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Genetically modified mouse
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<h2 id="history">History</h2> <p>In 1974 <a href="/facts/Beatrice_Mintz/97masqIe">Beatrice Mintz</a> and <a href="/facts/Rudolf_Jaenisch/l0GvdIjm">Rudolf Jaenisch</a> created the first genetically modified animal by inserting a DNA virus into an early-stage mouse <a href="/facts/Embryo/9QHnLVLN">embryo</a> and showing that the inserted genes were present in every cell.<a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a> However, the mice did not pass the <a href="/facts/Transgene/8DvIYSGt">transgene</a> to their offspring, and the impact and applicability of this experiment were, therefore, limited. In 1981 the laboratories of <a href="/facts/Frank_Ruddle/eaxdJbqo">Frank Ruddle</a><a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a> from <a href="/facts/Yale_University/KUdS6jt1">Yale University</a>, Frank Costantini and Elizabeth Lacy from <a href="/facts/University_of_Oxford/ExVVQL6V">Oxford</a>, and <a href="/facts/Ralph_L._Brinster/TbSLAGLo">Ralph L. Brinster</a> and Richard Palmiter in collaboration from the <a href="/facts/University_of_Pennsylvania/LBBBULox">University of Pennsylvania</a> and the <a href="/facts/University_of_Washington/36PG6qkG">University of Washington</a> injected purified DNA into a <a href="/facts/Zygote/mSu2xMWA">single-cell mouse embryo</a> utilizing techniques developed by Brinster in the 1960s and 1970s, showing transmission of the genetic material to subsequent generations for the first time.<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a><a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a><a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> During the 1980s, Palmiter and Brinster developed and led the field of transgenesis, refining methods of <a href="/facts/Germline/QI4bKK8Q">germline</a> modification and using these techniques to elucidate the activity and function of genes in a way not possible before their unique approach.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> </p> <h2 id="methods">Methods</h2> <p>There are two basic technical approaches to produce genetically modified mice. The first involves <a href="/facts/Microinjection/NTqLhvVL">pronuclear injection</a>, a technique developed and refined by <a href="/facts/Ralph_L._Brinster/TbSLAGLo">Ralph L. Brinster</a> in the 1960s and 1970s, into a single cell of the mouse embryo, where it will randomly integrate into the mouse genome.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> This method creates a <a href="/facts/Transgenic/8DvIYSGt">transgenic</a> mouse and is used to insert new genetic information into the mouse genome or to over-express <a href="/facts/Endogenous/DFkSLkRI">endogenous</a> genes. The second approach, pioneered by <a href="/facts/Oliver_Smithies/eIUL3fnp">Oliver Smithies</a> and <a href="/facts/Mario_Capecchi/bHdj7ozM">Mario Capecchi</a>, involves modifying <a href="/facts/Embryonic_stem_cells/P1n1eS1p">embryonic stem cells</a> with a <a href="/facts/DNA_construct/Ww5pxHRc">DNA construct</a> containing DNA sequences <a href="/facts/Homology_(biology)/muctKlyT">homologous</a> to the target gene. Embryonic stem cells that <a href="/facts/Genetic_recombination/uocNH0m7">recombine</a> with the genomic DNA are selected for and they are then injected into the mice <a href="/facts/Blastocysts/WkRkxdzc">blastocysts</a>.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> This method is used to manipulate a single gene, in most cases <a href="/facts/Gene_knockout/RJTMDbUR">"knocking out"</a> the target gene, although increasingly more subtle and complex genetic manipulation can occur (e.g. humanisation of a specific protein, or only changing single <a href="/facts/Nucleotides/pQKEwlJI">nucleotides</a>). A <a href="/facts/Humanised_mouse/mpUDbpcv">humanised mouse</a> can also be created by direct addition of human genes, thereby creating a <a href="/facts/Murinae/7ds8prdo">murine</a> form of <a href="/facts/Human%E2%80%93animal_hybrid/EL7qxd93">human–animal hybrid</a>. For example, genetically modified mice may be born with <a href="/facts/Human_leukocyte_antigen/6QRXe5QI">human leukocyte antigen</a> genes in order to provide a more realistic environment when introducing human <a href="/facts/White_blood_cells/vsDunUK0">white blood cells</a> into them in order to study <a href="/facts/Immune_system/HRCTf1pb">immune system</a> responses.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> One such application is the identification of <a href="/facts/Hepatitis_C_virus/DFUwAzlB">hepatitis C virus</a> (HCV) peptides that bind to HLA, and that can be recognized by the human immune system, thereby potentially being targets for future vaccines against HCV.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> </p> <h2 id="uses">Uses</h2> <p>Genetically modified mice are used extensively in research as models of human disease.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> Mice are a useful model for genetic manipulation and research, as their <a href="/facts/Tissue_(biology)/H7CpML7A">tissues</a> and <a href="/facts/Organ_(anatomy)/FUYsLaxz">organs</a> are similar to that of a human and they carry virtually all the same genes that operate in humans.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> They also have advantages over other mammals, in regards to research, in that they are available in hundreds of genetically homogeneous strains.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> Also, due to their size, they can be kept and housed in large numbers, reducing the cost of research and experiments.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> Transgenic mice are found in two main models of either loss or gain of function. The most common type is loss of function mice or the <a href="/facts/Knockout_mouse/Aw50cobf">knockout mouse</a>, where the activity of a single (or in some cases multiple) genes are removed or silenced. Gain of function mice, in other hand, overexpress a specific gene.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> They have been used to study and model obesity, heart disease, diabetes, arthritis, substance abuse, anxiety, aging, temperature, pain reception, and Parkinson disease.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a><a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> Genetically modified mice further be divided into constitutive mouse model, in which the target gene is permanently activated or inactivated in all the cells of the animal, or conditional mouse model, in which the knockout or the overexpressed gene can be regulated in a spatiotemporal manner, which enables targeting of a specific type or subset of cells in the animal from a specific time in the life of the animal.<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a> </p><p>Transgenic mice generated to carry cloned <a href="/facts/Oncogene/WLFu6Ma5">oncogenes</a> and knockout mice lacking <a href="/facts/Tumor_suppressor_gene/Awte4S51">tumor suppressing genes</a> have provided good models for human <a href="/facts/Cancer/PVW6n1D0">cancer</a>. Hundreds of these <a href="/facts/Oncomouse/9XY9vYX0">oncomice</a> 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.<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> The disease symptoms and potential drugs or treatments can be tested against these mouse models. </p><p>A mouse has been genetically engineered to have increased muscle growth and strength by overexpressing the <a href="/facts/Insulin-like_growth_factor_I/2n0nPvtD">insulin-like growth factor I</a> (IGF-I) in differentiated <a href="/facts/Muscle_fibers/cP7Jea3q">muscle fibers</a>.<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a><a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> Another mouse has had a gene altered that is involved in <a href="/facts/Glucose_metabolism/h2WvuF14">glucose metabolism</a> and runs faster, lives longer, is more sexually active and eats more without getting fatter than the average mouse (see <a href="/facts/Metabolic_supermice/mmdn8vSN">Metabolic supermice</a>).<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a><a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> Another mouse had the <a href="/facts/TRPM8/kPkUT87u">TRPM8 receptor</a> blocked or removed in a study involving <a href="/facts/Capsaicin/aXaaFxDp">capsaicin</a> and <a href="/facts/Menthol/Pdg9F3pS">menthol</a>.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a> With the TRPM8 receptor removed, the mouse was unable to detect small changes in temperature and the pain associated with it.<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a> </p><p>Great care should be taken when deciding how to use genetically modified mice in research.<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a> Even basic issues like choosing the correct "wild-type" control mouse to use for comparison are sometimes overlooked.<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a> </p> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/Humanized_mouse/mpUDbpcv">Humanized mouse</a></li></ul> <h2 id="external-links">External links</h2> <ul><li><a href="http://www.informatics.jax.org/">Mouse Genome Informatics (informatics.jax.org)</a></li> <li><a href="https://web.archive.org/web/20071024135546/http://www.mgu.har.mrc.ac.uk/">Mammalian Genetics Unit Harwell: Mouse models for human disease</a></li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Singh, M.; Murriel, C. L.; Johnson, L. (16 May 2012). "Genetically Engineered Mouse Models: Closing the Gap between Preclinical Data and Trial Outcomes". Cancer Research. 72 (11): 2695–2700. doi:10.1158/0008-5472.CAN-11-2786. PMID 22593194. <a href="https://doi.org/10.1158%2F0008-5472.CAN-11-2786" target="_blank">https://doi.org/10.1158%2F0008-5472.CAN-11-2786</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Abate-Shen, C.; Pandolfi, P. P. (30 September 2013). "Effective Utilization and Appropriate Selection of Genetically Engineered Mouse Models for Translational Integration of Mouse and Human Trials". Cold Spring Harbor Protocols. 2013 (11): 1006–1011. doi:10.1101/pdb.top078774. PMC 4382078. PMID 24173311. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382078" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382078</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Sharpless, Norman E.; DePinho, Ronald A. (September 2006). 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Retrieved 2020-05-14. <a href="https://www.ibiology.org/neuroscience/sensory-receptors/" target="_blank">https://www.ibiology.org/neuroscience/sensory-receptors/</a> <a href="#fnref:28" class="footnote-back-ref">↩</a></p></li> <li id="fn:29"><p>Crusio, W.E.; Goldowitz, D.; Holmes, A.; Wolfer, D. (2009). "Standards for the publication of mouse mutant studies". Genes, Brain and Behavior. 8 (1): 1–4. doi:10.1111/j.1601-183X.2008.00438.x. PMID 18778401. S2CID 205853147. <a href="/wiki/Wim_Crusio" target="_blank">/wiki/Wim_Crusio</a> <a href="#fnref:29" class="footnote-back-ref">↩</a></p></li> <li id="fn:30"><p>Mohammed Bourdi; John S. Davies; Lance R. Pohl (2011). "Mispairing C57BL/6 Substrains of Genetically Engineered Mice and Wild-Type Controls Can Lead to Confounding Results as It Did in Studies of JNK2 in Acetaminophen and Concanavalin A Liver Injury". Chemical Research in Toxicology. 24 (6): 794–796. doi:10.1021/tx200143x. PMC 3157912. 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