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Speaker: Jaume Casademunt (Universitat de Barcelona)
Date: 18/01/2024
Time: 10:00

The collective migration of cohesive groups of cells is a hallmark of the tissue remodeling events that underlie embryonic morphogenesis, wound repair, and cancer invasion. Collective cell migration is characterized by the emergence of supra-cellular properties that control large-scale tissue organization. This suggests that a coarse-grained approach based on a hydrodynamic description of tissues as continuous active materials may shed some light on our understanding of the underlying physics of various tissue processes. Within this spirit, we reflect on the extent to which biological complexity can be encoded in a series of material parameters to build predictive, purely mechanical models of tissues based on very general physical principles. We present an overview of such a hydrodynamic approach to cell tissues as active polar fluids and discuss some examples where relatively simple models have been instrumental in elucidating relevant physical mechanisms behind collective cell behavior in epithelia, including active wetting, collective durotaxis, and spontaneous motility of cell clusters.

 
 

Speaker: Amélie Baud (CRG, Barcelona)
Date: 11/01/2024
Time: 10:00

Our goal is to better understand why individuals from a population differ from each other in terms of their phenotypes and susceptibility to disease. We focus on genetic effects, considering not only the individual’s own genes but also the genes of their social partners and the genes of their microbiome. I will present the conceptual framework and quantitative genetics models we use to study this extended genotype to phenotype map.

 

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Speaker: Matthias Merkel (CENTURI, Marseille)
Date: 30/11/2023
Time: 10:00

I will talk about two project involving oriented tissue flows.

1) Most animals display one or more body axes (e.g. head-to-tail, left-right, ventral-dorsal), which usually emerge during early embryogenesis. In our work, we demonstrate that large-scale tissue flows can play an important role for the formation of body axes. To this end, we used aggregates of mouse stem cells, called gastruloids. Gastruloids are initially spherically symmetric, but later form an axis defined by the polarized expression patterns of specific proteins such as T/Brachyury or E-cadherin. While such early embryonic pattern formation is usually studied in the context of genetic and bio-chemical interactions, we show that also advection of cells with tissue flows contribute approximately 1/3 to the overall polarization. We then more closely analyzed the flow field in the gastruloids and found that the dominant component was a recirculating flow. We further showed that this large-scale flow could be understood as a Marangoni flow, i.e. driven by interface and surface tension differences. We further independently confirmed the existence of differential interface and surface tensions though aggregate fusion experiments. Taken together, we found that in polarized gastruloids, differential tensions drive recirculation flows, which in turn further amplify polarization. We expect such a feedback loop to act also in many other systems in vitro and in vivo.

2) Oriented tissue deformation is a fundamental process omnipresent during animal development. However, how exactly cells coordinate to achieve robust oriented deformation on the tissue scale remains elusive. From a physics perspective, deforming tissues can be described as oriented active materials. However, it is known that oriented active materials can inherently exhibit instabilities such as the Simha-Ramaswamy instability. This instability destroys the homogeneously deforming state of active materials. This raises the question of how robust anisoropic tissue deformation can be possible during animal development. In particular, we ask whether the presence of a chemical signalling gradient (e.g. a morphogen gradient) can help stabilize oriented tissue deformation. Using a combination of vertex and hydrodynamic models, we find that stability depends on whether the signalling gradient acts to extend or contract the tissue along the gradient direction. In particular, gradient-extensile coupling can be stable, while gradient-contractile coupling is generally unstable. Intriguingly, developing tissues seem to exclusively use the gradient-extensile and not the unstable gradient-contractile coupling, suggesting that nature might just never have evolved the latter. Our work points to a potential new developmental principle that is directly rooted in active matter physics.

 

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Speaker: Loren Williams (Georgia Institute of Technology, US)
Date: 23/11/2023
Time: 10:00

Around four billion years ago, chemical and geological processes on the ancient Earth caused increases in complexity of organic molecules, creating RNA, DNA, protein, polysaccharide, membrane-forming amphipaths, and metabolism. But how?

In our center are learning to understand the origins of life through the geology, physics, chemistry and biochemistry of water. Water serves as a medium, as a chemical hub, and as an energy currency during experimental chemical evolution. We have developed an experimental platform that allows us to perform and evaluate chemical evolution. Based in part on our results, here we describe why (we think) the origins of life:

(i) represents an experimentally addressable and solvable problem that one day will be understood and generally accepted,
(ii) is not technically difficult - it happened on the Hadean Earth, in the absence of post docs, pH meters, rotavaps, HPLCs, NMRs, and mass spectrometers,
(iii) is not a series of idiosyncratic and spectacular one-off events but is reproducible and even mundane,
(iv) is a specific example of a class of processes that we call general chemical evolution, and
(v) can be redirected and exploited for a broad array of chemical applications ranging from materials science, to nanotechnology, to medicine, to astrobiology (i.e., there is money to be made).

 

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Speaker: Lars Velten (Centre de Regulació Genòmica, Barcelona)
Date: 02/11/2023
Time: 10:00

During the differentiation of blood stem cells, gene expression needs to be tightly controlled, but it is unclear how gene regulatory elements encode this specificity. Here, we took a bottom-up approach and attempted to engineer lineage- and stage-specific enhancers from scratch, by systematically embedding transcription factor (TF) binding sites into random DNA. In total, we designed 60,000 candidate enhancers, and measured their ability to drive transcription in seven hematopoietic progenitor states, using a primary cell differentiation model. Our results reveal dose- and context-dependent duality behavior of TFs, encoding of specificity by low-affinity sites, and an unexpected ability of stem cell TFs to turn lineage TFs into repressors. I will also discuss ideas to describe our results with mechanistic models.

 

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Speaker: Isaac Salazar  (Universitat Autònoma de Barcelona, Centre de Recerca Matemàtica, Barcelona)
Date: 26/10/2023
Time: 10:00

A fundamental question of developmental biology is how pattern formation occur. In this article we restrict ourselves to the pattern formation that occurs without cell movement (i.e. no cell division, cell contraction or any cell behaviors leading to cell movement) but just by signaling and gene networks. Our questions are:

1-Which are the topologies of the gene networks that can lead to pattern transformation?

2-Is there a limited number of classes into which pattern-transformation gene networks can be classified according to their topology, dynamics and pattern transformation capacities?

3-Can we characterize such classes and relate them to experimental gene networks underlying specific pattern transformations in embryos?

By gene network topology we mean which gene products regulate each other and which of these regulations are positive or negative (see FIG). In this article we show that, in spite of the huge size of the space of possible gene networks and the complexity of development, the gene network topologies capable of pattern transformation can be classified into just three topological classes and their combinations. Gene networks within these classes share the same logic on how they lead to pattern transformations and very similar pattern transformations.

 
 

Speaker: Mariano Vasquez (Barcelona Supercomputing Centre)
Date: 14/09/2023
Time: 10:00

In this talk, we will show how ELEM Biotech (http://elem.bio), a spinoff company of the Barcelona Supercomputing Center, is developing Virtual Humans to decisively contribute
to develop new therapeutical strategies, helping to personalize and optimize them. We are highly focused on cardiovascular and respiratory diseases, but in the talk we will show some results on other organs and systems. Virtual Humans are combinations of mathematical models and patient's data, which deployed in the cloud in High Performance instances, can predict the outcome of the therapy. We will show how ELEM technology allows us to create a population of such avatars to perform in-silico clinical trials.

 
 

Speaker: Fran Supek (Institute for Research in Biomedicine, Barcelona)
Date: 21/09/2023
Time: 10:00

Somatic mutations in human cells have a highly heterogeneous genomic distribution, with increased burden in late-replication time (RT), heterochromatic domains of chromosomes. This regional mutation density (RMD) landscape is known to vary between cancer types, in association with tissue-specific RT or chromatin organization. Here, we hypothesized that regional mutation rates additionally vary between individual tumors in a manner independent of cell type, and that recurrent alterations in DNA replication programs and/or chromatin organization may underlie this. Here, we identified various RMD signatures that describe a global genome-wide mutation redistribution across many megabase-sized domains in >4000 tumors. We identified two novel global RMD signatures of somatic mutation landscapes that were universally observed across various cancer types. First, we identified a mutation rate redistribution preferentially affecting facultative heterochromatin, Polycomb-marked domains, and enriched in subtelomeric regions. This RMD signature strongly reflects regional plasticity in DNA replication time and in heterochromatin domains observed across tumors and cultured cells, which was linked with a stem-like phenotype and a higher expression of cell cycle genes. Consistently, occurrence of this global mutation pattern in cancers is associated with altered cell cycle control via loss of activity of the RB1 tumor suppressor gene. Second, we identified another independant global RMD signature associated with loss-of-function of the TP53 pathway, mainly affecting the redistribution of mutation rates away from late RT regions. The local mutation supply towards 26%-75% cancer driver genes is altered in the tumors affected by the global RMD signatures detected herein, including additionally a known pattern of a general loss of mutation rate heterogeneity due to DNA repair failures that we quantify. Our study highlights that somatic mutation rates at the domain scale are variable across tumors in a manner associated with loss of cell cycle control via RB1 or TP53, which may trigger the local remodeling of chromatin state and the RT program in cancers.

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Speaker: Atsuko Sato (Ochanomizu University, Japan)
Date: 28/09/2023
Time: 10:00

Predicting development has been a major challenge in genetics, medicine and evolutionary biology. More than half a century ago, Conrad Hal Waddington famously raised several issues in understanding ‘cybernetics’ of development in his book ‘The Strategy of the Genes’, such as impact of environment, maternal effect and developmental buffering. My previous study showed that buffering level is maternally inherited, and identified key maternal mRNAs that predicts level of developmental buffering. Since maternal mRNAs are a major cause of embryonic defects, delivering necessary maternal mRNAs can safeguard eggs from environmental impacts. I will introduce my ongoing work on predicting impact of thermal stress on development.

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Speaker: Marc Güell (Universitat Pompeu Fabra, Barcelona)
Date: 14/09/2023
Time: 10:00

Gene editing is revolutionizing bioscience and therapy. Our lab has developed a gene writing tool combining the precision of CRISPR and gene transfer capacity of a transposase (Pallarès-Masmitjà et al, Nat Com 2021). We are planning to develop improved gene writers for safer and more efficient therapies with aid of the B-bio (new retrovirus-based directed evolution platform developed by our lab (Ivancic et al, in preparation). A key part for the success of this massively genotype testing platform is library design and analysis using AI. Large language models are being very powerful to represent protein language and will be used to fuel genotypes and accelerate evolution. Coupling this biological hardware with AI is generating a fascinating synergy for enhancing the evolutionary rate of new CRISPR based editors and writers.


If you would like to attend the seminar, please register here