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Restoring comparative expertise to improve translation of animal models.

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Title: Restoring comparative expertise to improve translation of animal models.
Authors: Lloyd KCK; Department of Surgery, School of Medicine, Mouse Biology Program, and NAMs Testing Center, University of California Davis, Davis, CA 95618, USA.
Source: Disease models & mechanisms [Dis Model Mech] 2026 Aug 01; Vol. 19 (8). Date of Electronic Publication: 2026 Aug 26.
Publication Type: Journal Article; Review
Language: English
Journal Info: Publisher: Company of Biologists Ltd Country of Publication: England NLM ID: 101483332 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1754-8411 (Electronic) Linking ISSN: 17548403 NLM ISO Abbreviation: Dis Model Mech Subsets: MEDLINE
Imprint Name(s): Original Publication: Cambridge : Company of Biologists Ltd., c2008-
MeSH Terms: Translational Research, Biomedical* , Models, Animal* , Disease Models, Animal*, Animals ; Humans
Abstract: Animal models remain indispensable in biomedical research, particularly for discovering disease mechanisms within intact living organisms. Yet confidence in their human translational relevance has been weakened by apparent failures of preclinical findings to predict clinical outcomes. Although often attributed to species differences, such failures also reflect correctable problems in model selection, experimental design, endpoint choice and phenotype interpretation. A key, but overlooked, contributor is the erosion of comparative expertise in pathobiology and clinical medicine needed to relate animal phenotypes to human disease across species, strain, and developmental, physiological and pathological contexts. This expertise gap can lead investigators to mismatch models to biological questions, misinterpret background abnormalities as engineered phenotypes or extend mechanism-focused models beyond the questions they are suited to answer. New approach methodologies (NAMs), such as in vitro and in silico models, provide important complementary tools, but do not eliminate the need for whole-organism models or resolve this interpretive problem. Ensuring the reliability of biomedical research will require preserving well-justified animal models where whole-organism systems biology remains necessary, integrating validated NAMs only where they are fit for purpose, and rebuilding the comparative expertise needed to interpret both model types rigorously.
(© 2026. Published by The Company of Biologists.)
References: Sci Transl Med. 2011 Jul 6;3(90):90cm17. (PMID: 21734173)
Dis Model Mech. 2026 Apr 1;19(4):. (PMID: 42084366)
J Transl Med. 2019 Jul 15;17(1):223. (PMID: 31307492)
PLoS Biol. 2024 Jun 13;22(6):e3002667. (PMID: 38870090)
Nat Rev Genet. 2018 Jun;19(6):357-370. (PMID: 29626206)
PLoS Biol. 2010 Mar 30;8(3):e1000344. (PMID: 20361022)
Vet Pathol. 2000 May;37(3):199-207. (PMID: 10810984)
BMJ. 2007 Jan 27;334(7586):197. (PMID: 17175568)
Lab Invest. 2008 Jan;88(1):18-26. (PMID: 18040269)
Nat Rev Drug Discov. 2014 Jun;13(6):419-31. (PMID: 24833294)
Cell. 2021 Sep 2;184(18):4597-4611. (PMID: 34478657)
Toxicol Pathol. 2015 Feb;43(2):257-66. (PMID: 24939892)
Toxicol Pathol. 2011 Feb;39(2):381-9. (PMID: 21422264)
Vet Pathol. 2023 May;60(3):374-383. (PMID: 36727841)
Hum Genet. 2013 Oct;132(10):1077-130. (PMID: 23820649)
Mamm Genome. 2024 Dec;35(4):537-543. (PMID: 39254744)
JAMA. 2006 Oct 11;296(14):1731-2. (PMID: 17032985)
Vet Pathol. 2021 Nov;58(6):1158-1171. (PMID: 34269122)
Am J Transl Res. 2014 Jan 15;6(2):114-8. (PMID: 24489990)
Dis Model Mech. 2014 May;7(5):515-24. (PMID: 24652767)
Vet Pathol. 2020 Jan;57(1):172-182. (PMID: 31272300)
Nat Rev Drug Discov. 2010 Mar;9(3):203-14. (PMID: 20168317)
Nature. 2016 Sep 22;537(7621):508-514. (PMID: 27626380)
Nat Biotechnol. 2014 Jan;32(1):40-51. (PMID: 24406927)
Theranostics. 2026 Apr 23;16(12):6463-6484. (PMID: 42244996)
Pharmacology. 2021;106(7-8):356-368. (PMID: 34023819)
Vet Rec. 2014 Jun 28;174(26):650-4. (PMID: 24970632)
Nat Rev Genet. 2005 Jun;6(6):507-12. (PMID: 15931173)
Nat Rev Mol Cell Biol. 2020 Oct;21(10):571-584. (PMID: 32636524)
PLoS Med. 2010 Mar 30;7(3):e1000245. (PMID: 20361020)
Nature. 2025 Oct;646(8086):802-803. (PMID: 41116075)
Nat Rev Drug Discov. 2021 May;20(5):345-361. (PMID: 32913334)
Dis Model Mech. 2012 Jan;5(1):19-25. (PMID: 22028326)
Dis Model Mech. 2016 Feb;9(2):101-3. (PMID: 26839397)
Contributed Indexing: Keywords: Animal models; Comparative pathology; New approach methodologies; Translational research
Entry Date(s): Date Created: 20260826 Date Completed: 20260826 Latest Revision: 20260918
Update Code: 20260918
PubMed Central ID: PMC13580584
DOI: 10.1242/dmm.053172
PMID: 42643125
Database: MEDLINE
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  Data: Animal models remain indispensable in biomedical research, particularly for discovering disease mechanisms within intact living organisms. Yet confidence in their human translational relevance has been weakened by apparent failures of preclinical findings to predict clinical outcomes. Although often attributed to species differences, such failures also reflect correctable problems in model selection, experimental design, endpoint choice and phenotype interpretation. A key, but overlooked, contributor is the erosion of comparative expertise in pathobiology and clinical medicine needed to relate animal phenotypes to human disease across species, strain, and developmental, physiological and pathological contexts. This expertise gap can lead investigators to mismatch models to biological questions, misinterpret background abnormalities as engineered phenotypes or extend mechanism-focused models beyond the questions they are suited to answer. New approach methodologies (NAMs), such as in vitro and in silico models, provide important complementary tools, but do not eliminate the need for whole-organism models or resolve this interpretive problem. Ensuring the reliability of biomedical research will require preserving well-justified animal models where whole-organism systems biology remains necessary, integrating validated NAMs only where they are fit for purpose, and rebuilding the comparative expertise needed to interpret both model types rigorously.<br /> (© 2026. Published by The Company of Biologists.)
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  Data: Sci Transl Med. 2011 Jul 6;3(90):90cm17. (PMID: <searchLink fieldCode="PM" term="%2221734173%22">21734173)</searchLink><br />Dis Model Mech. 2026 Apr 1;19(4):. (PMID: <searchLink fieldCode="PM" term="%2242084366%22">42084366)</searchLink><br />J Transl Med. 2019 Jul 15;17(1):223. (PMID: <searchLink fieldCode="PM" term="%2231307492%22">31307492)</searchLink><br />PLoS Biol. 2024 Jun 13;22(6):e3002667. (PMID: <searchLink fieldCode="PM" term="%2238870090%22">38870090)</searchLink><br />Nat Rev Genet. 2018 Jun;19(6):357-370. (PMID: <searchLink fieldCode="PM" term="%2229626206%22">29626206)</searchLink><br />PLoS Biol. 2010 Mar 30;8(3):e1000344. (PMID: <searchLink fieldCode="PM" term="%2220361022%22">20361022)</searchLink><br />Vet Pathol. 2000 May;37(3):199-207. (PMID: <searchLink fieldCode="PM" term="%2210810984%22">10810984)</searchLink><br />BMJ. 2007 Jan 27;334(7586):197. (PMID: <searchLink fieldCode="PM" term="%2217175568%22">17175568)</searchLink><br />Lab Invest. 2008 Jan;88(1):18-26. (PMID: <searchLink fieldCode="PM" term="%2218040269%22">18040269)</searchLink><br />Nat Rev Drug Discov. 2014 Jun;13(6):419-31. (PMID: <searchLink fieldCode="PM" term="%2224833294%22">24833294)</searchLink><br />Cell. 2021 Sep 2;184(18):4597-4611. (PMID: <searchLink fieldCode="PM" term="%2234478657%22">34478657)</searchLink><br />Toxicol Pathol. 2015 Feb;43(2):257-66. (PMID: <searchLink fieldCode="PM" term="%2224939892%22">24939892)</searchLink><br />Toxicol Pathol. 2011 Feb;39(2):381-9. (PMID: <searchLink fieldCode="PM" term="%2221422264%22">21422264)</searchLink><br />Vet Pathol. 2023 May;60(3):374-383. (PMID: <searchLink fieldCode="PM" term="%2236727841%22">36727841)</searchLink><br />Hum Genet. 2013 Oct;132(10):1077-130. (PMID: <searchLink fieldCode="PM" term="%2223820649%22">23820649)</searchLink><br />Mamm Genome. 2024 Dec;35(4):537-543. (PMID: <searchLink fieldCode="PM" term="%2239254744%22">39254744)</searchLink><br />JAMA. 2006 Oct 11;296(14):1731-2. (PMID: <searchLink fieldCode="PM" term="%2217032985%22">17032985)</searchLink><br />Vet Pathol. 2021 Nov;58(6):1158-1171. (PMID: <searchLink fieldCode="PM" term="%2234269122%22">34269122)</searchLink><br />Am J Transl Res. 2014 Jan 15;6(2):114-8. (PMID: <searchLink fieldCode="PM" term="%2224489990%22">24489990)</searchLink><br />Dis Model Mech. 2014 May;7(5):515-24. (PMID: <searchLink fieldCode="PM" term="%2224652767%22">24652767)</searchLink><br />Vet Pathol. 2020 Jan;57(1):172-182. (PMID: <searchLink fieldCode="PM" term="%2231272300%22">31272300)</searchLink><br />Nat Rev Drug Discov. 2010 Mar;9(3):203-14. (PMID: <searchLink fieldCode="PM" term="%2220168317%22">20168317)</searchLink><br />Nature. 2016 Sep 22;537(7621):508-514. (PMID: <searchLink fieldCode="PM" term="%2227626380%22">27626380)</searchLink><br />Nat Biotechnol. 2014 Jan;32(1):40-51. (PMID: <searchLink fieldCode="PM" term="%2224406927%22">24406927)</searchLink><br />Theranostics. 2026 Apr 23;16(12):6463-6484. (PMID: <searchLink fieldCode="PM" term="%2242244996%22">42244996)</searchLink><br />Pharmacology. 2021;106(7-8):356-368. (PMID: <searchLink fieldCode="PM" term="%2234023819%22">34023819)</searchLink><br />Vet Rec. 2014 Jun 28;174(26):650-4. (PMID: <searchLink fieldCode="PM" term="%2224970632%22">24970632)</searchLink><br />Nat Rev Genet. 2005 Jun;6(6):507-12. (PMID: <searchLink fieldCode="PM" term="%2215931173%22">15931173)</searchLink><br />Nat Rev Mol Cell Biol. 2020 Oct;21(10):571-584. (PMID: <searchLink fieldCode="PM" term="%2232636524%22">32636524)</searchLink><br />PLoS Med. 2010 Mar 30;7(3):e1000245. (PMID: <searchLink fieldCode="PM" term="%2220361020%22">20361020)</searchLink><br />Nature. 2025 Oct;646(8086):802-803. (PMID: <searchLink fieldCode="PM" term="%2241116075%22">41116075)</searchLink><br />Nat Rev Drug Discov. 2021 May;20(5):345-361. (PMID: <searchLink fieldCode="PM" term="%2232913334%22">32913334)</searchLink><br />Dis Model Mech. 2012 Jan;5(1):19-25. (PMID: <searchLink fieldCode="PM" term="%2222028326%22">22028326)</searchLink><br />Dis Model Mech. 2016 Feb;9(2):101-3. (PMID: <searchLink fieldCode="PM" term="%2226839397%22">26839397)</searchLink>
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