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An image-based systems biology approach to symmetry breaking in collective cell behavior

English title An image-based systems biology approach to symmetry breaking in collective cell behavior
Applicant Liberali Prisca
Number 157531
Funding scheme SNSF Professorships
Research institution Friedrich Miescher Institute for Biomedical Research
Institution of higher education Institute Friedrich Miescher - FMI
Main discipline Cellular Biology, Cytology
Start/End 01.07.2015 - 30.06.2019
Approved amount 1'569'834.00
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All Disciplines (3)

Discipline
Cellular Biology, Cytology
Genetics
Embryology, Developmental Biology

Keywords (13)

Membrane traffic and cell signalling; Symmetry breaking mechanism; Wnt signalling; Intestinal organoids; System Biology; Single-cell approaches; Environment sensing mechanism; Cell-to-cell variability; Pattern formation; Image-based genetic screens; membrane traffick; endocytosis; signalling networks

Lay Summary (Italian)

Lead
Simmetria e variabilità durante il comportamento collettivo nella formazione di organoid intestinali.
Lay summary

“Collective behavior” o comportamento collettivo, è un comportamento complesso nel quale l’analisi approfondita dei singoli elementi non necessariamente può spiegare il comportamento collettivo di molti singoli individui. Questo ricorda la citazione di Aristotele: "Il tutto è più della somma delle sue parti". Il comportamento non spiegabile è l'auto-organizzazione del sistema. Spesso questa auto-organizzazione crea dei pattern (o schemi). Ad esempio, nell'universo, la materia è distribuita in cluster, lasciandolo in gran parte vuoto. Sulla terra, si formano diversi tipi di onde, come ad esempio le correnti oceaniche. In biologia molecolare e dello sviluppo, la formazione di pattern è un meccanismo attraverso il quale cellule inizialmente identiche in un tessuto assumono varie forme e funzioni nello spazio e nel tempo. Questo progetto svilupperà un nuovo quadro teorico e sperimentale per comprendere le proprietà collettive di cellule in una popolazione complessa e i pattern creati da singole cellule che interagiscono tra loro per formare un tessuto funzionale.

Per questo progetto useremo un sistema modello di strutture intestinali in vitro chiamate organoid, che possono creare un tessuto intestinale funzionale  da una singola cellula staminale intestinale. Svilupperemo imaging avanzato in modo quantitativo, con una risoluzione alla singola cellula e analisi d’immagine combinata con perturbazioni genetiche delle cellule staminali intestinali in culture 2D e 3D durante lo sviluppo dell’organoid. Complessivamente, questo progetto di ricerca mettera' in luce  un’unica mappa genetica del comportamento collettivo, che troverà applicazioni generali di là del sistema modello specifico del organoid intestinale. Essa fornirà un esempio concreto di come un approccio quantitativo interdisciplinare, combinando diversi elementi sperimentali e teorici, consenta lo studio del comportamento collettivo che rimane, da molto tempo, uno degli aspetti fondamentali in biologia molecolare e dello sviluppo.

Direct link to Lay Summary Last update: 03.03.2015

Lay Summary (English)

Lead
Symmetry breaking during collective cell behaviour of intestinal organoid formation
Lay summary

Collective behavior is a complex behavior where the understanding of the individual components in more depth does not necessarily explain the collective behavior of many individuals. This is reminiscent of Aristotle’s quote: “The whole is more than the sum of its parts”. The unexplainable behavior is the self-organization of the system. Often this self-organization creates patterns. For example, in the universe, matter is distributed in clusters, leaving much of the universe empty. On earth, different types of wave patterns are formed, such as jet streams, ocean currents, and continental drifts. In molecular and developmental biology, pattern formation is the mechanism by which initially identical cells in a developing tissue assume different forms and functions in space and time. This project will develop a new theoretical and experimental framework to understand the collective population-level properties and the patterns of large interacting systems of  single cells

For this reason we will use a model system of intestinal organoid structures in vitro which can create a function intestinal tissue from a single intestinal stem cell. We will develop quantitative advanced single-cell imaging and image analysis combined with genetic perturbation of intestinal stem cells in 2D culture and during 3D organoid development. Together, this research proposal will reveal a unique genetic map of collective behaviour, which will find general applications beyond the specific model system of the intestinal organoid. It will provide a concrete example of how an interdisciplinary quantitative approach, combining discovery-driven and hypothesis-driven elements, allows the unraveling of a long-standing fundamental question in developmental biology.

Direct link to Lay Summary Last update: 03.03.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Self-organization and symmetry breaking in intestinal organoid development
Serra Denise, Mayr Urs, Boni Andrea, Lukonin Ilya, Rempfler Markus, Challet Meylan Ludivine, Stadler Michael B., Strnad Petr, Papasaikas Panagiotis, Vischi Dario, Waldt Annick, Roma Guglielmo, Liberali Prisca (2019), Self-organization and symmetry breaking in intestinal organoid development, in Nature, 569(7754), 66-72.
Trajectories of cell-cycle progression from fixed cell populations.
Gut Gabriele, Tadmor Michelle D, Pe'er Dana, Pelkmans Lucas, Liberali Prisca (2015), Trajectories of cell-cycle progression from fixed cell populations., in Nature methods, 12(10), 951-4.

Collaboration

Group / person Country
Types of collaboration
Prof. Dana Pe'er, Colombia university, New York United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Prof. Hugo Snippert Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Jan Skotheim United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel
Prof. Anne Grapin Botton Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Tissue formation and regeneration: from molecules to models Talk given at a conference Self-organization of intestinal organoid development 27.03.2019 Titisee, Germany Liberali Prisca;
Single Cell Biology Keystone Talk given at a conference Self-organisation of intestinal organoid development 13.01.2019 Colorado, United States of America Liberali Prisca;
From Stem Cells to Human Development Talk given at a conference Self-organization in intestinal organoid development 23.09.2018 UK, Germany Liberali Prisca;
EMBL Symposium Organoids Talk given at a conference Self-organisation of intestinal organoid development 10.09.2018 Heidelberg, Germany Liberali Prisca;
Stem cell Self-Organisation Talk given at a conference Self-organisation in organoid development 03.09.2018 UK, Cambridge, Germany Liberali Prisca;
cell and development system Talk given at a conference Self-organization and symmetry breaking in intestinal organoids 20.08.2018 Arolla, Switzerland Liberali Prisca;
Medicine by design. Global Speaker Series Toronto Individual talk Self-organization in intestinal organoids 19.06.2018 Toronto, Canada Liberali Prisca;
Integrating systems biology: From networks to mechanisms to models Poster Molecular mechanisms underlying intestinal organoid development 15.04.2018 Heidelberg, Germany Lukonin Ilya;
EMBO|EMBL Symposium: Tissue self-organisation: challenging the system. Heidelberg, Germany Talk given at a conference Self-organization in intestinal organoids 13.03.2018 Heidelberg, Germany Liberali Prisca;
EMBO|EMBL Symposium: Tissue self-organisation: challenging the system Talk given at a conference Self-organization in intestinal organoids development 11.03.2018 Heidelberg, Germany Liberali Prisca;
EMBO | EMBL Symposium: Tissue Self-Organisation: Challenging the Systems Poster Spatial self-organisation driving neural cell fate decisions 11.03.2018 Heidelberg, Germany Zinner Marietta;
Single Cell Biology, Wellcome Genome Talk given at a conference Self-organization in intestinal organoids development 06.03.2018 Hinxton, Great Britain and Northern Ireland Liberali Prisca;
EMBL Heidelberg, Developmental Biology unit Individual talk Self-organization in intestinal organoids development 10.01.2018 Heidelberg, Germany Liberali Prisca;
Engineering multicellular self-organization Talk given at a conference Self-organization in intestinal organoids 12.11.2017 EPFL, Switzerland Liberali Prisca;
Emergence and Self-Organization in Living Systems Poster Screening for modulators of intestinal organoid development 07.11.2017 Zurich, Switzerland Lukonin Ilya;
University of Bern Individual talk Self-organization in intestinal organoids 30.10.2017 Bern, Switzerland Liberali Prisca;
EMBO workshop on the Hippo pathway across species and disciplines, Poster Temporal organisation of organoid development 25.10.2017 Rome, Italy Serra Denise;
4th Swiss Image-Based Screening Conference, SIBS 2017, Zurich, Switzerland Talk given at a conference Screening for self-organization 17.10.2017 Zurich, Switzerland Liberali Prisca;
SIBS2017 – Swiss Image-based Screening Poster Screening for modulators of intestinal organoid development 12.10.2017 Zurich, Switzerland Lukonin Ilya;
Danish Stem Cell Centre Individual talk Self-organization in intestinal organoids 05.10.2017 Copenhagen, Denmark Liberali Prisca;
EMBO Conference: Endocytic trafficking and signaling in health and disease Talk given at a conference Self-organization in intestinal organoids 11.09.2017 Krakov, Poland Liberali Prisca;
Hydra XIII Summer school Poster Spatial self-organization driving neural cell fate decisions 10.09.2017 Hydra, Greece Zinner Marietta;
Human Cell Atlas. Computational methods Talk given at a conference Spatially resolved methods 01.06.2017 Stockholm, Sweden Liberali Prisca;
PhD retreat FMI and IGC Poster Identification of the molecular programs driving self-organization and cell fate decisions in neural development 28.05.2017 Lisbon, Portugal Zinner Marietta;
FMI-IGC joint PhD student retreat Poster Intestinal organoid development 28.05.2017 Vimeiro, Portugal Serra Denise;
Workshop on Statistical Challenges in Single-Cell Biology Talk given at a conference Inferring genetic interaction in organoid self-organization 01.05.2017 Ascona, Switzerland Liberali Prisca;
Advances in Cell Engineering, Imaging and Screening VIB tools and technology conference Poster Screening for modulators of organoid self-organization 17.11.2016 Leuven, Belgium Lukonin Ilya;
Bioinformatics for Human Health and Disease Talk given at a conference Inferring genetic interaction in intestinal organoids self-organization 11.10.2016 Heidelberg, Germany Liberali Prisca;
EMBO Workshop: Molecular mechanisms of ageing and regeneration: From pluripotency to senescence Poster Temporal organization of organoids development 16.08.2016 Spetses, Greece Serra Denise;
ETH D-BSSE Seminar Series Individual talk Self-organisation of organoid formation 25.05.2016 Basel, Switzerland Liberali Prisca;
Basel Stem Cell Network (BSCN) Annual meeting 2016 Talk given at a conference Self-organisation of organoid formation 25.04.2016 Basel, Switzerland Liberali Prisca;
“Ask the Expert” event. Individual talk Organoid formation 17.02.2016 Fribourg, Switzerland Liberali Prisca;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
TEDx Basel Performances, exhibitions (e.g. for education institutions) 26.05.2018 Basel, Switzerland Liberali Prisca;


Communication with the public

Communication Title Media Place Year
Video/Film My Lab International 2018
Talks/events/exhibitions TEDx Basel International 2018
Video/Film Human Cell Atlas International 2017
Media relations: print media, online media Novartis news letter inteview German-speaking Switzerland 2017

Associated projects

Number Title Start Funding scheme
183726 An image-based systems biology approach to symmetry breaking in collective cell behavior. 01.07.2019 SNSF Professorships
189956 engineering gastruloids to study the impact of mechanical constraints upon mammalian development 01.02.2020 Sinergia

Abstract

A model system of intestinal organoid structures in vitro, which recapitulates most of the processes of morphogenesis and patterning observed in intestinal tissue, will be used to understand the symmetry-breaking events during collective cell behavior. The symmetry-breaking event can be observed when, despite all single cells in a growing organoid are exposed to a uniform growth-promoting environment, only a fraction of cells acquires specific cell fates, generating asymmetric structures such as crypts and villi. To understand this process in a quantitative and unbiased manner, advanced single-cell imaging and image analysis of intestinal stem cells in 2D culture and during 3D organoid development will be applied, as well as a newly developed approach for mapping regulatory genetic interactions. In a first step, predictive models will be created to identify microenvironmental or cell state predictors of symmetry breaking. Then, image-based genetic perturbation screens on a focused set of genes involved in collective cell behavior, symmetry breaking and differentiation in intestinal stem cells will be performed to identify regulatory genetic interactions that govern the symmetry-breaking event. These interactions will be further validated and followed up by in-depth cell biological mechanistic studies. Together, this research proposal will reveal a unique genetic interaction map of symmetry breaking in pattern formation, which will find general applications beyond the specific model system of the intestinal organoid. It will provide a concrete example of how an interdisciplinary quantitative approach, combining discovery-driven and hypothesis-driven elements, allows the unraveling of a long-standing fundamental question in developmental biology, namely how symmetry breaking occurs.
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