Self Organization in Competition and Diversity

Informations projet

SOURCE

N° de convention de subvention: 740704

DOI

10.3030/740704

Projet clôturé

Date de signature de la CE 10 Mai 2017

Date de début 1 Septembre 2017

Date de fin 28 Février 2023

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 2 211 015,00

Contribution de l’UE

€ 2 211 015,00

Coordonné par

KOBENHAVNS UNIVERSITET
Denmark

Periodic Reporting for period 4 - SOURCE (Self Organization in Competition and Diversity)

Période du rapport: 2022-03-01 au 2023-02-28

Résumé du contexte et des objectifs généraux du projet

SOURCE is a trans-disciplinary project
that explore mechanisms behind the many diverse
forms of life that surrounds us. We use mathematical models and computer simulations
to mimic life phenomena, from gene regulation inside cells
to interactions between viruses and their host.
The methodology is from theoretical physics used to study life, in particular the ability of life
take many different forms.


SOURCE is basic research with computers as primary tool, with implications manipulations of ourselves and diseases that may attack us.
Our models of organ formations is associated to synthetic formation of organs,
whereas bacterial viruses caries important clues about our own infectious diseases.


SOURCE is divided in work packages:

WP1 focus on cell differentiation, how cells keep their identity (epigenetics), an
how many cells build organs. Both topics is deeply connected to how a organism keep
order within its organization, and the research thus couples to cancer where there
is disorder in both gene regulation and cell cooperation. Cancer cell often loose their
polarity, and a major part of WP1 study how cell polarity helps maintain biological shapes.

WP2 is on ecosystems. Here we focus on microbial systems where phages and bacteria
teaches us how spatial organization is part of way that virus spread is limited and host
population maintained. This interplay host properties like the receptor density and spread
of a virus may teach us about viral dynamics inside our body, where for example the lethality
of Covid-19 correlates negatively with amount of the Ace2 receptors in host cells.

WP3 deals directly with epidemics, a topic that suddenly (just after the current reporting
period ended), turned out to be hugely important for society. Questions like why
standard epidemic models (SEIR) typically overestimate the final attack rate is
important for guiding policy decisions during a real epidemic.


In a broad perspective we aim to understand
life as a self organized phenomenon that can be understood from a few basic principles.
Understanding self guiding processes in biology can help us to guide and use them in
battling diseases.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

SOURE addressed biological diversity an emergent property of extended dynamical systems, and demonstrated ways that this diversity could emerge
through directed interactions. The project initiated and completed completely new research directions within cell-cell interactions,
on virus-host interactions and on heterogeneity in disease spreading.

The project aimed to develop models for how our cells maintain their specific identities through epigenetic variability and how this us subsequently used in defining organ shapes.
Essentially, this means how our genes are turned on and off to create different types of cells like skin, muscle, and bone.

The study looked at stem cells at various levels and considered the complex genetic networks that control their fate, allowing them to differentiate and subsequently maintain different cell types.
Using computer simulations, we were able to model how different cells emerge and interact during morphogenesis. Enclosed please find picture from our in-silico simulation of Gastrulation.
Thereby the project has contributed to our understanding of how our cells work and collaborate in forming diverse organs. In-silico models of neurulation. blood vessel formation and early pancreas
development was published, where early pancreas growth and cell differentiation was included and compared to experiments hat could differentiate progenitor cells with oscillations in gene expression
from differentiated cells on surface and the interior of the growing pancreas.
In future such models could be used as a guide in in-vitro organoids formation, which potentially can be used as transplants.

The project further investigated how viruses interact with their hosts. The researchers found that spatial limitations hugely affect how viruses spread, including how their hosts are distributed in space.
Apart from being tested in controlled laboratory where virus infect bacteria (see figure on microcolonies below),
The research on the interaction between viruses and their hosts is a crucial area of study as it helps us understand how viruses spread and how we can develop
strategies to mitigate their impact on human health. The fact that we found spatial limitations to be a significant factor in how viruses spread is particularly
noteworthy as it highlights the importance of social distancing and other measures to limit human-to-human contact during an epidemic outbreak.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

One truly new result was the development of a point particle for cells that participate in organogenesis that allowed in silico simulations of cells that have both polarity and deformation of their shape.
The model is simple, fast and a allow for much more transparent description than the vertex models that are the normal state of the art in the field.
The model with its interplay of apical-basal cell polarity and planar cell polarity is illustrated for Gastrulation in the figure below.
The simple phenomenology puts the focus on the underlying principles in cell-cell collaborations and multi cell movement as they dynamically moves to shape the particular organ.
We want to extend our methodology to a quantitative tool for analyzing how biological form and gene expression play together.
We want to make organs in silico, and use this to guide future experiments on organs growth.

SOURCE also explored the spatial interactions between virus and its host, where it was predicted that a large microcolony can defend itself against virus attack, provided that the virus does nor proliferate to fast.
The prediction was verifies experimentally. Below we show the in-silico simulation of two colonies, exposed to virus attack at two different stages during their growth. One sees that a large enough colony indeed
survive and persistently grow even after the virus proliferate on its surface.

The project had one further result that was beyond anything expected. Due to the failure of our initial SIRS model to predict the large effect of lock-downs, we was forced to
reconsider the basic epidemic methodology. This lead to the invention of an agent based model for an epidemic driven by superspreaders.
This type of model explicitly takes into account the limited contacts of each individual, and thereby goes beyond the averaging that is inherent in all other epidemic modeling used during the Covid-19 epidemic.
The model allow us to quantify the mitigation that was needed to stop the spread of the original Covid-19 strain,
and will have important for future epidemic mitigation in situations where these epidemics turns out to be driven by superspreading. One figure below illustrate
the possibility that the fact that Covid-19 is transmitted by aerosol.

A model for the dynamical process of Gastrulation: A transition from a sphere to a torus.

Growing microcolonies, exposed to phages at different sizes during growth.

Exploring aerosol transmitted diseases for superspreading