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because of the enormous degree of evolutionary re¬nement behind
every modern-day organism, eliminating some features to produce a
simpli¬ed model risks throwing the baby out with the bath water.
Analyzing the role of any component of a living system is made
all the more dif¬cult by the fact that whereas many cellular and or-
ganismal features are functional adaptations resulting from natural
selection, some of these may no longer serve the same function in
the modern-day organism. Still others are ˜˜side effects” or are charac-
teristic (˜˜generic”) properties of all such material systems. To a major
extent, therefore, living systems have to be treated ˜˜as is”, with com-
plexity as a fundamental and irreducible property.
One property of a living organism that sets it apart from other
physical systems is its ability and drive to reproduce. When physics
is used to understand biological systems it must be kept in mind
that many of the physical processes taking place in the body will be
organized to serve this goal, and all others must at least be consistent
with it. The notion of goal-directed behavior is totally irrelevant for
the inanimate world.
2 BIOLOGICAL PHYSICS OF THE DEVELOPING EMBRYO


Physics and biology differ not only in their objects of study but
also in their methods. Physics seeks to discover universal laws, valid
everywhere in time and space (e.g., Newton™s laws of motion, the laws
of thermodynamics). Theory expresses these general laws in mathe-
matical form and provides ˜˜models” for complex processes in terms
of simpler ones (e.g., the Ising model for phase transitions, diffusion-
limited aggregation models of crystal growth). Biology also seeks gen-
eral principles. However, these are recognized either to be mechan-
isms or modes of organization limited to broadly de¬ned classes of
organisms (eukaryotes vs. prokaryotes; animals vs. plants) or to be
molecular commonalities re¬‚ecting a shared evolutionary history (the
use of DNA as hereditary material; the use of phospholipids to de¬ne
cell boundaries). Biological ˜˜laws,” where they exist (e.g., the promo-
tion of evolution by natural selection, the promotion of development
by differential gene expression) are rarely formulated in mathemati-
cal terms. (See Nanjundiah, 2005, for a discussion of the role of math-
ematics in biology.) There are very few general laws in biology and
the ones that exist are much less exact than in physics.
This is not to say that there are no good models for biological
processes, but only that they have a different function from models
in physics. Biologists can study subcellular systems, such as protein
synthesis or microtubule assembly, in a test tube, and cellular inter-
actions, such as those producing heartbeats and skeletons, in culture
dishes. Both types of experimental set-up -- for cell-free systems and
for living tissues outside the body -- have been referred to as in vitro.
It is always acknowledged, however, that, unlike in physics, the fun-
damental process is the in vivo version in its full complexity, not the
abstracted version. There is always the hope that the experimentally
accumulated knowledge of biological systems will lead eventually to
the establishment of fundamental organizing principles such as those
expressed in physical laws. It is however possible that the multileveled
and evolutionarily established nature of cells and organisms will con-
tinue to defeat this hope.
Physicists and biologists also look at the same things in different
ways. For a physicist, DNA may simply be a long polymer with interest-
ing elastic properties. For the biologist, DNA is the carrier of genetic
information. The sequence of bases, irrelevant to the physicist™s con-
cerns, becomes of central importance to the biologist studying how
this information is stored in the molecule and how it is processed to
produce speci¬c RNAs and proteins. Because biologists must pay at-
tention to the goal-directed aspects of living systems, the properties
studied are always considered in relation to possible contributions
toward the major goal of reproduction and subsidiary goals such as
locomotion toward nutrients and increase in size and complexity.
Because biological systems are also physical systems, phenomena
¬rst identi¬ed in the nonliving world can provide models for bio-
logical processes too. In many instances, in fact, we may assume
that complexity and integration in living organisms have evolved
in the context of forms and functions that originally emerged by
INTRODUCTION: BIOLOGY AND PHYSICS 3


straightforward physical means. In the following chapters we will in-
troduce physical mechanisms that may underlie and guide a variety
of the processes of early animal development. In certain cases simple
physical properties and driving forces are the determining factors in
a developmental episode. In other cases developmental causality may
be multifactorial, which is to say that evolution has recruited physico-
chemical properties of cells and tissues on many levels. An appreci-
ation of the connection between physics and biology and the utility
of biological physics for the life scientist will ultimately depend on
the recognition of both the ˜˜simple” and the multifactorial physical
determination of biological phenomena. When we come to consider
the evolution of developmental mechanisms we will discuss scenar-
ios in which simple physical determination of a biological feature
appears to have been transformed into multifactorial determination
over time.
The role and importance of physics in the study of biological sys-
tems at various levels of complexity (the operation of molecular mo-
tors, the architectural organization of the cell, the biomechanical
properties of tissues, and so forth) is being recognized to an increas-
ing extent by biologists. The objective of the book is to present a
framework within which physics can be used to analyze biological
phenomena on multiple scales. In order to bring coherence to this
attempt we concentrate on one corner of the living world -- early
embryonic development. Our choice of this domain is not entirely
arbitrary. 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.
Physics has often been used to understand properties of fully
formed organisms. The mechanics of locomotion in a vertebrate an-
imal, for example, involves the suspension and change in orienta-
tion of rigid bodies (bones) connected by elastic elements (ligaments,
tendons, muscles). The ability of some of the elastic elements (the
muscles) to generate their own contractile forces distinguishes mus-
culoskeletal systems from most nonliving mechanical systems -- hence
˜˜biomechanics.” A developing embryo, in contrast, is much less rigid:
rather than simply changing the orientation of its parts, it continu-
ously undergoes remodeling in shape and form. Embryonic cells can
slip past one another or be embedded in pliable, semi-solid matrices.
Thus, the physical processes acting in an early organism are predomi-
nantly those characterizing the behavior of viscoelastic ˜˜soft matter”
(a term coined by the physicist Pierre-Gilles de Gennes; de Gennes,
1992), rather than the more rigid body systems typical of adult or-
ganisms.
Another reason to concentrate on early development is that it is
here that the role of physics in constraining and in¬‚uencing the out-
comes of biological processes is particularly obvious. Early develop-
mental phenomena such as blastula formation and gastrulation are
examples of morphogenesis, the set of mechanisms that create complex
4 BIOLOGICAL PHYSICS OF THE DEVELOPING EMBRYO


biological forms out of simpler structures. While each episode of de-
velopmental change is typically accompanied by changes in the ex-
pression of certain genes, it is clear that gene products -- RNA and
protein molecules -- must act in a speci¬c physical context in order to
produce three-dimensional forms and patterns. The laws of physics
establish that not every structure is possible and that programs of
gene expression can only produce shapes and forms of organisms and
organs within de¬ned limits.
The development of the embryo is followed from the fertilized
egg to the establishment of body plan and organ forms. We close the
developmental circle by discussing fertilization, the coming together
of two specialized products of development -- the egg and sperm --
whose interaction employs certain physical processes (such as elec-
trical phenomena) in a fashion distinct from other developmental
events.
We conclude with a discussion of how developmental systems were
likely to have originated from the physical properties of the ¬rst mul-
ticellular forms. The topology and complexity of gene regulatory net-
works may have had independent evolutionary histories from their
associated biological forms. We therefore also review in this section
computational models that test such possibilities.
Major stages of the developmental process and the major parti-
cipating cellular and molecular components are introduced in terms
familiar to students of biology, and suf¬cient background is provided
to make these descriptions accessible to non-biologists. These develop-
mental episodes are then analyzed from the viewpoint of physics (to
the extent allowed by our present knowledge). No preparation beyond
that of introductory calculus and physics courses will be needed for
an understanding of the physics presented. Physical quantities and
concepts will be introduced mostly as needed for the analysis of each
biological process or phenomenon. Complex notions that are impor-
tant but not essential for comprehending the main ideas are collected
in boxes in the text and a few worked examples are included in the
early chapters. We avoid presenting the basics of cell and molecular
biology (for which many excellent sources already exist), beyond what
is absolutely needed for understanding the developmental phenom-
ena discussed. Each chapter concludes with a ˜˜Perspective,” which
brie¬‚y summarizes its major points and, where relevant, their rela-
tion to the material of the preceding chapters.
We have drawn on an abundant and growing literature of physi-
cal models of biological processes, including phenomena of early de-
velopment. The choice of models re¬‚ects our attempt to introduce
the biology student to the spirit of the physical approach in the
most straightforward fashion and to help the physics student appre-
ciate the range of biological phenomena susceptible to this approach.
We continually emphasize the constraints associated with any realis-
tic application of physical models to biological systems. In line with
this, we focus on the biology-motivated formulation of quantitative
INTRODUCTION: BIOLOGY AND PHYSICS 5


models, rather than the solution of the resulting mathematical
equations.
We have attempted, as far as possible, to make each chapter self-
contained (with ample cross-referencing). Moreover, because biologi-
cal development employs a wide range of physical processes at mul-
tiple spatial and temporal scales, we have made a point, wherever
relevant, of introducing novel physical concepts and models for each
new biological topic addressed.
Finally, biological physics is a relatively young discipline. With
the constant improvement of experimental and computational tech-
niques, the possibility of studying complex biological processes in
a rigorous and detailed fashion has emerged. To be capable in this
endeavor one has to be versatile. Biologists and medical researchers
today and in the future will increasingly use sophisticated inves-
tigative techniques invented by physicists and engineers (e.g., atomic
force microscopy, magnetic resonance, neutron scattering, confocal
microscopy). Physicists will be called on to characterize systems of
increasing complexity, of which living systems are the ultimate cate-
gory. There is no way in which anyone can be an expert in all aspects
of this enterprise. What will be required of the scientist of tomorrow
is the ability to speak the language of other disciplines. The present
book attempts to help the reader to become at least bilingual.
Chapter 1




The cell: fundamental unit
of developmental systems

For the biologist the cell is the basic unit of life. Its functions may
depend on physics and chemistry but it is the functions themselves --
DNA replication, the transcription and processing of RNA molecules,
the synthesis of proteins, lipids, and polysaccharides and their build-
ing blocks, protein modi¬cation and secretion, the selective transport
of molecules across bounding membranes, the extraction of energy
from nutrients, cell locomotion and division -- that occupy the at-
tention of the life scientist (Fig. 1.1). These functions have no direct
counterparts in the nonliving world.
For the physicist the cell represents a complex material system
made up of numerous subsystems (e.g., organelles, such as mito-
chondria, vesicles, nucleus, endoplasmic reticulum, etc.), interacting
through discrete but interconnected biochemical modules (e.g., gly-
colysis, the Krebs cycle, signaling pathways, etc.) embedded in a partly
organized, partly liquid medium (cytoplasm) surrounded by a lipid-
based membrane. Tissues are even more complex physically -- they are
made up of cells bound to one another by direct adhesive interactions
or via still another medium (which may be ¬‚uid or solid) known as the
˜˜extracellular matrix.” These components all have their own physical
characteristics (elasticity, viscosity, etc.), which eventually contribute
to those of the cell itself and to the tissues they comprise. To decipher
the working of even an isolated cell by physical methods is clearly a
daunting task.


The eukaryotic cell
The types of cells discussed in this book, those with true nuclei
(˜˜eukaryotic”), came into being at least a billion years ago through
an evolutionary process that brought together previously evolved
˜˜prokaryotic” living units. Among these were ˜˜eubacteria” and
˜˜archaebacteria,” organisms of simpler structure in which informa-
tion specifying the sequence of proteins was inherited on DNA present
as naked strands in the cytosol, rather than in the highly organized
DNA--protein complexes known as ˜˜chromatin,” found in the nuclei
of eukaryotes.
1 THE CELL: FUNDAMENTAL UNIT OF DEVELOPMENTAL SYSTEMS 7



Microvilli
Lysosome

Microtubule
Peroxisome
Intermediate filaments
Ribosomes in
cytosol
Centromere with pair
of centrosomes
Golgi apparatus
Attachment plaque
Smooth
endoplasmic
Nucleolus
reticulum

Nuclear envelope
Vesicle
with nuclear pores

Actin filaments
Chromatin
in nucleus

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