/ en /news/brain-chimeroids-offer-window-relationships-between-genetics-and-exposures <span class="field field--name-title field--type-string field--label-hidden"><h1>Brain chimeroids offer window into relationships between genetics and exposures</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Tom Ulrich</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-07-08T10:30:38-04:00" class="datetime">July 8, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Brain chimeroids offer window into relationships between genetics and exposures</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>New model system allows researchers to study the influence of genetic background on brain cells' responses to neurotoxins, disease mutations, and potential therapeutics</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Alice McCarthy, Harvard University </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-07-08T10:30:38-04:00" title="Monday, July 8, 2024 - 10:30" class="datetime">July 8, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=5VyOntI1 1x" media="all and (min-width: 1921px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=5VyOntI1 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=O8QMXmqM 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=aLTBeADi 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=l2192yL6 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=bADgyMxg 1x" media="all and (max-width: 539px)" type="image/png" width="499" height="294"> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=bADgyMxg" alt="Color microscope image of a brain chimeroid, with red and green colors highlighting different types of cells and different structures." title="Color microscope image of a brain chimeroid, with red and green colors highlighting different types of cells and different structures." typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Arlotta laboratory </div> <div class="media-caption__description"> A brain chimeroid </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section 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href="/stanley-center-for-psychiatric-research">Stanley Center for Psychiatric Research</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related news</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/molecular-map-brain-organoids-reveals-unprecedented-levels-neuronal-cell-maturation-and" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/molecular-map-brain-organoids-reveals-unprecedented-levels-neuronal-cell-maturation-and"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=bb0Vsxsf 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=bb0Vsxsf 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=9y-4pm3P 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=9y-4pm3P 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=2Ja6exy9 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=1dZ21ixd 1x" media="all and (max-width: 539px)" type="image/jpeg" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=1dZ21ixd" alt="Synapse development in organoids. Expression of the synaptic marker SYN1 (green) is absent at 1 month (upper left) and appears with organoid maturation by 3 months (upper right). Organoids continue maturing at 6 months (lower left) and 9 months (lower right)." title="Synapse development in organoids. Expression of the synaptic marker SYN1 (green) is absent at 1 month (upper left) and appears with organoid maturation by 3 months (upper right). Organoids continue maturing at 6 months (lower left) and 9 months (lower right)." typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/molecular-map-brain-organoids-reveals-unprecedented-levels-neuronal-cell-maturation-and" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Molecular map of brain organoids reveals unprecedented levels of neuronal cell maturation and diversity</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/human-brain-organoids-come-age" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/human-brain-organoids-come-age"><picture> <source 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href="/news/human-brain-organoids-come-age" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Human brain organoids come of age</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/three-autism-risk-genes-have-similar-effects-brain-development-different-routes" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/three-autism-risk-genes-have-similar-effects-brain-development-different-routes"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=FJtNfzyb 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=FJtNfzyb 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=eNxnB5gG 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=eNxnB5gG 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=t4Lif9cH 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=bhXHlqXC 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=bhXHlqXC" alt="Microscopy image of a brain organoid showing individual neurons spontaneously firing" title="Microscopy image of a brain organoid showing individual neurons spontaneously firing" typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/three-autism-risk-genes-have-similar-effects-brain-development-different-routes" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Three autism risk genes have similar effects on brain development, but by different routes</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/brain-organoids-replicate-key-events-human-brain-development" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/brain-organoids-replicate-key-events-human-brain-development"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=lstySHBC 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=lstySHBC 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=4HlxIV8e 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=4HlxIV8e 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=T0IPiSz3 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=njI3T1Gw 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=njI3T1Gw" alt="Human brain organoids showing neurons and their dendrites (green), telencephalic (forebrain) cells (blue), and a kind of cell-cell contact called tight junctions (red)." title="Human brain organoids showing neurons and their dendrites (green), telencephalic (forebrain) cells (blue), and a kind of cell-cell contact called tight junctions (red)." typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/brain-organoids-replicate-key-events-human-brain-development" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Brain organoids replicate key events in human brain development</span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Researchers at the Harvard Department of Stem Cell and Regenerative Biology (HSCRB) and the ӳ����ý of MIT and Harvard have developed a new platform for modeling at the cellular level how the human brain responds to a variety of stimuli. Described in <a href="https://www.nature.com/articles/s41586-024-07578-8" target="_blank"><em>Nature</em></a>, these ‘brain chimeroids’ provide an approach for studying how genetic background can affect the outcome of neurotoxic exposures, disease-associated&nbsp;genetic variants, and potential therapeutic compounds.&nbsp;</p> <p>Chimeroids are brain organoids made up of cells representing multiple cell types found in the human brain (neurons, glial cells, etc.), derived from induced pluripotent stem cells generated from several human donors. By incorporating cells from many individuals, chimeroids allow researchers to observe&nbsp;<em>in vitro</em> how cells and brain circuits from individuals with unique genetic backgrounds, including those with family histories of neurodevelopmental or neuropsychiatric disorders, respond to the same stimulus.&nbsp;</p> <p>People carry a vast reservoir of genetic variation; any two individuals differ from each other at about one base pair out of every 1,000 across the three billion-base pair genome. Risk for conditions like schizophrenia or autism spectrum disorder (ASD) often arises from the complex interplay of many genetic variations, rather than from variations in a single gene. By incorporating large numbers of individuals across a spectrum of polygenic risk, chimeroids allow researchers to leverage this genetic diversity to understand its functional effects on the brain.</p> <p>"The idea of generating organoids that contain cells from multiple donors was directly motivated by our long-term interest in modeling psychiatric conditions, such as schizophrenia, and developmental disorders, such as autism spectrum disorder," said senior author <a href="/node/4635">Paola Arlotta</a>, chair of HSCRB and an institute member in the <a href="http://www.broadinstitute.org/node/8513">Stanley Center for Psychiatric Research</a> at ӳ����ý. "The ability to grow cells from distinct donors within the same organoid opens the door to investigating at scale and in a controlled way the responses of brain cells of many different individuals to many different types of stimuli, from genetic mutations, to infections, to drugs, and more."</p> <h2>Embracing variation</h2> <p>Brain chimeroids build on a decade of research by the Arlotta lab, which has pioneered the use of human organoids to study neuropsychiatric disorders. The process of creating a chimeroid involves several steps. First, pluripotent stem cells — which can be generated from any donor (healthy or patient) — from multiple people are differentiated in individual 3D cultures and coaxed to become neural progenitors, particularly those of a brain cortical fate. Next, the cells are removed from culture, disassociated from each other, and reassembled.</p> <p>The resulting 3D chimeroids are composed of multiple brain cell types from multiple donors, each contributing to the overall structure. The researchers used cells from five different donors for this study, but the platform is designed to be flexible and scalable, potentially accommodating hundreds of donors in future studies.</p> <p>"In this context, the goal was to develop a way of looking at different cells of the brain that are affected by a trigger in a more scalable way and develop a platform to read solid responses in these different cells," said Irene Faravelli, a postdoctoral researcher in the Arlotta lab and co-first author of the study with postdoctoral fellow Noelia Antón-Bolaños.</p> <p>The development of chimeroids was not without its challenges, such as ensuring that the cells from different donors maintained a balanced proportion over time. "A major technical challenge was that single donors would take over the culture over time, even if mixes were donor-balanced initially," Antón-Bolaños recalled. Overcoming this challenge required a deep understanding of embryonic brain development and innovative computational analysis techniques.</p> <h2>Putting exposure in context</h2> <p>To test their system, the team exposed chimeroids to two compounds with well-known neurotoxic effects in the developing brain: ethanol and valproic acid. Ethanol exposure during pregnancy can lead to fetal alcohol spectrum disorder, while valproic acid (VPA), a drug used to treat mood disorders and seizures, has been linked to an increased risk of ASD. Clinicians have long noted that not all children exposed to these compounds experience the same outcomes, suggesting that genetic variations&nbsp;may influence susceptibility. &nbsp;</p> <p>Using a transcriptomic readout, which allows researchers to explore cells' molecular responses to stimuli, the team identified significant changes in the cell type composition of ethanol- or VPA-exposed chimeroids compared to unexposed controls. They also found that the proportion of cells from specific donors changed within exposed organoids, as did the gene expression profiles of cells from different donors in response to VPA.&nbsp;</p> <p>The team believes chimeroids may accelerate the study of complex polygenic states associated with psychiatric disorders like schizophrenia and ASD, or could enable prediction of responses to new therapeutics, which could have significant implications for personalized medicine. This could lead to more accurate preclinical trials and better predictions of clinical outcomes.</p> <p>"Success in this area would mean that organoids could become pre-clinical trial 'avatars' informing on the differential responses of the cells of the brain of each individual to begin to predict clinical outcomes," Arlotta said. "What if one day we could use chimeroids as avatars to predict individual responses to new therapeutics before testing it in a trial? Or to stratify and better classify and diagnose patients to tailor more effective therapeutics to them? I like to imagine that future, frankly."&nbsp;</p> <p><em>Adapted from <a href="https://hscrb.harvard.edu/news/brain-chimeroids-reveal-susceptibility-to-brain-triggers/" target="_blank">a story published by the Harvard Department of Stem Cell and Regenerative Biology</a></em>.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this study was provided by the National Institute of Mental Health, the Stanley Center for Psychiatric Research, the Klarman Cell Observatory, the ӳ����ý of MIT and Harvard, and the Blavatnik Biomedical Accelerator at Harvard University.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Antón-Bolaños&nbsp;N, Favarelli I, et al.&nbsp;<a href="https://www.nature.com/articles/s41586-024-07578-8" target="_blank">Brain chimeroids reveal individual susceptibility to neurotoxic triggers</a>. <em>Nature</em>. Online June 26, 2024. DOI:&nbsp;10.1038/s41586-024-07578-8.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/stanley-center-psychiatric-research" hreflang="en">Stanley Center for Psychiatric Research</a></div> <div class="field__item"><a href="/broad-tags/neurodevelopmental-conditions" hreflang="en">Neurodevelopmental conditions</a></div> <div class="field__item"><a href="/broad-tags/psychiatric-disease" hreflang="en">Brain Health</a></div> <div class="field__item"><a href="/broad-tags/paola-arlotta" hreflang="en">Paola Arlotta</a></div> </div> </div> </div> </div> </div> Mon, 08 Jul 2024 14:30:38 +0000 tulrich@broadinstitute.org 5557106 at /news/brain-organoids-replicate-key-events-human-brain-development <span class="field field--name-title field--type-string field--label-hidden"><h1>Brain chimeroids offer window into relationships between genetics and exposures</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Tom Ulrich</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-07-08T10:30:38-04:00" class="datetime">July 8, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Brain chimeroids offer window into relationships between genetics and exposures</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>New model system allows researchers to study the influence of genetic background on brain cells' responses to neurotoxins, disease mutations, and potential therapeutics</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Alice McCarthy, Harvard University </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-07-08T10:30:38-04:00" title="Monday, July 8, 2024 - 10:30" class="datetime">July 8, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=5VyOntI1 1x" media="all and (min-width: 1921px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=5VyOntI1 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=O8QMXmqM 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=aLTBeADi 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=l2192yL6 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=bADgyMxg 1x" media="all and (max-width: 539px)" type="image/png" width="499" height="294"> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=bADgyMxg" alt="Color microscope image of a brain chimeroid, with red and green colors highlighting different types of cells and different structures." title="Color microscope image of a brain chimeroid, with red and green colors highlighting different types of cells and different structures." typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Arlotta laboratory </div> <div class="media-caption__description"> A brain chimeroid </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous"></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/981/feed&amp;title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use 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block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related people</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/bios/paola-arlotta">Paola Arlotta</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related programs</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/stanley-center-for-psychiatric-research">Stanley Center for Psychiatric Research</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related news</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/molecular-map-brain-organoids-reveals-unprecedented-levels-neuronal-cell-maturation-and" class="node"> <div class="field 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Expression of the synaptic marker SYN1 (green) is absent at 1 month (upper left) and appears with organoid maturation by 3 months (upper right). Organoids continue maturing at 6 months (lower left) and 9 months (lower right)." title="Synapse development in organoids. Expression of the synaptic marker SYN1 (green) is absent at 1 month (upper left) and appears with organoid maturation by 3 months (upper right). 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srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=t4Lif9cH 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=bhXHlqXC 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=bhXHlqXC" alt="Microscopy image of a brain organoid showing individual neurons spontaneously firing" title="Microscopy image of a brain organoid showing individual neurons spontaneously firing" 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srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=lstySHBC 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=lstySHBC 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=4HlxIV8e 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=4HlxIV8e 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=T0IPiSz3 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=njI3T1Gw 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=njI3T1Gw" alt="Human brain organoids showing neurons and their dendrites (green), telencephalic (forebrain) cells (blue), and a kind of cell-cell contact called tight junctions (red)." title="Human brain organoids showing neurons and their dendrites (green), telencephalic (forebrain) cells (blue), and a kind of cell-cell contact called tight junctions (red)." typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/brain-organoids-replicate-key-events-human-brain-development" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Brain organoids replicate key events in human brain development</span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Researchers at the Harvard Department of Stem Cell and Regenerative Biology (HSCRB) and the ӳ����ý of MIT and Harvard have developed a new platform for modeling at the cellular level how the human brain responds to a variety of stimuli. Described in <a href="https://www.nature.com/articles/s41586-024-07578-8" target="_blank"><em>Nature</em></a>, these ‘brain chimeroids’ provide an approach for studying how genetic background can affect the outcome of neurotoxic exposures, disease-associated&nbsp;genetic variants, and potential therapeutic compounds.&nbsp;</p> <p>Chimeroids are brain organoids made up of cells representing multiple cell types found in the human brain (neurons, glial cells, etc.), derived from induced pluripotent stem cells generated from several human donors. By incorporating cells from many individuals, chimeroids allow researchers to observe&nbsp;<em>in vitro</em> how cells and brain circuits from individuals with unique genetic backgrounds, including those with family histories of neurodevelopmental or neuropsychiatric disorders, respond to the same stimulus.&nbsp;</p> <p>People carry a vast reservoir of genetic variation; any two individuals differ from each other at about one base pair out of every 1,000 across the three billion-base pair genome. Risk for conditions like schizophrenia or autism spectrum disorder (ASD) often arises from the complex interplay of many genetic variations, rather than from variations in a single gene. By incorporating large numbers of individuals across a spectrum of polygenic risk, chimeroids allow researchers to leverage this genetic diversity to understand its functional effects on the brain.</p> <p>"The idea of generating organoids that contain cells from multiple donors was directly motivated by our long-term interest in modeling psychiatric conditions, such as schizophrenia, and developmental disorders, such as autism spectrum disorder," said senior author <a href="/node/4635">Paola Arlotta</a>, chair of HSCRB and an institute member in the <a href="http://www.broadinstitute.org/node/8513">Stanley Center for Psychiatric Research</a> at ӳ����ý. "The ability to grow cells from distinct donors within the same organoid opens the door to investigating at scale and in a controlled way the responses of brain cells of many different individuals to many different types of stimuli, from genetic mutations, to infections, to drugs, and more."</p> <h2>Embracing variation</h2> <p>Brain chimeroids build on a decade of research by the Arlotta lab, which has pioneered the use of human organoids to study neuropsychiatric disorders. The process of creating a chimeroid involves several steps. First, pluripotent stem cells — which can be generated from any donor (healthy or patient) — from multiple people are differentiated in individual 3D cultures and coaxed to become neural progenitors, particularly those of a brain cortical fate. Next, the cells are removed from culture, disassociated from each other, and reassembled.</p> <p>The resulting 3D chimeroids are composed of multiple brain cell types from multiple donors, each contributing to the overall structure. The researchers used cells from five different donors for this study, but the platform is designed to be flexible and scalable, potentially accommodating hundreds of donors in future studies.</p> <p>"In this context, the goal was to develop a way of looking at different cells of the brain that are affected by a trigger in a more scalable way and develop a platform to read solid responses in these different cells," said Irene Faravelli, a postdoctoral researcher in the Arlotta lab and co-first author of the study with postdoctoral fellow Noelia Antón-Bolaños.</p> <p>The development of chimeroids was not without its challenges, such as ensuring that the cells from different donors maintained a balanced proportion over time. "A major technical challenge was that single donors would take over the culture over time, even if mixes were donor-balanced initially," Antón-Bolaños recalled. Overcoming this challenge required a deep understanding of embryonic brain development and innovative computational analysis techniques.</p> <h2>Putting exposure in context</h2> <p>To test their system, the team exposed chimeroids to two compounds with well-known neurotoxic effects in the developing brain: ethanol and valproic acid. Ethanol exposure during pregnancy can lead to fetal alcohol spectrum disorder, while valproic acid (VPA), a drug used to treat mood disorders and seizures, has been linked to an increased risk of ASD. Clinicians have long noted that not all children exposed to these compounds experience the same outcomes, suggesting that genetic variations&nbsp;may influence susceptibility. &nbsp;</p> <p>Using a transcriptomic readout, which allows researchers to explore cells' molecular responses to stimuli, the team identified significant changes in the cell type composition of ethanol- or VPA-exposed chimeroids compared to unexposed controls. They also found that the proportion of cells from specific donors changed within exposed organoids, as did the gene expression profiles of cells from different donors in response to VPA.&nbsp;</p> <p>The team believes chimeroids may accelerate the study of complex polygenic states associated with psychiatric disorders like schizophrenia and ASD, or could enable prediction of responses to new therapeutics, which could have significant implications for personalized medicine. This could lead to more accurate preclinical trials and better predictions of clinical outcomes.</p> <p>"Success in this area would mean that organoids could become pre-clinical trial 'avatars' informing on the differential responses of the cells of the brain of each individual to begin to predict clinical outcomes," Arlotta said. "What if one day we could use chimeroids as avatars to predict individual responses to new therapeutics before testing it in a trial? Or to stratify and better classify and diagnose patients to tailor more effective therapeutics to them? I like to imagine that future, frankly."&nbsp;</p> <p><em>Adapted from <a href="https://hscrb.harvard.edu/news/brain-chimeroids-reveal-susceptibility-to-brain-triggers/" target="_blank">a story published by the Harvard Department of Stem Cell and Regenerative Biology</a></em>.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this study was provided by the National Institute of Mental Health, the Stanley Center for Psychiatric Research, the Klarman Cell Observatory, the ӳ����ý of MIT and Harvard, and the Blavatnik Biomedical Accelerator at Harvard University.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Antón-Bolaños&nbsp;N, Favarelli I, et al.&nbsp;<a href="https://www.nature.com/articles/s41586-024-07578-8" target="_blank">Brain chimeroids reveal individual susceptibility to neurotoxic triggers</a>. <em>Nature</em>. Online June 26, 2024. DOI:&nbsp;10.1038/s41586-024-07578-8.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/stanley-center-psychiatric-research" hreflang="en">Stanley Center for Psychiatric Research</a></div> <div class="field__item"><a href="/broad-tags/neurodevelopmental-conditions" hreflang="en">Neurodevelopmental conditions</a></div> <div class="field__item"><a href="/broad-tags/psychiatric-disease" hreflang="en">Brain Health</a></div> <div class="field__item"><a href="/broad-tags/paola-arlotta" hreflang="en">Paola Arlotta</a></div> </div> </div> </div> </div> </div> Thu, 29 Sep 2022 15:01:07 +0000 adicorat 1203406 at /news/new-study-shows-how-microglia-are-prompted-change-their-state-adapt-different-areas-brain <span class="field field--name-title field--type-string field--label-hidden"><h1>Brain chimeroids offer window into relationships between genetics and exposures</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Tom Ulrich</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-07-08T10:30:38-04:00" class="datetime">July 8, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Brain chimeroids offer window into relationships between genetics and exposures</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>New model system allows researchers to study the influence of genetic background on brain cells' responses to neurotoxins, disease mutations, and potential therapeutics</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Alice McCarthy, Harvard University </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-07-08T10:30:38-04:00" title="Monday, July 8, 2024 - 10:30" class="datetime">July 8, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=5VyOntI1 1x" media="all and (min-width: 1921px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=5VyOntI1 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=O8QMXmqM 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=aLTBeADi 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=l2192yL6 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=bADgyMxg 1x" media="all and (max-width: 539px)" type="image/png" width="499" height="294"> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=bADgyMxg" alt="Color microscope image of a brain chimeroid, with red and green colors highlighting different types of cells and different structures." title="Color microscope image of a brain chimeroid, with red and green colors highlighting different types of cells and different structures." typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Arlotta laboratory </div> <div class="media-caption__description"> A brain chimeroid </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous"></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/981/feed&amp;title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use 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block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related people</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/bios/paola-arlotta">Paola Arlotta</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related programs</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/stanley-center-for-psychiatric-research">Stanley Center for Psychiatric Research</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related news</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/molecular-map-brain-organoids-reveals-unprecedented-levels-neuronal-cell-maturation-and" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/molecular-map-brain-organoids-reveals-unprecedented-levels-neuronal-cell-maturation-and"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=bb0Vsxsf 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=bb0Vsxsf 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=9y-4pm3P 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=9y-4pm3P 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=2Ja6exy9 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=1dZ21ixd 1x" media="all and (max-width: 539px)" type="image/jpeg" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=1dZ21ixd" alt="Synapse development in organoids. Expression of the synaptic marker SYN1 (green) is absent at 1 month (upper left) and appears with organoid maturation by 3 months (upper right). Organoids continue maturing at 6 months (lower left) and 9 months (lower right)." title="Synapse development in organoids. Expression of the synaptic marker SYN1 (green) is absent at 1 month (upper left) and appears with organoid maturation by 3 months (upper right). Organoids continue maturing at 6 months (lower left) and 9 months (lower right)." typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/molecular-map-brain-organoids-reveals-unprecedented-levels-neuronal-cell-maturation-and" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Molecular map of brain organoids reveals unprecedented levels of neuronal cell maturation and diversity</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/human-brain-organoids-come-age" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/human-brain-organoids-come-age"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2019/Paola%20Image.jpg?h=d1cb525d&amp;itok=X_CewRnF 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2019/Paola%20Image.jpg?h=d1cb525d&amp;itok=X_CewRnF 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2019/Paola%20Image.jpg?h=d1cb525d&amp;itok=kDnxOAhY 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2019/Paola%20Image.jpg?h=d1cb525d&amp;itok=kDnxOAhY 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2019/Paola%20Image.jpg?h=d1cb525d&amp;itok=2crt6PVW 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2019/Paola%20Image.jpg?h=d1cb525d&amp;itok=0GZNeYQq 1x" media="all and (max-width: 539px)" type="image/jpeg" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2019/Paola%20Image.jpg?h=d1cb525d&amp;itok=0GZNeYQq" alt="“Organoids have dramatically advanced our ability to study the human developing brain,” says Paola Arlotta." title="“Organoids have dramatically advanced our ability to study the human developing brain,” says Paola Arlotta." typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/human-brain-organoids-come-age" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Human brain organoids come of age</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/three-autism-risk-genes-have-similar-effects-brain-development-different-routes" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/three-autism-risk-genes-have-similar-effects-brain-development-different-routes"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=FJtNfzyb 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=FJtNfzyb 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=eNxnB5gG 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=eNxnB5gG 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=t4Lif9cH 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=bhXHlqXC 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=bhXHlqXC" alt="Microscopy image of a brain organoid showing individual neurons spontaneously firing" title="Microscopy image of a brain organoid showing individual neurons spontaneously firing" typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/three-autism-risk-genes-have-similar-effects-brain-development-different-routes" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Three autism risk genes have similar effects on brain development, but by different routes</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/brain-organoids-replicate-key-events-human-brain-development" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/brain-organoids-replicate-key-events-human-brain-development"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=lstySHBC 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=lstySHBC 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=4HlxIV8e 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=4HlxIV8e 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=T0IPiSz3 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=njI3T1Gw 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=njI3T1Gw" alt="Human brain organoids showing neurons and their dendrites (green), telencephalic (forebrain) cells (blue), and a kind of cell-cell contact called tight junctions (red)." title="Human brain organoids showing neurons and their dendrites (green), telencephalic (forebrain) cells (blue), and a kind of cell-cell contact called tight junctions (red)." typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/brain-organoids-replicate-key-events-human-brain-development" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Brain organoids replicate key events in human brain development</span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Researchers at the Harvard Department of Stem Cell and Regenerative Biology (HSCRB) and the ӳ����ý of MIT and Harvard have developed a new platform for modeling at the cellular level how the human brain responds to a variety of stimuli. Described in <a href="https://www.nature.com/articles/s41586-024-07578-8" target="_blank"><em>Nature</em></a>, these ‘brain chimeroids’ provide an approach for studying how genetic background can affect the outcome of neurotoxic exposures, disease-associated&nbsp;genetic variants, and potential therapeutic compounds.&nbsp;</p> <p>Chimeroids are brain organoids made up of cells representing multiple cell types found in the human brain (neurons, glial cells, etc.), derived from induced pluripotent stem cells generated from several human donors. By incorporating cells from many individuals, chimeroids allow researchers to observe&nbsp;<em>in vitro</em> how cells and brain circuits from individuals with unique genetic backgrounds, including those with family histories of neurodevelopmental or neuropsychiatric disorders, respond to the same stimulus.&nbsp;</p> <p>People carry a vast reservoir of genetic variation; any two individuals differ from each other at about one base pair out of every 1,000 across the three billion-base pair genome. Risk for conditions like schizophrenia or autism spectrum disorder (ASD) often arises from the complex interplay of many genetic variations, rather than from variations in a single gene. By incorporating large numbers of individuals across a spectrum of polygenic risk, chimeroids allow researchers to leverage this genetic diversity to understand its functional effects on the brain.</p> <p>"The idea of generating organoids that contain cells from multiple donors was directly motivated by our long-term interest in modeling psychiatric conditions, such as schizophrenia, and developmental disorders, such as autism spectrum disorder," said senior author <a href="/node/4635">Paola Arlotta</a>, chair of HSCRB and an institute member in the <a href="http://www.broadinstitute.org/node/8513">Stanley Center for Psychiatric Research</a> at ӳ����ý. "The ability to grow cells from distinct donors within the same organoid opens the door to investigating at scale and in a controlled way the responses of brain cells of many different individuals to many different types of stimuli, from genetic mutations, to infections, to drugs, and more."</p> <h2>Embracing variation</h2> <p>Brain chimeroids build on a decade of research by the Arlotta lab, which has pioneered the use of human organoids to study neuropsychiatric disorders. The process of creating a chimeroid involves several steps. First, pluripotent stem cells — which can be generated from any donor (healthy or patient) — from multiple people are differentiated in individual 3D cultures and coaxed to become neural progenitors, particularly those of a brain cortical fate. Next, the cells are removed from culture, disassociated from each other, and reassembled.</p> <p>The resulting 3D chimeroids are composed of multiple brain cell types from multiple donors, each contributing to the overall structure. The researchers used cells from five different donors for this study, but the platform is designed to be flexible and scalable, potentially accommodating hundreds of donors in future studies.</p> <p>"In this context, the goal was to develop a way of looking at different cells of the brain that are affected by a trigger in a more scalable way and develop a platform to read solid responses in these different cells," said Irene Faravelli, a postdoctoral researcher in the Arlotta lab and co-first author of the study with postdoctoral fellow Noelia Antón-Bolaños.</p> <p>The development of chimeroids was not without its challenges, such as ensuring that the cells from different donors maintained a balanced proportion over time. "A major technical challenge was that single donors would take over the culture over time, even if mixes were donor-balanced initially," Antón-Bolaños recalled. Overcoming this challenge required a deep understanding of embryonic brain development and innovative computational analysis techniques.</p> <h2>Putting exposure in context</h2> <p>To test their system, the team exposed chimeroids to two compounds with well-known neurotoxic effects in the developing brain: ethanol and valproic acid. Ethanol exposure during pregnancy can lead to fetal alcohol spectrum disorder, while valproic acid (VPA), a drug used to treat mood disorders and seizures, has been linked to an increased risk of ASD. Clinicians have long noted that not all children exposed to these compounds experience the same outcomes, suggesting that genetic variations&nbsp;may influence susceptibility. &nbsp;</p> <p>Using a transcriptomic readout, which allows researchers to explore cells' molecular responses to stimuli, the team identified significant changes in the cell type composition of ethanol- or VPA-exposed chimeroids compared to unexposed controls. They also found that the proportion of cells from specific donors changed within exposed organoids, as did the gene expression profiles of cells from different donors in response to VPA.&nbsp;</p> <p>The team believes chimeroids may accelerate the study of complex polygenic states associated with psychiatric disorders like schizophrenia and ASD, or could enable prediction of responses to new therapeutics, which could have significant implications for personalized medicine. This could lead to more accurate preclinical trials and better predictions of clinical outcomes.</p> <p>"Success in this area would mean that organoids could become pre-clinical trial 'avatars' informing on the differential responses of the cells of the brain of each individual to begin to predict clinical outcomes," Arlotta said. "What if one day we could use chimeroids as avatars to predict individual responses to new therapeutics before testing it in a trial? Or to stratify and better classify and diagnose patients to tailor more effective therapeutics to them? I like to imagine that future, frankly."&nbsp;</p> <p><em>Adapted from <a href="https://hscrb.harvard.edu/news/brain-chimeroids-reveal-susceptibility-to-brain-triggers/" target="_blank">a story published by the Harvard Department of Stem Cell and Regenerative Biology</a></em>.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this study was provided by the National Institute of Mental Health, the Stanley Center for Psychiatric Research, the Klarman Cell Observatory, the ӳ����ý of MIT and Harvard, and the Blavatnik Biomedical Accelerator at Harvard University.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Antón-Bolaños&nbsp;N, Favarelli I, et al.&nbsp;<a href="https://www.nature.com/articles/s41586-024-07578-8" target="_blank">Brain chimeroids reveal individual susceptibility to neurotoxic triggers</a>. <em>Nature</em>. Online June 26, 2024. DOI:&nbsp;10.1038/s41586-024-07578-8.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/stanley-center-psychiatric-research" hreflang="en">Stanley Center for Psychiatric Research</a></div> <div class="field__item"><a href="/broad-tags/neurodevelopmental-conditions" hreflang="en">Neurodevelopmental conditions</a></div> <div class="field__item"><a href="/broad-tags/psychiatric-disease" hreflang="en">Brain Health</a></div> <div class="field__item"><a href="/broad-tags/paola-arlotta" hreflang="en">Paola Arlotta</a></div> </div> </div> </div> </div> </div> Wed, 10 Aug 2022 21:47:28 +0000 kzusi@broadinstitute.org 1161661 at /news/three-autism-risk-genes-have-similar-effects-brain-development-different-routes <span class="field field--name-title field--type-string field--label-hidden"><h1>Brain chimeroids offer window into relationships between genetics and exposures</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Tom Ulrich</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-07-08T10:30:38-04:00" class="datetime">July 8, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Brain chimeroids offer window into relationships between genetics and exposures</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>New model system allows researchers to study the influence of genetic background on brain cells' responses to neurotoxins, disease mutations, and potential therapeutics</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Alice McCarthy, Harvard University </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-07-08T10:30:38-04:00" title="Monday, July 8, 2024 - 10:30" class="datetime">July 8, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=5VyOntI1 1x" media="all and (min-width: 1921px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=5VyOntI1 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=O8QMXmqM 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=aLTBeADi 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=l2192yL6 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=bADgyMxg 1x" media="all and (max-width: 539px)" type="image/png" width="499" height="294"> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=bADgyMxg" alt="Color microscope image of a brain chimeroid, with red and green colors highlighting different types of cells and different structures." title="Color microscope image of a brain chimeroid, with red and green colors highlighting different types of cells and different structures." typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Arlotta laboratory </div> <div class="media-caption__description"> A brain chimeroid </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous"></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/981/feed&amp;title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use 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block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related people</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/bios/paola-arlotta">Paola Arlotta</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related programs</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/stanley-center-for-psychiatric-research">Stanley Center for Psychiatric Research</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related news</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/molecular-map-brain-organoids-reveals-unprecedented-levels-neuronal-cell-maturation-and" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/molecular-map-brain-organoids-reveals-unprecedented-levels-neuronal-cell-maturation-and"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=bb0Vsxsf 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=bb0Vsxsf 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=9y-4pm3P 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=9y-4pm3P 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=2Ja6exy9 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=1dZ21ixd 1x" media="all and (max-width: 539px)" type="image/jpeg" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=1dZ21ixd" alt="Synapse development in organoids. Expression of the synaptic marker SYN1 (green) is absent at 1 month (upper left) and appears with organoid maturation by 3 months (upper right). Organoids continue maturing at 6 months (lower left) and 9 months (lower right)." title="Synapse development in organoids. Expression of the synaptic marker SYN1 (green) is absent at 1 month (upper left) and appears with organoid maturation by 3 months (upper right). Organoids continue maturing at 6 months (lower left) and 9 months (lower right)." typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/molecular-map-brain-organoids-reveals-unprecedented-levels-neuronal-cell-maturation-and" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Molecular map of brain organoids reveals unprecedented levels of neuronal cell maturation and diversity</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/human-brain-organoids-come-age" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/human-brain-organoids-come-age"><picture> <source 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href="/news/human-brain-organoids-come-age" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Human brain organoids come of age</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/three-autism-risk-genes-have-similar-effects-brain-development-different-routes" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/three-autism-risk-genes-have-similar-effects-brain-development-different-routes"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=FJtNfzyb 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=FJtNfzyb 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=eNxnB5gG 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=eNxnB5gG 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=t4Lif9cH 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=bhXHlqXC 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=bhXHlqXC" alt="Microscopy image of a brain organoid showing individual neurons spontaneously firing" title="Microscopy image of a brain organoid showing individual neurons spontaneously firing" typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/three-autism-risk-genes-have-similar-effects-brain-development-different-routes" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Three autism risk genes have similar effects on brain development, but by different routes</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/brain-organoids-replicate-key-events-human-brain-development" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/brain-organoids-replicate-key-events-human-brain-development"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=lstySHBC 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=lstySHBC 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=4HlxIV8e 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=4HlxIV8e 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=T0IPiSz3 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=njI3T1Gw 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=njI3T1Gw" alt="Human brain organoids showing neurons and their dendrites (green), telencephalic (forebrain) cells (blue), and a kind of cell-cell contact called tight junctions (red)." title="Human brain organoids showing neurons and their dendrites (green), telencephalic (forebrain) cells (blue), and a kind of cell-cell contact called tight junctions (red)." typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/brain-organoids-replicate-key-events-human-brain-development" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Brain organoids replicate key events in human brain development</span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Researchers at the Harvard Department of Stem Cell and Regenerative Biology (HSCRB) and the ӳ����ý of MIT and Harvard have developed a new platform for modeling at the cellular level how the human brain responds to a variety of stimuli. Described in <a href="https://www.nature.com/articles/s41586-024-07578-8" target="_blank"><em>Nature</em></a>, these ‘brain chimeroids’ provide an approach for studying how genetic background can affect the outcome of neurotoxic exposures, disease-associated&nbsp;genetic variants, and potential therapeutic compounds.&nbsp;</p> <p>Chimeroids are brain organoids made up of cells representing multiple cell types found in the human brain (neurons, glial cells, etc.), derived from induced pluripotent stem cells generated from several human donors. By incorporating cells from many individuals, chimeroids allow researchers to observe&nbsp;<em>in vitro</em> how cells and brain circuits from individuals with unique genetic backgrounds, including those with family histories of neurodevelopmental or neuropsychiatric disorders, respond to the same stimulus.&nbsp;</p> <p>People carry a vast reservoir of genetic variation; any two individuals differ from each other at about one base pair out of every 1,000 across the three billion-base pair genome. Risk for conditions like schizophrenia or autism spectrum disorder (ASD) often arises from the complex interplay of many genetic variations, rather than from variations in a single gene. By incorporating large numbers of individuals across a spectrum of polygenic risk, chimeroids allow researchers to leverage this genetic diversity to understand its functional effects on the brain.</p> <p>"The idea of generating organoids that contain cells from multiple donors was directly motivated by our long-term interest in modeling psychiatric conditions, such as schizophrenia, and developmental disorders, such as autism spectrum disorder," said senior author <a href="/node/4635">Paola Arlotta</a>, chair of HSCRB and an institute member in the <a href="http://www.broadinstitute.org/node/8513">Stanley Center for Psychiatric Research</a> at ӳ����ý. "The ability to grow cells from distinct donors within the same organoid opens the door to investigating at scale and in a controlled way the responses of brain cells of many different individuals to many different types of stimuli, from genetic mutations, to infections, to drugs, and more."</p> <h2>Embracing variation</h2> <p>Brain chimeroids build on a decade of research by the Arlotta lab, which has pioneered the use of human organoids to study neuropsychiatric disorders. The process of creating a chimeroid involves several steps. First, pluripotent stem cells — which can be generated from any donor (healthy or patient) — from multiple people are differentiated in individual 3D cultures and coaxed to become neural progenitors, particularly those of a brain cortical fate. Next, the cells are removed from culture, disassociated from each other, and reassembled.</p> <p>The resulting 3D chimeroids are composed of multiple brain cell types from multiple donors, each contributing to the overall structure. The researchers used cells from five different donors for this study, but the platform is designed to be flexible and scalable, potentially accommodating hundreds of donors in future studies.</p> <p>"In this context, the goal was to develop a way of looking at different cells of the brain that are affected by a trigger in a more scalable way and develop a platform to read solid responses in these different cells," said Irene Faravelli, a postdoctoral researcher in the Arlotta lab and co-first author of the study with postdoctoral fellow Noelia Antón-Bolaños.</p> <p>The development of chimeroids was not without its challenges, such as ensuring that the cells from different donors maintained a balanced proportion over time. "A major technical challenge was that single donors would take over the culture over time, even if mixes were donor-balanced initially," Antón-Bolaños recalled. Overcoming this challenge required a deep understanding of embryonic brain development and innovative computational analysis techniques.</p> <h2>Putting exposure in context</h2> <p>To test their system, the team exposed chimeroids to two compounds with well-known neurotoxic effects in the developing brain: ethanol and valproic acid. Ethanol exposure during pregnancy can lead to fetal alcohol spectrum disorder, while valproic acid (VPA), a drug used to treat mood disorders and seizures, has been linked to an increased risk of ASD. Clinicians have long noted that not all children exposed to these compounds experience the same outcomes, suggesting that genetic variations&nbsp;may influence susceptibility. &nbsp;</p> <p>Using a transcriptomic readout, which allows researchers to explore cells' molecular responses to stimuli, the team identified significant changes in the cell type composition of ethanol- or VPA-exposed chimeroids compared to unexposed controls. They also found that the proportion of cells from specific donors changed within exposed organoids, as did the gene expression profiles of cells from different donors in response to VPA.&nbsp;</p> <p>The team believes chimeroids may accelerate the study of complex polygenic states associated with psychiatric disorders like schizophrenia and ASD, or could enable prediction of responses to new therapeutics, which could have significant implications for personalized medicine. This could lead to more accurate preclinical trials and better predictions of clinical outcomes.</p> <p>"Success in this area would mean that organoids could become pre-clinical trial 'avatars' informing on the differential responses of the cells of the brain of each individual to begin to predict clinical outcomes," Arlotta said. "What if one day we could use chimeroids as avatars to predict individual responses to new therapeutics before testing it in a trial? Or to stratify and better classify and diagnose patients to tailor more effective therapeutics to them? I like to imagine that future, frankly."&nbsp;</p> <p><em>Adapted from <a href="https://hscrb.harvard.edu/news/brain-chimeroids-reveal-susceptibility-to-brain-triggers/" target="_blank">a story published by the Harvard Department of Stem Cell and Regenerative Biology</a></em>.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this study was provided by the National Institute of Mental Health, the Stanley Center for Psychiatric Research, the Klarman Cell Observatory, the ӳ����ý of MIT and Harvard, and the Blavatnik Biomedical Accelerator at Harvard University.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Antón-Bolaños&nbsp;N, Favarelli I, et al.&nbsp;<a href="https://www.nature.com/articles/s41586-024-07578-8" target="_blank">Brain chimeroids reveal individual susceptibility to neurotoxic triggers</a>. <em>Nature</em>. Online June 26, 2024. DOI:&nbsp;10.1038/s41586-024-07578-8.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/stanley-center-psychiatric-research" hreflang="en">Stanley Center for Psychiatric Research</a></div> <div class="field__item"><a href="/broad-tags/neurodevelopmental-conditions" hreflang="en">Neurodevelopmental conditions</a></div> <div class="field__item"><a href="/broad-tags/psychiatric-disease" hreflang="en">Brain Health</a></div> <div class="field__item"><a href="/broad-tags/paola-arlotta" hreflang="en">Paola Arlotta</a></div> </div> </div> </div> </div> </div> Wed, 02 Feb 2022 16:32:08 +0000 tulrich@broadinstitute.org 1127196 at /news/detailed-atlas-developing-brain <span class="field field--name-title field--type-string field--label-hidden"><h1>Brain chimeroids offer window into relationships between genetics and exposures</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Tom Ulrich</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-07-08T10:30:38-04:00" class="datetime">July 8, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Brain chimeroids offer window into relationships between genetics and exposures</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>New model system allows researchers to study the influence of genetic background on brain cells' responses to neurotoxins, disease mutations, and potential therapeutics</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Alice McCarthy, Harvard University </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-07-08T10:30:38-04:00" title="Monday, July 8, 2024 - 10:30" class="datetime">July 8, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=5VyOntI1 1x" media="all and (min-width: 1921px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=5VyOntI1 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=O8QMXmqM 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=aLTBeADi 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=l2192yL6 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=bADgyMxg 1x" media="all and (max-width: 539px)" type="image/png" width="499" height="294"> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=bADgyMxg" alt="Color microscope image of a brain chimeroid, with red and green colors highlighting different types of cells and different structures." title="Color microscope image of a brain chimeroid, with red and green colors highlighting different types of cells and different structures." typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Arlotta laboratory </div> <div class="media-caption__description"> A brain chimeroid </div> </div> </article> </div> </div> </div> </div> </div> </div> <div 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text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related people</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/bios/paola-arlotta">Paola Arlotta</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related programs</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/stanley-center-for-psychiatric-research">Stanley Center for Psychiatric Research</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related news</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/molecular-map-brain-organoids-reveals-unprecedented-levels-neuronal-cell-maturation-and" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/molecular-map-brain-organoids-reveals-unprecedented-levels-neuronal-cell-maturation-and"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=bb0Vsxsf 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=bb0Vsxsf 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=9y-4pm3P 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=9y-4pm3P 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=2Ja6exy9 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=1dZ21ixd 1x" media="all and (max-width: 539px)" type="image/jpeg" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=1dZ21ixd" alt="Synapse development in organoids. Expression of the synaptic marker SYN1 (green) is absent at 1 month (upper left) and appears with organoid maturation by 3 months (upper right). Organoids continue maturing at 6 months (lower left) and 9 months (lower right)." title="Synapse development in organoids. Expression of the synaptic marker SYN1 (green) is absent at 1 month (upper left) and appears with organoid maturation by 3 months (upper right). Organoids continue maturing at 6 months (lower left) and 9 months (lower right)." typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/molecular-map-brain-organoids-reveals-unprecedented-levels-neuronal-cell-maturation-and" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Molecular map of brain organoids reveals unprecedented levels of neuronal cell maturation and diversity</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/human-brain-organoids-come-age" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/human-brain-organoids-come-age"><picture> <source 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srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2019/Paola%20Image.jpg?h=d1cb525d&amp;itok=2crt6PVW 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2019/Paola%20Image.jpg?h=d1cb525d&amp;itok=0GZNeYQq 1x" media="all and (max-width: 539px)" type="image/jpeg" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2019/Paola%20Image.jpg?h=d1cb525d&amp;itok=0GZNeYQq" alt="“Organoids have dramatically advanced our ability to study the human developing brain,” says Paola Arlotta." title="“Organoids have dramatically advanced our ability to study the human developing brain,” says Paola Arlotta." typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/human-brain-organoids-come-age" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Human brain organoids come of age</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/three-autism-risk-genes-have-similar-effects-brain-development-different-routes" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/three-autism-risk-genes-have-similar-effects-brain-development-different-routes"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=FJtNfzyb 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=FJtNfzyb 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=eNxnB5gG 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=eNxnB5gG 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=t4Lif9cH 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=bhXHlqXC 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=bhXHlqXC" alt="Microscopy image of a brain organoid showing individual neurons spontaneously firing" title="Microscopy image of a brain organoid showing individual neurons spontaneously firing" typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/three-autism-risk-genes-have-similar-effects-brain-development-different-routes" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Three autism risk genes have similar effects on brain development, but by different routes</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/brain-organoids-replicate-key-events-human-brain-development" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/brain-organoids-replicate-key-events-human-brain-development"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=lstySHBC 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=lstySHBC 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=4HlxIV8e 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=4HlxIV8e 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=T0IPiSz3 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=njI3T1Gw 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=njI3T1Gw" alt="Human brain organoids showing neurons and their dendrites (green), telencephalic (forebrain) cells (blue), and a kind of cell-cell contact called tight junctions (red)." title="Human brain organoids showing neurons and their dendrites (green), telencephalic (forebrain) cells (blue), and a kind of cell-cell contact called tight junctions (red)." typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/brain-organoids-replicate-key-events-human-brain-development" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Brain organoids replicate key events in human brain development</span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Researchers at the Harvard Department of Stem Cell and Regenerative Biology (HSCRB) and the ӳ����ý of MIT and Harvard have developed a new platform for modeling at the cellular level how the human brain responds to a variety of stimuli. Described in <a href="https://www.nature.com/articles/s41586-024-07578-8" target="_blank"><em>Nature</em></a>, these ‘brain chimeroids’ provide an approach for studying how genetic background can affect the outcome of neurotoxic exposures, disease-associated&nbsp;genetic variants, and potential therapeutic compounds.&nbsp;</p> <p>Chimeroids are brain organoids made up of cells representing multiple cell types found in the human brain (neurons, glial cells, etc.), derived from induced pluripotent stem cells generated from several human donors. By incorporating cells from many individuals, chimeroids allow researchers to observe&nbsp;<em>in vitro</em> how cells and brain circuits from individuals with unique genetic backgrounds, including those with family histories of neurodevelopmental or neuropsychiatric disorders, respond to the same stimulus.&nbsp;</p> <p>People carry a vast reservoir of genetic variation; any two individuals differ from each other at about one base pair out of every 1,000 across the three billion-base pair genome. Risk for conditions like schizophrenia or autism spectrum disorder (ASD) often arises from the complex interplay of many genetic variations, rather than from variations in a single gene. By incorporating large numbers of individuals across a spectrum of polygenic risk, chimeroids allow researchers to leverage this genetic diversity to understand its functional effects on the brain.</p> <p>"The idea of generating organoids that contain cells from multiple donors was directly motivated by our long-term interest in modeling psychiatric conditions, such as schizophrenia, and developmental disorders, such as autism spectrum disorder," said senior author <a href="/node/4635">Paola Arlotta</a>, chair of HSCRB and an institute member in the <a href="http://www.broadinstitute.org/node/8513">Stanley Center for Psychiatric Research</a> at ӳ����ý. "The ability to grow cells from distinct donors within the same organoid opens the door to investigating at scale and in a controlled way the responses of brain cells of many different individuals to many different types of stimuli, from genetic mutations, to infections, to drugs, and more."</p> <h2>Embracing variation</h2> <p>Brain chimeroids build on a decade of research by the Arlotta lab, which has pioneered the use of human organoids to study neuropsychiatric disorders. The process of creating a chimeroid involves several steps. First, pluripotent stem cells — which can be generated from any donor (healthy or patient) — from multiple people are differentiated in individual 3D cultures and coaxed to become neural progenitors, particularly those of a brain cortical fate. Next, the cells are removed from culture, disassociated from each other, and reassembled.</p> <p>The resulting 3D chimeroids are composed of multiple brain cell types from multiple donors, each contributing to the overall structure. The researchers used cells from five different donors for this study, but the platform is designed to be flexible and scalable, potentially accommodating hundreds of donors in future studies.</p> <p>"In this context, the goal was to develop a way of looking at different cells of the brain that are affected by a trigger in a more scalable way and develop a platform to read solid responses in these different cells," said Irene Faravelli, a postdoctoral researcher in the Arlotta lab and co-first author of the study with postdoctoral fellow Noelia Antón-Bolaños.</p> <p>The development of chimeroids was not without its challenges, such as ensuring that the cells from different donors maintained a balanced proportion over time. "A major technical challenge was that single donors would take over the culture over time, even if mixes were donor-balanced initially," Antón-Bolaños recalled. Overcoming this challenge required a deep understanding of embryonic brain development and innovative computational analysis techniques.</p> <h2>Putting exposure in context</h2> <p>To test their system, the team exposed chimeroids to two compounds with well-known neurotoxic effects in the developing brain: ethanol and valproic acid. Ethanol exposure during pregnancy can lead to fetal alcohol spectrum disorder, while valproic acid (VPA), a drug used to treat mood disorders and seizures, has been linked to an increased risk of ASD. Clinicians have long noted that not all children exposed to these compounds experience the same outcomes, suggesting that genetic variations&nbsp;may influence susceptibility. &nbsp;</p> <p>Using a transcriptomic readout, which allows researchers to explore cells' molecular responses to stimuli, the team identified significant changes in the cell type composition of ethanol- or VPA-exposed chimeroids compared to unexposed controls. They also found that the proportion of cells from specific donors changed within exposed organoids, as did the gene expression profiles of cells from different donors in response to VPA.&nbsp;</p> <p>The team believes chimeroids may accelerate the study of complex polygenic states associated with psychiatric disorders like schizophrenia and ASD, or could enable prediction of responses to new therapeutics, which could have significant implications for personalized medicine. This could lead to more accurate preclinical trials and better predictions of clinical outcomes.</p> <p>"Success in this area would mean that organoids could become pre-clinical trial 'avatars' informing on the differential responses of the cells of the brain of each individual to begin to predict clinical outcomes," Arlotta said. "What if one day we could use chimeroids as avatars to predict individual responses to new therapeutics before testing it in a trial? Or to stratify and better classify and diagnose patients to tailor more effective therapeutics to them? I like to imagine that future, frankly."&nbsp;</p> <p><em>Adapted from <a href="https://hscrb.harvard.edu/news/brain-chimeroids-reveal-susceptibility-to-brain-triggers/" target="_blank">a story published by the Harvard Department of Stem Cell and Regenerative Biology</a></em>.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this study was provided by the National Institute of Mental Health, the Stanley Center for Psychiatric Research, the Klarman Cell Observatory, the ӳ����ý of MIT and Harvard, and the Blavatnik Biomedical Accelerator at Harvard University.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Antón-Bolaños&nbsp;N, Favarelli I, et al.&nbsp;<a href="https://www.nature.com/articles/s41586-024-07578-8" target="_blank">Brain chimeroids reveal individual susceptibility to neurotoxic triggers</a>. <em>Nature</em>. Online June 26, 2024. DOI:&nbsp;10.1038/s41586-024-07578-8.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/stanley-center-psychiatric-research" hreflang="en">Stanley Center for Psychiatric Research</a></div> <div class="field__item"><a href="/broad-tags/neurodevelopmental-conditions" hreflang="en">Neurodevelopmental conditions</a></div> <div class="field__item"><a href="/broad-tags/psychiatric-disease" hreflang="en">Brain Health</a></div> <div class="field__item"><a href="/broad-tags/paola-arlotta" hreflang="en">Paola Arlotta</a></div> </div> </div> </div> </div> </div> Thu, 24 Jun 2021 13:52:17 +0000 tulrich@broadinstitute.org 954006 at /news/large-scale-tool-helps-reveal-function-autism-spectrum-disorder-genes <span class="field field--name-title field--type-string field--label-hidden"><h1>Brain chimeroids offer window into relationships between genetics and exposures</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Tom Ulrich</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-07-08T10:30:38-04:00" class="datetime">July 8, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Brain chimeroids offer window into relationships between genetics and exposures</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>New model system allows researchers to study the influence of genetic background on brain cells' responses to neurotoxins, disease mutations, and potential therapeutics</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Alice McCarthy, Harvard University </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-07-08T10:30:38-04:00" title="Monday, July 8, 2024 - 10:30" class="datetime">July 8, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=5VyOntI1 1x" media="all and (min-width: 1921px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=5VyOntI1 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=O8QMXmqM 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=aLTBeADi 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=l2192yL6 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=bADgyMxg 1x" media="all and (max-width: 539px)" type="image/png" width="499" height="294"> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=bADgyMxg" alt="Color microscope image of a brain chimeroid, with red and green colors highlighting different types of cells and different structures." title="Color microscope image of a brain chimeroid, with red and green colors highlighting different types of cells and different structures." typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Arlotta laboratory </div> <div class="media-caption__description"> A brain chimeroid </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous"></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/981/feed&amp;title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use 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block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related people</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/bios/paola-arlotta">Paola Arlotta</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related programs</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/stanley-center-for-psychiatric-research">Stanley Center for Psychiatric Research</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related news</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/molecular-map-brain-organoids-reveals-unprecedented-levels-neuronal-cell-maturation-and" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/molecular-map-brain-organoids-reveals-unprecedented-levels-neuronal-cell-maturation-and"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=bb0Vsxsf 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=bb0Vsxsf 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=9y-4pm3P 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=9y-4pm3P 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=2Ja6exy9 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=1dZ21ixd 1x" media="all and (max-width: 539px)" type="image/jpeg" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=1dZ21ixd" alt="Synapse development in organoids. Expression of the synaptic marker SYN1 (green) is absent at 1 month (upper left) and appears with organoid maturation by 3 months (upper right). Organoids continue maturing at 6 months (lower left) and 9 months (lower right)." title="Synapse development in organoids. Expression of the synaptic marker SYN1 (green) is absent at 1 month (upper left) and appears with organoid maturation by 3 months (upper right). Organoids continue maturing at 6 months (lower left) and 9 months (lower right)." typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/molecular-map-brain-organoids-reveals-unprecedented-levels-neuronal-cell-maturation-and" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Molecular map of brain organoids reveals unprecedented levels of neuronal cell maturation and diversity</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/human-brain-organoids-come-age" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/human-brain-organoids-come-age"><picture> <source 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href="/news/human-brain-organoids-come-age" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Human brain organoids come of age</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/three-autism-risk-genes-have-similar-effects-brain-development-different-routes" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/three-autism-risk-genes-have-similar-effects-brain-development-different-routes"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=FJtNfzyb 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=FJtNfzyb 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=eNxnB5gG 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=eNxnB5gG 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=t4Lif9cH 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=bhXHlqXC 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=bhXHlqXC" alt="Microscopy image of a brain organoid showing individual neurons spontaneously firing" title="Microscopy image of a brain organoid showing individual neurons spontaneously firing" typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/three-autism-risk-genes-have-similar-effects-brain-development-different-routes" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Three autism risk genes have similar effects on brain development, but by different routes</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/brain-organoids-replicate-key-events-human-brain-development" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/brain-organoids-replicate-key-events-human-brain-development"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=lstySHBC 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=lstySHBC 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=4HlxIV8e 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=4HlxIV8e 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=T0IPiSz3 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=njI3T1Gw 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=njI3T1Gw" alt="Human brain organoids showing neurons and their dendrites (green), telencephalic (forebrain) cells (blue), and a kind of cell-cell contact called tight junctions (red)." title="Human brain organoids showing neurons and their dendrites (green), telencephalic (forebrain) cells (blue), and a kind of cell-cell contact called tight junctions (red)." typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/brain-organoids-replicate-key-events-human-brain-development" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Brain organoids replicate key events in human brain development</span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Researchers at the Harvard Department of Stem Cell and Regenerative Biology (HSCRB) and the ӳ����ý of MIT and Harvard have developed a new platform for modeling at the cellular level how the human brain responds to a variety of stimuli. Described in <a href="https://www.nature.com/articles/s41586-024-07578-8" target="_blank"><em>Nature</em></a>, these ‘brain chimeroids’ provide an approach for studying how genetic background can affect the outcome of neurotoxic exposures, disease-associated&nbsp;genetic variants, and potential therapeutic compounds.&nbsp;</p> <p>Chimeroids are brain organoids made up of cells representing multiple cell types found in the human brain (neurons, glial cells, etc.), derived from induced pluripotent stem cells generated from several human donors. By incorporating cells from many individuals, chimeroids allow researchers to observe&nbsp;<em>in vitro</em> how cells and brain circuits from individuals with unique genetic backgrounds, including those with family histories of neurodevelopmental or neuropsychiatric disorders, respond to the same stimulus.&nbsp;</p> <p>People carry a vast reservoir of genetic variation; any two individuals differ from each other at about one base pair out of every 1,000 across the three billion-base pair genome. Risk for conditions like schizophrenia or autism spectrum disorder (ASD) often arises from the complex interplay of many genetic variations, rather than from variations in a single gene. By incorporating large numbers of individuals across a spectrum of polygenic risk, chimeroids allow researchers to leverage this genetic diversity to understand its functional effects on the brain.</p> <p>"The idea of generating organoids that contain cells from multiple donors was directly motivated by our long-term interest in modeling psychiatric conditions, such as schizophrenia, and developmental disorders, such as autism spectrum disorder," said senior author <a href="/node/4635">Paola Arlotta</a>, chair of HSCRB and an institute member in the <a href="http://www.broadinstitute.org/node/8513">Stanley Center for Psychiatric Research</a> at ӳ����ý. "The ability to grow cells from distinct donors within the same organoid opens the door to investigating at scale and in a controlled way the responses of brain cells of many different individuals to many different types of stimuli, from genetic mutations, to infections, to drugs, and more."</p> <h2>Embracing variation</h2> <p>Brain chimeroids build on a decade of research by the Arlotta lab, which has pioneered the use of human organoids to study neuropsychiatric disorders. The process of creating a chimeroid involves several steps. First, pluripotent stem cells — which can be generated from any donor (healthy or patient) — from multiple people are differentiated in individual 3D cultures and coaxed to become neural progenitors, particularly those of a brain cortical fate. Next, the cells are removed from culture, disassociated from each other, and reassembled.</p> <p>The resulting 3D chimeroids are composed of multiple brain cell types from multiple donors, each contributing to the overall structure. The researchers used cells from five different donors for this study, but the platform is designed to be flexible and scalable, potentially accommodating hundreds of donors in future studies.</p> <p>"In this context, the goal was to develop a way of looking at different cells of the brain that are affected by a trigger in a more scalable way and develop a platform to read solid responses in these different cells," said Irene Faravelli, a postdoctoral researcher in the Arlotta lab and co-first author of the study with postdoctoral fellow Noelia Antón-Bolaños.</p> <p>The development of chimeroids was not without its challenges, such as ensuring that the cells from different donors maintained a balanced proportion over time. "A major technical challenge was that single donors would take over the culture over time, even if mixes were donor-balanced initially," Antón-Bolaños recalled. Overcoming this challenge required a deep understanding of embryonic brain development and innovative computational analysis techniques.</p> <h2>Putting exposure in context</h2> <p>To test their system, the team exposed chimeroids to two compounds with well-known neurotoxic effects in the developing brain: ethanol and valproic acid. Ethanol exposure during pregnancy can lead to fetal alcohol spectrum disorder, while valproic acid (VPA), a drug used to treat mood disorders and seizures, has been linked to an increased risk of ASD. Clinicians have long noted that not all children exposed to these compounds experience the same outcomes, suggesting that genetic variations&nbsp;may influence susceptibility. &nbsp;</p> <p>Using a transcriptomic readout, which allows researchers to explore cells' molecular responses to stimuli, the team identified significant changes in the cell type composition of ethanol- or VPA-exposed chimeroids compared to unexposed controls. They also found that the proportion of cells from specific donors changed within exposed organoids, as did the gene expression profiles of cells from different donors in response to VPA.&nbsp;</p> <p>The team believes chimeroids may accelerate the study of complex polygenic states associated with psychiatric disorders like schizophrenia and ASD, or could enable prediction of responses to new therapeutics, which could have significant implications for personalized medicine. This could lead to more accurate preclinical trials and better predictions of clinical outcomes.</p> <p>"Success in this area would mean that organoids could become pre-clinical trial 'avatars' informing on the differential responses of the cells of the brain of each individual to begin to predict clinical outcomes," Arlotta said. "What if one day we could use chimeroids as avatars to predict individual responses to new therapeutics before testing it in a trial? Or to stratify and better classify and diagnose patients to tailor more effective therapeutics to them? I like to imagine that future, frankly."&nbsp;</p> <p><em>Adapted from <a href="https://hscrb.harvard.edu/news/brain-chimeroids-reveal-susceptibility-to-brain-triggers/" target="_blank">a story published by the Harvard Department of Stem Cell and Regenerative Biology</a></em>.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this study was provided by the National Institute of Mental Health, the Stanley Center for Psychiatric Research, the Klarman Cell Observatory, the ӳ����ý of MIT and Harvard, and the Blavatnik Biomedical Accelerator at Harvard University.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Antón-Bolaños&nbsp;N, Favarelli I, et al.&nbsp;<a href="https://www.nature.com/articles/s41586-024-07578-8" target="_blank">Brain chimeroids reveal individual susceptibility to neurotoxic triggers</a>. <em>Nature</em>. Online June 26, 2024. DOI:&nbsp;10.1038/s41586-024-07578-8.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/stanley-center-psychiatric-research" hreflang="en">Stanley Center for Psychiatric Research</a></div> <div class="field__item"><a href="/broad-tags/neurodevelopmental-conditions" hreflang="en">Neurodevelopmental conditions</a></div> <div class="field__item"><a href="/broad-tags/psychiatric-disease" hreflang="en">Brain Health</a></div> <div class="field__item"><a href="/broad-tags/paola-arlotta" hreflang="en">Paola Arlotta</a></div> </div> </div> </div> </div> </div> Thu, 03 Dec 2020 18:09:52 +0000 tulrich@broadinstitute.org 694431 at /news/organoids-emerge-powerful-tools-disease-modeling-and-drug-discovery <span class="field field--name-title field--type-string field--label-hidden"><h1>Brain chimeroids offer window into relationships between genetics and exposures</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Tom Ulrich</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-07-08T10:30:38-04:00" class="datetime">July 8, 2024</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Brain chimeroids offer window into relationships between genetics and exposures</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>New model system allows researchers to study the influence of genetic background on brain cells' responses to neurotoxins, disease mutations, and potential therapeutics</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Alice McCarthy, Harvard University </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2024-07-08T10:30:38-04:00" title="Monday, July 8, 2024 - 10:30" class="datetime">July 8, 2024</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=5VyOntI1 1x" media="all and (min-width: 1921px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=5VyOntI1 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="754" height="503"> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=O8QMXmqM 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="736" height="520"> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=aLTBeADi 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="641" height="451"> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=l2192yL6 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="706" height="417"> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=bADgyMxg 1x" media="all and (max-width: 539px)" type="image/png" width="499" height="294"> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/Arlotta%20lab_chimeroid_Figure1_120mm_V4_CMYK-02.png?itok=bADgyMxg" alt="Color microscope image of a brain chimeroid, with red and green colors highlighting different types of cells and different structures." title="Color microscope image of a brain chimeroid, with red and green colors highlighting different types of cells and different structures." typeof="foaf:Image"> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Arlotta laboratory </div> <div class="media-caption__description"> A brain chimeroid </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous"></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/981/feed&amp;title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" style="border-radius:100%;"> <use 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block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related people</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/bios/paola-arlotta">Paola Arlotta</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-menu sidebar-menu"> <div class="sidebar-menu__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related programs</p> </div> <div class="field field--name-field-links field--type-link field--label-hidden field__items"> <div class="field__item"><a href="/stanley-center-for-psychiatric-research">Stanley Center for Psychiatric Research</a></div> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related news</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/molecular-map-brain-organoids-reveals-unprecedented-levels-neuronal-cell-maturation-and" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/molecular-map-brain-organoids-reveals-unprecedented-levels-neuronal-cell-maturation-and"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=bb0Vsxsf 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2017/Arlotta_BrainOrganoids_main_v2.jpg?h=d3e04ee7&amp;itok=bb0Vsxsf 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="104" height="104"> <source 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Expression of the synaptic marker SYN1 (green) is absent at 1 month (upper left) and appears with organoid maturation by 3 months (upper right). Organoids continue maturing at 6 months (lower left) and 9 months (lower right)." title="Synapse development in organoids. Expression of the synaptic marker SYN1 (green) is absent at 1 month (upper left) and appears with organoid maturation by 3 months (upper right). Organoids continue maturing at 6 months (lower left) and 9 months (lower right)." typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/molecular-map-brain-organoids-reveals-unprecedented-levels-neuronal-cell-maturation-and" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Molecular map of brain organoids reveals unprecedented levels of neuronal cell maturation and diversity</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/human-brain-organoids-come-age" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/human-brain-organoids-come-age"><picture> <source 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srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=t4Lif9cH 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=bhXHlqXC 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/Arlotta_Nature_Feb2022_individual_neurons_c_Harvard_University_crop_0.png?h=d3e04ee7&amp;itok=bhXHlqXC" alt="Microscopy image of a brain organoid showing individual neurons spontaneously firing" title="Microscopy image of a brain organoid showing individual neurons spontaneously firing" typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/three-autism-risk-genes-have-similar-effects-brain-development-different-routes" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Three autism risk genes have similar effects on brain development, but by different routes</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/brain-organoids-replicate-key-events-human-brain-development" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <a href="/news/brain-organoids-replicate-key-events-human-brain-development"><picture> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=lstySHBC 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=lstySHBC 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=4HlxIV8e 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=4HlxIV8e 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=T0IPiSz3 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=njI3T1Gw 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/news/images/2022/edited_CNTMix_PGP1_MAP2-488_Foxg1-647_ZO1-546_merge5_flat.png?itok=njI3T1Gw" alt="Human brain organoids showing neurons and their dendrites (green), telencephalic (forebrain) cells (blue), and a kind of cell-cell contact called tight junctions (red)." title="Human brain organoids showing neurons and their dendrites (green), telencephalic (forebrain) cells (blue), and a kind of cell-cell contact called tight junctions (red)." typeof="foaf:Image"> </picture></a> </div> </article> </div> <div class="node__content"> <a href="/news/brain-organoids-replicate-key-events-human-brain-development" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Brain organoids replicate key events in human brain development</span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Researchers at the Harvard Department of Stem Cell and Regenerative Biology (HSCRB) and the ӳ����ý of MIT and Harvard have developed a new platform for modeling at the cellular level how the human brain responds to a variety of stimuli. Described in <a href="https://www.nature.com/articles/s41586-024-07578-8" target="_blank"><em>Nature</em></a>, these ‘brain chimeroids’ provide an approach for studying how genetic background can affect the outcome of neurotoxic exposures, disease-associated&nbsp;genetic variants, and potential therapeutic compounds.&nbsp;</p> <p>Chimeroids are brain organoids made up of cells representing multiple cell types found in the human brain (neurons, glial cells, etc.), derived from induced pluripotent stem cells generated from several human donors. By incorporating cells from many individuals, chimeroids allow researchers to observe&nbsp;<em>in vitro</em> how cells and brain circuits from individuals with unique genetic backgrounds, including those with family histories of neurodevelopmental or neuropsychiatric disorders, respond to the same stimulus.&nbsp;</p> <p>People carry a vast reservoir of genetic variation; any two individuals differ from each other at about one base pair out of every 1,000 across the three billion-base pair genome. Risk for conditions like schizophrenia or autism spectrum disorder (ASD) often arises from the complex interplay of many genetic variations, rather than from variations in a single gene. By incorporating large numbers of individuals across a spectrum of polygenic risk, chimeroids allow researchers to leverage this genetic diversity to understand its functional effects on the brain.</p> <p>"The idea of generating organoids that contain cells from multiple donors was directly motivated by our long-term interest in modeling psychiatric conditions, such as schizophrenia, and developmental disorders, such as autism spectrum disorder," said senior author <a href="/node/4635">Paola Arlotta</a>, chair of HSCRB and an institute member in the <a href="http://www.broadinstitute.org/node/8513">Stanley Center for Psychiatric Research</a> at ӳ����ý. "The ability to grow cells from distinct donors within the same organoid opens the door to investigating at scale and in a controlled way the responses of brain cells of many different individuals to many different types of stimuli, from genetic mutations, to infections, to drugs, and more."</p> <h2>Embracing variation</h2> <p>Brain chimeroids build on a decade of research by the Arlotta lab, which has pioneered the use of human organoids to study neuropsychiatric disorders. The process of creating a chimeroid involves several steps. First, pluripotent stem cells — which can be generated from any donor (healthy or patient) — from multiple people are differentiated in individual 3D cultures and coaxed to become neural progenitors, particularly those of a brain cortical fate. Next, the cells are removed from culture, disassociated from each other, and reassembled.</p> <p>The resulting 3D chimeroids are composed of multiple brain cell types from multiple donors, each contributing to the overall structure. The researchers used cells from five different donors for this study, but the platform is designed to be flexible and scalable, potentially accommodating hundreds of donors in future studies.</p> <p>"In this context, the goal was to develop a way of looking at different cells of the brain that are affected by a trigger in a more scalable way and develop a platform to read solid responses in these different cells," said Irene Faravelli, a postdoctoral researcher in the Arlotta lab and co-first author of the study with postdoctoral fellow Noelia Antón-Bolaños.</p> <p>The development of chimeroids was not without its challenges, such as ensuring that the cells from different donors maintained a balanced proportion over time. "A major technical challenge was that single donors would take over the culture over time, even if mixes were donor-balanced initially," Antón-Bolaños recalled. Overcoming this challenge required a deep understanding of embryonic brain development and innovative computational analysis techniques.</p> <h2>Putting exposure in context</h2> <p>To test their system, the team exposed chimeroids to two compounds with well-known neurotoxic effects in the developing brain: ethanol and valproic acid. Ethanol exposure during pregnancy can lead to fetal alcohol spectrum disorder, while valproic acid (VPA), a drug used to treat mood disorders and seizures, has been linked to an increased risk of ASD. Clinicians have long noted that not all children exposed to these compounds experience the same outcomes, suggesting that genetic variations&nbsp;may influence susceptibility. &nbsp;</p> <p>Using a transcriptomic readout, which allows researchers to explore cells' molecular responses to stimuli, the team identified significant changes in the cell type composition of ethanol- or VPA-exposed chimeroids compared to unexposed controls. They also found that the proportion of cells from specific donors changed within exposed organoids, as did the gene expression profiles of cells from different donors in response to VPA.&nbsp;</p> <p>The team believes chimeroids may accelerate the study of complex polygenic states associated with psychiatric disorders like schizophrenia and ASD, or could enable prediction of responses to new therapeutics, which could have significant implications for personalized medicine. This could lead to more accurate preclinical trials and better predictions of clinical outcomes.</p> <p>"Success in this area would mean that organoids could become pre-clinical trial 'avatars' informing on the differential responses of the cells of the brain of each individual to begin to predict clinical outcomes," Arlotta said. "What if one day we could use chimeroids as avatars to predict individual responses to new therapeutics before testing it in a trial? Or to stratify and better classify and diagnose patients to tailor more effective therapeutics to them? I like to imagine that future, frankly."&nbsp;</p> <p><em>Adapted from <a href="https://hscrb.harvard.edu/news/brain-chimeroids-reveal-susceptibility-to-brain-triggers/" target="_blank">a story published by the Harvard Department of Stem Cell and Regenerative Biology</a></em>.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Funding</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Support for this study was provided by the National Institute of Mental Health, the Stanley Center for Psychiatric Research, the Klarman Cell Observatory, the ӳ����ý of MIT and Harvard, and the Blavatnik Biomedical Accelerator at Harvard University.</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Antón-Bolaños&nbsp;N, Favarelli I, et al.&nbsp;<a href="https://www.nature.com/articles/s41586-024-07578-8" target="_blank">Brain chimeroids reveal individual susceptibility to neurotoxic triggers</a>. <em>Nature</em>. Online June 26, 2024. DOI:&nbsp;10.1038/s41586-024-07578-8.</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/stanley-center-psychiatric-research" hreflang="en">Stanley Center for Psychiatric Research</a></div> <div class="field__item"><a href="/broad-tags/neurodevelopmental-conditions" hreflang="en">Neurodevelopmental conditions</a></div> <div class="field__item"><a href="/broad-tags/psychiatric-disease" hreflang="en">Brain Health</a></div> <div class="field__item"><a href="/broad-tags/paola-arlotta" hreflang="en">Paola Arlotta</a></div> </div> </div> </div> </div> </div> Mon, 14 Sep 2020 13:18:06 +0000 Corie Lok 650171 at