Animal morphogenesis, the development of an organism’s body form, is commonly
perceived
as a dire... more Animal morphogenesis, the development of an organism’s body form, is commonly perceived as a directed and almost deterministic process. However, noise and stochastic fluctuations are ubiquitous in biological systems. The questions on the role of fluctuations in morphogenesis and what ensures the robustness of this process under noisy conditions remain elusive. Here, we utilize Hydra regeneration, subjected to an external electric field, to provide unique insights into these questions. We found that during Hydra morphogenesis, a phase can be induced where fluctuations lead to stochastic morphological swings, back and forth, between a nearly spherical structure (the incipient tissue’s state) and an elongated cylindrical shape (the final body form of a mature Hydra). Despite these prolonged swings, the tissue regenerates into a normal Hydra. The stochastic transitions between two well-defined shapes imply that morphological development occurs through an activation process. Indeed, by introducing a periodic perturbation through modulation of the electric field, we were able to demonstrate morphogenesis dynamics with characteristics of stochastic resonance—the tissue’s response to the perturbation displayed a resonance-like behavior as a function of the noise level. Our findings add a dynamic layer to the problem of morphogenesis and offer an unconventional physical framework based on an activation transition in a slowly varying double-well potential that ensures a canalized regeneration of the body form under fluctuations.
The emergence and stabilization of a body axis is a major step in animal morphogenesis, determini... more The emergence and stabilization of a body axis is a major step in animal morphogenesis, determining the symmetry of the body plan as well as its polarity. To advance our understanding of the emergence of body-axis polarity we study regenerating Hydra. Axis polarity is strongly memorized in Hydra regeneration even in small tissue segments. What type of processes confer this memory? To gain insight into the emerging polarity, we utilize frustrating initial conditions by studying regenerating tissue strips which fold into hollow spheroids by adhering their distal ends, of opposite original polarities. Despite the convoluted folding process and the tissue rearrangements during regeneration, these tissue strips develop a new organizer in a reproducible location preserving the original polarity and yielding an ordered body plan. These observations suggest that the integration of mechanical and biochemical processes supported by their mutual feedback attracts the tissue dynamics towards a ...
One of the major events in animal morphogenesis is the emergence of a polar body axis. Here, we c... more One of the major events in animal morphogenesis is the emergence of a polar body axis. Here, we combine classic grafting techniques with live imaging to study the emergence of body axis polarity during whole body regeneration in Hydra. Composite tissues are made by fusing two rings, excised from separate animals, in different configurations that vary in the polarity and original positions of the rings along the body axes of the parent animals. Under frustrating initial configurations, body axis polarity that is otherwise stably inherited from the parent animal, can become labile and even be reversed. Importantly, the site of head regeneration exhibits a strong bias toward the edges of the tissue, even when this involves polarity reversal. In particular, we observe head formation at an originally aboral tissue edge, which is not compatible with models of Hydra regeneration based only on preexisting morphogen gradients or an injury response. Rather, we suggest that the structural bias...
Animal morphogenesis arises from the interaction of multiple biochemical and mechanical processes... more Animal morphogenesis arises from the interaction of multiple biochemical and mechanical processes, spanning several orders of magnitude in space and time, from local dynamics at the molecular level to global, organism-scale morphology. How these numerous processes are coordinated and integrated across scales to form robust, functional outcomes remains an outstanding question1–4. Developing an effective, coarse-grained description of morphogenesis can provide essential insight towards addressing this important challenge. Here we show that the nematic order of the supra-cellular actin fibers in regenerating Hydra5, 6 defines a slowly-varying field, whose dynamics provide an effective description of the morphogenesis process. The nematic orientation field necessarily contains defects constrained by the topology of the regenerating tissue. These nematic topological defects are long-lived, yet display rich dynamics that can be related to the major morphological events during regeneration...
Highlights d The actin fiber organization in tissue segments is inherited from the parent Hydra d... more Highlights d The actin fiber organization in tissue segments is inherited from the parent Hydra d The inherited actin organization determines the body axis in regenerating tissues d Multiple body axes can be traced to discrepancies in initial actin fiber alignment d Anchoring regenerating Hydra on wires suppresses the emergence of multiple body axes Authors
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
One of the major events in animal morphogenesis is the emergence of a polar body axis. Here, we c... more One of the major events in animal morphogenesis is the emergence of a polar body axis. Here, we combine classic grafting techniques with live imaging to explore the plasticity of polarity determination during whole body regeneration in Hydra. Composite tissues are made by fusing two rings, excised from separate animals, in different configurations that vary in the polarity and original positions of the rings along the body axes of the parent animals. Under frustrating initial configurations, body axis polarity that is otherwise stably inherited from the parent animal, can become labile and even be reversed. Importantly, the site of head regeneration exhibits a strong bias toward the edges of the tissue, even when this involves polarity reversal. In particular, we observe head formation at an originally aboral tissue edge, which is not compatible with models of Hydra regeneration based only on preexisting morphogen gradients or an injury response. The site of the new head invariably contains an aster-like defect in the organization of the supra-cellular ectodermal actin fibers. While a defect is neither required nor sufficient for head formation, we show that the defect at the new head site can arise via different routes, either appearing directly following excision as the tissue seals at its edge or through de novo defect formation at the fusion site. Altogether, our results show that the emergence of a polar body axis depends on the original polarity and position of the excised tissues as well as structural factors, suggesting that axis determination is an integrated process that arises from the dynamic interplay of multiple biochemical and mechanical processes.
Understanding the collective physical processes that drive robust morphological transitions in an... more Understanding the collective physical processes that drive robust morphological transitions in animal development necessitates the characterization of the relevant fields involved in morphogenesis. Calcium (Ca 2+) is recognized as one such field. In this study, we demonstrate that the spatial fluctuations of Ca 2+ during Hydra regeneration exhibit universal characteristics. To investigate this phenomenon, we employ two distinct controls, an external electric field and heptanol, a gap junction-blocking drug. Both lead to the modulation of the Ca 2+ activity and a reversible halting of the regeneration process. The application of an electric field enhances Ca 2+ activity in the Hydra's tissue and increases its spatial correlations, while the administration of heptanol inhibits its activity and diminishes the spatial correlations. Remarkably, the statistical characteristics of Ca 2+ spatial fluctuations, including the coefficient of variation and skewness, manifest universal shape distributions across tissue samples and conditions. We introduce a field-theoretic model, describing fluctuations in a tilted double-well potential, which successfully captures these universal properties. Moreover, our analysis reveals that the Ca 2+ activity is spatially localized, and the Hydra's tissue operates near the onset of bistability, where the local Ca 2+ activity fluctuates between low and high excited states in distinct regions. These findings highlight the prominent role of the Ca 2+ field in Hydra morphogenesis and provide insights into the underlying mechanisms governing robust morphological transitions.
We utilize whole-body Hydra regeneration from a small tissue segment to develop a physics framewo... more We utilize whole-body Hydra regeneration from a small tissue segment to develop a physics framework for animal morphogenesis. Introducing experimental controls over this process, an external electric field and a drug that blocks gap junctions, allows us to characterize the essential step in the morphological transition-from a spherical shape to an elongated spheroid. We find that spatial fluctuations of the Ca 2+ distribution in the Hydra's tissue drive this transition and construct a field-theoretic model that explains the morphological transition as a first-order-like phase transition resulting from the coupling of the Ca 2+ field and the tissue's local curvature. Various predictions of this model are verified experimentally.
Topological defects in the nematic order of actin fibres as organization centres of Hydra morphogenesis, 2021
Animal morphogenesis arises from the complex interplay between multiple mechanical and biochemica... more Animal morphogenesis arises from the complex interplay between multiple mechanical and biochemical processes with mutual feedback. Developing an effective, coarse-grained description of morphogenesis is essential for understanding how these processes are coordinated across scales to form robust, functional outcomes. Here we show that the nematic order of the supracellular actin fibres in regenerating Hydra defines a slowly varying field, whose dynamics provide an effective description of the morphogenesis process. We show that topological defects in this field, which are long-lived yet display rich dynamics, act as organization centres with morphological features developing at defect sites. These observations suggest that the nematic orientation field can be considered a ‘mechanical morphogen’ whose dynamics, in conjugation with various biochemical and mechanical signalling processes, result in the robust emergence of functional patterns during morphogenesis.
Topological defects in the nematic order of actin fibres as organization centres of Hydra morphogenesis, 2021
A nimal morphogenesis involves multiple mechanical and biochemical processes, spanning several or... more A nimal morphogenesis involves multiple mechanical and biochemical processes, spanning several orders of magnitude in space and time, from local dynamics at the molecular level to global, organism-scale morphology. How these numerous processes are coordinated and integrated across scales to form robust, functional outcomes remains an outstanding question 1-4. Developing an effective, coarse-grained description of morphogenesis can provide essential insights towards addressing this important challenge. Here we focus on whole-body regeneration in Hydra, a small freshwater predatory animal, and provide an effective description of the mor-phogenesis process that is based on the dynamic organization of the supracellular actin fibres in regenerating tissues 5,6. Hydra is a classic model system for morphogenesis, owing to its simple body plan and remarkable regeneration capabilities. Historically, research on Hydra regeneration inspired the development of many of the fundamental concepts on the biochemical basis of morphogenesis, including the role of an 'organizer' 7 , the idea of pattern formation by reaction-diffusion dynamics of mor-phogens 8,9 and the concept of positional information 10. However, in these studies, as well as in the majority of subsequent works, the role of mechanics in Hydra morphogenesis was largely overlooked. Here we revisit this classic model system, and investigate the cytoskeletal dynamics during the regeneration process from a biophysical point of view, revealing a relation between cytoskeletal organization and the morphogenesis process. A mature Hydra has a simple uniaxial body plan, with a head on one end and a foot on the other. Its tubular body consists of a double layer of epithelial cells, which contain highly organized arrays of parallel supracellular actin fibres (Extended Data Fig. 1). The fibres are globally aligned along the body axis in the outer (ectoderm) layer, and perpendicular to the body axis in the inner (endoderm) layer 5. The actin fibres are decorated with myosin motors, forming contractile bundles called myonemes, which are akin to muscular structures in other organisms. The fibres lie along the basal surfaces of each epithelial layer and are connected through cell-cell junctions to form supracellular bundles, which exhibit long-range directional order over scales comparable to the size of the animal, ranging from ~300 μm in small regenerated Hydra to several millimetres in fully grown Hydra. The myonemes are coupled via adhesion complexes to a thin, viscoelastic extracellular matrix layer (the mesoglea) sandwiched between the two cell layers (Extended Data Fig. 1) 11. Large-scale supracellular arrays of contractile actin-myosin fibres are a common organizational theme found in many animal tissues 12-14. Although the mechanism for the development of these parallel fibre arrays is not entirely clear, mechanical feedback has been shown to play a central role in their formation and alignment 14,15. Such parallel alignment is characteristic of systems with nematic order; that is, systems in which the microscopic constituents tend to locally align parallel to each other, exhibiting long-range orientational order 16. Nematic systems can be described by a director field that denotes the local orientation, and its spatio-temporal evolution reflects the dynamics of the system. Such systems can be further classified as 'active' if their constituents consume energy and generate forces, giving rise to a wealth of interesting dynamic behaviours 17. Recently, the framework of active nematics has been found to be informative in understanding various phenomena in a variety of biophysical systems 17,18 including in vitro cytoskeletal networks 19-23 , cell monolayers 24-26 and bacterial cultures 27. Here we describe the organization of the supracellular actin fibres in regenerating Hydra as an active nematic system. Hydra contains two distinct perpendicular arrays of nematic supracellular actin fibres in the ectoderm and in the endoderm (Extended Data Fig. 1). Here we primarily consider the thicker and more continuous ectodermal actin fibres, which are the most prominent cytoskeletal feature affecting Hydra mechanics 5,6. The director field describing the alignment of the ectodermal fibres defines a Topological defects in the nematic order of actin fibres as organization centres of Hydra morphogenesis Animal morphogenesis arises from the complex interplay between multiple mechanical and biochemical processes with mutual feedback. Developing an effective, coarse-grained description of morphogenesis is essential for understanding how these processes are coordinated across scales to form robust, functional outcomes. Here we show that the nematic order of the supra-cellular actin fibres in regenerating Hydra defines a slowly varying field, whose dynamics provide an effective description of the morphogenesis process. We show that topological defects in this field, which are long-lived yet display rich dynamics, act as organization centres with morphological features developing at defect sites. These observations suggest that the nematic orientation field can be considered a 'mechanical morphogen' whose dynamics, in conjugation with various biochemical and mechanical signalling processes, result in the robust emergence of functional patterns during morphogenesis. NATurE PhYSicS | www.nature.com/naturephysics
Phenotypic switching: Implications in Biology and Medicine; Ch 12, 2020
Cell-state organization, manifested in metabolism, morphology and functionality of the cell, is o... more Cell-state organization, manifested in metabolism, morphology and functionality of the cell, is of a dual nature; highly stable even under fluctuating conditions on the one hand, and flexible to adapt to novel conditions on the other hand. Here, based on our experiments studying the adaptation of yeast cells to an unforeseen challenge, we discuss the organization principles enabling the emergence of order, the organization of a cell state, given this duality. We propose that a cell state emerges by self-organized exploratory dynamics. We further discuss the barriers toward a physical framework for cell-state organization; our inability to reverse engineer living systems and the difficulties in identifying the underlying relevant degrees of freedom. We finally hypothesize that the living cell is a sloppy dynamical system, in which the dynamics are largely insensitive to the kinetics of its interacting molecules. Therefore, a physical picture of cell-state organization should go beyond the framework of pre-structured networks of interactions, and treat the evolving intracellular interactions as part of the self-organization dynamics. These dynamics reflect coupling of the cell’s internal processes with the environment and integration over its physiological as well as evolutionary histories.
Cells can rapidly adapt to changing environments through nongenetic processes; however, the metab... more Cells can rapidly adapt to changing environments through nongenetic processes; however, the metabolic cost of such adaptation has never been considered. Here we demonstrate metabolic coupling in a remarkable, rapid adaptation process (1 in 1,000 cells adapt per hour) by simultaneously measuring metabolism and division of thousands of individual Saccharomyces cerevisiae cells using a droplet microfluidic system: droplets containing single cells are immobilized in a two-dimensional (2D) array, with osmotically induced changes in droplet volume being used to measure cell metabolism, while simultaneously imaging the cells to measure division. Following a severe challenge, most cells, while not dividing, continue to metabolize, displaying a remarkably wide diversity of metabolic trajectories from which adaptation events can be anticipated. Adaptation requires a characteristic amount of energy, indicating that it is an active process. The demonstration that metabolic trajectories predict a priori adaptation events provides evidence of tight energetic coupling between metabolism and regulatory reorganization in adaptation. This process allows S. cerevisiae to adapt on a physiological timescale, but related phenomena may also be important in other processes, such as cellular differentiation, cellular reprogramming, and the emergence of drug resistance in cancer.
Morphogenesis involves the dynamic interplay of biochemical, mechanical, and electrical processes... more Morphogenesis involves the dynamic interplay of biochemical, mechanical, and electrical processes. Here, we ask to what extent can the course of morphogenesis be modulated and controlled by an external electric field? We show that at a critical amplitude, an external electric field can halt morphogenesis in Hydra regeneration. Moreover, above this critical amplitude, the electric field can lead to reversal dynamics: a fully developed Hydra folds back into its incipient spheroid morphology. The potential to renew morphogenesis is reexposed when the field is reduced back to amplitudes below criticality. These dynamics are accompanied by modulations of the Wnt3 activity, a central component of the head organizer in Hydra. The controlled backward-forward cycle of morphogenesis can be repeated several times, showing that the reversal trajectory maintains the integrity of the tissue and its regeneration capability. Each cycle of morphogenesis leads to a newly emerged body plan in the redeveloped folded tissue, which is not necessarily similar to the one before the reversal process. Reversal of morpho-genesis is shown to be triggered by enhanced electrical excitations in the Hydra tissue, leading to intensified calcium activity. Folding back of the body-plan morphology together with the decay of a central biosignaling system, indicate that electrical processes are tightly integrated with biochemical and mechanical-structural processes in morphogenesis and play an instructive role to a level that can direct developmental trajectories. Reversal of morphogenesis by external fields calls for extending its framework beyond program-like, forward-driven, hierarchical processes based on reaction diffusion and positional information.
Biological cells present a paradox, in that they show simultaneous stability and flexibility,
all... more Biological cells present a paradox, in that they show simultaneous stability and flexibility, allowing them to adapt to new environments and to evolve over time. The emergence of stable cell states depends on genotype-to-phenotype associations, which essentially reflect the organization of gene regulatory modes. The view taken here is that cell-state organization is a dynamical process in which the molecular disorder manifests itself in a macroscopic order. The genome does not determine the ordered cell state; rather, it participates in this process by providing a set of constraints on the spectrum of regulatory modes, analogous to boundary conditions in physical dynamical systems. We have developed an experimental framework, in which cell populations are exposed to unforeseen challenges; novel perturbations they had not encountered before along their evolutionary history. This approach allows an unbiased view of cell dynamics, uncovering the potential of cells to evolve and develop adapted stable states. In the last decade, our experiments have revealed a coherent set of observations within this framework, painting a picture of the living cell that in many ways is not aligned with the conventional one. Of particular importance here, is our finding that adaptation of cell-state organization is essentially an efficient exploratory dynamical process rather than one founded on random mutations. Based on our framework, a set of concepts underlying cell-state organization—exploration evolving by global, non-specific, dynamics of gene activity—is presented here. These concepts have significant consequences for our understanding of the emergence and stabilization of a cell phenotype in diverse biological contexts. Their implications are discussed for three major areas of biological inquiry: evolution, cell differentiation and cancer. There is currently no unified theoretical framework encompassing the emergence of order, a stable state, in the living cell. Hopefully, the integrated picture described here will provide a modest contribution towards a physics theory of the cell.
Understanding how mechanics complement biosignaling
in defining patterns during morphogenesis
is ... more Understanding how mechanics complement biosignaling in defining patterns during morphogenesis is an outstanding challenge. Here, we utilize the multicellular polyp Hydra to investigate the role of the actomyosin cytoskeleton in morphogenesis. We find that the supra-cellular actin fiber organization is inherited from the parent Hydra and determines the body axis in regenerating tissue segments. This form of structural inheritance is non-trivial because of the tissue folding and dynamic actin reorganization involved. We further show that the emergence of multiple body axes can be traced to discrepancies in actin fiber alignment at early stages of the regeneration process. Mechanical constraints induced by anchoring regenerating Hydra on stiff wires suppressed the emergence of multiple body axes, highlighting the importance of mechanical feedbacks in defining and stabilizing the body axis. Together, these results constitute an important step toward the development of an integrated view of morphogenesis that incorporates mechanics.
The convergence of morphogenesis into viable organisms under variable conditions suggests closed-... more The convergence of morphogenesis into viable organisms under variable conditions suggests closed-loop dynamics involving multiscale functional feedback. We develop the idea that morphogenesis is based on synergy between mechanical and bio-signaling processes, spanning all levels of organization: molecular, cellular, tissue, up to the whole organism. This synergy provides feedback within and between all levels of organization, to close the loop between the dynamics of the morphogenesis process and its robust functional outcome. Hydra offer a powerful platform to explore this direction, thanks to their simple body plan, extraordinary regeneration capabilities, and the accessibility and flexibility of their tissues. Our recent experiments show that structural inheritance of the actomyosin organization directs body-axis formation during Hydra regeneration. Morphogenesis is then stabilized through dynamic cytoskeletal reorganization induced by the inherited structure. The observed cytoskeletal stability and reorganization capabilities suggest that mechanical feedback integrates with biochemical processes to establish viable patterns and ensure canalization.
The living cell is a complex system in which metabolism, gene expression and regulation, protein ... more The living cell is a complex system in which metabolism, gene expression and regulation, protein and other molecular interactions are interconnected, leading to strong cross-talks between different parts of the genome. Modularity and specificity are sometimes found in cellular responses to external cues such as nutrient change or a common stress response. However, under more general stressful conditions with no pre-existing regulatory program, ad-hoc solutions must be invoked, which likely involve multiple components of the system. Experiments have shown that indeed cells exhibit a remarkable ability to overcome such unforeseen challenges without any pre-defined program (1, 2). While the underlying mechanisms are not well understood yet, the phenomenon can be quantitatively characterized in terms of growth patterns (3) gene expression (4-6) and more. Such measurements have demonstrated that large portions of the genome are involved in the response to the challenge, with coherence across the genome and with a stochastic non-repeatable nature. Many features of this global response remain to be studied. A recent paper by Freddolino et al. (7), proposes that under similar stressful conditions improved fitness is achieved by the stochastic tuning of an individual gene. Their experiments follow precisely our methodology developed to understand the adaptation of cells to an unforeseen challenge (1). However, in contrast to our experimental approach which consists of global measurements of the genome over extended time scales, they focused on local measurements of a single gene of interest and one other control gene, at two time points. The results are used to deduce an underlying mechanism for cellular adaptation, proposed to rely on the stochastic tuning of a single gene which in turn determines cellular fitness. The question whether the expression of a gene reflects its own tuning, or is a part of a more global response, cannot be answered by local measurements on the gene of interest alone. This is a general statement on experimental methodology that follows simply because anything that is measured locally is consistent with both local and global effects. We therefore argue that as a necessary stage, prior to interpretation of mechanisms, the phenomenon needs to be characterized on a global scale to determine its extent across the genome and its characteristic timescales. In this case, the conclusion drawn from local measurements by Freddolino et al. is found to contradict previously published global data.
The recruitment of a gene to a foreign regulatory system is a major evolutionary event that can l... more The recruitment of a gene to a foreign regulatory system is a major evolutionary event that can lead
to novel phenotypes. However, the evolvability potential of cells depends on their ability to cope with
challenges presented by gene recruitment. To study this ability, we combined synthetic gene recruitment
with continuous culture and online measurements of the metabolic and regulatory dynamics over long
timescales. The gene HIS3 from the histidine synthesis pathway was recruited to the GAL system, responsible
for galactose utilization in the yeast S. cerevisiae. Following a switch from galactose to glucose—from
induced to repressed conditions of the GAL system—in histidine-lacking chemostats (where the recruited
HIS3 is essential), the regulatory system reprogrammed to adaptively tune HIS3 expression, allowing the
cells to grow competitively in pure glucose. The adapted state was maintained for hundreds of generations
in various environments. The timescales involved and the reproducibility of separate experiments render
spontaneous mutations an unlikely underlying mechanism. Essentially all cells could adapt, excluding
selection over a genetically variable population. The results reveal heritable adaptation induced by
the exposure to glucose. They demonstrate that genetic regulatory networks have the potential to support
highly demanding events of gene recruitment.
The phenotypic state of the cell is commonly thought to be determined by the set of expressed gen... more The phenotypic state of the cell is commonly thought to be determined by the set of expressed genes. However, given the apparent complexity of genetic networks, it remains open what processes stabilize a particular phenotypic state. Moreover, it is not clear how unique is the mapping between the vector of expressed genes and the cell’s phenotypic state. To gain insight on these issues, we study here the expression dynamics of metabolically essential genes in twin cell populations. We show that two yeast cell populations derived from a single steady-state mother population and exhibiting a similar growth phenotype in response to an environmental challenge, displayed diverse expression patterns of essential genes. The observed diversity in the mean expression between populations could not result from stochastic cell-to-cell variability, which would be averaged out in our large cell populations. Remarkably, within a population, sets of expressed genes exhibited coherent dynamics over many generations. Thus, the emerging gene expression patterns resulted from collective population dynamics. It suggests that in a wide range of biological contexts, gene expression reflects a self-organization process coupled to population-environment dynamics.
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Papers by Erez Braun
perceived
as a directed and almost deterministic process. However, noise and stochastic
fluctuations are ubiquitous in biological systems. The questions on the role of fluctuations
in morphogenesis and what ensures the robustness of this process under noisy
conditions remain elusive. Here, we utilize Hydra regeneration, subjected to an external
electric field, to provide unique insights into these questions. We found that during
Hydra morphogenesis, a phase can be induced where fluctuations lead to stochastic
morphological swings, back and forth, between a nearly spherical structure (the incipient
tissue’s state) and an elongated cylindrical shape (the final body form of a mature Hydra).
Despite these prolonged swings, the tissue regenerates into a normal Hydra. The stochastic
transitions between two well-defined
shapes imply that morphological development
occurs through an activation process. Indeed, by introducing a periodic perturbation
through modulation of the electric field, we were able to demonstrate morphogenesis
dynamics with characteristics of stochastic resonance—the tissue’s response to the perturbation
displayed a resonance-like
behavior as a function of the noise level. Our findings
add a dynamic layer to the problem of morphogenesis and offer an unconventional
physical framework based on an activation transition in a slowly varying double-well
potential that ensures a canalized regeneration of the body form under fluctuations.
allowing them to adapt to new environments and to evolve over time. The emergence of stable cell
states depends on genotype-to-phenotype associations, which essentially reflect the organization
of gene regulatory modes. The view taken here is that cell-state organization is a dynamical
process in which the molecular disorder manifests itself in a macroscopic order. The genome
does not determine the ordered cell state; rather, it participates in this process by providing a set
of constraints on the spectrum of regulatory modes, analogous to boundary conditions in physical
dynamical systems. We have developed an experimental framework, in which cell populations are
exposed to unforeseen challenges; novel perturbations they had not encountered before along their
evolutionary history. This approach allows an unbiased view of cell dynamics, uncovering the
potential of cells to evolve and develop adapted stable states. In the last decade, our experiments
have revealed a coherent set of observations within this framework, painting a picture of the
living cell that in many ways is not aligned with the conventional one. Of particular importance
here, is our finding that adaptation of cell-state organization is essentially an efficient exploratory
dynamical process rather than one founded on random mutations. Based on our framework, a
set of concepts underlying cell-state organization—exploration evolving by global, non-specific,
dynamics of gene activity—is presented here. These concepts have significant consequences for
our understanding of the emergence and stabilization of a cell phenotype in diverse biological
contexts. Their implications are discussed for three major areas of biological inquiry: evolution,
cell differentiation and cancer. There is currently no unified theoretical framework encompassing
the emergence of order, a stable state, in the living cell. Hopefully, the integrated picture described
here will provide a modest contribution towards a physics theory of the cell.
in defining patterns during morphogenesis
is an outstanding challenge. Here, we utilize the
multicellular polyp Hydra to investigate the role of
the actomyosin cytoskeleton in morphogenesis. We
find that the supra-cellular actin fiber organization
is inherited from the parent Hydra and determines
the body axis in regenerating tissue segments. This
form of structural inheritance is non-trivial because
of the tissue folding and dynamic actin reorganization
involved. We further show that the emergence
of multiple body axes can be traced to discrepancies
in actin fiber alignment at early stages of the regeneration
process. Mechanical constraints induced by
anchoring regenerating Hydra on stiff wires suppressed
the emergence of multiple body axes, highlighting
the importance of mechanical feedbacks in
defining and stabilizing the body axis. Together,
these results constitute an important step toward
the development of an integrated view of morphogenesis
that incorporates mechanics.
to novel phenotypes. However, the evolvability potential of cells depends on their ability to cope with
challenges presented by gene recruitment. To study this ability, we combined synthetic gene recruitment
with continuous culture and online measurements of the metabolic and regulatory dynamics over long
timescales. The gene HIS3 from the histidine synthesis pathway was recruited to the GAL system, responsible
for galactose utilization in the yeast S. cerevisiae. Following a switch from galactose to glucose—from
induced to repressed conditions of the GAL system—in histidine-lacking chemostats (where the recruited
HIS3 is essential), the regulatory system reprogrammed to adaptively tune HIS3 expression, allowing the
cells to grow competitively in pure glucose. The adapted state was maintained for hundreds of generations
in various environments. The timescales involved and the reproducibility of separate experiments render
spontaneous mutations an unlikely underlying mechanism. Essentially all cells could adapt, excluding
selection over a genetically variable population. The results reveal heritable adaptation induced by
the exposure to glucose. They demonstrate that genetic regulatory networks have the potential to support
highly demanding events of gene recruitment.
apparent complexity of genetic networks, it remains open what processes stabilize a particular phenotypic state. Moreover,
it is not clear how unique is the mapping between the vector of expressed genes and the cell’s phenotypic state. To gain
insight on these issues, we study here the expression dynamics of metabolically essential genes in twin cell populations. We
show that two yeast cell populations derived from a single steady-state mother population and exhibiting a similar growth
phenotype in response to an environmental challenge, displayed diverse expression patterns of essential genes. The
observed diversity in the mean expression between populations could not result from stochastic cell-to-cell variability,
which would be averaged out in our large cell populations. Remarkably, within a population, sets of expressed genes
exhibited coherent dynamics over many generations. Thus, the emerging gene expression patterns resulted from collective
population dynamics. It suggests that in a wide range of biological contexts, gene expression reflects a self-organization
process coupled to population-environment dynamics.