Editing Laboratory mouse (section)

==Limitations==

While mice are by far the most widely used animals in biomedical research, recent studies have highlighted their limitations.<ref name="nytimes.com">{{cite news| vauthors = Kolata G |title=Mice Fall Short as Test Subjects for Some of Humans' Deadly Ills|work=The New York Times |url=https://www.nytimes.com/2013/02/12/science/testing-of-some-deadly-diseases-on-mice-mislead-report-says.html?_r=0|access-date=6 August 2015|agency=New York Times|date=11 February 2013}}</ref> For example, the utility of rodents in testing for [[sepsis]],<ref name="Mouse Models of Sepsis and Septic">{{cite journal | vauthors = Korneev KV | title = [Mouse Models of Sepsis and Septic Shock] | journal = Molekuliarnaia Biologiia | volume = 53 | issue = 5 | pages = 799–814 | date = 18 October 2019 | pmid = 31661479 | doi = 10.1134/S0026893319050108 | doi-access = free }}</ref><ref name="pnas.org">{{cite journal | vauthors = Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, Richards DR, McDonald-Smith GP, Gao H, Hennessy L, Finnerty CC, López CM, Honari S, Moore EE, Minei JP, Cuschieri J, Bankey PE, Johnson JL, Sperry J, Nathens AB, Billiar TR, West MA, Jeschke MG, Klein MB, Gamelli RL, Gibran NS, Brownstein BH, Miller-Graziano C, Calvano SE, Mason PH, Cobb JP, Rahme LG, Lowry SF, Maier RV, Moldawer LL, Herndon DN, Davis RW, Xiao W, Tompkins RG | display-authors = 6 | title = Genomic responses in mouse models poorly mimic human inflammatory diseases | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 9 | pages = 3507–12 | date = February 2013 | pmid = 23401516 | pmc = 3587220 | doi = 10.1073/pnas.1222878110 | bibcode = 2013PNAS..110.3507S | doi-access = free }}</ref> [[burn]]s,<ref name="pnas.org"/> [[inflammation]],<ref name="pnas.org"/> [[stroke]],<ref>{{cite journal | vauthors = Ramsay I | title = Attempted prevention of neonatal thyrotoxicosis | journal = British Medical Journal | volume =  2| issue =  6048| date = December 1976 | page = 1385 | pmid =  1000245| pmc =  1690299| doi = 10.1136/bmj.2.6048.1385-a }}</ref><ref name="The Trouble With Animal Models">{{cite news| vauthors = Gawrylewski A |title=The Trouble With Animal Models|url=http://www.the-scientist.com/?articles.view/articleNo/25184/title/The-Trouble-with-Animal-Models/|access-date=6 August 2015|agency=The Scientist|date=1 July 2007}}</ref> [[Amyotrophic lateral sclerosis|ALS]],<ref>{{cite journal | vauthors = Benatar M | title = Lost in translation: treatment trials in the SOD1 mouse and in human ALS | journal = Neurobiology of Disease | volume = 26 | issue = 1 | pages = 1–13 | date = April 2007 | pmid = 17300945 | doi = 10.1016/j.nbd.2006.12.015 | s2cid = 24174675 }}</ref><ref name="nature.com">{{cite news| vauthors = Hayden EC |title=Misleading mouse studies waste medical resources|url=http://www.nature.com/news/misleading-mouse-studies-waste-medical-resources-1.14938|access-date=6 August 2015|agency=Nature|date=26 March 2014}}</ref><ref name="ReferenceA">{{cite news| vauthors = Perrin S |title=Preclinical research: Make mouse studies work|url=http://www.nature.com/news/preclinical-research-make-mouse-studies-work-1.14913|access-date=6 August 2015|agency=Nature|date=26 March 2014}}</ref> [[Alzheimer's disease]],<ref>{{cite journal | vauthors = Cavanaugh SE, Pippin JJ, Barnard ND | title = Animal models of Alzheimer disease: historical pitfalls and a path forward | journal = Altex | volume = 31 | issue = 3 | pages = 279–302 | date = 10 April 2013 | pmid = 24793844 | doi = 10.14573/altex.1310071 | doi-access = free }}</ref> [[diabetes]],<ref>{{cite journal | vauthors = Roep BO, Atkinson M, von Herrath M | title = Satisfaction (not) guaranteed: re-evaluating the use of animal models of type 1 diabetes | journal = Nature Reviews. Immunology | volume = 4 | issue = 12 | pages = 989–97 | date = December 2004 | pmid = 15573133 | doi = 10.1038/nri1502 | s2cid = 21204695 }}</ref><ref>{{cite journal | vauthors = Chandrasekera PC, Pippin JJ | title = Of rodents and men: species-specific glucose regulation and type 2 diabetes research | journal = Altex | volume = 31 | issue = 2 | pages = 157–76 | date = 21 November 2013 | pmid = 24270692 | doi = 10.14573/altex.1309231 | doi-access = free }}</ref> [[cancer]],<ref>{{cite journal | vauthors = Begley CG, Ellis LM | title = Drug development: Raise standards for preclinical cancer research | journal = Nature | volume = 483 | issue = 7391 | pages = 531–3 | date = March 2012 | pmid = 22460880 | doi = 10.1038/483531a | s2cid = 4326966 | bibcode = 2012Natur.483..531B | doi-access = free }}</ref><ref>{{cite journal | vauthors = Voskoglou-Nomikos T, Pater JL, Seymour L | title = Clinical predictive value of the in vitro cell line, human xenograft, and mouse allograft preclinical cancer models | journal = Clinical Cancer Research | volume = 9 | issue = 11 | pages = 4227–39 | date = September 2003 | pmid = 14519650 | url = http://clincancerres.aacrjournals.org/content/9/11/4227.full.pdf }}</ref><ref>{{cite journal | vauthors = Dennis C | title = Cancer: off by a whisker | journal = Nature | volume = 442 | issue = 7104 | pages = 739–41 | date = August 2006 | pmid = 16915261 | doi = 10.1038/442739a | s2cid = 4382984 | bibcode = 2006Natur.442..739D | doi-access = free }}</ref><ref>{{cite journal | vauthors = Garber K | title = Realistic rodents? Debate grows over new mouse models of cancer | journal = Journal of the National Cancer Institute | volume = 98 | issue = 17 | pages = 1176–8 | date = September 2006 | pmid = 16954466 | doi = 10.1093/jnci/djj381 | doi-access = free }}</ref><ref>{{cite news| vauthors = Begley S |title=Rethinking the war on cancer|url=http://www.newsweek.com/rethinking-war-cancer-88941|access-date=6 August 2015|agency=Newsweek|date=5 September 2008}}</ref> [[multiple sclerosis]],<ref name="ReferenceB">{{cite news| vauthors = Bolker J |title=There's more to life than rats and flies|url=http://www.nature.com/articles/491031a.epdf|access-date=6 August 2015|agency=Nature|date=1 November 2012}}</ref> [[Parkinson's disease]],<ref name="ReferenceB"/> and other illnesses has been called into question by a number of researchers. Regarding experiments on mice, some researchers have complained that "years and billions of dollars have been wasted following false leads" as a result of a preoccupation with the use of these animals in studies.<ref name="nytimes.com"/>

Mice differ from humans in several immune properties: mice are more resistant to some [[toxins]] than humans; have a lower total [[neutrophil]] fraction in the [[blood]], a lower [[neutrophil]] [[enzymatic]] capacity, lower activity of the [[complement system]], and a different set of [[pentraxins]] involved in the [[inflammatory process]]; and lack genes for important components of the immune system, such as [[Interleukin 8|IL-8]], [[IL-37]], [[TLR10]], [[ICAM3|ICAM-3]], etc.<ref name="Mouse Models of Sepsis and Septic"/> Laboratory mice reared in [[specific-pathogen-free]] (SPF) conditions usually have a rather immature immune system with a deficit of [[memory T cells]]. These mice may have limited diversity of the [[microbiota]], which directly affects the immune system and the development of pathological conditions. Moreover, persistent virus infections (for example, [[Herpesviridae|herpesviruses]]) are activated in humans, but not in [[specific-pathogen-free|SPF]] mice with [[Sepsis|septic]] complications and may change the resistance to bacterial [[coinfections]]. "Dirty" mice are possibly better suitable for mimicking human pathologies. In addition, inbred mouse strains are used in the overwhelming majority of studies, while the [[human population]] is heterogeneous, pointing to the importance of studies in interstrain hybrid, [[outbred]], and nonlinear mice.<ref name="Mouse Models of Sepsis and Septic"/>

An article in ''[[The Scientist (magazine)|The Scientist]]'' notes, "The difficulties associated with using animal models for human disease result from the metabolic, anatomic, and cellular differences between humans and other creatures, but the problems go even deeper than that" including issues with the design and execution of the tests themselves.<ref name="The Trouble With Animal Models"/> In addition, the caging of laboratory animals may render them irrelevant models of human health because these animals lack day-to-day variations in experiences, agency, and challenges that they can overcome.<ref>{{cite journal | vauthors = Lahvis GP | title = Unbridle biomedical research from the laboratory cage | journal = eLife | volume = 6 | pages = e27438 | date = June 2017 | pmid = 28661398 | doi = 10.7554/eLife.27438 | pmc = 5503508 | url = | veditors = Shailes S | doi-access = free }}</ref> The impoverished environments inside small mouse cages can have deleterious influences on biomedical results, especially with respect to studies of mental health and of systems that depend upon healthy psychological states.<ref>{{Cite web|title=The inescapable problem of lab animal restraint {{!}} Garet Lahvis {{!}} TEDxMtHood – YouTube|url=https://www.youtube.com/watch?v=2Q1aDrGRlrU|access-date=2020-11-30|website=www.youtube.com| date=5 December 2019 }}</ref>

For example, researchers have found that many mice in laboratories are obese from excess food and minimal exercise, which alters their physiology and drug metabolism.<ref>{{cite journal | vauthors = Cressey D | title = Fat rats skew research results | journal = Nature | volume = 464 | issue = 7285 | pages = 19 | date = March 2010 | pmid = 20203576 | doi = 10.1038/464019a | doi-access = free }}</ref> Many laboratory animals, including mice, are chronically stressed, which can also negatively affect research outcomes and the ability to accurately extrapolate findings to humans.<ref>{{cite journal | vauthors = Balcombe JP, Barnard ND, Sandusky C | title = Laboratory routines cause animal stress | journal = Contemporary Topics in Laboratory Animal Science | volume = 43 | issue = 6 | pages = 42–51 | date = November 2004 | pmid = 15669134 }}</ref><ref>{{cite journal | vauthors = Murgatroyd C, Patchev AV, Wu Y, Micale V, Bockmühl Y, Fischer D, Holsboer F, Wotjak CT, Almeida OF, Spengler D | display-authors = 6 | title = Dynamic DNA methylation programs persistent adverse effects of early-life stress | journal = Nature Neuroscience | volume = 12 | issue = 12 | pages = 1559–66 | date = December 2009 | pmid = 19898468 | doi = 10.1038/nn.2436 | s2cid = 3328884 }}</ref> Researchers have also noted that many studies involving mice are poorly designed, leading to questionable findings.<ref name="The Trouble With Animal Models"/><ref name="nature.com"/><ref name="ReferenceA"/>

Some studies suggests that inadequate published data in animal testing may result in irreproducible research, with missing details about how experiments are done are omitted from published papers or differences in testing that may introduce bias. Examples of hidden bias include a 2014 study from [[McGill University]] which suggests that mice handled by men rather than women showed higher stress levels.<ref>{{cite journal | vauthors = Sorge RE, Martin LJ, Isbester KA, Sotocinal SG, Rosen S, Tuttle AH, Wieskopf JS, Acland EL, Dokova A, Kadoura B, Leger P, Mapplebeck JC, McPhail M, Delaney A, Wigerblad G, Schumann AP, Quinn T, Frasnelli J, Svensson CI, Sternberg WF, Mogil JS | display-authors = 6 | title = Olfactory exposure to males, including men, causes stress and related analgesia in rodents | journal = Nature Methods | volume = 11 | issue = 6 | pages = 629–32 | date = June 2014 | pmid = 24776635 | doi = 10.1038/nmeth.2935 | s2cid = 8163498 }}</ref><ref name="economist.com"/><ref>{{Cite journal| vauthors = Katsnelson A |title=Male researchers stress out rodents|url=http://www.nature.com/news/male-researchers-stress-out-rodents-1.15106|journal=Nature|doi=10.1038/nature.2014.15106|year=2014|s2cid=87534627|doi-access=free}}</ref><ref>{{Cite news|url=https://www.science.org/content/article/male-scent-may-compromise-biomedical-research|title=Male Scent May Compromise Biomedical Research|date=2014-04-28|newspaper=Science {{!}} AAAS|access-date=2017-01-10}}</ref> Another study in 2016 suggested that gut [[Microbiota|microbiome]]s in mice may have an impact upon scientific research.<ref>{{Cite news|url=https://www.science.org/content/article/mouse-microbes-may-make-scientific-studies-harder-replicate|title=Mouse microbes may make scientific studies harder to replicate|date=2016-08-15|newspaper=Science {{!}} AAAS|access-date=2017-01-10}}</ref>