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Biological Physics of the Developing Embryo
During development, cells and tissues undergo dynamic changes in pattern
and form that employ a wider range of physical mechanisms than at any other
time during an organism™s life. Biological Physics of the Developing Embryo presents
a framework within which physics can be used to analyze these biological
Written to be accessible to both biologists and physicists, major stages
and components of biological development are introduced and then analyzed
from the viewpoint of physics. The presentation of physical models requires no
mathematics beyond basic calculus. Physical concepts introduced include dif-
fusion, viscosity and elasticity, adhesion, dynamical systems, electrical poten-
tial, percolation, fractals, reaction--diffusion systems, and cellular automata.
With full-color figures throughout, this comprehensive textbook teaches
biophysics by application to developmental biology and is suitable for graduate
and upper-undergraduate courses in physics and biology.

G a b o r F o r g a c s is George H. Vineyard Professor of Biological Physics at the
University of Missouri, Columbia. He received his Ph.D. in condensed matter
physics from the Roland Eötvös University in Budapest. He made contributions
to the physics of phase transitions, surface and interfacial phenomena and to
statistical mechanics before moving to biological physics, where he has stud-
ied the biomechanical properties of living materials and has modeled early
developmental phenomena. His recent research on constructing models of liv-
ing structures of prescribed geometry using automated printing technology
has been the topic of numerous articles in the international press.
Professor Forgacs has held positions at the Central Research Institute for
Physics, Budapest, at the French Atomic Energy Agency, Saclay, and at Clark-
son University, Potsdam. He has been a Fulbright Fellow at the Institute of Bio-
physics of the Budapest Medical University and has organized several meetings
on the frontiers between physics and biology at the Les Houches Center for
Physics. He has also served as advisor to several federal agencies of the USA on
the promotion of interdisciplinary research, in particular at the interface of
physics and biology. He is a member of a number of professional associations,
such as The Biophysical Society, The American Society for Cell Biology, and
The American Physical Society.

S t u a r t A . N e w m a n is Professor of Cell Biology and Anatomy at New York
Medical College, Valhalla, New York. He received an A.B. from Columbia Uni-
versity and a Ph.D. in Chemical Physics from the University of Chicago. He
has contributed to several scientific fields, including developmental pattern
formation and morphogenesis, cell differentiation, the theory of biochemical
networks, protein folding and assembly, and mechanisms of morphological
evolution. He has also written on the philosophy, cultural background and
social implications of biological research.
Professor Newman has been an INSERM Fellow at the Pasteur Institute,
Paris, and a Fogarty Senior International Fellow at Monash University, Aus-
tralia. He is a co-editor (with Brian K. Hall) of Cartilage: Molecular Aspects (CRC
Press, 1991) and (with Gerd B. Müller) of Origination of Organismal Form: Beyond
the Gene in Developmental and Evolutionary Biology (MIT Press, 2003). He has tes-
tified before US Congressional committees on cloning, stem cells, and the
patenting of organisms and has served as a consultant to the US National
Institutes of Health on both technical and societal issues.
Biological Physics of the
Developing Embryo

Gabor Forgacs
University of Missouri

Stuart A. Newman
New York Medical College
cambridge university press
Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, São Paulo

Cambridge University Press
The Edinburgh Building, Cambridge cb2 2ru, UK
Published in the United States of America by Cambridge University Press, New York
Information on this title: www.cambridge.org/9780521783378

© G. Forgacs and S. A. Newman 2005

This publication is in copyright. Subject to statutory exception and to the provision of
relevant collective licensing agreements, no reproduction of any part may take place
without the written permission of Cambridge University Press.

First published in print format 2005

isbn-13 978-0-511-13689-4 eBook (NetLibrary)
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for external or third-party internet websites referred to in this publication, and does not
guarantee that any content on such websites is, or will remain, accurate or appropriate.

page vii
Introduction: Biology and physics 1

1 The cell: fundamental unit of developmental systems 6
The eukaryotic cell 6
Diffusion 8
Osmosis 15
Viscosity 16
Elasticity and viscoelasticity 21
Perspective 22

2 Cleavage and blastula formation 24
The cell biology of early cleavage and blastula
formation 24
Physical processes in the cleaving blastula 29
Physical models of cleavage and blastula formation 39
Perspective 50

3 Cell states: stability, oscillation, differentiation 51
Gene expression and biochemical state 52
How physics describes the behavior of a complex system 53
Oscillatory processes in early development 57
Multistability in cell-type diversi¬cation 63
Perspective 76

4 Cell adhesion, compartmentalization, and lumen
formation 77
Adhesion and differential adhesion in development 78
The cell surface 80
Cell adhesion: speci¬c and nonspeci¬c aspects 81
The kinetics of cell adhesion 84
Differential adhesion of embryonic tissues 90
The physics of cell sorting 95
Perspective 97

5 Epithelial morphogenesis: gastrulation and
neurulation 99
Physical properties of epithelia 100
Gastrulation 108
Convergence and extension 117
Neurulation 122
vi Contents

Perspective 128
Appendix: Linear stability analysis

6 Mesenchymal morphogenesis 131
Development of the neural crest 134
The extracellular matrix: networks and phase
transformations 138
Mesenchymal condensation 149

7 Pattern formation: segmentation, axes, and
asymmetry 155
Basic mechanisms of cell pattern formation 157
Segmentation 162
Epithelial patterning by juxtacrine signaling 168
Mesoderm induction by diffusion gradients 171
Reaction--diffusion systems 173
Control of axis formation and left--right asymmetry 177

8 Organogenesis 188
Development of the cardiovascular system 190
Fractals and their biological signi¬cance 197
Branching morphogenesis: development of the
salivary gland 203
Vertebrate limb development 210

9 Fertilization: generating one living dynamical system
from two 223
Development of the egg and sperm 224
Interaction of the egg and sperm 233
Propagation of calcium waves: spatiotemporal
encoding of postfertilization events 236
Surface contraction waves and the initiation of
development 242

10 Evolution of developmental mechanisms 248
The physical origins of developmental systems 249
Analyzing an evolutionary transition using physical
concepts: segmentation in insects 256
The evolution of developmental robustness 262
Perspective 272

The writing of this text, addressed simultaneously to biologists and
physicists, presented us with many challenges. Without the help of
colleagues in both ¬elds the book would still be on the drawing board.
Of the many who advised us, made constructive remarks, and pro-
vided suggestions on the presentation of complex issues, we wish to
thank particularly Mark Alber, Daniel Ben-Avraham, Andras Czirók,
Scott Gilbert, James Glazier, Tilmann Glimm, Michel Grandbois,
George Hentschel, Kunihiko Kaneko, Ioan Kosztin, Roeland Merks,
Gerd M¨ ller, Vidyanand Nanjundiah, Adrian Neagu, Olivier Pourqui©,
Diego Rasskin-Gutman and Isaac Salazar-Ciudad. Commentary from
students was indispensable; in this regard we received invaluable help
from Richard Jamison, an undergraduate at Clemson University, and
Yvonne Solbrekken, an undergraduate at the University of Missouri,
Columbia, who read most of the chapters.
We thank the members of our laboratories for their patience with
us during the last ¬ve years. Their capabilities and independence have
made it possible for us to pursue our research programs while writing
this book. Gabor Forgacs was on the faculty of Clarkson University,
Potsdam, NY, when this project was initiated, and some of the writ-
ing was done while he was a visiting scholar at the Institute for Ad-
vanced Study of the Collegium Budapest. Stuart Newman bene¬ted
from study visits to the Indian Institute of Science, Bangalore, the
Konrad Lorenz Institute, Vienna, and the University of Tokyo-Komaba,
in the course of this work.
In a cross-disciplinary text such as this one, graphic materials are
an essential element. Sue Seif, an experienced medical illustrator,
was, like us, new to the world of textbook writing. Our interactions
with her in the design of the ¬gures in many instances deepened
our understanding of the material presented here. Any reader who
accompanies us across this dif¬cult terrain will appreciate the fresh-
ness and clarity of Sue™s visual imagination.
Harry Frisch introduced the authors to one another more than a
quarter century ago and thought that we had things to teach each
other. Malcolm Steinberg, a valued colleague of both of us, showed
the way to an integration of biological and physical ideas. Judith
Plesset, our program of¬cer at the National Science Foundation, was
instrumental in fostering our scienti¬c collaboration during much of
the intervening period, when many of the ideas in this book were
gestated. We are grateful to each of them and for the support of our
Introduction: Biology and physics

Physics deals with natural phenomena and their explanations. Biolo-
gical systems are part of nature and as such should obey the laws of
physics. However correct this statement may be, it is of limited value
when the question is how physics can help unravel the complexity of
Physicists are intellectual idealists, drawing on a tradition that ex-
tends back more than 2000 years to Plato. They try to model the sys-
tems they study in terms of a minimal number of ˜˜relevant” features.
What is relevant depends on the question of interest and is typically
arrived at by intuition. This approach is justi¬ed (or abandoned) after
the fact, by comparing the results obtained using the model system
with experiments performed on the ˜˜real” system. As an example,
consider the trajectory of the Earth around the Sun. Its precise de-
tails can be derived from Newton™s law of gravity, in which the two
extensive bodies are each reduced to a point particle characterized by
a single quantity, its mass. If one is interested in the pattern of earth-
quakes, however, the point-particle description is totally inadequate
and knowledge of the Earth™s inner structure is needed.
An idealized approach to living systems has several pitfalls -- some-
thing recognized by Plato™s student Aristotle, perhaps the ¬rst to at-
tempt a scienti¬c analysis of living systems. In the ¬rst place, intu-
ition helps little in determining what is relevant. The functions of
an organism™s many components, and the interactions among them
in its overall economy, are complex and highly integrated. Organ-
isms and their cells may act in a goal-directed fashion, but how the
various parts and pathways serve these goals is often obscure. And

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