connecticut. Established in 1701 as the Collegiate School, it is the List of Colonial Colleges, third-oldest institution of higher education in the United Sta ...

, Frank Costantini and Elizabeth Lacy from

Oxford Oxford () is a city in England. It is the county town and only city of Oxfordshire. In 2020, its population was estimated at 151,584. It is north-west of London, south-east of Birmingham and north-east of Bristol. The city is home to the ...

, and Ralph L. Brinster and Richard Palmiter in collaboration from the

University of Pennsylvania The University of Pennsylvania (also known as Penn or UPenn) is a private research university in Philadelphia. It is the fourth-oldest institution of higher education in the United States and is ranked among the highest-regarded universitie ...

and the

University of Washington The University of Washington (UW, simply Washington, or informally U-Dub) is a public research university in Seattle, Washington. Founded in 1861, Washington is one of the oldest universities on the West Coast; it was established in Seattl ...

injected purified DNA into a single-cell mouse embryo utilizing techniques developed by Brinster in the 1960s and 1970s, showing transmission of the genetic material to subsequent generations for the first time. During the 1980s, Palmiter and Brinster developed and led the field of transgenesis, refining methods of germline modification and using these techniques to elucidate the activity and function of genes in a way not possible before their unique approach.

Methods

There are two basic technical approaches to produce genetically modified mice. The first involves pronuclear injection, a technique developed and refined by Ralph L. Brinster in the 1960s and 1970s, into a single cell of the mouse embryo, where it will randomly integrate into the mouse genome. This method creates a

transgenic A transgene is a gene that has been transferred naturally, or by any of a number of genetic engineering techniques, from one organism to another. The introduction of a transgene, in a process known as transgenesis, has the potential to change the ...

mouse and is used to insert new genetic information into the mouse genome or to over-express endogenous genes. The second approach, pioneered by

Oliver Smithies Oliver Smithies (23 June 1925 – 10 January 2017) was a British-American geneticist and physical biochemist. He is known for introducing starch as a medium for gel electrophoresis in 1955, and for the discovery, simultaneously with Mario Cape ...

and

Mario Capecchi Mario Ramberg Capecchi (born 6 October 1937) is an Italian-born molecular geneticist and a co-awardee of the 2007 Nobel Prize in Physiology or Medicine for discovering a method to create mice in which a specific gene is turned off, known as knock ...

, involves modifying

embryonic stem cells Embryonic stem cells (ESCs) are pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre- implantation embryo. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they consist ...

with a

DNA construct A DNA construct is an artificially-designed segment of DNA borne on a vector that can be used to incorporate genetic material into a target tissue or cell. A DNA construct contains a DNA insert, called a transgene, delivered via a transformation ...

containing DNA sequences homologous to the target gene. Embryonic stem cells that recombine with the genomic DNA are selected for and they are then injected into the mice blastocysts. This method is used to manipulate a single gene, in most cases "knocking out" the target gene, although increasingly more subtle and complex genetic manipulation can occur (e.g. humanisation of a specific protein, or only changing single

nucleotides Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules with ...

Uses

Genetically modified mice are used extensively in research as models of human disease. Mice are a useful model for genetic manipulation and research, as their tissues and

organs In biology, an organ is a collection of tissues joined in a structural unit to serve a common function. In the hierarchy of life, an organ lies between tissue and an organ system. Tissues are formed from same type cells to act together in a f ...

are similar to that of a human and they carry virtually all the same genes that operate in humans. They also have advantages over other mammals, in regards to research, in that they are available in hundreds of genetically homogeneous strains. Also, due to their size, they can be kept and housed in large numbers, reducing the cost of research and experiments. The most common type is the

knockout mouse A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importa ...

, where the activity of a single (or in some cases multiple) genes are removed. They have been used to study and model obesity, heart disease, diabetes, arthritis, substance abuse, anxiety, aging, temperature and pain reception, and Parkinson disease. Transgenic mice generated to carry cloned

oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

s and knockout mice lacking tumor suppressing genes have provided good models for human

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

. Hundreds of these oncomice have been developed covering a wide range of cancers affecting most organs of the body and they are being refined to become more representative of human cancer. The disease symptoms and potential drugs or treatments can be tested against these mouse models. A mouse has been genetically engineered to have increased muscle growth and strength by overexpressing the

insulin-like growth factor I Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in molecular structure to insulin which plays an important role in childhood growth, and has anabolic effects in adults. IGF-1 is a protein that in humans is ...

(IGF-I) in differentiated muscle fibers. Another mouse has had a gene altered that is involved in

glucose metabolism Carbohydrate metabolism is the whole of the biochemical processes responsible for the metabolic formation, breakdown, and interconversion of carbohydrates in living organisms. Carbohydrates are central to many essential metabolic pathways. Pla ...

and runs faster, lives longer, is more sexually active and eats more without getting fatter than the average mouse (see

Metabolic supermice PEPCK-Cmus mice are genetically modified mice (''Mus musculus'') which as a result of their modification have up to 100 times the concentration of the PEPCK-C enzyme in their muscles, compared to ordinary mice. They were created by a team of Ame ...

). Another mouse had the TRPM8 receptor blocked or removed in a study involving

capsaicin Capsaicin (8-methyl-''N''-vanillyl-6-nonenamide) ( or ) is an active component of chili peppers, which are plants belonging to the genus ''Capsicum''. It is a chemical irritant for mammals, including humans, and produces a sensation of burnin ...

and menthol. With the TRPM8 receptor removed, the mouse was unable to detect small changes in temperature and the pain associated with it. Great care should be taken when deciding how to use genetically modified mice in research. Even basic issues like choosing the correct "wild-type" control mouse to use for comparison are sometimes overlooked.

References

External links

Mouse Genome Informatics (informatics.jax.org)Mammalian Genetics Unit Harwell: Mouse models for human disease
{{genetic engineering Mouse genetics 1974 in biotechnology Genetic engineering