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However, growing evidence indicates that many diseases persist and progress as complex distributed systems, maintained by interactions among multiple sites. Building on the emerging framework of selection for function, which can be applied to understand the evolutionary persistence of both replicating and non\u2010replicating entities, we propose that metastases, amyloidoses, fibroses, autoimmune syndromes, granulomatous diseases, and multifocal reproductive disorders can all be understood as complex evolving pathological systems within individuals. In these contexts, local units such as metastatic nodules, amyloid plaques, or fibrotic foci act as semi\u2010autonomous entities, yet achieve collective persistence through systemic flows, feedback loops, and network\u2010level interactions, where local structuration gives rise to systemic effects. At certain points, lesions that produce mediators can trigger systemic alterations that, in turn, favor the emergence and persistence of additional lesions. This creates a vicious cycle in which local and systemic dynamics reinforce one another, helping these specific pathological networks to overcome host defense mechanisms and persist (i.e., be \u2018selected\u2019 via differential persistence). This perspective unifies seemingly disparate conditions under the principle of system persistence, reframing pathology as an emergent organizational property of a pathological system rather than as isolated local breakdowns of organismal components. It also carries important implications for evolutionary medicine, suggesting a taxonomy of diseases that distinguishes localized from distributed functional pathologies. Clinically, it underscores the need to go beyond focal interventions, advocating instead for therapies that disrupt pathological connectivity, destabilize network coherence, and monitor systemic biomarkers of disease persistence. Recognizing the role of selection for function in the emergence and persistence of complex pathological systems opens new avenues for both theoretical integration and therapeutic innovation in evolutionary medicine.<\/jats:p>","DOI":"10.1111\/eva.70202","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T04:10:12Z","timestamp":1770091812000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Selection for Function in Complex Distributed Pathological Systems"],"prefix":"10.1111","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2238-1978","authenticated-orcid":false,"given":"Fr\u00e9d\u00e9ric","family":"Thomas","sequence":"first","affiliation":[{"name":"CREEC\/CANECEV, MIVEGEC (CREES) Department University of Montpellier, CNRS, IRD  Montpellier France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1579-9156","authenticated-orcid":false,"given":"Antoine M.","family":"Dujon","sequence":"additional","affiliation":[{"name":"CREEC\/CANECEV, MIVEGEC (CREES) Department University of Montpellier, CNRS, IRD  Montpellier France"},{"name":"School of Life and Environmental Sciences, Deakin University  Waurn Ponds Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1915-0717","authenticated-orcid":false,"given":"Daniel","family":"Vaiman","sequence":"additional","affiliation":[{"name":"Institut Cochin, U1016, INSERM, UMR8104 CNRS, Universit\u00e9 de Paris  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1119-5638","authenticated-orcid":false,"given":"Gerard","family":"Eberl","sequence":"additional","affiliation":[{"name":"Microenvironment &amp; Immunity Unit, Institut Pasteur  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6401-2903","authenticated-orcid":false,"given":"Catherine","family":"Alix\u2010Panabi\u00e8res","sequence":"additional","affiliation":[{"name":"CREEC\/CANECEV, MIVEGEC (CREES) Department University of Montpellier, CNRS, IRD  Montpellier France"},{"name":"Laboratory of Rare Human Circulating Cells and Liquid Biopsy (LCCRH), University Medical Centre of Montpellier  Montpellier France"},{"name":"European Liquid Biopsy Society (ELBS)  Hamburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8315-4715","authenticated-orcid":false,"given":"Pascal","family":"Pujol","sequence":"additional","affiliation":[{"name":"Oncogenetic Department University Medical Centre of Montpellier  Montpellier France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2391-2988","authenticated-orcid":false,"given":"Beata","family":"Ujvari","sequence":"additional","affiliation":[{"name":"School of Life and Environmental Sciences, Deakin University  Waurn Ponds Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8517-8727","authenticated-orcid":false,"given":"Jordan","family":"Meliani","sequence":"additional","affiliation":[{"name":"CREEC\/CANECEV, MIVEGEC (CREES) Department University of Montpellier, CNRS, IRD  Montpellier France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7517-2419","authenticated-orcid":false,"given":"Aurora M.","family":"Nedelcu","sequence":"additional","affiliation":[{"name":"Department of Biology University of New Brunswick  Fredericton New Brunswick Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6470-079X","authenticated-orcid":false,"given":"Jean\u2010Pascal","family":"Capp","sequence":"additional","affiliation":[{"name":"Toulouse Biotechnology Institute, University of Toulouse, INSA, CNRS, INRAE  Toulouse France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,2,2]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41584\u2010024\u201001217\u20102"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.07.013"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/bcr2561"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/795976"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365\u2010294X.2007.03535.x"},{"key":"e_1_2_13_7_1","unstructured":"Asselin K. 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