The biophysics of the developing embryo€¦ · Biological physics of the developing embryo During development, cells and tissues undergo changes in pattern and form in a highly dynamic

The biophysics of the developing embryo

a new challenge in theoretical integration Laura Nuño de la Rosa

Universidad Complutense de Madrid & IHPST (Paris 1)

Outline

1. Developmental genetics vs. developmental mechanics

2. The biophysics of the developing embryo

3. Epistemological and ontological challenges

Outline


Developmental biology today

Developmental biology today

Developmental biology

… mechanisms of development, differentiation, and growth in animals and plants at the molecular, cellular, and genetic levels. Areas of particular emphasis include transcriptional control mechanisms, embryonic patterning, cell-cell interactions, growth factors and signal transduction, and regulatory hierarchies.

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Developmental genetics

● Genes involved in the development of X


● Developmental genetic networks

● Computational and complex systems-based approaches to the analysis of gene expression data sets


● But they continue to be largely gene-centered (i.e. the control of gene activities by other gene activities)

● The physics of soft condensed materials has been slower to enter into mainstream developmental biology

● The physics of soft condensed materials has been slower to enter into mainstream developmental biology

● Why?

Hierarchical vs. Cyclical scheme

Alberch, P. (1982)


Alberch, P. (1982)


Alberch, P. (1982)


Alberch, P. (1982)

Developmental dynamics

... articles ranging from the theoretical to the analytical, and it covers all levels of biological organization and model systems. Emphasizing tissue, cellular and molecular-genetic mechanisms of morphogenesis...

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Developmental biologists have worked for nearly a century in the perturbation-consequence

mode, in which explanation resembles Aristotelian efficient causation. We are on the verge of a shift toward something much more like formal causation; that is, explanation in terms of dynamical formulation and behavior

(von Dassow and Munro 1999)

“

”

A new conception of causality

Outline



We have focused on the phenomena of transitions between cell types, changes in the shape of tissues... and have approached them as problems in physics. In contrast,.. in most contemporary treatments of development it is primarily as problems in regulated differential gene expression.

“ Forgacs & Newman (2005)

Biological physics of the developing embryo

● During development, cells and tissues undergo changes in pattern and form in a highly dynamic fashion, using a wider range of physical processes than at any other time during the organism’s life cycle.

● those characterizing the behavior of viscoelastic ‘‘soft matter” ..., rather than the more rigid body systems typical of adult organisms.

Hierarchy of emergent processes

● Stages & interactions: – zigote: maternal

proteins– cleavage: cells– gastrulation: cell

groups & germ layes– organogenesis:

tissues

Hierarchy of emergent processes

Development starts with a few ordered manifoldnesses; but the manifoldnesses create, by interactions, new manifoldnesses, and these are able, by acting back on the original ones, to provoke new differences, and so on. With each

new response, a new cause is immediately provided, and a new specific reactivity for further

specific responses (Driesch 1894)

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Mechanisms of pattern formation

● Autonomous – Mitosis (maternal proteins)

● Inductive (hierarchical, emergent)– Reaction-diffusion mechanisms

● Morphogenetic– differential growth, apoptosis, diferential

adhesion, migration, contraction, matrix swelling, deposition and loss

Salazar-Ciudad et al. 2003

Cleavage and blastula formation

The White-Borisy model

Drasdo-Forgacs model

Cortical tension

Generic physics

● The ‘‘generic” physical forces and mechanisms ... are capable of acting on living tissues and nonliving materials [viscoelastic materials and chemically and mechanically excitable systems] alike to produce similar shapes, patterns, and dynamical activities ... In principle, a rough sort of "development", i.e., a sequence of form-changes in an aggregate of cells, could be driven solely by physics (e.g., Turing reaction-difussion patterns).

Cleavage and blastula formation

The White-Borisy model

Drasdo-Forgacs model

Morphological instability

Physical forces are not enough...

It is the multileveled determination of cells and embryos which ensures that each driving force is constrained by other driving forces and that the whole complex of forces is subordinated to the survival and propagation of the organism. Central to the integration of the various physical determinants are the complex biochemical signaling processes taking place in each individual cell, and across the blastula and later-forming cell aggregates, which control the values of cellular physical parameters and with them the consequences of the physical interactions.

Genetic regulation

● developmental steps ... are typically associated with the appearance of one or more specific gene products at a particular time and place.

● Genetic regulation of physical parameters

Cell states: stability, oscillation, differentiation

Cell adhesion, compartmentalization, and lumen formation

Differential adhesion and minimization of configurational energy in lumen formation

Shaping of a leg segment.

A compromise between maximizing the work of adhesion and minimizing the strain (Mittenthal and Mazo 1983)

Organogenesis

Organogenesis

Organogenesis

Organogenesis

Organogenesis

Organogenesis

Organogenesis

Organogenesis

Outline



3. Epistemological and ontological challenges

Epistemological problems

Developmental laws?● The idealization and generalization that

characterizes physical models clash with the particularities of living systems.

● There are very few general laws in biology and the ones that exist are much less exact than in physics.

The specificity of living matter

● Neither cytoplasm nor multicellular aggregates are the sort of ‘‘ideal” materials that physics excels in describing.

● Each cellular and tissue property are a result of many superimposed physical properties.

● Thus any standard physical quantity (e.g., a diffusion coefficient, an elastic modulus) will not be constant and the temporal and spatial range of any simple physical law will be limited.

● However, it is possible to build a certain amount of complexity into a physical representation and come closer to capturing biological reality.

● This can be achieved by defining ‘‘effective” physical parameters, which incorporate the complexity of the biological system, and using them in standard physical equations.

● The validity of such equations cannot be deduced from first principles and must be checked experimentally ... establishing analogies rather than equivalences between complex biological phenomena and well-understood processes in the inanimate world.

Ontological challenges

● if a genetic preformationism is not defended, how are we going to deal with the problem of teleology in development?


Spemann's organizer

zigot's totipotency

● The physicist’s aim of isolating relevant variables to account for the system’s behavior would seem to be all but impossible under these circumstances.

Morphogenetic fields

Waddington vs Thom● Organisms as attractors● Organisms as processes

of becoming“Cells cannot be said to follow a

program, but are rather moved along a developmental trajectory by

continual interaction with a changing molecular-geometric

microenvironment” (Salazar-Ciudad et al.)

Teleology

Teleology and Evolution

● The result of millions of years of natural selection for such properties is that a change in any one of a cell’s subsystems (by genetic mutation or environmental perturbation) will have repercussions in other subsystems that tend either to restore the original functional state or to bring the subsystem in question to another appropriate state.

● how to deal with the evolutionary history underlying living organisms?


History

In the earliest arising multicellular forms these physical determinants [viscosity, elasticity, dynamical-state transitions, differential adhesion, and reaction-diffusion coupling] must have acted in an even less constrained fashion, potentially allowing new forms to arise with little or no genetic change

Mechanical recapitulation

...long before complex, modern-type, body morphologies emerged in the course of evolution, simpler forms resembling gastrulae and budding and segmented tubes (i.e., the forms that can be generated by relatively simple physical mechanisms acting on cell aggregates) should have arisen.

● Developmental function


Developmental function

● Roux: two periods– 1st: independent

development– 2nd: dependent

development● Müller et al. (1991)

– movement and skeletogenesis

Conclusions● Developmental genetics is far from complete, but for

different reasons than DST's– Genes do not control but specify the parameters of a set

of equations that are both physical




● Biophysics: Living matter requires superimposed physical models that are particular to different kinds of organisms





● Developmental teleology cannot be understood without the light of evolution and evolution cannot be understood without the light of physics





● Developmental teleology cannot be understood without the light of evolution and evolution cannot be understood without the light of physics

● Main challenge: How to biophysicalize developmental function?

Documents

The biophysics of the developing embryo€¦ · Biological physics of the developing embryo During development, cells and tissues undergo changes in pattern and form in a highly dynamic