Top-down models in biology: explanation and control of complex living systems above the molecular level

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usa-input-error-message selection-validation-message"> Name must be less than 100 characters </div> </div> <div class="action-panel-control-wrap existing-collections-controls"> <label for="collections-action-panel-add-to-existing" class="action-panel-label"> Choose a collection: </label> <select id="collections-action-panel-add-to-existing" class="action-panel-selector collections-action-add-to-existing" data-ga-category="save_share" data-ga-action="select_collection" data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'"> </select> <div class="collections-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your collection due to an error<br> <a href="#">Please try again</a> </div> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore data-ga-category="save_share" data-ga-action="collections" data-ga-label="add"> Add </button> <button class="action-panel-cancel" aria-label="Close 'Add to Collections' panel" ref="linksrc=close_collections_panel" aria-controls="collections-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="collections" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="bibliography-action-panel" class="bibliography-action-panel action-panel in-progress-dots-panel" aria-hidden="true" data-bibliography-open-panel-enabled="false" data-bibliography-open-panel-url-hash="#open-bibliography-panel"> <div class="inner-wrap"> <h3 class="action-panel-heading"> Add to My Bibliography </h3> <form id="bibliography-action-panel-form" class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors" data-add-to-bibliography-max-amount="100" data-add-to-bibliography-batch-size="10" data-bibliography-delegates-url="/list-bibliography-delegates/" data-add-to-bibliography-url="/add-to-bibliography/" data-get-article-ids-by-search-url="/get-article-ids-by-search/" data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/"> <input type="hidden" name="csrfmiddlewaretoken" value="Lt5DIU9heIuxfQr5YVP87WdCa0QHRnx95csK5tmsRMoNThrquXk2ClJKL9B8drdC"> <div class="action-panel-control-wrap bibliographies-controls"> <div class="choice-group"> <ul class="bibliographies-action-add radio-group-items"> <li> <input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/> <label for="my-bibliography">My Bibliography</label> </li> </ul> </div> </div> <div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your delegates due to an error<br> <a href="#">Please try again</a> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore> Add </button> <button class="action-panel-cancel" aria-label="Close 'Add to bibliography' panel" ref="linksrc=close_bibliography_panel" aria-controls="bibliography-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="mybib" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true" data-saved-search-open-panel-enabled="false" data-saved-search-open-panel-url-hash="#open-saved-search-panel"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Your saved search </h2> <form id="saved-search-action-panel-form" class="saved-search-action-panel-form action-panel-content action-form" data-create-saved-search-url="/create-saved-search/" data-try-search-terms-url="/try-search-term/" data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/"> <input type="hidden" name="csrfmiddlewaretoken" value="Lt5DIU9heIuxfQr5YVP87WdCa0QHRnx95csK5tmsRMoNThrquXk2ClJKL9B8drdC"> <div class="action-panel-control-wrap"> <label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk"> Name of saved search: </label> <input maxlength="200" type="text" name="saved-search-name" id="saved-search-name" class="saved-search-name" value="" required pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"> </div> <div class="action-panel-control-wrap"> <label for="saved-search-term" class="action-panel-label required-field-asterisk"> Search terms: </label> <textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea> </div> <div class="test-search-term-wrap"> <a href="#" class="try-search-term">Test search terms</a> </div> <div class="choice-group action-panel-extra-margin-top"> <span class="action-panel-label" id="fieldset-label"> Would you like email updates of new search results? </span> <fieldset id="saved-search-alert" aria-describedby="fieldset-label"> <legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend> <ul class="radio-group-items"> <li> <input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked> <label for="saved-search-alert-yes" class="action-panel-label">Yes</label> </li> <li> <input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no"> <label for="saved-search-alert-no" class="action-panel-label">No</label> </li> </ul> </fieldset> </div> <div class="alert-schedule-wrap"> <div class="action-panel-control-wrap"> <label class="action-panel-label"> Email: </label> <span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span> </div> <div class="action-panel-control-wrap action-panel-extra-margin-top"> <label for="saved-search-frequency" class="action-panel-label"> Frequency: </label> <select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency"> <option value="monthly">Monthly</option> <option value="weekly">Weekly</option> <option value="daily">Daily</option> </select> </div> <div class="action-panel-control-wrap saved-search-monthly-additional"> <label for="saved-search-monthly-on-day" class="action-panel-label"> Which day? </label> <select id="saved-search-monthly-on-day" class="no-border-panel-selector"> <option value="Sunday">The first Sunday</option> <option value="Monday">The first Monday</option> <option value="Tuesday">The first Tuesday</option> <option value="Wednesday">The first Wednesday</option> <option value="Thursday">The first Thursday</option> <option value="Friday">The first Friday</option> <option value="Saturday">The first Saturday</option> <option value="day">The first day</option> <option value="weekday">The first weekday</option> </select> </div> <div class="action-panel-control-wrap saved-search-weekly-additional"> <label for="saved-search-weekly-on-day" class="action-panel-label"> Which day? </label> <select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day"> <option value="Sunday">Sunday</option> <option value="Monday">Monday</option> <option value="Tuesday">Tuesday</option> <option value="Wednesday">Wednesday</option> <option value="Thursday">Thursday</option> <option value="Friday">Friday</option> <option value="Saturday">Saturday</option> </select> </div> <div class="action-panel-control-wrap"> <label for="saved-search-report" class="action-panel-label"> Report format: </label> <select id="saved-search-report" class="no-border-panel-selector saved-search-report"> <option value="DocSum">Summary</option> <option value="DocSumText">Summary (text)</option> <option value="Abstract">Abstract</option> <option value="AbstractText">Abstract (text)</option> <option value="MEDLINE">PubMed</option> </select> </div> <div class="action-panel-control-wrap"> <label for="saved-search-amount" class="action-panel-label"> Send at most: </label> <select id="saved-search-amount" class="no-border-panel-selector saved-search-amount"> <option value="1">1 item</option> <option value="5" selected>5 items</option> <option value="10">10 items</option> <option value="20">20 items</option> <option value="50">50 items</option> <option value="100">100 items</option> <option value="200">200 items</option> </select> </div> <div> <input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result"> <label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox"> Send even when there aren't any new results </label> </div> <div class="action-panel-control-wrap option-text-in-email-wrap"> <label for="saved-search-email-text" class="action-panel-label"> Optional text in email: </label> <textarea name="saved-search-email-text" id="saved-search-email-text" class="saved-search-email-text"></textarea> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Saving..." data-ga-category="save_share" data-ga-action="alert" data-ga-label="save"> Save </button> <button class="action-panel-cancel" aria-label="Close 'Your saved search' panel" ref="linksrc=close_saved_search_panel" aria-controls="saved-search-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="alert" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Create a file for external citation management software </h2> <form id="citation-manager-action-panel-form" class="action-panel-content action-form" action="/results-export-ids/" data-by-search-action="/results-export-search-data/" data-by-ids-action="/results-export-ids/" method="post" data-by-search-method="post" data-by-ids-method="post"> <input type="hidden" name="csrfmiddlewaretoken" value="Lt5DIU9heIuxfQr5YVP87WdCa0QHRnx95csK5tmsRMoNThrquXk2ClJKL9B8drdC"> <input name="results-format" type="hidden" value="pubmed"/> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Sending..." data-ga-category="save_share" data-ga-action="citation_manager" data-ga-label="save"> Create file </button> <button class="action-panel-cancel" aria-label="Close 'Send citations to citation manager' panel" ref="linksrc=close_citation_manager_panel" aria-controls="citation-manager-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="citation_manager" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Your RSS Feed </h2> <form id="rss-action-panel-form" class="rss-action-panel-form action-panel-content action-form" data-create-rss-feed-url="/create-rss-feed-url/" data-search-form-term-value=""> <input type="hidden" name="csrfmiddlewaretoken" value="Lt5DIU9heIuxfQr5YVP87WdCa0QHRnx95csK5tmsRMoNThrquXk2ClJKL9B8drdC"> <div class="action-panel-control-wrap"> <label for="rss-name" class="action-panel-label required-field-asterisk"> Name of RSS Feed: </label> <input maxlength="200" placeholder="Name" type="text" name="rss-name" id="rss-name" class="rss-name" value='' required pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"> </div> <div class="rss-limit-wrap"> <div class="action-panel-control-wrap action-panel-extra-margin-top"> <label for="rss-limit" class="action-panel-label"> Number of items displayed: </label> <select id="rss-limit" class="no-border-panel-selector rss-limit"> <option value="5">5</option> <option value="10">10</option> <option value="15" selected="selected">15</option> <option value="20">20</option> <option value="50">50</option> <option value="100">100</option> </select> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Creating..." data-ga-category="save_share" data-ga-action="alert" data-ga-label="save"> Create RSS </button> <button class="action-panel-cancel" aria-label="Close 'Your RSS' panel" ref="linksrc=close_rss_panel" aria-controls="rss-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="alert" data-ga-label="cancel"> Cancel </button> </div> <div class="action-panel-control-wrap rss-link-copy-wrap"> <label for="rss-link" class="usa-sr-only">RSS Link</label> <input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link"> <button type="button" disabled class="rss-link-copy-button disabled" data-ga-category="save_share" data-ga-action="rss" data-ga-label="copy"> Copy </button> </div> </form> </div> </div> </div> </div> <div class="article-page" id="article-page" data-article-pmid="27807271"> <aside class="page-sidebar"> <div class="inner-wrap"> <div class="full-text-links"> <div class="full-view"> <h3 class="title"> Full text links </h3> <div class="full-text-links-list"> <a class="link-item dialog-focus" 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class="inline-authors"> <div class="authors"> <div class="authors-list"> <span class="authors-list-item "><a class="full-name" href="/?term=Pezzulo+G&cauthor_id=27807271" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Giovanni Pezzulo">Giovanni Pezzulo</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Institute of Cognitive Sciences and Technologies, National Research Council, Rome, Italy." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Levin+M&cauthor_id=27807271" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Michael Levin">Michael Levin</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Biology Department, Allen Discovery Center at Tufts, Tufts University, Medford, MA 02155, USA michael.levin@tufts.edu." href="#full-view-affiliation-2" ref="linksrc=author_aff"> 2 </a></sup></span> </div> </div> </div> <div class="short-article-details"> Affiliations <button class="more-details" id="toggle-authors" data-alt-text="Collapse" aria-controls="expanded-authors" aria-expanded="false" data-pinger-ignore data-fetch-url="/27807271/long-authors/" data-id-prefix=""> <span class="title"> Expand </span> </button> </div> <div class="extended-article-details" id="expanded-authors" aria-hidden="true"> <div class="expanded-authors" id="full-view-expanded-authors"> <div class="affiliations"> <h3 class="title"> Affiliations </h3> <ul class="item-list"> <li data-affiliation-id="full-view-affiliation-1" id="full-view-affiliation-1" ><sup class="key">1</sup> Institute of Cognitive Sciences and Technologies, National Research Council, Rome, Italy.</li> <li data-affiliation-id="full-view-affiliation-2" id="full-view-affiliation-2" ><sup 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10.1098/rsif.2016.0555 </a> </span> </li> </ul> <div class="in-clipboard-label " hidden> Item in Clipboard </div> </div> <div class="short-view" id="short-view-heading"> <div class="publication-type" >Review</div> <h1 class="heading-title"> Top-down models in biology: explanation and control of complex living systems above the molecular level </h1> <div class="short-citation"> <span class="authors-list"> <span class="authors-list-item "><span class="full-name">Giovanni Pezzulo</span><span class="citation-separator"> et al.</span></span> </span> <span class="citation-journal"> J R Soc Interface<span class="citation-separator">.</span> </span> <span class="date"> <span class="citation-year">2016 Nov</span><span class="citation-separator">.</span> </span> </div> <div class="more-article-details-section with-display-settings"> <button class="more-article-details" id="toggle-article-details" data-alt-text="Hide details" ref="linksrc=toggle_article_details" 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class="expanded-authors" id="short-view-expanded-authors"> <div class="authors"> <h3 class="title"> Authors </h3> <div class="authors-list"> <span class="authors-list-item "><a class="full-name" href="/?term=Pezzulo+G&cauthor_id=27807271" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Giovanni Pezzulo">Giovanni Pezzulo</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Institute of Cognitive Sciences and Technologies, National Research Council, Rome, Italy." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Levin+M&cauthor_id=27807271" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Michael Levin">Michael Levin</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Biology Department, Allen Discovery Center at Tufts, Tufts University, Medford, MA 02155, USA michael.levin@tufts.edu." href="#short-view-affiliation-2" ref="linksrc=author_aff"> 2 </a></sup></span> </div> </div> <div class="affiliations"> <h3 class="title"> Affiliations </h3> <ul class="item-list"> <li data-affiliation-id="short-view-affiliation-1" id="short-view-affiliation-1" ><sup class="key">1</sup> Institute of Cognitive Sciences and Technologies, National Research Council, Rome, Italy.</li> <li data-affiliation-id="short-view-affiliation-2" id="short-view-affiliation-2" ><sup class="key">2</sup> Biology Department, Allen Discovery Center at Tufts, Tufts University, Medford, MA 02155, USA michael.levin@tufts.edu.</li> </ul> </div> </div> <ul class="identifiers" id="short-view-identifiers"> <li> <span class="identifier pubmed"> <span class="id-label"> PMID: </span> <strong class="current-id" title="PubMed ID">27807271</strong> </span> </li> <li> <span class="identifier pmc"> <span class="id-label"> PMCID: </span> <a class="id-link" target="_blank" rel="noopener" ref="linksrc=article_id_link&article_id=PMC5134011&id_type=PMC" href="https://pmc.ncbi.nlm.nih.gov/articles/PMC5134011/" data-ga-category="full_text" data-ga-action="PMCID" > PMC5134011 </a> </span> </li> <li> <span class="identifier doi"> <span class="id-label"> DOI: </span> <a class="id-link" target="_blank" rel="noopener" ref="linksrc=article_id_link&article_id=10.1098/rsif.2016.0555&id_type=DOI" href="https://doi.org/10.1098/rsif.2016.0555" data-ga-category="full_text" data-ga-action="DOI" > 10.1098/rsif.2016.0555 </a> </span> </li> </ul> <div class="in-clipboard-label " hidden> Item in Clipboard </div> </div> </div> </header> <div class="actions-buttons inline"><div class="inner-wrap"><button class="full-text-links-button full-text-links-dialog-trigger" title="Open dialog with full text links" ref="linksrc=full_text_links"> Full text links </button><button 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</span><select name="format" data-initial-value="abstract" aria-label="Display format" id="inline-actions-display-format"><option value="abstract">Abstract</option><option value="pubmed">PubMed</option><option value="pmid">PMID</option></select></div></div></div></div></div></div> <div class="abstract" id="abstract"> <h2 class="title"> Abstract </h2> <div class="abstract-content selected" id="eng-abstract"> <p> It is widely assumed in developmental biology and bioengineering that optimal understanding and control of complex living systems follows from models of molecular events. The success of reductionism has overshadowed attempts at top-down models and control policies in biological systems. However, other fields, including physics, engineering and neuroscience, have successfully used the explanations and models at higher levels of organization, including least-action principles in physics and control-theoretic models in computational neuroscience. Exploiting the dynamic regulation of pattern formation in embryogenesis and regeneration requires new approaches to understand how cells cooperate towards large-scale anatomical goal states. Here, we argue that top-down models of pattern homeostasis serve as proof of principle for extending the current paradigm beyond emergence and molecule-level rules. We define top-down control in a biological context, discuss the examples of how cognitive neuroscience and physics exploit these strategies, and illustrate areas in which they may offer significant advantages as complements to the mainstream paradigm. By targeting system controls at multiple levels of organization and demystifying goal-directed (cybernetic) processes, top-down strategies represent a roadmap for using the deep insights of other fields for transformative advances in regenerative medicine and systems bioengineering. </p> </div> <p> <strong class="sub-title"> Keywords: </strong> cognitive modelling; developmental biology; integrative; regeneration; remodelling; top-down. </p> </div> <p class="copyright" id="copyright"> © 2016 The Author(s). </p> <p class="disclaimer" id="disclaimer"> <a href="/disclaimer/" target="_blank" ga_category="literature_resources" ga_action="disclaimer_link" ga_label="under_abstract">PubMed Disclaimer</a> </p> <div class="figures" id="figures"> <h2 class="title"> Figures </h2> <div class="figures-list" id="slides-container" itemscope itemtype="http://schema.org/ImageGallery"> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="0" data-label-slug="figure-1"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c12/5134011/a7f267dad99a/rsif20160555-g1.jpg" itemprop="contentUrl" aria-describedby="figure-caption-0" role="button" data-image-width="610" data-image-height="1083" data-image-alt="Figure 1." data-pmc-id="PMC5134011" data-figure-id="RSIF20160555F1"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-0" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c12/5134011/be2b2c5459ad/rsif20160555-g1.gif" alt="Figure 1." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="610"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="1083"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 1. </p> </strong> <div class="figure-caption-contents"><p> Flexible, goal-directed shape homeostasis. (… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 1. </p> </strong> <div class="figure-caption-contents"><p> Flexible, goal-directed shape homeostasis. ( <i> a </i> ) A tail grafted to the flank… </p></div> </div> <figcaption id="figure-caption-0" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 1. </strong> <div class="figure-caption-contents">Flexible, goal-directed shape homeostasis. (<i>a</i>) A tail grafted to the flank of a salamander slowly remodels to a limb, a structure more appropriate for its new location, illustrating shape homeostasis towards a normal amphibian body plan. Even the tail tip cells (in red) slowly become fingers, showing that the remodelling is not driven by only local information. Image taken with permission from [2]. (<i>b</i>) In some species of deer, the cell behaviour of bone growth during antler regeneration each year is modified by a memory of the three-dimensional location of damage made in prior years. Image taken with permission from [3]. (<i>c</i>) Kidney tubules in the newt are made with a constant size, whereas cell size can vary drastically under polyploidy (image taken with permission from: Fankhauser G. 1945 Maintenance of normal structure in heteroploid salamander larvae, through compensation of changes in cell size by adjustment of cell number and cell shape. <i>J. Exper. Zool.</i> <b>100</b>, 445–455). Thus, the tubule pattern (a macroscopic goal state) can be implemented by diverse underlying molecular mechanisms such as cell : cell interactions (when there are many small cells) or cytoskeletal bending that curls one cell around itself, to make a tubule (when cells are very large). This illustrates the many-to-one relationship observed across scales of organization observed in statistical mechanics, computer science (implementation independence) and cognitive neuroscience (flexible pursuit of plans).</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="1" data-label-slug="figure-2"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c12/5134011/25deb01a3425/rsif20160555-g2.jpg" itemprop="contentUrl" aria-describedby="figure-caption-1" role="button" data-image-width="673" data-image-height="711" data-image-alt="Figure 2." data-pmc-id="PMC5134011" data-figure-id="RSIF20160555F2"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-1" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c12/5134011/7cb7a14b5035/rsif20160555-g2.gif" alt="Figure 2." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="673"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="711"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 2. </p> </strong> <div class="figure-caption-contents"><p> The functioning of the test,… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 2. </p> </strong> <div class="figure-caption-contents"><p> The functioning of the test, operate, test, exit (TOTE) model for action control… </p></div> </div> <figcaption id="figure-caption-1" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 2. </strong> <div class="figure-caption-contents">The functioning of the test, operate, test, exit (TOTE) model for action control and regeneration. (<i>a</i>) Generic functioning scheme of the TOTE model (which exemplifies a class of cybernetic models that operate using similar principles, see the main text). The ‘test’ operation corresponds to the comparison between desired and sensed state values. If a discrepancy is detected, then an action is activated (‘operate’) that tries to reduce it. When there is no discrepancy, the ‘exit’ operation is selected, corresponding to no action. (<i>b</i>) An example in the domain of action control. Here, the red box corresponds to a desired state value (handle grasped), which can trigger a series of (grasping) actions; see [69] for an example implementation. (<i>c</i>) The same mechanism at work in regeneration, where a discrepancy between the organism's target morphology and the current anatomical state (caused by injury) activates pattern homeostatic remodelling and growth. In highly regenerative animals, such as salamanders, cells proliferate, differentiate and migrate as needed to restore the correct pattern, and cease when the correct shape has been achieved.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="2" data-label-slug="figure-3"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c12/5134011/ffb4f9de47e5/rsif20160555-g3.jpg" itemprop="contentUrl" aria-describedby="figure-caption-2" role="button" data-image-width="784" data-image-height="542" data-image-alt="Figure 3." data-pmc-id="PMC5134011" data-figure-id="RSIF20160555F3"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-2" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c12/5134011/017220e7a6cf/rsif20160555-g3.gif" alt="Figure 3." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="784"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="542"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 3. </p> </strong> <div class="figure-caption-contents"><p> An example of application of… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 3. </p> </strong> <div class="figure-caption-contents"><p> An example of application of the free energy principle to morphogenesis. ( <i> a… </i> </p></div> </div> <figcaption id="figure-caption-2" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 3. </strong> <div class="figure-caption-contents">An example of application of the free energy principle to morphogenesis. (<i>a</i>) Illustration of the target morphology that the cells have to achieve: a simple morphology with head, body and tail. The cells have to ‘find their place’ in this morphology, but are initially undifferentiated; this means that, in principle, each cell could become part of the head, body or tail (although constraints can be introduced on this process). (<i>b</i>) When cells occupy a given positions, they emit chemical signals that can be sensed by the surrounding cells. The figure illustrates the signals that each cell ‘expects’ to sense when it occupies a given spatial position. Of note, the cells can only sense these signals (and thus minimize their prediction error or free energy) if all the other cells are in the right place and emit the right signal. (<i>c</i>) In turn, this triggers a multi-agent migration (or differentiation) process, in which cells that ‘search’ their own place in the morphology influence and are influenced by the other cells. (<i>d</i>) There is only one solution to this multi-cell process—one in which each cell occupies its place and emits (and senses) the right signals. This corresponds to the target morphology. (<i>e</i>) It is only in this ‘solution’ state that the free energy of the system is minimized. Overall, it is a free energy minimization imperative that drives the pattern formation and morphogenetic process at the level of the whole system, with the cell–cell signalling mechanism playing a key role by permitting cells to influence one another. Images re-used according to the Creative Commons licence from ref. [52].</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="3" data-label-slug="figure-4"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c12/5134011/a512183ce1e6/rsif20160555-g4.jpg" itemprop="contentUrl" aria-describedby="figure-caption-3" role="button" data-image-width="771" data-image-height="656" data-image-alt="Figure 4." data-pmc-id="PMC5134011" data-figure-id="RSIF20160555F4"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-3" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c12/5134011/a7558f4c6642/rsif20160555-g4.gif" alt="Figure 4." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="771"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="656"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 4. </p> </strong> <div class="figure-caption-contents"><p> Bioelectric signalling in the brain… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 4. </p> </strong> <div class="figure-caption-contents"><p> Bioelectric signalling in the brain and body. ( <i> a </i> ) The hardware of… </p></div> </div> <figcaption id="figure-caption-3" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 4. </strong> <div class="figure-caption-contents">Bioelectric signalling in the brain and body. (<i>a</i>) The hardware of neural systems is composed of ion channel proteins which set the voltage level (node activation) of cells, and electrical synapses (gap junctions) that allow circuits to form via voltage propagation. These networks execute software—a diverse collection of modes and dynamics of bioelectrical states that evolve through time within cells (a true epigenetic system; transcriptional or translational changes are not required, as channels and gap junctions regulate and are regulated by voltage post-translationally). Efforts in computational neuroscience are ongoing to extract semantic content from readings of the electric activity (rightmost panel in row (<i>a</i>) is taken with permission from Naselaris T, Prenger RJ, Kay KN, Oliver M, Gallant JL. 2009 Bayesian reconstruction of natural images from human brain activity. <i>Neuron</i> <b>63</b>, 902–915). (<i>b</i>) Precisely this system, albeit functioning at a slower timescale, occurs in non-excitable tissues, which use exactly those electrogenic proteins to form electrical networks in tissues during embryogenesis, regeneration and cancer. On the right-hand side is shown an image of an endogenous bioelectrical gradient (red = depolarized, blue = hyperpolarized) that serves as an instructive prepattern to regeneration in a planarian flatworm. The cracking of the bioelectric code to understand the anatomical outputs of bioelectric states is a key open problem in this field. Bioelectricity may be an important entry point to understand the integration of information across levels of organization during pattern regulation. Gene regulatory networks that regulate ion channel expression (<i>c</i>) constrain bioelectric circuits within tissue (<i>d</i>) which have their own dynamics that likewise regulate transcription of other genes. Together, these interplay to set up chemical and electrical gradients on an organism-wide scale which define anatomical regions and set organ size and identity (<i>e</i>). Events during remodelling and regeneration are controlled by high-level anatomical properties and topological interactions (<i>f</i>). Each of these levels have their own unique concepts, key variables, datasets and models. Top-down strategies may assist in the merging of these different levels of description towards an algorithmic (<i>g</i>) understanding of shape control, greatly facilitating rational control of outcomes. Images courtesy of Alexis Pietak, Jeremy Guay of Peregrine Creative, and Allegra Westfall.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="4" data-label-slug="figure-5"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c12/5134011/38e0280422ef/rsif20160555-g5.jpg" itemprop="contentUrl" aria-describedby="figure-caption-4" role="button" data-image-width="790" data-image-height="497" data-image-alt="Figure 5." data-pmc-id="PMC5134011" data-figure-id="RSIF20160555F5"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-4" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c12/5134011/c7045019b9fb/rsif20160555-g5.gif" alt="Figure 5." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="790"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="497"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 5. </p> </strong> <div class="figure-caption-contents"><p> Representation of multiple levels within… </p></div> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 5. </p> </strong> <div class="figure-caption-contents"><p> Representation of multiple levels within bioelectric (neural-like) networks. ( <i> a </i> ) Neural networks… </p></div> </div> <figcaption id="figure-caption-4" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 5. </strong> <div class="figure-caption-contents">Representation of multiple levels within bioelectric (neural-like) networks. (<i>a</i>) Neural networks of different kinds—e.g. deep nets, attractor nets—are able to learn internal representations of external entities directly from (unannotated) input data, at multiple levels, as they become tuned to the statistics of their inputs during learning [47]. For example, <i>generative</i> neural networks trained to reproduce in output the same figures (e.g. faces, objects or numbers) they receive in input often learn simpler-to-more-complex object or face features at increasingly higher hierarchical layers of the network, in ways that are (sometimes) biologically realistic [118,119]. Learning proceeds differently depending on the specific neural network architecture. For example, basins of attraction in the state space of attractor neural networks can represent specific memories [65]. If somatic tissues undergoing remodelling can be represented by similar frameworks, then it is possible that stable states in the network can represent specific patterning outcomes (like the one- or two-headed flatworms that result from editing of bioelectric networks <i>in vivo</i> [–122]). (<i>b</i>) One advantage of neural network architectures is that they show a proof of principle of how collections of cells can represent higher-level topological information; here are shown analogies between information representation in an ANN during a face recognition tasks and in flatworm regeneration. Neural network layers represent progressively increasingly abstract features of the input, in well-understood ways. The functioning of specific neural network architectures such as attractor, generative or deep nets (or other [–125]) may give clues as to how collections of somatic cells can learn and store memories about tissues, organs, and entire body plan layouts. The current state of the art in the field of developmental bioelectricity is that it is known, at the cellular level, how resting potentials are transduced into downstream gene cascades, as well as which transcriptional and epigenetic targets are sensitive to change in developmental bioelectrical signals [–128]. What is largely missing however (and may be provided by a network approach or other possible conceptualizations) is a quantitative understanding of how the global dynamics of bioelectric circuits make decisions that orchestrate large numbers of individual cells, spread out over considerable anatomical distances, towards specific pattern outcomes. The mechanisms by which bioelectrics and chromatin state interact at a single cell level will be increasingly clarified by straightforward reductive analysis. The more difficult, major advances in prediction and control will require a systems-level model of pattern memory and encoding implemented in somatic bioelectrical networks whose output is signals that control growth and form. Images in panels (<i>a</i>) and (<i>b</i>) drawn by Jeremy Guay of Peregrine Creative.</div> </figcaption> </figure> </div>  <div class="pswp figures-dialog" id="figures-dialog" tabindex="-1" role="dialog" aria-hidden="true" data-image-gallery-uid="article-figures" aria-label="Figures Dialog">  <div class="pswp__bg"></div>  <div class="pswp__scroll-wrap">  <div class="pswp__container"> <div class="pswp__item"></div> <div class="pswp__item"></div> <div class="pswp__item"></div> </div>  <div class="pswp__ui pswp__ui--hidden"> <div class="pswp__top-bar">  <div class="pswp__counter"></div> <button class="pswp__button pswp__button--close" title="Close (Esc)"></button> <button class="pswp__button pswp__button--share" title="Share"></button> <button class="pswp__button pswp__button--fs" title="Toggle fullscreen"></button> <button class="pswp__button pswp__button--zoom" title="Zoom in/out"></button>   <div class="pswp__preloader"> <div class="pswp__preloader__icn"> <div class="pswp__preloader__cut"> <div class="pswp__preloader__donut"></div> </div> </div> </div> </div> <div class="pswp__share-modal pswp__share-modal--hidden pswp__single-tap"> <div class="pswp__share-tooltip"></div> </div> <button class="pswp__button pswp__button--arrow--left" title="Previous (arrow left)"> </button> <button class="pswp__button pswp__button--arrow--right" title="Next (arrow right)"> </button> <div class="pswp__caption"> <div class="pswp__caption__center"></div> </div> </div> </div> </div> <div class="figure-dialog-caption"> <div class="figure-caption-link-container"> <a class="figure-caption-link" href="#">See this image and copyright information in PMC</a> </div> <div class="figure-caption-center" data-expand-title="click to show full caption" data-collapse-title="click to hide full caption"> </div> <button class="figure-caption-toggle-btn" aria-label="show full caption" data-expand-text="show full caption" data-collapse-text="hide full caption">  </button> </div> </div> <div class="similar-articles" id="similar"> <h2 class="title"> Similar articles </h2> <ul class="articles-list" id="similar-articles-list"> <li class="full-docsum"> <div class="docsum-content" style="display:inline;"> <a class="docsum-title" href="/26571046/" ref="article_id=26571046&linksrc=similar_articles_link&ordinalpos=1" data-ga-category="similar_article" data-ga-action="26571046" data-ga-label=""> Re-membering the body: applications of computational neuroscience to the top-down control of regeneration of limbs and other complex organs. </a> <div class="docsum-citation full-citation"> <span class="docsum-authors full-authors">Pezzulo G, Levin M.</span> <span class="docsum-authors short-authors">Pezzulo G, et al.</span> <span class="docsum-journal-citation full-journal-citation">Integr Biol (Camb). 2015 Dec;7(12):1487-517. doi: 10.1039/c5ib00221d. 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